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A headspace GC method was developed for the analysis of residual solvents in transdermal skin patches. These solvents could arise from the manufacture and process of the patch material.
A total of 305 subjects from Sydney were randomly allocated to receive either an active (24 hour transdermal nicotine patch over a 10 week course) or placebo nicotine patch. All subjects participated in a multicomponent cognitive-behavioural smoking cessation programme over five weeks in two-hour group sessions. The continuous abstinence rates at three years (validated by expired carbon monoxide) were 13.8% for the active group and 5.2% for placebo group (p = 0.011). The active nicotine patch with behavioural therapy achieved more than double the abstinence rates early in treatment compared with placebo and this difference was maintained throughout the three year follow up.
CONTEXT: There is concern that a new transdermal contraceptive patch containing ethinyl estradiol (EE) and the progestin norelgestromin increases the risk for venous thromboembolism (VTE) compared to previously marketed oral contraceptives (OCs). OBJECTIVE: Quantitative information was obtained on the risk of nonfatal VTE in women using the contraceptive patch in comparison to women using OCs, norgestimate (either monophasic or triphasic) and 35 microg EE (norgestimate-35), an OC that has been marketed for over a decade. DESIGN, SETTING AND PARTICIPANTS: Nested case-control design based on information from PharMetrics, a US-based company that collects and organizes information on claims paid by managed care plans. The study was nested among all women aged 15 to 44, who started either the contraceptive patch or norgestimate-35 after April 1, 2002. Cases were women with current use of one of these two study drugs and a documented diagnosis of VTE in the absence of identifiable clinical risk factors (idiopathic VTE). Up to four controls were matched to each case by age and calendar time. MAIN OUTCOME MEASURES: Odds ratios (ORs) comparing the risk of nonfatal VTE in new users of the two contraceptives and incidence rates of nonfatal VTE for new users of each of the study contraceptives. RESULTS: We identified 68 newly diagnosed, idiopathic cases of VTE in the study population. In the case-control analysis, the OR comparing the contraceptive patch to norgestimate-35 was 0.9 (95% CI 0.5-1.6). The overall incidence rate for VTE was 52.8 per 100,000 women-years (95% CI 35.8-74.9) among users of the contraceptive patch and 41.8 per 100,000 women-years among users of norgestimate-35 (95% CI 29.4-57.6), and the age-adjusted VTE incidence rate ratio (IRR) for current use of the contraceptive patch vs. norgestimate-35 was 1.1 (95% CI 0.7-1.8). CONCLUSIONS: The risk of nonfatal VTE for the contraceptive patch is similar to the risk for OCs containing 35 microg ethinylestradiol and norgestimate.
A case of a dystonic reaction is presented that occurred after the use of prochlorperazine, metoclopramide and ondansetron for the treatment of post-operative nausea and vomiting. The onset of dystonia coincided temporally with the removal of a transdermal scopolamine patch used as adjunctive antiemetic therapy. Withdrawal of concurrently administered anticholinergic medication, after recent use of antiemetic medications with dopamine receptor (D2) inhibition, can unmask a dystonic reaction. This case also suggests that transdermal scopolamine may offer an innovative therapy for the treatment of acute dystonic reactions.
OBJECTIVE: A 1-year, randomized, multicenter study was carried out to assess the effects of estradiol/levonorgestrel, delivered transdermally by 7-day patches in a sequential combined regimen, on bleeding pattern and acceptability in postmenopausal women. METHODS: A total of 468 postmenopausal women were randomized to 15-cm2, 22.5-cm2 or 30-cm2 patches containing 17 beta-estradiol alone (50, 75 or 100 micrograms/24 h, respectively) for 2 weeks followed by 17 beta-estradiol/levonorgestrel (50/10, 75/15 or 100/20 micrograms/24 h) for 2 weeks. RESULTS: The occurrence of cyclic bleeds was dose-dependent, with an increase at higher dosages; the frequency of a cyclic bleed per treatment cycle was 40% in the 50/10 micrograms/24 h patch, 62% in the 75/15 micrograms/24 h patch and 76% in the 100/20 micrograms/24 h patch. The incidence of intermittent bleeding also increased with higher doses, from 22% in the 50/10 group to 35% in the 100/20 group; 20% of women in the 50/10 group did not bleed at all; the corresponding figures for the 75/15 and 100/20 groups were 7% and 0%, respectively. Time of onset of cyclic bleeding was constant in all groups. The mean duration of cyclic bleeding was constant within each group, but increased from 4.4 days in the 50/10 to 6.3 days in the 100/20 group. The regularity and predictability of cyclic bleeding were high in all groups. Recurrence of cyclic bleeds was acceptable for most women (90%). CONCLUSIONS: Sequential combined transdermal 17 beta-estradiol/levonorgestrel shows very good cycle control that is well accepted by postmenopausal women.
We conducted a study to assess the clinical usefulness of transdermal clonidine for heroin detoxification in an outpatient drug treatment clinic. Twenty-two young otherwise healthy heroin addicts participated. Outcome was assessed on the basis of (a) hypotension and other side effects of clonidine; (b) patient retention; (c) concomitant drug use; (d) subjective symptoms of withdrawal; and (e) objective signs of withdrawal. Side effects were present but in no case necessitated discontinuation of treatment. Drop-out rates were equal to conventional treatment offered at the clinic. The availability of clonidine broadens the therapeutic options available to patients and clinicians in treating the opiate-addicted patient. Transdermal clonidine offers several advantages over the oral form: patches can be applied weekly, fewer supplemental medications are required, and patches supply an even blood level of medication. A protocol for use is recommended.
There is only limited knowledge of how chemical permeation enhancers release from transdermal drug delivery systems of the drug-in-adhesive type. In this study, the release of eight commonly known enhancers from eight types of polymer adhesives was evaluated using Franz diffusion cells. It was shown that all the enhancers released completely from the adhesives and followed a square root of time kinetic (Higuchi law). Using a statistical analysis it was shown that the release rate was more dependent on the type of enhancer than on the type of polymers. The mean release rates were in the range from 2.2 to 11.1%/ radical t for the slowest and fastest releasing enhancers, which correspond to a 50% release within 500 and 20 min, respectively. Furthermore, the release rates were inversely proportional to the cube root of the molal volumes of the enhancers and to their logarithmic partition coefficients between the polymer adhesive and the receptor fluid. It was found that the observed release rates were probably due to a high diffusion coefficient of the enhancers rather than due to an inhomogeneous embedment of the enhancers in the adhesives. The type of adhesive showed minor influence on the release rate, especially among the acrylic polymers no difference was seen. However, compared to the acrylic adhesives, the polyisobutylene adhesive showed slower release rates, while the silicone adhesive showed slightly faster release rates.
This work investigated the permeation of primaquine across full-thickness excised human skin from two acrylate transdermal adhesives. Primaquine base was formulated with National Starch 387-2516 and 387-2287 to provide aluminium foil-backed 1-cm diameter patches, each loaded with 10 mg drug. Other patches were prepared that included Migliol 840 as a potential penetration enhancer. The patches were applied to cadaver skin in Franz-type diffusion cells and the permeation of primaquine determined over a 24-h period. Relatively high fluxes were found, the highest being from those formulations lacking the Migliol 840: 5.68+/-0.30x10(-2) mg cm(-2) h(-1) from 387-2516; 4.94+/-0.20x10(-2) mg cm(-2) h(-1) from 387-2287. It was determined that a simple patch with a diameter of approximately 13 cm(2) could deliver a therapeutic in vivo dose, with possibilities for the treatment and prophylaxis of Plasmodium vivax, P. ovale and P. falciparum forms of malaria. The presence of Migliol 840 failed to produce the anticipated enhancing effect: flux rates that were approximately halved. These results could to a certain extent be rationalised in terms of thermodynamic activity.
While patient-controlled analgesia and intermittent intravenous opioids are primarily used for pain control, transdermal drug delivery is a possible adjuvant treatment.
Previously, transdermal patches with internal pH-controlled release were described. The aim of this study was to test the suitability of the patch design in transdermal delivery and, further, to select such transdermal patch formulations to a clinical study with timolol. In vitro release of timolol from the patches was determined as well as timolol permeation across the human cadaver skin. The effect of the skin on drug release were evaluated in vitro. In vitro data and pharmacokinetic parameters from the literature were used to construct a pharmacokinetic model for the prediction of in vivo performance of the devices. With water-activated, pH-controlled silicone reservoir devices, both the rate of drug release and the duration of constant release were controlled. The rate of timolol release was decreased when the devices were placed on human cadaver skin, and thus, the skin partly controls the rate and extent of timolol delivery to the systemic circulation in vivo. On the basis of in vitro data and kinetic simulations, devices of 10-cm(2) volume releasing timolol in vitro at the rates of 119 and 10 microgh(-1)cm(-2) were selected for human tests.
OBJECTIVE: Rotigotine (Neupro) is formulated as a transdermal delivery system designed to provide a selective, non-ergot D3/D2/D1 agonist to the systemic blood flow over a 24-hour period. In clinical trials, patches were applied once daily and uptitrated to the individual effective dose in increments of 2 mg/24 h every week. The aim of this analysis was to determine the safety of a more rapid titration of rotigotine by assessing the tolerability of escalating transdermal doses of rotigotine given in 2 different titration schemes. METHODS: We analyzed the safety of rotigotine in 2 groups of patients with advanced stage Parkinson Disease. The starting dose of 4 mg/24 h was increased every week by 2 mg/24 h in the slow-titration group and 4 mg/24 h in the fast-titration group. The primary focus of this subanalysis was the separate tolerability of rotigotine in each randomized treatment arm, during the dose-escalation period. However, the 2 titration schemes were also compared with each other. RESULTS: The dose of first reported nausea and/or vomiting was 8 mg/24 h for the fast-titration group and 4 mg/ 24 h for the slow-titration group. There were no remarkable differences concerning the side-effect profile between the 2 different titration schemes. CONCLUSIONS: The fast-titration regimen had a similar adverse event profile to slower titration, and allowed rotigotine to be introduced quickly. This subanalysis suggests that rotigotine may be uptitrated more rapidly.
The purpose of this study was to evaluate the application of confocal laser scanning microscopy (CLSM) in the examination of the embedment and the release characteristics of chemical permeation enhancers from transdermal drug delivery systems (TDDSs) of the "drug-in-adhesive" type. The enhancer lauric acid and a lauric acid fluorescing probe of the Bodipy type were incorporated into TDDSs consisting of an acrylic, a polyisobutylene, or a silicone polymer adhesive. Three-dimensional confocal images of the distribution were obtained before and during release into an aqueous medium. The images showed that the lauric acid fluorescing probe was homogeneously embedded in all the adhesives except for 1 polyisobutylene. The release profiles and release rate constants of the lauric acid fluorescing probe were consistent with data from a release study of lauric acid performed using conventional measurements of the released amounts. This indicated that lauric acid was distributed in a homogeneous manner. Furthermore, it was possible to illustrate the mechanics of the diffusion process inside the TDDS and compare these patterns with theoretically drawn profiles, based on Fick's law of diffusion. CLSM was demonstrated to be an excellent tool to study how enhancers are incorporated and diffuse into a TDDS.
The antianginal efficacy of nitroglycerin (NTG), given in a new transdermal therapeutic system (TTS), was compared with that of nifedipine and verapamil, both in slow-release (SR) formulation, in a randomized, double-blind, placebo-controlled study, carried out in 8 patients with stable exercise-induced angina pectoris. TTS NTG 40 cm2 (releasing 20 mg of NTG over 24 hours), nifedipine 20 mg SR, verapamil 120 mg SR and placebo were given once on 4 consecutive days according to a 4 X 4 latin-square design, twice replicated. A cycloergometric symptom-limited exercise test was performed 4 and 8 hours after the administration of each drug. Four hours post-dosing, mean exercise duration was 407 sec. after placebo and 523 (+28%) and 485 (+ 19%) sec. after TTS NTG and nifedipine SR respectively, while at the 8th hour it was 375 sec. after placebo, and 515 (+ 37%) and 457 (+ 21%) sec. after TTS NTG and nifedipine SR. Exercise duration after verapamil was similar to that after placebo. In comparison with placebo maximal workload and total work performed were significantly higher on TTS NTG and on nifedipine at both times of observation, but no significant differences were seen after verapamil. Peak exercise systolic blood pressure was nearly identical after all the treatments tested. Peak exercise heart rate and pressure rate product were both significantly higher on TTS NTG, as well as on nifedipine, in comparison with placebo, while values after verapamil did not differ from those after placebo.(ABSTRACT TRUNCATED AT 250 WORDS)
MDL 73,745 (2,2,2-trifluoro-1-(3-trimethylsilylphenyl) ethanone, CAS 132236(18-1) is a novel tight-binding inhibitor of acetylcholinesterase (AChE), which is in development as a potential therapeutic compound in the symptomatic treatment of Alzheimer's disease. Pharmacokinetics and pharmacodynamics of the compound were studied in the dog after single intravenous (i.v. 2 mg/kg), oral p.o. 10 mg/kg) and sub-cutaneous (s.c., 10 mg/kg) administrations of [14C]-MDL 73,745. Plasma concentrations of total radioactivity were much higher than those of parent drug after i.v., p.o. and s.c. administration, indicating extensive metabolism of the compound, although this was less after, s.c. administration than after p.o. administration. The bioavailability (F) was 34% after s.c. administration, compared with 4% after p.o. administration. The low bioavailability after p.o. administration was not due to poor drug absorption, as over 64% of the dose was absorbed. Pharmacokinetic parameters, calculated after i.v. administration, showed a terminal elimination half-life of 24 h, total body plasma clearance of around 70 ml/min/kg and apparent volume of distribution of 150 l/kg. AChE activity was almost 100% inhibited after i.v. administration, and over 80% inhibited 1 h after p.o. administration. In both cases, AChE activity returned to baseline levels by 12 h. AChE was around 80% inhibited 4 h after s.c. administration, and did not return to baseline levels until 36 h after drug administration. A combined pharmacokinetic-pharmacodynamic (PK-PD) effect model demonstrated that the extent of AChE inhibition could be correlated with plasma levels of the parent compound. As s.c. administration increased F, and led to longer AChE inhibition, transdermal (t.d.) delivery was assessed in the same animals. Patches, corresponding to a dose of 50 mg/kg, were applied to the shaved lateral abdominal skin for a period of 96 h. Sustained plasma concentrations of the parent drug were observed over the 96 h period of t.d. application. Mean (+/- SD) maximum plasma concentrations (Cmax) of 26.9 +/- 4.3 ng/ml were found 3.7 +/- 2.5 h after t.d. patch application und F was around 13%. AChE inhibition reached a maximum of 72% at 6 h after t.d. application and was still 35% at 96 h. The rate of release from the delivery system, per unit surface area, (ko) was calculated to be 7.7 micrograms/cm2. Transdermal delivery of MDL 73,745 thus decreased the important hepatic first-pass effect, and led to sustained plasma concentrations of drug, thus avoiding peaks and troughs which could lead to side-effects or poor efficacy.
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The feasibility of a monolayer patch based on polydimethylsiloxane pressure sensitive adhesive containing ibuprofen (IB) in supersaturated condition was studied. The efficacy of three low molecular weight excipients (propylene glycol, PG, Cremophor EL and Cremophor RH) and of two copolymers of methacrylic acid (Eudragit((R)) E, EuE, and Eudragit((R)) RL, EuRL) as IB crystallization inhibitors was tested. The performances of the patches were evaluated in terms of drug release and human stratum corneum and epidermis (SCE) permeation profile. The interactions between IB and the other excipients were investigated by ATR-FT-IR spectroscopy. The stability of the patches, prepared without adding crystallization inhibitors, was unsatisfactory because crystals grew in less than 1 month. Among the low molecular weight molecules, only PG inhibited the IB crystallization up to 50 days without affecting the IB skin permeation profile. The addition of EuE or EuRL in the matrices prevented drug crystallization for more than 12 months. EuE significantly reduced the IB in vitro release rate and the IB permeated amount through the SCE compared to other formulations. These phenomena are attributed to a stronger association between IB and EuE than IB and EuRL.
The prophylactic efficacy of a combinational patch system containing physostigmine and procyclidine against soman intoxication was evaluated using dogs. Female beagle dogs (body weights 9-10 kg) were shaved on the abdominal side, attached with a matrix-type patch (7x7 cm) containing 1.5% of physostigmine plus 6% procyclidine for 2 days, and challenged with subcutaneous injection of serial doses (2-10 LD50) of soman. Separately, in combination with the patch attachment, atropine (2 mg/dog) plus 2-pralidoxime (600 mg/dog) or atropine plus 1-[([4-(aminocarbonyl)pyridinio]methoxy)methyl]-2-[(hydroxyimino)methyl]pyridinium (HI-6, 500 mg/dog) were injected intramuscularly 1 min after soman poisoning. The LD50 value of soman was determined to be 9.1 microg/kg, and high doses (> or = 1.4 LD50) of soman induced salivation, emesis, defecation and diarrhea, tremors and seizures, and recumbency of dogs, leading to 100% mortality in 24 h. The prophylactic patch, which led to mean 18.5-18.8% inhibition of blood cholinesterase activity by physostigmine and mean 7.9-8.3 ng/ml of blood concentration of procyclidine, exerted a high protection ratio (4.7 LD50), in comparison with relatively-low effects of traditional antidotes, atropine plus 2-pralidoxime (2.5 LD50) and atropine plus HI-6 (2.7 LD50). Noteworthy, a synergistic increase in the protection ratio was achieved by the combination of the patch with atropine plus HI-6 (9 LD50), but not with atropine plus 2-pralidoxime (5 LD50). In addition, the patch system markedly attenuated the cholinergic signs and seizures induced by soman, especially when combined with atropine plus HI-6, leading to elimination of brain injuries and physical incapacitation up to 6 LD50 of soman poisoning. Taken together, it is suggested that the patch system containing physostigmine and procyclidine, especially in combination with atropine and HI-6, could be a choice for the quality survival from nerve-agent poisoning.