image of silk fabric and dry skin

Sailesh Konda, MD1; Susan R. Meier-Davis, DVM, PhD2; Brenda Cayme, RN2;
Jutaro Shudo, PhD2; Howard I. Maibach, MD3

1Department of Dermatology, Howard University College of Medicine, Washington, DC, USA
2Teikoku Pharma USA, Inc., San Jose, CA, USA
3Department of Dermatology, University of California, San Francisco, CA, USA

Conflict of interest: The authors have no conflicts of interest to declare.

Transdermal drug delivery allows for a constant rate of drug administration and prolonged action, which can be beneficial to elderly patients who are often polymedicated. Several studies have compared dermatopharmacokinetics in the young and elderly with conflicting results. Despite the potential limitations of age-related changes in skin factors and cutaneous metabolism, marketed transdermal products generally do not report age-related differences in pharmacokinetics. This overview discusses the current data, summarizes marketed product findings and highlights the importance of further studies to evaluate age-related dermatopharmacokinetics.

Key Words:
transdermal, elderly, dermatopharmacokinetics, percutaneous penetration, cutaneous metabolism


The rate of growth of the older population (65 years old and over) has greatly exceeded the growth rate of the US population as a whole. According to the United States Census Bureau’s projections, about 1 in 8 Americans were elderly in 1994 and by the year 2030 it will increase to 1 in 5.1 Furthermore, there has been a surge of interest in transdermal drug delivery to produce systemic effects. Transdermally delivered drugs include scopolamine, nitroglycerin, nicotine, clonidine, fentanyl, estradiol, testosterone, lidocaine, and oxybutynin. Recently, transdermal formulations have also been introduced for rivastigmine, rotigotine, selegiline, buprenorphine, granisetron, and methylphenidate. The current US transdermal market exceeds $3 billion annually.2

The advantages of percutaneous drug penetration over the oral route include circumvention of gastrointestinal absorption and hepatic first-pass metabolism (contrary to assumption, the skin also has a first-pass effect for some compounds), minimization of adverse effects secondary to peak plasma drug concentrations, and improved patient compliance. Additionally, percutaneous drug delivery harbors no risk of infection, which can be a complication with parenteral administration. Disadvantages include skin sensitivity and irritation by patches and the reservoir effect of skin, which allows for continued diffusion after patch removal. This overview provides a basis for understanding the effect of aging on dermatopharmacokinetics and discusses currently marketed transdermal products.


Percutaneous absorption depends on passive diffusion across the stratum corneum, which has an excellent barrier function that undergoes structural and functional changes with increasing age. Typically, drugs that are candidates for percutaneous absorption must be pharmacologically potent and satisfy the following physicochemical properties when considering a formulation: aqueous solubility >1 mg/ml, lipophilicity 10<Ko/w (oil-water partition coefficient) <1000, molecular weight <500 Da, melting point <200°C, pH 5-9, and a dose deliverable <10 mg/day.3 Changes in the barrier properties of aged skin may have an impact on the type and amount of drugs that are able to undergo successful percutaneous absorption.

Substantial literature reviews in vivo percutaneous absorption in neonates and normal healthy adults.4-8 However, the quantitative evaluation of skin barrier function has been minimally addressed in the elderly. Christophers and Kligman conducted studies in the 1960s that suggested the skin permeability in the elderly (>66 years old) was different from that of younger adults (<29 years old).9 In vitro studies using human cadaver skin demonstrated the permeability of fluorescein was seven times greater in skin from older than younger subjects. However, another in vitro study using skin from living subjects found no difference in the permeability of water between the two groups. They also conducted an in vivo study with 14C-testosterone applied to the backs of young and old subjects and found penetration to be greater in the younger (19-30 years) than the older (71-82 years) group over 24 hours.9 Furthermore, the absorption capability of the skin microcirculation was assessed by the clearance of intradermally injected radiolabeled sodium and was shown to be decreased in the elderly, suggesting that changes in the microcirculation occurred in the dermis of the elderly.9

DeSalva and Thompson reported contrasting results; they observed similar clearance rates of intradermally injected radiolabeled sodium administered in the face and hands of subjects 50 years of age or older, but the rates were slower in subjects 30 years of age or younger.10 However, when administered into the hand, the clearance of radiolabeled sodium was slower in subjects aged 71 years or older than subjects 60 years of age or younger.

Tagami measured the permeability of tetrachlorosalicylanilide (TCSA) across the stratum corneum in vivo and discovered that the permeation times of TCSA through the skin of both flexor and extensor forearm sites were significantly shorter in young (22-39 years) than in old (62-82 years) subjects. The TCSA penetration time took 2-2.5 hours in the former and about 1.5 hours in the latter. This was accomplished by stripping the stratum corneum at various time points after application and assaying for the TCSA via fluorescence.11 The efficiency of cutaneous microcirculation was also assessed by the clearance of intradermally injected radiolabeled sodium. Clearance was unchanged between age groups for the extensor forearm, but significantly longer in aged (61-80 years) than in young (20-32 years) subjects for the midback area.11

Roskos and colleagues made in vivo measurements of percutaneous absorption in young (18-40 years) and old (>65 years) subjects using standard radiotracer methodology with 14C-radiolabeled compounds.12 Percutaneous absorption was quantified from urinary excretion profiles and corrected for incomplete renal elimination. Permeation of hydrocortisone, benzoic acid, acetylsalicylic acid, and caffeine was significantly lower in aged subjects, while the absorption of testosterone and estradiol was similar in the two groups (Table 1). This suggests that aging can affect percutaneous absorption in vivo and that relatively hydrophilic compounds are more sensitive, while highly lipophilic compounds may still be able to dissolve readily across the stratum corneum.

While the aforementioned studies indicate there are age-related differences in the percutaneous penetration and clearance of drugs, discrepancies abound. Some suggested greater absorption in the older subjects, others suggested greater absorption in younger subjects, and still others found no difference. Consequently, based on these studies, it is difficult to elucidate if the elderly are at increased risk secondary to altered percutaneous penetration. Furthermore, in practice, no significant differences in absorption of drugs from transdermal delivery systems have been demonstrated between young and old individuals.

CompoundMolecular WeightAqueous Solubilitylog Ko/waCumulative % Dose Absorbedb
Young (22-40 years)Old (>65 years)
Testosterone288.4Insoluble3.3219.0 ± 4.4 (n=6)16.6 ± 2.5c (n=8)
Estradiol272.4Almost insoluble2.497.1 ± 1.1 (n=5)5.4 ± 0.4c (n=5)
Hydrocortisone362.50.28 g/L1.611.5 ± 0.6d (n=3)0.54 ± 0.15d,e (n=7)
Benzoic acid121.13.4 g/L1.8336.2 ± 4.6 (n=7)19.5 ± 1.6f (n=8)
Acetylsalicylic acid180.23.3 g/L1.2631.2 ± 7.3 (n=5)13.6 ± 1.9g (n=7)
Caffeine194.221.7 g/L0.0148.2 ± 4.1 (n=5)25.2 ± 4.8f (n=7)
Table 1. Percutaneous penetration data and physicochemical parameters for six drugs
aData from Bucks et al. (1988)13; solubilities obtained from the Merck Index.
bMean ± SE (standard error).
cNot significantly different from the young control group (p > 0.05).
dIf averaged together with the data from Bucks et al. (1988)13 (mean ± SE = 3.27 ± 0.73; n=8), then p < 0.01.
eSignificantly different from the young control group (p = 0.06).
fSignificantly different from the young control group (p < 0.01).
gSignificantly different from the young control group (p < 0.05).Table from Roskos KV, Maibach HI, Guy RH. The effect of aging on percutaneous absorption in man. J Pharmacokinet Biopharm 1989;17(6):page 623, Table 1.12 Reprinted with kind permission from Springer Science and Business Media.

Marketed Transdermal Products

Given the potential differences in skin from individuals of varying age, pharmacokinetics with transdermal delivery may be altered. Table 2 summarizes the available pharmacokinetic data reported in the US FDA’s New Drug Application (NDA) submissions and drug labels for transdermal products relative to the subjects’ age. As shown, in studies where the subject age was stratified relative to pharmacokinetic parameters, the majority of transdermal products do not report age-related differences in their pharmacokinetic profiles. The lack of age-related reports indicates that the skin, although the rate-limiting step for absorption, is not the major factor for observations of age-related effects. In other words, the skin in addition to other factors, including the active ingredient’s physiochemical characteristics and patch formulation components, determine whether a specific drug will have pharmacokinetic differences across age groups.

ProductActive DrugWear DurationAge Groups TestedPharmacokinetics (According to Label)
Catapres-TTS® (NDA 018891)ClonidineWeeklyAdultNo age-relationship reported
Estraderm® (NDA 019081)EstradiolTwice weeklyPost-menopausal and agedNo age-relationship reported
Durogesic® (NDA 019813)Fentanyl72 hoursChild and adultIn children, 1.5 to 5 years old that are non-opioid-tolerant, the fentanyl plasma concentrations were approximately twice as high as that of adult patients. In older pediatric patients, the pharmacokinetic parameters were similar to that of adults.
Nicoderm CQ® (NDA 020165)NicotineDailyAdultNo age-relationship reported
Testoderm® (NDA 020489)TestosteroneDailyAdult and agedNo age-relationship reported
Lidoderm® (NDA 020612)Lidocaine12 hoursAdultNo age-relationship reported
Flector® (NDA 021234)Diclofenac epolamineTwice dailyAdultNo age-relationship reported
Butrans® (NDA 021306)Buprenorphine7 daysAdultNo age-relationship reported
Emsam® (NDA 021336)SelegilineDailyAdult and agedThe effect of age on the pharmacokinetics or metabolism of selegiline has not been systematically evaluated.
Oxytrol® (NDA 021351)Oxybutynin3 to 4 daysAdultNo age-relationship reported
Daytrana® (NDA 021514)Methylphenidate9 hoursChildren and adolescentsNo age-relationship reported
Neupro® (NDA 021829)RotigotineDailyMiddle-aged and elderlyPlasma concentrations in patients 65 to 80 years of age were similar to those in younger patients, approximately 40 to 64 years of age. Although not studied, exposures in older subjects (>80 years) may be higher due to skin changes with aging.
Exelon® (NDA 022083)Rivastigmine tartrateDailyYounger adults and elderlyNo age-relationship reported
Sancuso® (NDA 022198)GranisetronUp to 5 daysAdultNo studies have been performed to investigate the pharmacokinetics of granisetron in elderly subjects.
Qutenza® (NDA 022395)Capsaicin1 hourAdult and elderlyNo dose adjustments are required in geriatric patients.
Table 2. Pharmacokinetics and age relationship in marketed transdermal products


Comorbid medical conditions in the elderly are often treated with polypharmacy, which may result in unwanted drugdrug interactions and adverse effects.14 Swallowing difficulty either as a symptom of the disease or secondary to aging is an additional consideration. Transdermal delivery of drugs may alleviate complications due to polypharmacy and swallowing difficulties while facilitating steady-state concentrations. Marketed transdermal products generally do not report agerelated differences in pharmacokinetics, suggesting that skin factors play a minor role in comparison to the drug’s chemistry and transdermal formulation.

Additional investigations may be beneficial in helping determine if the elderly should have different topical dosing regimens to ensure efficaciousness with minimal adverse effects. This is especially important for drugs that have a narrow therapeutic window, such as fentanyl and clonidine.15 Also, future studies would benefit from the inclusion of older subjects, as prior studies have largely focused on individuals younger than 70 years. Continued efforts should be directed at enhancing transdermal delivery design and predicting which topical drugs are likely to have altered pharmacodynamics in the elderly.


  1. Day JC. Population projections of the United States, by age, sex, race, and Hispanic origin: 1993-2050. Washington, DC: US Department of Commerce, Bureau of the Census, 1993. (Current population reports; series P25, no. 1104).
  2. Langer R. Transdermal drug delivery: past progress, current status, and future prospects. Adv Drug Deliv Rev. 2004 Mar 27;56(5):557-8.
  3. Naik A, Kalia YN, Guy RH. Transdermal drug delivery: overcoming the skin’s barrier function. Pharm Sci Technolo Today. 2000 Sep 1;3(9):318-26.
  4. Fisher LB. In vitro studies on the permeability of infant skin. In: Bronaugh RL, Maibach HI, eds. Percutaneous absorption. New York: Marcel Dekker, 1985; p213-22.
  5. McCormack JJ, Boisits EK, Fisher LB. An in vitro comparison of the permeability of adult versus neonatal skin. In: Maibach HI, Boisits EK, eds. Neonatal skin: structure and function. New York: Marcel Dekker, 1982; p149-66.
  6. Wilson DR, Maibach HI. An in vivo comparison of skin barrier function. In: Maibach HI, Boisits EK, eds. Neonatal skin: structure and function. New York: Marcel Dekker, 1982; p101-10.
  7. Feldmann RJ, Maibach HI. Percutaneous penetration of steroids in man. J Invest Dermatol. 1969 Jan;52(1):89-94.
  8. Feldmann RJ, Maibach HI. Absorption of some organic compounds through the skin in man. J Invest Dermatol. 1970 May;54(5):399-404.
  9. Christophers E, Kligman AM. Percutaneous absorption in aged skin. In: Montagna W, ed. Advances in biology of the skin. Vol 6: Aging. Long Island City: Pergaman Press, 1965; p163-75.
  10. DeSalva SJ, Thompson G. Na22Cl skin clearance in humans and its relation to skin age. J Invest Dermatol. 1965 Nov;45(5):315-8.
  11. Tagami H. Functional characteristics of aged skin. Acta Dermatol Kyoto (English Edition). 1972;67:131-8.
  12. Roskos KV, Maibach HI, Guy RH. The effect of aging on percutaneous absorption in man. J Pharmacokinet Biopharm. 1989 Dec;17(6):617-30.
  13. Bucks DA, McMaster JR, Maibach HI, et al. Bioavailability of topically administered steroids: a “mass balance” technique. J Invest Dermatol. 1988 Jul;91(1):29-33.
  14. Levy RH, Collins C. Risk and predictability of drug interactions in the elderly. Int Rev Neurobiol. 2007;81:235-51.
  15. Nelson L, Schwaner R. Transdermal fentanyl: pharmacology and toxicology. J Med Toxicol. 2009 Dec;5(4):230-41.