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 5°C 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 32°C and 37°C. Over this 5-degree range, the drug flux approximately doubled. Given the doubling of release rate in vitro with a 5°C 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 3°C 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 36.2°C occurred at 4 am in the morning and the highest mean body temperature of about 36.9°C 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 1.7°C. 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 4°C 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 43°C 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, 90°C; peak skin temperature, 39°C).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, 77ºC to 84ºC) 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 23ºC. 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 40ºC 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 22ºC or 40ºC. 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 42ºC 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 40ºC (102ºF). 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 (10ºC) and warm (30ºC) 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 85ºC 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.

REFERENCES

 1. Byl NN: The use of ultrasound as an enhancer for transcutaneous drug delivery: Phonophoresis. Phys Therap June; 75 (6):539-553, 1995.

 2. Roberts MS: Targeted drug delivery to the skin and deeper tissues: Role of physiology,       solute structure and disease. Clin Exp Pharmacol Physiol Nov;24 (11):874-879, 1997.

 3. Lehmann Klaus A, Zech, Detlev. J Pain Symptom Management 7(3);S8-S16, 1992.

 4. McDaid DM, Deasy PB: An investigation into the transdermal delivery of nifedipine. Pharmaceutica Acta Helvetiae 71(4):253-258, 1996.

 5. Kligman AM: A biological brief on percutaneous absorption. Drug Dev Industr Pharm 9:521-560, 1983.          

 6. Knutson K, Krill WJ, Lambert WJ, Higuchi WI: Physicochemical aspects of transdermal permeation. J Cont Rel 6:59, 1987.

 7. Gupta SK, Southam M, Gale R, Hwang SS: System functionality and physicochemical model of fentanyl transdermal system. J Pain Symptom Management April; 7(3) Suppl: S17-S26, 1992.

 8. Yosipovitch G, Xiong GL, Haus E, et al: Time-dependent variations of the skin barrier function in humans: Transepidermal water loss, stratum corneum hydration, skin surface pH, and skin temperature. J Invest Dermatol Jan;110(1):20-23, 1998.

 9. Drake MJF: Nature 215; 896, 1967.

10. Refinetti R, Menaker M: The circadian rhythm of body temperature. Physiol Behavior 51:613-637, 1992.

11. Ballard BE: Pharmacokinetics and temperature. J Pharmaceutical Sci 63(9);1345-1358, 1974.

12. Rabkin JM, Hunt TK: Local heat increases blood flow and oxygen tension in wounds. Arch Surg Feb;122(2):221-225, 1987.

13. Song CW, Kang MS, Rhee JG, et al: Effect of hyperthermia on vascular function in normal and neoplastic tissues. Ann NY Acad Sci 335:32-47, 1980.

14. Lokshina AM, Song CW, Rhee JG, et al: Effect of fractionated heating on the blood flow in normal tissues. Int J Hyperthermia 1:117-129, 1985.

15. Vanakoski J, Seppala T: Heat exposure and drugs: A review of the effects of hyperthermia on pharmacokinetics. Clin Pharmacokinetics Apr;34(4):311-322, 1998.

16. Rowell LB, Brengelmann GL, Blackmon JR, et al: Redistribution of blood flow during sustained high skin temperature in resting man. J Appl Physiol 28(4):415-420, 1970.

17. Barkve TF, Langseth-Manrique K, Bredesen JE, et al: Increased uptake of transdermal glyceryl trinitrate during physical exercise and during high ambient temperature. Am Heart J 112(3):537-541, 1986.

18. Klemsdal TO, Gjesdal K, Bredesen J-E: Heating and cooling of the nitroglycerin patch application area modify the plasma level of nitroglycerin. Eur J Clin Pharmacol 43:625-628, 1992.

19. Vanakoski J, Seppala T, Sievi E, et al: Exposure to high ambient temperature increases absorption and plasma concentrations of transdermal nicotine. Clin Pharmacol Therap 60(3):308-315, 1996.

20. Danon A, Ben-Shimon S, Ben-Zvi Z: Effect of exercise and heat exposure on percutaneous absorption of methyl salicylate. Eur J Clin Pharmacol 31:49-52, 1986.

21. Fujimura A, Sasaki M, Harada K, et al: Influences of bathing and hot weather on the pharmacokinetics of a new transdermal clonidine, M-5041T. J Clin Pharmacol 36:892-896, 1996.

22. Duragesic Fentanyl Transdermal Application Instructions, Janssen Pharmaceutica Inc., December 1994.

23. Trumper M, Hutter AM: Science 100:432, 1944.

24. McInally M, Campbell JA, Robertson DF, Douglas DM: Clin Sci 11, 183, 1952.

25. Ronnemaa T, Koivisto VA: Combined effect of exercise and ambient temperature on insulin absorption and postprandial glycemia in type I patients. Diabetes Care 11(10):769-773, 1988.

26. Koivisto VA: Sauna-induced acceleration in insulin absorption from subcutaneous injection site. Br Med J 280:1411-1413, 1980.

27. Shoemaker TS, Zhang J, Ashburn MA: Assessing the Impact of Heat on the Systematic Delivery of Fentanyl Through the Transdermal Fentanyl Delivery System. Pain Medicine 1 (3):225-230, 2000.

 

 

Drug                                           Temperature                    Solubility                Percent Increase

                                                            (ºC)                           (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

 

Figure 2. Diagrammatic representation of transdermal absorption pathways2

Figure 1. Cross-sectional view of the skin5