Pharmacokinetics and efficacy of phenazepam after transdermal and enteral administration in rats

The concentration of fenazepam in the blood plasma of rats upon application of the transdermal therapeutic system (TTS) fenapercuten was very low, incomparable to the drug concentration (recalculated to equal input doses) upon intravenous or enteral administration. Nevertheless, the TTS exhibited a pronounced anxiolytic and weak sedative action in the absence of any side myorelaxant effect. The agent responsible for adverse side effects (3-hydroxyfenazepam) was not determined in the blood plasma upon the TTS application. A steady-state concentration of fenazepam in the blood plasma of rats was observed between 2nd and 8th hours upon fenapercuten application, which agrees with the duration of anxiolytic action of the parent drug.     

Pharmacokinetic Disposition of Multiple-Dose Transdermal Nicotine in Healthy Adult Smokers

The pharmacokinetics and cardiovascular effects of nicotine and its major metabolite, cotinine, were characterized during repeated once-daily application for 5 days of a 30-cm² nicotine transdermal system, Nicotine TTS (Habitrol), to nine healthy, black, adult, male smokers. Subjects abstained from smoking throughout the study. Pharmacokinetic analysis indicated that nicotine was delivered from Nicotine TTS for the 24-hr application period averaging 0.76 mg/ cm²/24 hr, and at a relatively constant rate compared to other modes of drug administration. The transdermal clearance of nicotine, 1351 ml/min, coincided with reported values following intravenous nicotine administration; however, the terminal-phase half-life, 5.0 hr, did not. An analysis of the components of variance contributing to the variability in nicotine delivery from repetitive application of Nicotine TTS indicated that the in vivo transdermal permeation of nicotine is rate limited by both the device and the intrinsic skin conductivity. Clinical cardiovascular side effects were negligible as an apparent result of subclinical vasopressive nicotine concentrations, although drug activity with regard to other effects was manifested.     

Rate and extent of absorption of clonidine from a transdermal therapeutic system

The in-vivo performance of a clonidine transdermal therapeutic system (TTS 3.5 cm2, 2.5 mg) was assessed in 12 healthy normal volunteers. Particular attention was paid to the rate and extent of absorption of clonidine from the TTS dosage form by reference to a 2 h i.v. infusion of clonidine. The absolute bioavailability of clonidine from the TTS dosage form was found to be approximately 60% with clonidine being released from the TTS at a relatively reproducible and consistent rate of 4.32 micrograms h-1 over a 7-day period.     

Formulation optimization and stability study of transdermal therapeutic system of nicorandil

The aim of this research investigation was to fabricate acrylate-based stable transdermal therapeutic system (TTS) of nicorandil, which could deliver drug through transdermal route. Monolithic TTS was fabricated in pressure sensitive adhesives (PSAs)--(a) terpolymer (PSA1) of 2-ethylhexyl acrylate, methyl methacrylate, and acrylic acid, (b) copolymer (PSA2) of 2-ethylhexyl acrylate, methyl methacrylate, acrylic acid, and vinyl acetate, and (c) Eudragit E100 pressure sensitive adhesive (PSA3). To enhance the flux of nicorandil, skin permeation enhancer N-methyl-2-pyrrolidone (NMP) was investigated at different concentrations (0.05-5%) in PSAs. Fabricated TTS was evaluated for in-vitro release and skin permeation through guinea pig skin. Maximum flux of nicorandil was observed from Eudragit E100 based TTS and kept for stability study at refrigeration, 25 degrees C/30% RH and 30 degrees C/60% RH. Patches were evaluated for various physicochemical parameters. Formulation was observed to be relatively more stable at refrigeration. Shelf life of the formulation was found to be 270, 270, and 30 days at refrigeration, 25 degrees C/30% RH and 30 degrees C/60% RH conditions, respectively. Nicorandil could be successfully derived from Eudragit E100 based TTS, but attention needs to be given to improve its chemical stability in formulation.     

Development of a membrane-controlled transdermal therapeutic system containing isosorbide dinitrate

The formulation of a transdermal delivery system for isosorbide dinitrate (ISDN) was examined. It was found that the target release rate should be 4.01 mg/h per 20 cm² for optimal dosing. In order to reach such this zero order release rate, a membrane permeation controlled transdermal therapeutic system (TTS) formulation was developed, with ethylene vinyl acetate copolymer (EVAC) and polyethylene (PE) membranes as rate controlling membranes; a carbomer gel was used as the drug reservoir. The release of ISDN from this drug delivery device was studied in vitro using FDA recommended method. PIB adhesive on the EVAC or PE membrane caused a decreased flux of ISDN; the release kinetics fitted Higuchi matrix kinetics. TTS with EVAC membrane release ISDN at a rate much lower than the calculated target release rate, but with PE membranes, the release rate was very close to the target. Release rate studies have revealed that, as the VA content in EVAC membrane increased, the flux of ISDN increased. All these results were compared with the commercial product Frandol^® Tape S from Japan. It was found that the release rate of Frandol was close to target release rate and fitted matrix kinetics. These results suggested that TTS that contain PE membrane as rate controlling membrane, polyisobutylene (PIB) adhesive and carbomer gel as a reservoir can be applicable as a TTS for ISDN.     

Diffusion model for the study of a drug from the hydrophilic matrix of a transdermal therapeutic system through a model polymeric membrane

Conclusions The kinetics of drug supply described above from gel-like hydrophilic matrices of a TTS through human skin, or a polymeric membrane imitating itin vitro, are analogous to the kinetics of the release of a drug from a reservoir TTS through an attached polymeric membrane controlling the rate. Studying the kinetics of drug supply from diffusion matrices of TTS through a polymeric membrane imitating skin enables modeling of the kinetics of transdermal drug supplyin vitro andin vivo. The adequacy of such modeling is determined by the correlation between the diffusion coefficients of the drug in the membrane and skin epidermis and the distribution coefficients of the drug between skin and matrix or between membrane and matrix, which are subject to experimental determination.The transdermal supply of drug with kinetics of zero order (i.e. at a rate constant with time) may be effected from a TTS of the membrane-reservoir type containing a membrane specially controlling the rate or from a matrix TTS. In the latter case the function of the membrane controlling the rate of drug supply is fulfilled by the human skin at the point of application of the TTS, while the TTS diffusion matrix acts as a reservoir containing drug on the skin surface and limits the maximally achievable rate of drug release from the TTS to the skin according to equation 12. The competence of such an approach is occasionally questioned because of fears that the permeability of skin for a drug depends markedly on the point of application of the TTS and on the special features of the patient's skin. The effect of skin permeability at the point of application on the rate of transdermal drug supply has been studied well in [21] and a standard place for the application of a TTS may be the correct choice. The vast scope for the clinical application of the various TTS available at the present time indicates that individual variability of skin permeability is not so great and may be displayed mainly by a reduced permeability of the skin for a drug. Unlike membrane-reservoir TTS the majority of matrix TTS may be divided into portions of various size without disturbing their efficiency. This raises the possibility of continuously regulating the dose (by the area of application for TTS of this type).Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 28, No. 10, pp. 38–45, October, 1994.     

Hydrophilic polymeric matrices for enhanced transdermal drug delivery

For many drugs with various chemical structures, delivery rates from the hydrophilic polyvinylpyrrolidone (PVP)-polyethylene oxide (PEO) based pressure sensitive adhesive (PSA) matrices of transdermal therapeutic systems (TTS) are higher compared to the hydrophobic TTS matrices. Delivery of propranolol, glyceryl trinitrate (GTN) and isosorbide dinitrate (ISDN) from the hydrophilic water soluble TTS matrix across human cadaver skin epidermis or skin-imitating polydimethylsiloxane-polycarbonate block copolymer Carbosil membrane in vitro is characterized by high rate values and zero-order drug delivery kinetics up to the point of 75–85% drug release from their initial contents in matrix. Both in vitro and in vivo drug delivery rates from the TTS hydrophilic diffusion matrix are controlled by the skin or membrane permeability and may be described by Fick's law. The contributions of various physicochemical determinants to the control of transdermal drug delivery kinetics are discussed. Pharmacokinetic and pharmacodynamic properties of hydrophilic TTS matrix with propranolol, GTN and ISDN are described.     

A comparative in vitro study of transdermal absorption of a series of calcium channel antagonists.

The in vitro transdermal absorption of five calcium channel antagonists (nifedipine, nitrendipine, nicardipine, felodipine, and nimodipine) was studied using the skin of hairless rats as a membrane. The aim of this study was to determine the penetration parameters [permeability constant (Kp), lag time (T1, and flux (J)] as measures of the intrinsic transdermal permeabilities of these drugs, in order to predict the potential capacity of these drugs to be formulated in a therapeutical transdermal system (TTS). Reliable prediction of Kp values, using K'w (extrapolated capacity factor in 100% water) and P (n-octanol-water partition coefficient) values as independent variables in the parabolic, bilinear, and hyperbolic functions, were assayed. Nicardipine showed a higher mean transdermal penetration (Kp; 4.9 x 10(-3) cm.h-1) value than the other dihydropyridines. Nifedipine showed the shortest mean T1 value (5.1 h). The permeability rate constants of the calcium channel antagonists assayed can be predicted from their n-octanol-water partition coefficients, using the parabolic function (r = 0.984, p less than 0.01). Nicardipine would be the most suitable candidate for formulation in a TTS design.     

Clinical pharmacokinetics of transdermal opioids: focus on transdermal fentanyl

Transdermal delivery allows continuous systemic application of opioids through the intact skin. This review analyses the pharmacokinetic properties of transdermal opioid administration in the context of clinical experience, with a focus on fentanyl. A transdermal therapeutic system (TTS) for fentanyl has been developed. The amount of fentanyl released is proportional to the surface area of the TTS, which is available in different sizes. After the first application of a TTS, a fentanyl depot concentrates in the upper skin layers and it takes several hours until clinical effects are observed. The time from application to minimal effective and maximum serum concentrations is 1.2 to 40 hours and 12 to 48 hours, respectively. Steady state is reached on the third day, and can be maintained as long as patches are renewed. Within each 72-hour period, serum concentrations decrease gradually over the second and third days. When a TTS is removed, fentanyl continues to be absorbed into the systemic circulation from the cutaneous depot. The terminal half-life for TTS fentanyl is approximately 13 to 25 hours. The interindividual variability of serum concentrations, partly caused by different clearance rates, is markedly larger than the intraindividual variability. The effectiveness of TTS fentanyl was first demonstrated in acute postoperative pain. However, the slow pharmacokinetics and large variability of TTS fentanyl, together with the relatively short duration of postoperative pain, precluded adequate dose finding and led to inadequate pain relief or, especially, a high incidence of respiratory depression; such use is now contraindicated. Conversely, in cancer pain, TTS fentanyl offers an interesting alternative to oral morphine, and its effectiveness and tolerability in this indication has been demonstrated by a number of trials. Its usefulness in chronic pain of nonmalignant origin remains to be confirmed in controlled trials. In general, TTS fentanyl produces the same adverse effects as other opioids, mainly sedation, nausea, vomiting and constipation. In comparison with oral morphine, TTS fentanyl causes fewer gastrointestinal adverse events. The risk of hypoventilation is comparatively low in cancer patients. Sufentanil and buprenorphine may also be suitable for transdermal delivery, but clinical results are not yet available. Transdermal morphine is only useful if applied to de-epithelialised skin. However, iontophoresis may allow transdermal administration of opioids, including morphine, with a rapid achievement of steady state concentrations and the ability to adjust delivery rates. This would be beneficial for acute and/or breakthrough pain, and initial clinical trials are in progress.     

Nitroglycerin in a transdermal therapeutic system in chronic heart failure

Nitroglycerin (NTG) in a transdermal therapeutic system (TTS) was evaluated in 16 patients with severe chronic heart failure. Eight patients were given NTG TTS with an in vivo release rate of 5 mg/24 h. No significant changes in heart rate or blood pressure were observed. Pulmonary capillary wedge (PCW) pressure was reduced significantly from a control value of 29 +/- 4 mm Hg to 17 +/- 2 mm Hg after 1 h (p less than 0.01), and significant reduction was maintained for 24 h. The system was then removed and PCW pressure rose to 27 +/- 2 mm Hg after 2 h. NTG TTS, 10 mg/24 h, was applied and PCW pressure was again reduced significantly. Significant reduction in systemic vascular resistance and increases in cardiac and stroke volume indices occurred on the first day at 4 h but were not maintained. In another eight patients, the haemodynamic effects of NTG TTS (5 mg/24 h), oral isosorbide dinitrate (20 mg), and topical NTG ointment (1 inch) were compared. Significant reductions in PCW pressure were achieved with each method of treatment, but no significant alterations in other haemodynamic measurements were observed. Haemodynamic reevaluation of 10 patients treated with NTG TTS for 3 months showed partial attenuation of the reduction in PCW pressure compared with the initial response.     

Transdermal clonidine. A preliminary review of its pharmacodynamic properties and therapeutic efficacy

The clonidine transdermal therapeutic system (TTS) is a cutaneous delivery device which provides therapeutically effective doses of clonidine at a constant rate over 7 days. In clinical trials it reduces blood pressure in patients with mild to moderate hypertension as effectively as oral clonidine but with greater stability of blood pressure control. Most patients find the transdermal system more convenient than oral treatments, and compliance may be improved. The side effects known to occur with orally administered clonidine, dry mouth and sedation in particular, are also produced with transdermal administration, but possibly at a lower incidence than during oral treatment. A proportion of patients experience adverse skin reactions with the transdermal system. At this stage of its development, transdermal clonidine has not been adequately compared with other 'standard' antihypertensive treatments such as diuretics or beta-adrenoceptor blocking drugs. However, despite the lack of such comparative studies, transdermal clonidine represents a worthwhile new approach to antihypertensive therapy, particularly in terms of patient convenience.     

Glycerol trinitrate (nitroglycerin) plasma concentrations achieved after application of transdermal therapeutic systems to healthy volunteers

Glycerol trinitrate (nitroglycerin, in the following briefly called GTN) plasma concentrations achieved upon application of a commercial scale produced transdermal therapeutic system containing GTN (TTS-GTN, Nitroderm-TTS) were compared to those induced by 2 TTS-GTN prototypes previously used for clinical trials. Each system was applied to the chest, lateral aspect, of 14 healthy volunteers for 24 h, in a 3-period change-over study. GTN in plasma was determined by gas chromatography-mass spectrometry. The 3 systems released the drug continuously over 24 h. The mean plasma concentrations for all subjects and all sampling times (nmol/l) +/- SE were 0.92 +/- 0.18, 0.80 +/- 0.12 and 0.97 +/- 0.18 for the commercial scale TTS and the 2 other systems, respectively. No significant differences were demonstrated. The mean delivery rate of GTN calculated from the initial and residual contents of the TTS was 6.8 micrograms/min as a mean for the 3 systems. In another study, three different application sites were compared (chest, upper arm and pelvis). The results did not demonstrate significantly different GTN plasma levels. A comparison with published data after intravenous infusion showed a good availability of GTN administered transdermally by means of TTS. Its magnitude seems comparable to that of the intravenous route.     

Transdermal therapeutic system of enalapril maleate using piperidine as penetration enhancer

The aim of this work was to formulate transdermal therapeutic system (TTS) of an antihypertensive drug, enalapril maleate (EM) using a new penetration enhancer, piperidine hydrochloride (PH), belonging to the class of Dihydropyridines. The TTS of EM was prepared by solvent evaporation technique using polymers Eudragit E100 and polyvinyl pyrrolidone K-30 in varying ratios, 5% w/w dibutylphthalate as plasticizer and 10% w/w PH as penetration enhancer. The TTS was evaluated for in-vitro drug release using paddle over disc method and ex-vivo skin permeation using modified Keshary and Chein diffusion cell. The interaction studies were carried out by comparing the results of assay, UV and TLC analysis for pure drug and medicated and TTS formulation. Skin irritation potential of TTS was assessed by visual examination of treated rat skin. Stability studies were conducted according to ICH guidelines at a temperature of 40+/-0.5 degrees C and 75+/-5% RH. The optimized formulation was evaluated for preclinical bioavailability and antihypertensive efficacy using albino rat model. The optimized formulation provided 87.3% drug release in-vitro and a flux of 380 microg/cm(2)/hr over a period of 48 hours. No chemical interaction was found between the drug and excipients and there were no signs of skin irritation on application of patch. The optimized formulation was stable with a tentative shelf life of two years. Significant fall in BP (p<0.001) was observed in experimental hypertensive rats which was maintained for 2 days. There was 3 fold improvement in bioavailability with TTS vis-à-vis marketed tablet (AUC(0 to t) : 1253.9 ng.h/ml vs. 422.88 ng.h/ml). These preclinicial studies indicate the feasibility of matrix-type TTS of EM for 2 day management of hypertension. Further studies on human beings are warranted to establish clinical utility of the above TTS.     

Studies on the transdermal delivery of nimodipine from a menthol-based TTS in human volunteers

The purpose of the present study was to design a membrane-moderated transdermal therapeutic system (TTS) of nimodipine using 2%w/w hydroxypropyl methylcellulose (HPMC) gel as a reservoir system containing menthol as penetration enhancer and 60%v/v ethanol-water as solvent system. The flux of nimodipine was markedly increased from 35.51 microg/cm2/h to 167.53+/-3.69 microg/cm2/h with the addition of 8%w/w menthol to HPMC drug reservoir. There was an increase in the flux of nimodipine through ethylene vinyl acetate (EVA) copolymer membrane with an increase in vinyl acetate content (9 to 28%w/w) of the copolymer. The permeability flux of nimodipine from the chosen EVA 2825 (with 28%w/w vinyl acetate content) was 152.05+/-2.68 microg/cm2/h, and this flux decreased to 132.69+/-1.45 microg/cm2/h on application of a water-based acrylic adhesive (TACKWHITE A 4MED) coat. However, the transdermal flux of nimodipine across EVA 2825 membrane coated with TACKWHITE A 4MED/ rat skin composite was found to be 116.05+/-2.39 microg/cm2/h, which is about 1.4 times greater than the required flux. Thus a new transdermal therapeutic system for nimodipine was designed using EVA 2825 membrane coated with a pressure-sensitive adhesive TACKWHITE 4A MED, and 2%w/w HPMC gel as reservoir containing 8%w/w of menthol as a penetration enhancer. The in vivo evaluation of nimodipine TTS patch was carried out to find the ability of the fabricated menthol-based TTS patch in providing the predetermined plasma concentration of the drug in human volunteers. The results showed that the menthol-based TTS patch of nimodipine provided steady plasma concentration of the drug with minimal fluctuations with improved bioavailability in comparison with the immediate release tablet dosage form.     

Effect of nerodilol, carvone and anethole on the in vitro transdermal delivery of selegiline hydrochloride

The aim of the study was to investigate the effect of terpene enhancers (nerodilol, carvone or anethole) on the in vitro transdermal delivery of selegiline hydrochloride with a broad objective of developing a membrane-moderated transdermal therapeutic system (TTS). The in vitro permeation studies were carried across the rat epidermis from hydroxypropyl methylcellulose (HPMC) gel drug reservoir containing selected concentrations of nerodilol, carvone or anethole and selegiline hydrochloride. The amount of selegiline hydrochloride permeated during the 24 h of the study (Q24) from HPMC gel drug reservoir without terpene enhancer was 2169 +/- 50 microg/cm2 and the corresponding flux of the drug was 92 +/- 1 microg/cm2 x h. The amount of drug permeated and its flux increased with an increase in terpne concentration in HPMC gel drug reservoir. Nerodilol provided an approximately 3.2-fold increase in the flux of selegiline hydrochloride followed by carvone with a 2.8-fold increase, and anethole with a 2.6-fold increase. It is concluded that the terpene nerodilol, carvone and anethole produced a marked penetration enhancing effect on the in vitro transdermal delivery of selegiline hydrochloride that could possibly be used in the formulation of membrane-moderated TTS.     

中药经皮给药佐治小儿支气管肺炎疗效观察

目的观察中药经皮给药（Transdermal Therapeutic System,TTS）佐治小儿支气管肺炎的疗效。方法支气管肺炎患儿206例,随机分为治疗组106例和对照组100例：对照组采用常规治疗方法;治疗组在对照组基础上,加用中药经皮给药治疗,比较其疗效。结果治疗组患儿临床症状及体征消失时间显著短于对照组（P〈0.01）;治愈率、总有效率均明显高于对照组（P〈0.01）。结论在常规治疗的基础上,加用中药经皮给药佐治小儿支气管肺炎,可明显缩短病程,提高治愈率,疗效确切,使用安全,为小儿肺炎的治疗提供了一种新的治疗方法。     

In vivo evaluation of limonene-based transdermal therapeutic system of nicorandil in healthy human volunteers

Hydroxypropyl methylcellulose (HPMC) gel drug reservoir system prepared with 70:30 v/v ethanol-water solvent system containing 6% w/w of limonene was effective in promoting the in vitro transdermal delivery of nicorandil. The objective of the present study was to fabricate and evaluate a limonene-based transdermal therapeutic system (TTS) for its ability to provide the desired steady-state plasma concentration of nicorandil in human volunteers. The in vitro permeation of nicorandil from a limonene-based HPMC gel drug reservoir was studied across excised rat skin (control), EVA2825 membrane, adhesive-coated EVA2825 membrane and adhesive-coated EVA2825 membrane-excised rat skin composite to account for their effect on the desired flux of nicorandil. The flux of nicorandil from the limonene-based HMPC drug reservoir across EVA2825 membrane decreased to 215.8 +/- 9.7 microg/cm(2).h when compared to that obtained from control, indicating that EVA2825 was effective as a rate-controlling membrane. The further decrease in nicorandil flux across adhesive-coated EVA2825 membrane and adhesive-coated EVA2825 membrane-excised rat skin composite showed that the adhesive coat and skin also controlled the in vitro transdermal delivery. The limonene-based drug reservoir was sandwiched between adhesive-coated EVA2825-release liner composite and a backing membrane. The resultant sandwich was heat-sealed as circle-shaped patch (20 cm(2)), trimmed and subjected to in vivo evaluation in human volunteers against immediate-release tablets of nicorandil (reference formulation). The fabricated limonene-based TTS of nicorandil provided a steady-state plasma concentration of 21.3 ng/ml up to 24 h in healthy human volunteers. It was concluded that the limonene-based TTS of nicorandil provided the desired plasma concentration of the drug for the predetermined period of time with minimal fluctuations and improved bioavailability.     

Inter- and intraindividual variabilities in pharmacokinetics of fentanyl after repeated 72-hour transdermal applications in cancer pain patients

Perception of pain by the patient is frequently one of the early signs preceding a diagnosis of cancer and, later, a sinister sign of disease progression. Among opioid drugs, transdermal fentanyl has been evaluated in the treatment of moderate to severe cancer pain. The objective of this study was to investigate the intra- and interindividual variabilities in pharmacokinetics after fentanyl drug delivery by the transdermal fentanyl patch delivery system in patients with cancer pain. As a first step, a liquid chromatography-mass spectrometry method was developed for the determination of the analgesic fentanyl in human plasma. This method was validated over the concentration range 0.15-100 ng/mL. The study group consisted of 29 inpatients (18 men and 11 women; age range 29-80 years). The initial transdermal fentanyl delivery rate was chosen depending on the patient's analgesic requirements. For 20 patients, the initial TTS fentanyl delivery rate was 25 or 50 microg/h. For 6 patients, the initial delivery rate was 75-150 microg/h. Two patients received up to 300 microg/h fentanyl delivery rate, and 3 patients received up to 350 microg/h fentanyl delivery rate. Fifteen of the 29 patients received rescue doses of subcutaneous or oral morphine, and 26 patients received paracetamol with codeine (30 mg per os). Blood samples were collected at the following intervals: 2-5, 22-26, or 45-47 hours following fentanyl patch application. The severity of pain experienced by the patient was assessed thrice daily using a visual analogue scale. The study period was 46 days. Large patient-to-patient variations in pharmacokinetic parameters occurred, although intraindividual variability was limited. A mean bioavailability of 78% was estimated; the total clearance averaged 41 L/h. From 25 to 100 mug/h fentanyl delivery rate, the pharmacokinetics was linear. At the 2 highest doses, an increase of total clearance was observed (>60 L/h). For the whole group, transdermal fentanyl treatment provided good to excellent pain relief in the majority of patients.     

Flow-Through System Effects on in Vitro Analysis of Transdermal Systems

The development of transdermal therapeutic systems (TTS) often involves in vitro evaluation of formulations and prototypes using flow-through diffusion cells. The apparent flux obtained from such methodologies does not accurately represent the actual (intrinsic) permeation of the compound through the skin. Flow-through system parameters, i.e., fraction collector tube volume, receiver cell volume, flow rate, and sampling interval, modify the flux yielding an apparent flux. Both finite-dose flux profiles and infinite-dose diffusional lag times are modified by these parameters. In this study, a transfer function is derived which describes the effect of these parameters. The intrinsic flux is calculated from apparent flux data using the transfer function and experimental flow-through system parameters. This allows the calculation of permeant flux profiles devoid of modification by the experimental methodology.     

A Phase III study to assess the clinical utility of low-dose fentanyl transdermal system in patients with chronic nonmalignant pain

BACKGROUND: The transdermal fentanyl delivery system (fentanyl TTS; Duragesic) is currently widely available in patch strengths of 25, 50, 75, and 100 microg/h. However, a lower dose of 12 microg/h would allow optimal titration and fine tuning of the analgesic effect, and may be beneficial in certain patient populations such as the elderly or opioid-na?ve. A 12 microg/h fentanyl TTS patch has been developed, and the clinical efficacy and safety tested in this single-arm, non-randomized, open-label, multicenter, 28-day trial in opioid-exposed and -na?ve patients with moderate to severe pain for at least 6 months. PATIENTS: Patients were treated with fentanyl TTS for 28 days in an intent-to-treat manner starting at 12 microg/h (one patch), titrated upwards in increments of 12 mug/h to a maximum dose of 36 microg/h (three patches). RESULTS: A total of 227 patients were enrolled. The majority of patients with a "global assessment of therapy" of fair/poor at baseline (63.4%) improved to good/very good, while 28.9% of patients with an assessment of good/very good at baseline worsened to fair/poor at endpoint. The average pain intensity levels for the efficacy evaluable population steadily decreased over the course of the trial. The adverse event (AE) profile of fentanyl TTS in this trial was generally similar to that identified in previous fentanyl TTS trials, and no unexpected safety issues or AEs were noted. Furthermore, the drop-out rate in this trial was lower than has been noted in previous trials. CONCLUSION: This trial demonstrated that the lower 12 microg/h dose of fentanyl TTS provided a therapeutic benefit in non-malignant chronic pain, with a similar AE rate but a lower drop-out rate than that seen in trials at higher doses. This lower dose may, therefore, be of particular benefit to elderly or opioid-na?ve patients.