Heat-Enhanced Transdermal Drug Delivery: A Survey Paper*

Wade Hull, MS
Director of Engineering
ZARS, Inc.
350 W. 800 N., Ste. 320
Salt Lake City, Utah 84103
*This study was sponsored by ZARS, Inc.

The delivery of drugs transdermally (through the skin) provides several important advantages
over traditional oral and intravenous delivery routes. Transdermally delivered drugs avoid the
risk and inconvenience of intravenous therapy, bypass the liver in terms of first pass
elimination, usually provide less chance of an overdose or underdose, allow easy termination,
and permit both local and systemic treatment effects.1 The major barrier to the delivery of
transcutaneous drugs is the skin. The skin is composed of three layers: the epidermis, the
dermis, and the hypodermis (Figure 1). The stratum corneum forms the outermost layer of the
dermis and consists of 10 to 20 layers of flattened, closely packed cells without nuclei (10 to
20 mm thick). The epidermis, which is 50 to 100 mm thick, has rapidly dividing basal cells
that flatten as they move into the stratum corneum to replace cells lost from the skin's outer
surface. The innermost layer is the 2- to 3-mm thick dermis, which is a matrix of various cells
including those that produce collagen and other fiber proteins. Hair follicles, sebaceous
glands, and sweat glands are also part of the dermis.
Compounds are thought to transfer through the skin by a predictable system of passive
diffusion, defined by Fick's Law and the rate of permeation. The stratum corneum is believed
to provide the major physical barrier for most drugs. Diffusion for most low-molecular-weight
substances seems to occur uniformly through the stratum corneum over a large fraction of its
area.2. Figure 2 shows a diagrammatic illustration of the potential routes of drug entry into
the skin. Drug molecules can penetrate the epithelium transcellularly or intercellularly
through channels between cells (route 2) or they may gain transappendageal entry through the
skin appendages such as hair follicles (route 3), sebaceous glands, and sweat ducts (route 1).
Given the small cross sections of the sweat and sebaceous pores along with the outward
movement of sweat or sebum, however, the stratum corneum serves as the primary means of
drug diffusion. Once diffusion through the stratum corneum is achieved, the molecules
permeate the dermis, are absorbed into the capillary plexus, and are then transferred into the
general circulation by local blood vessels. If absorbed molecules are able to bypass the dermal
blood supply, they can diffuse into the tissue layers below the dermis in a process known as
percutaneous penetration.2 Thus, from a physiologic perspective, the appearance of the drug
in the systemic circulation is governed by two factors: skin permeability and local blood
flow.3
In order for a drug to be a practical candidate for transdermal delivery, it must possess
physicochemical properties that are associated with relatively high permeability. These
properties include a low-molecular-weight (<1000) and adequate solubility in oil and water.
Since steady-state delivery of the drug across a membrane is subject to Fick's laws of
diffusion, the higher the aqueous solubility of a drug, the higher is its delivery rate.4 The drug
should also be potent enough to compensate for the limited ability to move a therapeutic dose
through a convenient area of skin. In practical terms, this means, for most drugs, a daily dose
of 1 to 2 mg. Presently there are several types of drugs that are being delivered transdermally,
including testosterone, estrogen, nitroglycerin, nicotine, fentanyl (a potent opioid analgesic),
scopolamine (for motion sickness), and clonodine (to lower blood pressure).
Much research is being done in order to find new and more effective ways to enhance the
topical delivery of these drugs. Although complex chemical enhancers have been integrated
into some transdermal delivery systems, physical agents such as electricity (iontophoresis),
ultrasound (phono- or sonophoresis), and magnetism are becoming increasingly popular as
enhancers.1 An even simpler mechanism for externally regulating transcutaneous drug
absorption is the application of heat.
Heat is expected to enhance the transdermal delivery of various drugs by increasing skin
permeability, body fluid circulation, blood vessel wall permeability, rate-limiting membrane
permeability, and drug solubility. According to Kligman, diffusion through the skin, as
elsewhere, is a temperature-dependent process, so raising the skin temperature should add
thermodynamic drive.5 Heat is known to increase the kinetic energy of both the drug
molecules and the proteins, lipids, and carbohydrates in the cell membrane. Heating prior to
or during topical application of a drug will dilate penetration pathways in the skin, increase
kinetic energy and the movement of particles in the treated area, and facilitate drug
absorption. Heating the skin after the topical application of a drug will increase drug
absorption into the vascular network, enhancing the systemic delivery but decreasing the local
delivery as the drug molecules are carried away from the local delivery site.1
Knutson et al. recently investigated the mechanisms involved in temperature-enhanced
skin permeability. Results indicated that the increased skin permeability of lipophilic drugs
results from temperature-induced alteration of the lipid structure, which involves the
disordered arrangement of the lipid bilayer structure and its fluidization.6 Further studies
indicate that temperature changes of approximately 5C are necessary to cause measurable
changes in cell membrane permeability.1
The effect of temperature on in vitro transdermal fentanyl flux was estimated by Gupta et
al using cadaver skin at controlled temperatures of 32C and 37C. Over this 5-degree range,
the drug flux approximately doubled. Given the doubling of release rate in vitro with a 5C
change in temperature, an in vivo study was conducted in 20 volunteers to determine regional
skin-temperature differences under occlusion. Transdermal placebo systems (10 cm2) were
placed on areas of the thigh, forearm, back, chest, and postauricular areas. The results
indicated that skin temperature under occlusion does not differ sufficiently from site to site to
cause different drug-input rates. Gupta et al predicted that since "the diffusion process
depends on the activation energy," an increase in body temperature would increase the
fentanyl permeation rate. Assuming that the diffusion rate from the delivery system remained
unchanged during a 3C temperature increase, they predicted that the maximum serum
concentration level at the middle of the 3-day application period would increase by 25%
(from 2.1 to 2.6 ng/mL for a 100-mg patch).7
The body's normal temperature regulation process has been found to follow a circadian
rhythm. In fact, the notion that body temperature oscillates on a daily basis has been around
for centuries.8 A pioneering study that measured the sublingual body temperature in 74
humans was performed by Drake in 1967. The lowest mean body temperature of about 36.2C
occurred at 4 AM in the morning and the highest mean body temperature of about 36.9C
occurred near 8 PM in the evening.9 Yosipovitch et al investigated the circadian rhythmicity
of skin variables related to skin barrier function in humans.8 They found that skin temperature
displayed time-dependent rhythms on all body sites measured (forearm, forehead, shin, and
upper back) with maximum values occurring at 6 P.M. for the forehead and upper back and at
2 A.M. for the forearm and shin. The minimum values for all locations occurred at around
10 A.M. in the morning. The average variation between maximum and minimum
temperatures at all locations was 1.7C. The researchers concluded that skin permeability may
be higher in the night than in the morning due to these natural circadian temperature
variations.10
Heat is also expected to enhance transdermal drug penetration by enhancing solubility of
the drug in formulation. As a general rule, the aqueous solubility of inorganic and organic
solid drugs increases with increasing temperature. The solubilities of several weak acids in
aqueous solutions at different temperatures are given in Table 1.11
External heating induces changes in hemodynamics, body fluid volume, and blood flow
distribution, which in turn may affect the pharmacokinetics or bioavailability of a
transdermally administered drug. The body's initial response to heat is peripheral vasodilation
followed by perspiration, which results in a large fraction of the total blood volume being
circulated through the skin vessels for cooling. Rabkin and Hunt found that a subcutaneous
temperature increase of 4C caused a threefold increase in local perfusion as estimated by
using the Fick principle.12 Song et al13 and Lokshina et al14 found a four- to sixfold increase
in the local skin perfusion of heated rat limbs at 43C during hot water immersion for 1 and 2
hours, respectively.
Additional research performed by Rowell et al indicates that cutaneous blood flow is
enhanced at a rate of 3 L/min/C increase in body core temperature.15,16 In practice, they
found that external heating induces a 10- to 12-fold increase in skin blood flow,
corresponding to more than half of cardiac output. During heat exposure, peripheral vascular
resistance is reduced and cardiac output is increased approximately twofold to compensate for
the effects of reduced venous return and centrally circulating blood volume on
haemodynamics.15,16 During heat exposure, hepatic, renal, and visceral blood flow are
reduced and skin blood flow is enhanced due to the redistribution of organ blood flow. Local
heating of the cutaneous tissue does not generally affect the body core temperature, however,
and will result in a local increase in subcutaneous blood flow rather than a body-wide
redistribution of systemic blood flow.
Numerous studies have been undertaken in order to demonstrate that marked enhancement
of cutaneous blood flow during heat exposure dramatically alters the pharmacokinetics of
transdermally administered drugs. The results of these studies indicate that external heating
significantly enhances transdermal as well as subcutaneous drug absorption resulting in
increased plasma drug concentrations. The overriding mechanism of enhanced drug delivery
appears to be increased local blood flow which is enhanced many-fold by the application of
heat.
Plasma nitroglycerin concentrations have been studied in 12 healthy volunteers (aged 28 to
63 years) by using 10-mg transdermal nitroglycerin patches during a 20-minute sauna (air
temperature, 90C; peak skin temperature, 39C).17 In the study, the mean plasma
concentrations of nitroglycerin increased significantly from 2.3 to 7.3 nmol/L (more than a
threefold increase) during heat exposure when compared with a control session at room
temperature. At the same time, a statistically significant fall in diastolic blood pressure and a
significant increase in heart rate were recorded. It was suggested that the increased
transdermal uptake of nitroglycerin was partly due to enhanced blood flow resulting from
heat-induced subcutaneous vasodilation. The authors concluded that elevated temperature can
significantly influence the subcutaneous circulation and, through vasodilation, can increase
the uptake of nitroglycerin, possibly from a subcutaneous reservoir. They also commented
that the bioavailibility of other drugs applied transdermally may also be affected by the degree
of cutaneous vasodilation induced by altered skin temperature.
The relationship between blood flow and the transdermal absorption of nitroglycerin has
been demonstrated in a study in which nitroglycerin patches applied to an area of the upper
arm were heated locally by infrared light for 15 minutes.18 In the study, infrared heating
enhanced local blood perfusion (measured by photoplethysmography) and at the same time,
plasma nitroglycerin concentrations were increased two- to threefold. Correspondingly, the
cooling off of the patch area was followed by a fall in plasma nitroglycerin concentrations,
indicating that the mechanism is reversible. The authors ascribe the changes in plasma
nitroglycerin levels to observed alterations in cutaneous blood flow induced by regional
temperature changes. The localized heating did not alter the body temperature and therefore,
should not have resulted in important changes in hepatic blood flow, cardiac output, or fluid
distribution.
Percutaneous delivery from most transdermal systems is limited either by skin
permeability or rate-limiting membrane permeability, which is typically fixed at a rate lower
than the maximal skin permeability. Based on these mechanisms, cutaneous blood flow
should not influence drug bioavailability. The study results indicate, however, that regional
temperature changes alone can cause a major change in the bioavailability of nitroglycerin.
This suggests that it is necessary to consider not only the drug passage through the skin but
also further diffusion from cutaneous and subcutaneous tissue under the patch into the
systemic circulation. As indicated in Table 2, temperature can be seen to affect both stages of
drug delivery:
By increasing skin permeability, rate-limiting membrane permeability, and drug solubility
in formulation, increases in temperature can be seen to enhance drug permeation through the
skin. By augmenting regional cutaneous blood circulation and increasing blood vessel wall
permeability, the application of heat should also increase further drug transportation into
adjacent tissues and systemic circulation because the transfer of drug is a concentration
dependent process. Increasing blood flow away from the site of administration would
theoretically reduce the concentration locally and allow more rapid transport. Detectable
plasma nitroglycerin levels up to an hour after patch removal indicate the existence of a
cutaneous or subcutaneous reservoir whose emptying is likely to be influenced by changes in
the regional blood flow. The authors suggest that heat-induced changes in regional blood flow
may also influence the plasma levels of other transdermally delivered drugs, such as
scopolamine and nicotine.18
The effects of heat exposure on the pharmacokinetics of transdermal nicotine have been
studied in a sauna (air temperature, 77C to 84C) in 12 healthy volunteers who smoked.19
Two transdermal nicotine patches (total nicotine content, 41.5 mg) were applied to the arm of
the volunteers 5 hours before heat exposure. The heat exposure consisted of three 10-minute
stays in a sauna separated by two 5-minute cooling periods at 23C. Having a sauna increased
the mean plasma nicotine concentrations significantly compared with the control session.
However, after the heat exposure, the plasma nicotine concentrations gradually decreased to
equal those of the pre-sauna period. The amount of nicotine remaining in the patches was
measured at the end of the study, and the nicotine concentration following the sauna session
was significantly lower than the control session concentration, indicating that a greater
amount of nicotine was released from the patch during the heated session. This result supports
the hypothesis that changes in bioavailability and plasma concentrations of transdermally
delivered drugs during heat exposure are related to an increase in local blood flow of the skin
area. In this study, it is unclear, however, whether the basic mechanism for this effect was
increased absorption of nicotine from the patches or enhanced transportation of nicotine from
subcutaneous tissues into systemic circulation.
Exposure to air temperatures of 40C has also been shown to increase the bioavailability
of methyl salicylate.20 Five grams of methyl salicylate was applied to the chest and back of
six male subjects who were then exposed to cross-over periods of rest or exercise at 22C or
40C. The absorption of methyl salicylate was increased more than threefold above control in
subjects exercising in the heat. The authors concluded that exercise and heat exposure
enhanced the percutaneous absorption of methyl salicylate by increasing skin temperature,
cutaneous blood flow, and skin hydration.
A recent study investigated the influences of bathing and hot weather on the
pharmacokinetics of a new transdermal clonidine system, M-5041T.21 An oral dosage form
of clonidine for the treatment of hypertension was found to elicit wide fluctuations in the
plasma concentrations of clonidine, even at steady state. A transdermal therapeutic system
was thus developed in order to provide constant plasma concentrations of clonidine and to
reduce the drug-related systemic adverse effects. The study found a significant (150% to
200%) increase in the plasma concentrations of clonidine during the summer trial when
compared to the winter trial. The mechanisms cited for this result included increased blood
flow through the dermal vessels and hydration of the stratum corneum by excessive sweating
due to increased temperature and relative humidity during the summer trial.
A 1993 case report describes a patient who suffered a fentanyl overdose when a hospital
heating pad came in direct contact with a transdermal fentanyl patch.22 The hospital heating
pad was found to increase cutaneous temperature to about 42C upon direct contact with skin.
The manufacturer of the transdermal fentanyl patch provides a precautionary statement in the
Physicians' Desk Reference that serum fentanyl concentrations may increase by
approximately one third in patients with a body temperature of 40C (102F). Based on a
pharmacokinetic model, this increase is due to two main factors: accelerated release of
fentanyl from the drug reservoir and increased skin permeability. Authors of the report also
state that cutaneous hyperthermia should increase skin blood flow, thereby accelerating
systemic uptake of drug. The authors of the case report caution the use of heating pads by
patients wearing fentanyl patches as they have the potential for causing severe drug overdose.
In its application instructions, the manufacturer expands this caution to include the use of
electric blankets, heat lamps, heated water beds, saunas, hot tubs or other sources of direct
heat on a patch as "direct sources of heat may increase the amount of medication you receive
through the skin from the patch."22
There may be instances, however, where an increased (yet controlled) dose of fentanyl is
desirable. For many terminal cancer patients, the chronic pain associated with their condition
is often unbearable and is typically treated with systemic analgesics such as morphine and
fentanyl. Often the prescribed dosage becomes insufficient over extended periods of time or
during periods of increased activity or "breakthrough" pain. It may be desirable and extremely
beneficial to the patient for the dose of drug to be quickly increased or titrated during such an
episode. This may be accomplished by the application of a controlled dose of heat to the local
patch application site. As heat has been shown to accelerate systemic uptake of drug by
increasing skin blood flow, increasing skin permeability, and accelerating release of drug
from the patch reservoir, it may also significantly reduce the time required for the drug to
reach systemic circulation and provide the desired effect. In a double cross-over study, a
transdermal fentanyl patch with and without a controlled heat-producing device was applied
to 6 healthy adult volunteers, and serum blood levels were measured. The study found that
during the heat application period, "statistically significant differences were noted between
the heat and no-heat groups."27
The application of heat (or cold) has also been found to modify drug delivery
from intramuscular and subcutaneous injection sites. Shortly after a drug is injected or
absorbed into the general circulation, the drug molecules tend to distribute among many
tissues, organs, and compartments. Changes in body temperature may influence the rate and
extent of drug distribution. In the 1940s, when penicillin was administered intramuscularly,
there were problems with the drug disappearing too rapidly both from the injection site and
the bloodstream. One method of prolonging the action of a single dose of penicillin was to
cool the injection site with an ice bag. Trumper and Hutter suggested that the absorption rate
of the penicillin solution was retarded by slowing the circulation around the injection site.23
McInally et al studied the clearance of sodium following the injection of isotonic saline
into the subcutaneous tissue of the legs of normal humans.24 The clearance of sodium was
increased in the subjects whose trunk and upper extremities were exposed to heat from an
electric blanket. The investigators concluded that the clearance of sodium from subcutaneous
tissue is largely governed by the blood flow surrounding the injection site, which is
presumably greater in heated subjects.
Several studies have demonstrated that the insulin absorption rate from an injection site is
related to ambient temperature: whereas warm temperature accelerates absorption, exposure
of the injection site to cold delays the rate of insulin absorption. Ronnemaa and Koivisto25
studied the effect of cool (10C) and warm (30C) ambient temperatures and physical exercise
on insulin absorption and postprandial glycemia. They found that warm temperature was
associated with a three- to fivefold higher insulin absorption and significantly lower blood
glucose concentration than cool temperature regardless of exercise. The authors noted that
skin blood flow and temperature are correlated and depend on environmental temperature.
They also observed that the absorption of soluble insulin and insulin suspension are correlated
to skin blood flow when injected subcutaneously. They concluded, therefore, that the greater
insulin absorption rates in warm compared with cool temperature is probably explained by
higher skin temperature and blood flow.
Another study measured the effect of the Finnish sauna on insulin absorption from a
subcutaneous injection site.26 Two 25-minute sauna sessions at 85C were found to double
the disappearance rate of insulin from the subcutaneous tissue when compared with control
periods at room temperature. The mechanism cited for this result is an increase in
subcutaneous blood flow due to local heating resulting in accelerated insulin absorption from
the injection site. It was also observed that a large depot of injected insulin may remain at the
injection site, such that the stimulatory effect of heat from the sauna on insulin absorption
may result in a rapid fall in blood glucose.
CONCLUSION
The many cited studies of transdermal and subcutaneous drug administration indicate that the
total amount of drug absorbed, and the consequent plasma drug concentrations increased
during heat exposure. Although numerous, more complex mechanisms may be involved, heat
is expected to increase skin permeability, blood vessel wall permeability, rate-limiting
membrane permeability, and drug solubility in formulation. In addition, changes in the
physicochemical properties of transdermal patches, sweating, and increased hydration of the
skin may contribute to the release and diffusion of transdermally administered drugs. The
dominant mechanism of this important phenomenon, however, appears to be heat-induced
local vasodilation and acceleration of skin blood flow. This mechanism has been seen to
affect both drug passage through the skin and diffusion from cutaneous and subcutaneous
tissue into the systemic circulation. The several-fold increases in plasma drug concentrations
seen in these studies suggest that the application of localized heating may provide a simple
and effective method for enhancing the transcutaneous delivery of a wide variety of drugs.
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Drug Temperature Solubility Percent Increase
(C) (g/100 mL)
Barbital 20 0.629 138%
37 0.949
Phenobarbital 20 0.088 209%
37 0.184
Sulfadiazine 20 0.00616 161%
38 0.0099
Tolbutamide 27 0.0077 184%
37.5 0.0142
Table 1. Solubilities of several drugs at different temperatures11



Drug Permeation Through the Skin Further Drug Transportation
. Surface area . Permeability of tissue between stratum
corneum and skin vessels
. System rate control: membrane/matrix . Blood vessel wall permeability
dissolution
. Stratum corneum: lipid and water . Cutaneous blood flow
content
. Temperature . Temperature
Table 2. Proposed major determinants of drug bioavailability during
transdermal treatment18