The transdermal delivery of fentanyl

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Contents lists available at SciVerse ScienceDirect

European Journal of Pharmaceutics and Biopharmaceutics journal homepage: www.elsevier.com/locate/ejpb

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Review article

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The transdermal delivery of fentanyl

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Majella E. Lane ⇑ Department of Pharmaceutics, School of Pharmacy, London, United Kingdom

a r t i c l e

i n f o

Article history: Received 28 November 2012 Accepted in revised form 25 January 2013 Available online xxxx Keywords: Fentanyl Transdermal patch Reservoir Matrix Pharmacokinetics

a b s t r a c t The fentanyl patch is one of the great commercial successes in transdermal drug delivery. The suitability of this molecule for delivery through skin had been identified in the 1970s, and subsequently, a number of transdermal formulations became available on the market. This article reviews the development of fentanyl patch technology with particular emphasis on the pharmacokinetics and disposition of the drug when delivered through the skin. The various patch designs are considered as well as the bioequivalence of the different designs. The influence of heat on fentanyl permeation is highlighted. Post-mortem redistribution of fentanyl is discussed in light of the reported discrepancies in serum levels reported in patients after death compared with therapeutic levels in living subjects. Finally, alternatives to patch technology are considered, and recent novel transdermal formulations are highlighted. Ó 2013 Published by Elsevier B.V.

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1. Introduction

2. Intravenous pharmacokinetics and metabolism

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Fentanyl is a potent opioid narcotic which was first synthesised by Janssen in 1960 [1]. Structurally, fentanyl, N-1(1-Phenethy l-4-piperidyl)propionanilide (Fig. 1), is related to pethidine, but it is not a pethidine derivative. It has a molecular weight of 336.5, a melting point of 83–84 °C and is sparingly soluble in water [2]. The development of fentanyl and related compounds resulted from the search for alternative intravenous analgesics to morphine. As a l-opioid receptor agonist, fentanyl is estimated to be 80 times more potent than morphine as an analgesic [3]. The initial application of fentanyl, when administered intravenously, was as a component of neuroleptanalgesia [4] usually in combination with a butyrophenone (droperidol). Subsequently, fentanyl was administered alone and to supplement balanced anaesthesia [5,6]. In addition to intravenous administration, there was awareness that fentanyl had potential as a transdermal drug candidate in the 1970s [7] at a time when transdermal drug delivery was in its infancy. This article reviews the historical development of transdermal fentanyl delivery and recent progress in the technology. The pharmacokinetics of transdermal fentanyl versus intravenous fentanyl are considered. Various patch designs are discussed. Side effects are considered, specifically in relation to fatalities associated with transdermal fentanyl patch use. Novel formulation strategies are compared with existing patch technology (Table 1) and examined critically.

When administered orally, fentanyl undergoes extensive firstpass metabolism and consequently was almost exclusively administered parenterally to achieve analgesia prior to the advent of transdermal or buccal formulations. An examination of the intravenous (i.v.) pharmacokinetics further confirms its suitability as a candidate for transdermal administration. When administered as the citrate salt by the intravenous route, fentanyl has a short duration of action. Originally, this was assumed to reflect rapid removal of fentanyl from the body [3]. Subsequently, when administered for narcotic-based anaesthesia, it became clear that redistribution of fentanyl within the body was occurring, resulting in delayed recovery and respiratory depression [8]. After i.v. administration, fentanyl is eliminated predominantly by hepatic biotransformation [3,9] via the cytochrome P-450 3A4 system [10]. In one study, about 8% of i.v. fentanyl was eliminated unchanged, with approximately 75% and 12% of this unchanged fentanyl appearing in the urine and faeces, respectively. More than 80% of the dose was recovered as metabolites, with 76% appearing in the urine and 8% in faeces [9]. The apparent volume of distribution (Vd; 3.99 ± 0.20 l/kg) and the volume of the central compartment (Vc: 0.36 ± 0.07 l/kg) were both large and independent of the dose [9]. The whole body clearance rate of fentanyl was also reported as 956 ± 65 ml/min and 698 ml/min. Fentanyl kinetics after i.v. dose was described by a 3-compartment model; after introduction into a central compartment, fentanyl is distributed to each of two peripheral compartments; plasma protein binding was also shown to be pH dependent [9]. The major route of metabolism after i.v. administration is N-dealkylation to norfentanyl [4-N(N-propionylanilino)piperidine] [11] which has been recovered in

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⇑ Address: Department of Pharmaceutics, School of Pharmacy, 29-39 Brunswick Square, London WC1N 1AX, United Kingdom. Tel.: +44 207 7535821; fax: +44 870 1659275. E-mail address: [email protected] 0939-6411/$ - see front matter Ó 2013 Published by Elsevier B.V. http://dx.doi.org/10.1016/j.ejpb.2013.01.018

Please cite this article in press as: M.E. Lane, The transdermal delivery of fentanyl, Eur. J. Pharm. Biopharm. (2013), http://dx.doi.org/10.1016/ j.ejpb.2013.01.018

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O

N

N

Fig. 1. Structure of fentanyl.

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plasma and urine [12,13]. Van Rooy et al. [12] also identified the despropionylfentanyl metabolite in plasma. Hydroxynorfentanyl and hydroxyfentanyl have also been identified in urine [11]. Early reports suggested that the analgetic plasma level of fentanyl was suggested to be in excess of 1 ng/ml [14–16]. The range of plasma fentanyl concentrations associated with analgesia and acceptable respiratory function was later confirmed to be 1–3 ng ml 1 [8,17].

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3. Transdermal fentanyl delivery – the early years

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The first report of fentanyl permeation in human skin samples in the scientific literature appears in the seminal paper by Michaels et al. [7], where the stratum corneum was likened to a ‘brick and mortar’ structure. The importance of ionisation was also noted in the paper, and it was further observed that the intrinsic permeability of the free base form of a drug should be greater than its ionised form. Permeation studies conducted on cadaver skin with fentanyl solutions (pH 8) indicated that flux in skin ranged from 0.8 to 3.8 lg/cm2 hr at 30 °C. The suitability of the transdermal route for fentanyl delivery was examined further by Roy and Flynn [18–20]. These authors investigated pH solubility profiles at 35 °C for the drug in citrate–phosphate buffer and determined the pKa of fentanyl to be 8.99 ± 0.13 based on solubility data. Over the pH range 5.48–12.47, fentanyl solubility decreased from 75.13 mg/mL to 0.012 mg/mL. The solubility of the free base form of fentanyl was reported to be

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9.9  10 3 mg/ml [19]. An octanol:water (pH 7.4) partition coefficient of 717 was determined by equilibrating aqueous solutions of fentanyl with octanol. Calculated and experimental solubility parameters for fentanyl were reported as 9.6 and 9.7 (cal/cm3)1/2, respectively. The permeability coefficient of fentanyl was also determined as a function of pH over the range 7.4–9.4 and was found to vary less than threefold over this range [20]. An apparent skin diffusion coefficient of 2.4  10 11 cm2/sec was reported for fentanyl using the Daynes and Barrer lag time equation [21,22]. The permeability coefficient for donor solutions with a pH of 8.0 was 2.2  10 2 cm/h which is in reasonable agreement with the value reported by Michaels et al. (1.0  10 2 cm/h) for the same pH, considering that Roy et al. [20] conducted their studies at 37 °C. The higher permeability coefficient of fentanyl relative to the other opioid alkaloids (morphine, codeine and hydromorphone) examined was also attributed to the more lipophilic nature of fentanyl [18]). It therefore was shown to have suitable physicochemical properties for transdermal delivery. Based on the permeation values reported in the earlier work of Michaels et al. [7], Roy and Flynn [20] also concluded that fentanyl was unaffected by enzymes in the skin under the conditions of the permeation study. In terms of drug delivery, daily dosages of the compounds along with calculated flux values for fentanyl were used to estimate the patch size required for drug delivery through intact skin at unit thermodynamic activity. Calculations based on clearance and therapeutic levels of fentanyl required for analgesic activity indicated that a patch operating to give 50–100 lg/h (equivalent to 2–5 lg/cm2/hr for a 20 cm2 patch) would meet the therapeutic requirement for transdermal fentanyl delivery. In a later study, Roy and Flynn [23] considered possible influences of pH of donor solution, anatomic and subject variation on fentanyl transdermal permeation. The permeability coefficients and lag times for fentanyl through isolated epidermis were no different from those found with dermatomed skin (p > 0.05). Permeability coefficients for stripped skin were roughly 50 times greater than for the epidermis. When the permeation of fentanyl was examined as a function of subject and to a limited extent, gender and age, these factors did not significantly affect the delivery. However, it must be pointed out that the number of actual samples from different donors in the study was small; for site variation, samples were taken from one cadaver and for other variables,

Table 1 Examples of fentanyl patches which are currently on the market. Product name

Patch design

Reservoir/matrix components

FentalisÒ

Reservoir

Ethanol

25/50/75/100 mcg/h

Durogesic DTRANSÒ

Hydroxyethyl cellulose Water Fentanyl Matrix

Polyacrylate Fentanyl

Matrix

Aloe vera leaf extract oil (on the basis of soya oil)

12/25/50/75/100 mcg/h FencinoÒ 25/50/75/100 mcg/h

MatrifenÒ 12/25/50/75/100 mcg/h

Colophonium resin Poly (2-ethylhexyl acrylate, vinylacetate) (50:50) Fentanyl Matrix/rate-controlling membrane

Matrix* Dipropylene glycol Silicone adhesive (amine resistant) Fentanyl Rate-controlling membrane Ethylenevinylacetate

*

Not all components of the patch are listed.

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and skin was sampled from 11 different donors. In terms of body site, permeability coefficients obtained on skin from a single cadaver for the upper arm, thigh, abdomen chest and sole were quite similar, ranging from 4  10 3 cm/h to 10  10 3 cm/h, with the lowest permeation observed for the sole of the foot. The authors suggested that transdermal patches of fentanyl could be applied to any convenient body surface. The free base form of fentanyl was clearly demonstrated to be the most permeable form of the drug with the data confirming the feasibility of delivering fentanyl at rates consistent with the requirements for pain therapy.

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4. Reservoir transdermal patches

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4.1. Patch design

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The first transdermal fentanyl patch was approved by the FDA in the 1990s. The ‘reservoir’ patch design (TTS) ensured release of fentanyl continuously for 3 days on application to intact skin, and it is still in use today. Systems are available to provide delivery rates ranging from 12.5 to 100 lg/h. The design of the patch comprises a four-layer laminate on a protective liner (Fig. 2). The backing layer comprises a clear polyester/ethylene film and is heat sealed around the perimeter of the rate-controlling membrane. The drug reservoir consists of fentanyl base dissolved in ethanol and gelled with hydroxyethyl cellulose. The rate-controlling membrane, an ethylene–vinyl acetate copolymer film, determines the rate of fentanyl release from the system to the skin surface. The adhesive layer permits free passage of the drug, effective attachment to the skin and releases the initial loading dose of drug to skin. During manufacture, fentanyl base is incorporated only into the drug reservoir. After manufacture, fentanyl from this source migrates through the rate-controlling membrane until the fentanyl concentration in the adhesive reaches equilibrium with that in the reservoir. Fentanyl in the adhesive is referred to as the loading dose. Fentanyl is maintained at saturation in the drug reservoir after the equilibration period. When applied to the skin, the drug partitions from the adhesive to the adhesive/skin interface and then diffuses through the skin and into the systemic circulation. As drug depletes from the adhesive, additional drug diffuses from the reservoir through the rate-controlling membrane into the adhesive. A 100 lg/h reservoir patch is designed to last for 3 days, and thus, a delivery of 7.2 mg is achieved. Given that the initial loading of the patch would have been 10 mg, the reservoir patch design represented a major transdermal formulation achievement with 28% residual fentanyl. This is particularly important given the abuse potential associated with fentanyl and the possibility of extracting fentanyl from the reservoir as well as cost of goods issues.

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4.2. Clinical evaluation and pharmacokinetics of the reservoir patch

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Duthie et al. [24] measured plasma concentrations during and after transdermal fentanyl delivery in groups of patients undergoing general surgery. TTS-fentanyl (100 lg/h) was applied 2 h before induction of anaesthesia and removed after 24 h. Blood samples

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Backing membrane Reservoir Rate controlling membrane Adhesive Fig. 2. Schematic of typical reservoir device.

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were taken up to 24 h after removal of the TTS. Patients were allocated to one of two groups. Group 1 received fentanyl 100 lg i.v. and group 2 received 200 lg fentanyl i.v. At 8 and 12 h, concentrations did not differ from those observed in a matched group of patients receiving fentanyl by i.v. infusion clearly demonstrating that it was possible to deliver fentanyl over a 24 h period. At 24 h, concentrations were significantly lower in Group 2 compared with the matched group receiving fentanyl by infusion. There were no significant differences between the groups 4 h after fentanyl removal. Plasma fentanyl concentrations decreased slowly in the TTSfentanyl groups after removal of the TTS. Mean plasma half-lives were 15.9 and 15.7 h, respectively. The mean half-life of approximately 16 h was noted to be much greater than for i.v. fentanyl and was consistent with a depot of the drug remaining in the skin when the patch was removed. The 100 lg/h TTS was shown to be as effective in obtaining analgesic serum fentanyl concentrations as a 24 h continuous i.v. infusion of fentanyl at a rate of 100 lg/h [25]. Eight patients received fentanyl via the transdermal route for 24 h in an open study during the perioperative period. The TTS was applied to the patient’s upper chest 2 h before induction of anaesthesia and left in place for 24 h. Patients received a loading dose of fentanyl (300 lg i.v.) at induction, followed by anaesthesia. Serum concentrations did not reach a plateau until approximately 15 h after application of the TTS. The mean apparent half-life of fentanyl concentrations after removal of the TTS was approximately 21 h. The slow decline of fentanyl concentration was suggested to reflect continued absorption from skin of the drug after removal of the TTS. Uptake by a skin depot was also proposed to explain the slow attainment of plateau fentanyl levels, that is, flip flop kinetics. Varvel et al. [26] observed a longer terminal elimination halflife for serum fentanyl concentrations after removal of a 100 lg/h TTS compared with intravenous administration (17.0 ± 2.3 h versus 6.1 ± 2.0 h). The rate of fentanyl absorption appeared to be relatively constant during a period starting 4–8 h after placement of the transdermal system until removal of the system at 24 h. The rate of absorption was 91.7 ± 2 25.7 lg/h. After removal of the transdermal fentanyl delivery system, absorption continued at a declining rate. The authors noted that the long terminal half-life of serum fentanyl concentrations after transdermal system removal reflected continuous slow absorption of fentanyl, probably from a cutaneous depot of drug at the site of prior transdermal patch application. There was no evidence of significant cutaneous metabolism or degradation by the skin’s bacterial flora. Gupta et al. [27] reported that in clinical trials, TTS were applied to skin sites on the chest, back and upper arm. No single site was associated with a higher incidence of side effects or lower efficacy in line with the earlier in vitro findings of Roy et al. [23]. In the case of the TTS-fentanyl reservoir patch, these workers also estimated that there is 50% control of fentanyl from the patch and 50% from the skin. Inter-subject variability in the drug-absorption rate was suggested to be minimally affected by skin-site temperature, because of temperature consistency among subjects. An open-label repeat dose pharmacokinetic study was conducted by Portenoy and co-workers [28] using fentanyl TTS (100 lg/h) in order to evaluate the stability of drug delivery and metabolism during long-term use. Ten opioid-tolerant cancer patients received five sequential applications of TTS-fentanyl at 72 h intervals, and blood samples were taken before each dose. Each patch was applied to a different area of the torso. For the final dose, the mean fentanyl serum concentration achieved in each patient during the 72 h dosing period was 1.6 ± 0.8 lg/ml, and the mean Cmax was 2.6 ± 1.3 lg/ml. The AUC from 0 to 72 h (AUC0–72) was 116.9 ± 59.9 lg-h/ml and following removal of the system serum fentanyl concentrations declined with an apparent half-life of 21.9 ± 8.9 h. No differences were observed in fentanyl serum levels

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measured before the second through to the final dose. Measurement of residual fentanyl following a 72 h application indicated that the mean dose delivered by all systems was 4.3 ± 1.1 mg. The results suggested that steady-state fentanyl levels are approached by the second dose and that the kinetics are stable with repeated dosing. In addition, the apparent half-life following system removal was relatively long, indicating ongoing absorption from a subcutaneous depot. Inter-subject variation in trough serum concentration was smaller than intra-subject variation indicating that individual differences accounted for most of the variability observed in the data. Furthermore, the authors suggested that taking the findings of the study together with previous chronic dosing surveys, intra-individual variation was small enough to be clinically irrelevant but qualified this observation by noting that further experience with the TTS was needed. As temperature is known to alter skin permeability, Shomaker and co-workers [29] investigated the effects of heat on the pharmacokinetics of fentanyl delivered from the reservoir patch in six adults in an open 2-period crossover randomised study. Heat was applied using a controlled heating patch applied over the fentanyl patch for 4 h followed by a period of 20 h without heat. Differences in Cmax and AUC were not statistically significant over the entire 24-h study period. However, for the 4-h period of heat application, statistically significant differences seen in both mean Cmax (heat: 0.4 lg/ml versus no heat: 0.1 lg/ml) and mean AUC (heat: 40 ng/ ml.min versus no heat: 10 ng/ml. min). In a later study from the same group, the effect of heat on transdermal fentanyl delivery was investigated in a 3-period crossover study design with 10 volunteers [30]. In sessions A and B, a reservoir patch (25 lg/h) was applied for 30 h. For session A, one hour of controlled heat was administered at 24 h; for session B, controlled heat was administered for the first 4 h and again for 1 h at 24 h. The patch was removed at 30 h. Five of the 10 subjects participated at a later date in session C, where the same strength patch was applied for 18 h and controlled heat was applied for the first 4 h. In addition, controlled heat was applied over one half of the patch for 15 min at the 12 and 16 h time points. The patch was removed at 18 h. Over 36 h, there was no difference in Cmax, AUC or Tmax comparing session A and B. However, significant differences were observed in the first 4 h with threefold higher Cmax (0.63 lg/ml versus 0.24 lg/ml) and AUC (1.22 lg/ml.h versus 0.42 ng/ml h) values observed for the heat treatment group compared with the group which received no heat treatment. The time to reach peak values (Tmax) did not differ significantly between groups A and B. At 24 h, the addition of heat resulted in rapid increases in fentanyl concentrations for both groups with higher serum levels for session A. Rapid but short duration increases in fentanyl were seen for session C at the 12 and 16 h time points. The FDA issued a public health advisory listing in 2005 which included cautions against using the patch in association with any heat exposure, external appliances, heating pads or in case of fever. In addition, the necessity to apply the patch to intact skin was stated as well as ensuring that the patch was not damaged. These concerns were reiterated in a later warning issued in December 2007 [31]. Recently, post-mortem redistribution (PMR) of fentanyl after transdermal administration has been highlighted [32,33]. PMR describes a process of drug diffusion along a concentration gradient from tissue to blood which may occur between actual death and time of blood sample collection at autopsy. The patches investigated in these two reports were a mixture of reservoir and matrix design (discussed in the next section). A more recent study by Andresen et al. [34] investigated post-mortem blood concentrations of 118 cases associated with therapeutic use of fentanyl reservoir patches, where the cause of death was considered to be unrelated to fentanyl. The data were compared with serum levels of 27 living

subjects also being treated with reservoir patches. On average, post-mortem fentanyl blood concentrations were up to nine times higher than in vivo serum levels at the same dose, and the authors suggested that these differences might be attributed to postmortem redistribution. These findings suggest that blood concentrations of fentanyl post-mortem need to be interpreted with caution in the context of forensic toxicology. The possibility of defects in reservoir patches contributing to leaking of the reservoir of the patch onto patients’ skin and consequent overdose has been raised. Potential toxicity arising from such an event was investigated by Oliveira et al. [35]. A commercially available fentanyl transdermal patch was evaluated in vitro using human skin from two donors. The results demonstrated that only 7.4 (±3.6) and 7.7 (±1.9)% of the applied dose of fentanyl had permeated after 48 h. Additionally, the maximum increase in plasma levels from a patch (100 lg/h) which leaked fentanyl over 100 cm2 was estimated to be 25% which would not represent a toxic dose.

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5. Matrix patches and matrix/rate-controlling membrane patches

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5.1. Matrix patch design and development

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Matrix patches typically contain a backing layer, a polymeric drug reservoir, an adhesive and a peelable liner (Fig. 3). In some cases, the system contains only the backing layer and the drug in adhesive which is covered by the liner. The simplicity of matrix systems is considered to reduce manufacturing costs, and they are typically thinner than their reservoir counterparts and hence may allow greater comfort and cosmetic applicability. However, the formulation of such devices is challenging, particularly for drug in adhesive systems, as the adhesive must serve multiple functions including containing the drug and controlling its release while maintaining adhesion to the skin. Rate control for the matrix patch. Roy et al. [36] investigated polyisobutylene (PIB), two types of silicone pressure-sensitive adhesives and acrylate pressure-sensitive adhesives for transdermal fentanyl delivery. The silicone pressure-sensitive adhesives evaluated were Dow Corning products, (Silicone-2675 and Silicone-2920) Fentanyl adhesive matrices were prepared for each polymer. The polymers were characterised with respect to drug solubility, diffusion coefficient and permeability coefficient. The solubility of fentanyl in the various adhesives at 32 °C and partition coefficient of the drug between the adhesive membrane and water were also determined. Drug release from the matrices was evaluated at room temperature in sodium phosphate buffer pH 6 under sink conditions. For the same drug loading, the release rate of fentanyl from the acrylate adhesive was about 2–3 times higher than the other adhesive membranes studied. However, the drug release rate from the PIB and silicone-2675 matrix was the lowest for all the adhesive membranes. The partition coefficient of fentanyl between the adhesive and water (Kp/w) for PIB and silicone-2920 was the lowest among the other adhesives studied because of low drug solubility in the former two adhesives. Overall, the solubility and partition coefficient of fentanyl in the adhesive membranes were in the following rank order: acrylate P silicone-2675 > silicone-2920 > PIB.

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Backing membrane Adhesive matrix Release liner Fig. 3. Drug in adhesive matrix monolithic device.

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Films of the various pressure-sensitive adhesives were prepared and mounted in Franz cells, and the permeation of fentanyl from saturated solutions across the films was assessed at 32 °C. The permeation of fentanyl through the acrylate and silicone membranes was significantly higher than that of the PIB adhesive which may reflect the higher fentanyl solubility and partition coefficient in acrylate and silicone adhesives. Diffusion coefficients of fentanyl were also calculated with the highest diffusion coefficient observed for silicone-2920; diffusion coefficients for fentanyl in silicone-2675 and acrylate adhesives were similar. The diffusivity of fentanyl in the PIB adhesive was roughly an order of magnitude lower than in the other adhesive membranes. The first commercial matrix patch, developed by Cygnus, was evaluated in the 1990s and subsequently a number of other companies developed matrix transdermal fentanyl patches.

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5.2. Clinical evaluation of the matrix patch and pharmacokinetics

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The biopharmaceutics of the matrix patch developed by Cygnus was evaluated in a number of studies [37,38]. Miguel et al. [37] investigated the application of the matrix patch developed by Cygnus for the relief of postoperative pain in 143 patients after gynaecologic exploratory laparatomy. The patches evaluated had surface areas of 40 and 60 cm2 (corresponding to 70–80 and 90– 100 lg kg 1 h 1 of fentanyl delivery respectively). Patients were randomly assigned to one of three study groups. Group 1 patients received two placebo patches; group 2 patches received a 40 cm2 fentanyl patch and a 60 cm2 placebo patch; group 3 patients received a 60 vcm2 fentanyl patch and a 40 vcm2 placebo patch. Patches were placed on the upper torso, one hour before surgery and remained in place for 24 h. Morphine-use (patient-controlled) as well as pain, sedation and comfort scores were assessed at 4 h intervals up to 36 h after patch placement. Less supplemental morphine was required for groups 2 and 3 to maintain adequate analgesia compared with group 1. However, patients in groups 2 and 3 exhibited higher incidences of pruritus, erythema and respiratory depression compared with group 1. The authors noted that because of the side effects observed, the patch would require further research before being recommended as an adjunct for control of postoperative pain. Fiset and co-workers [38] investigated the same Cygnus patch (60 cm2) in 14 male patients scheduled for elective surgery. Subjects received 650 or 750 lg i.v. fentanyl as part of anaesthesia induction. Plasma fentanyl concentrations were measured over the following 24-h period. On the first day, post-surgery, 24 h after the i.v. fentanyl dose, the fentanyl patch was placed on the upper torso for 24 h and then removed. Post-operative analgesia was provided via intramuscular administration of meperidine or morphine. Plasma fentanyl concentrations were subsequently measured for 72 h after patch application. Residual fentanyl in the patch was also measured. Clinically significant fentanyl toxicity was observed for three subjects resulting in early removal of the device. Plasma fentanyl in the remaining subjects ranged from 0.34 to 6.75 ng/ml, and the terminal half-life after patch removal was 16 h. The rate of drug absorption over 12–24 h ranged from 10 to 230 lg/h; in two subjects, the rate over the first 6 h briefly exceeded 300 lg/h resulting in early patch removal. The authors noted that the variability in fentanyl delivery for the Cygnus patch was considerably greater compared with the reservoir patch device. In addition, the prolonged terminal half-life was suggested to reflect continued absorption from a cutaneous depot. The greater variability in plasma fentanyl levels compared with the reservoir device was attributed to the lack of a rate-controlling membrane in the Cygnus patch. The matrix patch developed by Alza consists of an adhesive in which fentanyl is completely dissolved, without the necessity of

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a penetration enhancer. Rate control of fentanyl from the matrix patch lies in the skin and the ability of the drug to diffuse through the adhesive and into the skin. As for the reservoir patch, four dosage forms are available. The bioequivalence of the matrix patch (100 lg/h) was compared with the original Alza reservoir device by Sathyan and colleagues [39]. Two studies (single and multiple dose) were conducted with a randomised, single-centre and open-label design. The patch was applied to the upper outer arm. At steady-state, following repeated applications, the pharmacokinetic profile of the matrix patch was comparable to that of the fentanyl transdermal reservoir system. Intra-subject variability was slightly lower for the reservoir patch compared with the matrix patch. Inter-subject variability appeared to be slightly higher for both systems after repeated administration. The bioequivalence of reservoir and matrix patch designs was also confirmed in a later study by Moore et al. [40]. The effect of heat on fentanyl delivery from reservoir and matrix patches was investigated by Moore and colleagues [41] in a randomised open-label, 5-treatment, 5-sequence crossover study. External heat was applied with a standardised heating pad which was affixed to the patch (25 lg/h) application site. A temperature probe was placed under the patch to monitor skin temperature when heat was applied. Patches were worn for a period of 36 h. Heat was applied from 0 to 10 h and from 26 from 36 h, and skin temperatures of 36–37 °C were obtained with the heating pad. From 0 to 10 h, the application of heat significantly increased serum fentanyl concentrations for both patch designs when compared with the same systems without heat. However, minimal effects were observed for the later period of heat treatment.

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5.3. Matrix and rate-controlling membrane patches

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A ‘hybrid’ patch with a silicone matrix and a rate-controlling membrane has also recently become available. The drug is contained in the matrix, and the drug load is reduced compared with the conventional reservoir and matrix designs. The patch performance was comparable to reservoir or matrix patches when evaluated in a randomised non-blind multicentre trial in patients with cancer-related chronic pain [42]. Table 1 provides some examples of the major patch designs currently available.

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An alternative delivery approach to the patch device is the use of iontophoresis which harnesses an electric current to drive fentanyl (in the charged form) into the skin. The device consists of a power source, terminating with an anode and cathode and skin transport is mediated via electrorepulsion and electro-osmosis. The commercial fentanyl HCl iontophoretic transdermal system (ITS: Ionsys) was a patient-controlled analgesic delivery system that administered bolus doses of fentanyl transdermally upon patient activation. This device was initially approved and made available for the management of acute moderate-to-severe postoperative pain in the hospital environment in contrast to patches which are approved for management of chronic pain in the outpatient setting. However, this device has been withdrawn from the market. In addition to iontophoresis, ultrasound has also been explored in transdermal fentanyl delivery. Boucaud and co-workers [43] examined the effects of low-frequency sonophoresis on fentanyl permeation in human skin. Histological examination confirmed that the ultrasound treatment did not alter gross skin structure; however, the concept has not been progressed. Supersaturation has also been considered as an alternative approach to conventional patch devices. Santos et al. [44] investigated the skin permeation of

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subsaturated and supersaturated fentanyl preparations formulated in simple propylene glycol and water vehicles. However, supersaturation of the drug could not be maintained under finite dose conditions, because of depletion of the propylene glycol. Most recently, Schröder and co-workers [45,46] have developed an electrochemical transdermal patch for fentanyl delivery and evaluated its performance in a single-centre, open-label and dose escalation clinical trial. The patch comprises a drug loaded hydrogel sandwiched between two electrodes. The device is non-iontophoretic and produces flux enhancement via voltage-induced electrolysis of water in the hydrogel. Plasma levels of approximately 200 pg/ml were achieved after voltage application at 16 h, and consecutive voltage applications at 16 h and 40 h produced plasma levels of approximately 730 pg/mL. The authors claim that the major advantage of the system is the ability to produce systemic fentanyl levels without the use of potentially irritating iontophoresis. In addition, voltage application may be used to adjust the plasma profile, and a continual current is not necessary for drug delivery.

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The commercial success of transdermal fentanyl is impressive and will ensure that the drug has a place in the pipeline of many drug delivery companies for years to come. There are related narcotic analgesics that could be developed, and it is interesting that buprenorphine has been successfully marketed as a 7 days analgesic patch. The recent litigation surrounding the use of fentanyl patches is also likely to be a concern when considering alternative delivery strategies. This review provides a starting point for researchers to develop such strategies in an informed and systematic manner. Safety of transdermal patches is of paramount importance but with the approval of matrix patches by most of the leading regulatory authorities it seems that they are equally as safe as the original reservoir patch. Provided the patches are not abused they should continue to provide a useful means of pain control over extended periods of time.

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