A Population Pharmacokinetic Model of (R)- and (S-) Oxybutynin and Its Active Metabolites After Oral and Intravesical Administration to Healthy Volunteers.

Oxybutynin is a racemic anticholinergic drug used for the symptomatic treatment of detrusor overactivity. The formation of active metabolites related to tolerability problems depends on the route of administration. The objective of this evaluation was to develop a pharmacokinetic model for oral/intravesical administration as the basis for simulations with different dosages. Data from a published changeover clinical study with 18 healthy adults receiving a single oral dose of 5 mg immediate-release oxybutynin and single and multiple intravesical doses of 10 mg oxybutynin solution was evaluated. Enantioselective plasma concentrations of oxybutynin and N-desethyloxybutynin (NDO) were used to establish a population pharmacokinetic model using nonlinear mixed-effects modeling with NONMEM 7.4.1. For both enantiomers, the data were described well by a 2-compartment model for oxybutynin with an additional compartment for NDO. Oxybutynin absorption was modeled by transit compartments for oral and first-order absorption for intravesical application. Bioavailability of the more active (R)-enantiomer was 7% for oral and 10%-22% for intravesical administration. In simulations, intravesical doses of 5 to 15 mg (R)-oxybutynin administered 2 to 3 times daily decreased peak-trough fluctuations of NDO to 8% compared with 24% after oral administration. The NDO/oxybutynin ratio was reduced from 17 after oral administration to unity. Chronic intravesical versus oral administration of (R)-oxybutynin generates distinctly lower and less variable concentrations of (R)-NDO. Pharmacokinetic simulations suggest that exposure for 12.5 mg (R)-oxybutynin administered twice daily might not compromise efficacy and tolerability compared with exposure for standard thrice-daily administrations. This assumption needs to be assessed in clinical studies.

Stereoselective Pharmacokinetics and Chiral Inversions of Some Chiral Hydroxy Group Drugs.

BACKGROUND: Chiral safety, especially chiral drug inversion in vivo, is the top priority of current scientific research. Medicine researchers and pharmacists often ignore that one enantiomer will be converted or partially converted to another enantiomer when it is ingested in vivo. So that, in the context that more than 50% of the listed drugs are chiral drugs, it is necessary and important to pay attention to the inversion of chiral drugs. METHODS: The metabolic and stereoselective pharmacokinetic characteristics of seven chiral drugs with one chiral center in the hydroxy group were reviewed in vivo and in vitro including the possible chiral inversion of each drug enantiomer. These seven drugs include (S)-Mandelic acid, RS-8359, Tramadol, Venlafaxine, Carvedilol, Fluoxetine and Metoprolol. RESULTS: The differences in stereoselective pharmacokinetics could be found for all the seven chiral drugs, since R and S isomers often exhibit different PK and PD properties. However, not every drug has shown the properties of one direction or two direction chiral inversion. For chiral hydroxyl group drugs, the redox enzyme system may be one of the key factors for chiral inversion in vivo. CONCLUSION: In vitro and in vivo chiral inversion is a very complex problem and may occur during every process of ADME. Nowadays, research on chiral metabolism in the liver has the most attention, while neglecting the chiral transformation of other processes. Our review may provide the basis for the drug R&D and the safety of drugs in clinical therapy.

Simultaneous quantification of oxybutynin and its active metabolite N-desethyl oxybutynin in rat plasma by ultra-high-performance liquid chromatography-tandem mass spectrometry and its application in a pharmacokinetic study of oxybutynin transdermal patch.

A rapid, selective and sensitive ultra-high-performance liquid chromatography-tandem mass spectrometry method was developed to simultaneously determine oxybutynin and its active metabolite N-desethyl oxybutynin in rat plasma. A 0.1 mL sample of plasma was extracted with n-hexane. Chromatographic separation was performed on a UPLC BEH C18 column (2.1 × 100 mm i.d.,1.7 µm) with mobile phase of methanol-water (containing 2 mmol/L ammonium acetate and 0.1% formic acid; 90:10, v/v). The detection was performed in positive selected reaction monitoring mode. Each plasma sample was chromatographed within 3 min. The linear calibration curves were obtained in the concentration range of 0.0944-189 ng/mL (r ≥ 0.99) for oxybutynin and 0.226-18.0 ng/mL (r ≥ 0.99) for N-desethyl oxybutynin. The intra- and inter-day precision (relative standard deviation) values were not more than 14% and the accuracy (relative error) was within ±7.6%. The method described was superior to previous methods for the quantitation of oxybutynin with three product ions and was successfully applied to a pharmacokinetic study of oxybutynin and its active metabolite N-desethyl oxybutynin in rat plasma after transdermal administration.

Investigation of molecular mobility of pressure-sensitive-adhesive in oxybutynin patch in vitro and in vivo: Effect of sorbitan monooleate on drug release and patch mechanical property.

The aim of present study was to develop an oxybutynin (OXY) transdermal patch with good permeation behavior and mechanical property. Special attention was paid to the effect of chemical enhancer on the molecular mobility of pressure sensitive adhesive (PSA) at molecular level. PSAs and permeation enhancers were investigated through in vitro experiment using rat skin. The optimized formulation was evaluated through pharmacokinetic study using rat. In addition, the molecular mechanism of sorbitan monooleate (Span® 80) in the improvement of PSA molecular mobility was investigated using FT-IR, molecular dynamics simulation, DSC and rheological study. As a result, the optimized formulation using amide PSA demonstrated good adhesion property. And the AUC0-t and Cmax of optimized patch were 6435.8 ±â€¯747.8 h ∗ ng/mL and 127.8 ±â€¯18.0 ng/mL, respectively, which had no significant difference with commercial product. Furthermore, the improvement of the PSA mobility by Span® 80 rather than the decrease of interaction between drug and PSA was the main factor that enhanced the release of OXY from patch. In conclusion, a drug-in-adhesive OXY patch was developed, and the effect of PSA molecular mobility increase on the enhancement of drug skin permeation was proposed at molecular level.

Development of a Novel Simplified PBPK Absorption Model to Explain the Higher Relative Bioavailability of the OROS® Formulation of Oxybutynin.

A new minimal Segmented Transit and Absorption model (mSAT) model has been recently proposed and combined with intrinsic intestinal effective permeability (P eff,int ) to predict the regional gastrointestinal (GI) absorption (f abs ) of several drugs. Herein, this model was extended and applied for the prediction of oral bioavailability and pharmacokinetics of oxybutynin and its enantiomers to provide a mechanistic explanation of the higher relative bioavailability observed for oxybutynin's modified-release OROS® formulation compared to its immediate-release (IR) counterpart. The expansion of the model involved the incorporation of mechanistic equations for the prediction of release, transit, dissolution, permeation and first-pass metabolism. The predicted pharmacokinetics of oxybutynin enantiomers after oral administration for both the IR and OROS® formulations were in close agreement with the observed data. The predicted absolute bioavailability for the IR formulation was within 5% of the observed value, and the model adequately predicted the higher relative bioavailability observed for the OROS® formulation vs. the IR counterpart. From the model predictions, it can be noticed that the higher bioavailability observed for the OROS® formulation was mainly attributable to differences in the intestinal availability (F G ) rather than due to a higher colonic f abs , thus confirming previous hypotheses. The predicted f abs was almost 70% lower for the OROS® formulation compared to the IR formulation, whereas the F G was almost eightfold higher than in the IR formulation. These results provide further support to the hypothesis of an increased F G as the main factor responsible for the higher bioavailability of oxybutynin's OROS® formulation vs. the IR.

Treatment of Overactive Bladder in the Elderly Female: The Case for Trospium, Oxybutynin, Fesoterodine and Darifenacin.

Overactive bladder (OAB) is a common constellation of lower urinary tract storage symptoms that causes a significant impact on a person's quality of life. The elderly may be disproportionally impacted by these symptoms due to concomitant poor mobility, comorbid conditions such as diabetes and heart failure, and polypharmacy. While behavioral modification and pelvic floor muscle training should be considered first-line treatment options, pharmacotherapy remains the backbone of the therapeutic regimen. Trospium, oxybutynin, fesoterodine, and darifenacin all have unique properties that may confer certain advantages in the elderly population. The hydrophilicity and quaternary amine structure of trospium may limit its ability to cross the blood-brain barrier and thus minimize impact on cognition in the elderly. In its oral form, oxybutynin may have the most significant effect on cognition; however, the transdermal preparations may be favorable in the elderly population due to the ability to avoid first-pass metabolism and its limited antimuscarinic adverse effects. Fesoterodine may be the most extensively studied OAB medication in the elderly population. Darifenacin has a strong affinity for the M3 receptor in the bladder, while having a weak affinity for the M1 receptor commonly found in the brain. It must be noted that all muscarinic receptor antagonists are associated with common adverse effects to some degree, and frequent re-evaluation of the elderly patient is necessary to confirm the proper benefit-to-risk profile.

Development of supported liquid-phase microextraction probes for in vivo PK studies.

BACKGROUND: A new sample preparation method termed supported liquid-phase microextraction is proposed. With this technique, the extraction phase is a liquid immobilized inside the pores of a membrane coated on a solid support. METHODOLOGY: Supported liquid-phase microextraction probes were prepared by coating wires with porous polyacrylonitrile followed by saturation with 1-octanol. The probes were introduced inside hypodermic needles and used for in vivo extraction of oxybutynin from the blood and tissues of rabbits. The linear range of the method was from 0.5 to 500 ng/ml. CONCLUSION: The proposed method was successfully applied to monitor the PK profile of oxybutynin. The drug followed a two-compartment model, with a volume of distribution of 14 l/kg and a half-life of 76 min.

Drug development for pediatric neurogenic bladder dysfunction: dosing, endpoints, and study design.

Pediatric drug development is challenging when a product is studied for a pediatric disease that has a different underlying etiology and pathophysiology compared to the adult disease. Neurogenic bladder dysfunction (NBD) is such a therapeutic area with multiple unsuccessful development programs. The objective of this study was to critically evaluate clinical trial design elements that may have contributed to unsuccessful drug development programs for pediatric NBD. Trial design elements of drugs tested for pediatric NBD were identified from trials submitted to the U.S. Food and Drug Administration. Data were extracted from publically available FDA reviews and labeling and included trial design, primary endpoints, enrollment eligibilities, and pharmacokinetic data. A total of four products were identified. Although all four programs potentially provided clinically useful information, only one drug (oxybutynin) demonstrated efficacy in children with NBD. The lack of demonstrable efficacy for the remainder of the products illustrates that future trials should give careful attention to testing a range of doses, using objectively measured, clinically meaningful endpoints, and selecting clinical trial designs that are both interpretable and feasible. Compiling the drug development experience with pediatric NBD will facilitate an improved approach for future drug development for this, and perhaps other, therapeutic areas.

Methenamine: a forgotten drug for preventing recurrent urinary tract infection in a multidrug resistance era.

In the era of multidrug resistance, it is critical to utilize antibiotics in an appropriate manner and to identify new treatments or revisit the use of 'forgotten' drugs. Because urinary tract infections (UTIs) are common, particularly in an increasing elderly population, the 'forgotten' drug, methenamine, may become important as a preventive therapy for recurrent UTIs. Methenamine, a urinary antibacterial agent, can be used as methenamine hippurate or methenamine mandelate preparations and is United States Food and Drug Administration-approved. This article discusses the place of preventive therapy for recurrent UTIs, chemistry, mechanism of action, pharmacology, clinical uses, dosage, adverse reactions and safety, and drug interactions of methenamine. Because of its unique antiseptic property, the authors suggest that methenamine should be considered when more commonly used antibiotics fail to suppress recurrent UTIs.

Pharmacokinetics of intravesical versus oral oxybutynin in healthy adults: results of an open label, randomized, prospective clinical study.

PURPOSE: We investigated the pharmacokinetics of intravesical oxybutynin and discuss the clinical implications of the results. MATERIALS AND METHODS: We performed an open label, randomized, 3-period crossover clinical study in 20 healthy adults. In periods 1 and 2 subjects received a single dose of 10 mg oxybutynin HCl solution intravesically or a 5 mg tablet orally. Period 3 comprised repeat intravesical applications (7 doses) of 10 mg oxybutynin HCl. Enantioselective concentrations of oxybutynin and N-desethyloxybutynin were quantified by liquid chromatography-mass spectrometry. Pharmacokinetic parameters were calculated by noncompartmental methods, analyzed by descriptive statistics and compared using the average bioequivalence approach. RESULTS: Systemic exposure to racemic oxybutynin after intravesical administration was significantly greater, yielding 294% (90% CI 211-408) of that after oral intake of immediate release preparations, as measured by the dose normalized area under the plasma concentration time curve. In contrast, systemic exposure to racemic N-desethyloxybutynin reached only 21% (90% CI 15-29). The area under the plasma concentration time curve ratio of N-desethyloxybutynin to oxybutynin was 14-fold decreased for intravesical administration. After intravesical multidose administration, the cumulation of oxybutynin (1.3-fold) and N-desethyloxybutynin (1.6-fold) was weak, absorption was prolonged and apparent elimination half-lives were longer. The study medication was well tolerated with a third of participants reporting anticholinergic adverse effects. CONCLUSIONS: Our study provides evidence of significantly higher bioavailability of intravesical vs oral administration of oxybutynin due to circumvention of the intestinal first pass metabolism. Given the high efficacy and decreased rate of adverse effects, intravesical oxybutynin should be considered in patients with neurogenic lower urinary tract dysfunction who do not tolerate oral administration or in whom oral preparations fail to improve detrusor overactivity.

Oxybutynin gel for the treatment of overactive bladder.

INTRODUCTION: Overactive bladder (OAB) is a common condition that has a profound impact on an individual's overall health and quality of life. Muscarinic receptor antagonists are the mainstay of oral pharmacotherapy for OAB. While all of the medications in this class are significantly more effective than placebo, they are also associated with more adverse events that may limit their overall use. Transdermal application of oxybutynin has been shown to avoid first-pass metabolism and, thus, may be associated with fewer antimuscarinic side effects. AREAS COVERED: This paper reviews the pharmacology of transdermal oxybutynin gel and summarizes the available data regarding this product in the treatment of OAB. It also discusses the role of this product in the OAB treatment armamentarium. EXPERT OPINION: Oxybutynin transdermal gel has been shown to have significant advantages over placebo, in terms of urgency incontinence episodes, urinary frequency and voided volume in a Phase III study. Application site effects were higher in the gel group, but the incidence of antimuscarinic side effects were lower than those seen with oral preparations. The lower incidence of skin side effects, as compared with the transdermal patch, may confer a theoretical advantage toward the gel product. While promising, unanswered questions remain regarding persistence with treatment after this mode of therapy, and head-to-head comparisons with other antimuscarinics are absent.

Conclusive identification of the oxybutynin-hydrolyzing enzyme in human liver.

The aim of this study was to conclusively determine the enzyme responsible for the hydrolysis of oxybutynin in human liver. Hydrolysis in human liver microsomes (HLMs) and human liver cytosol (HLC) followed Michaelis-Menten kinetics with similar K(m) values. In recombinant human carboxylesterase (CES)-expressing microsomes, CES1 was much more efficient than CES2 and yielded a K(m) value more comparable with that found in HLMs or HLC than did CES2. A correlation analysis using a set of individual HLMs, in which both CESs acted independently showed that the hydrolysis rate of oxybutynin, correlated significantly with a CES1 marker reaction, clopidogrel hydrolysis, but not with a CES2 marker reaction, irinotecan (CPT-11) hydrolysis. Chemical inhibition studies using bis-(p-nitrophenyl) phosphate, clopidogrel, nordihydroguaiaretic acid, procainamide, physostigmine, and loperamide revealed that the effects of these compounds in HLMs, HLC, and recombinant CES1-expressing microsomes were similar, whereas those in CES2-expressing microsomes were clearly different. These results strongly suggest that CES1, rather than CES2, is the principal enzyme responsible for the hydrolysis of oxybutynin in human liver.

Pharmacokinetics of oxybutynin chloride topical gel: effects of application site, baths, sunscreen and person-to-person transference.

BACKGROUND: Oxybutynin chloride topical gel (OTG; Gelnique®) is an approved formulation for the transdermal administration of oxybutynin, an established antimuscarinic therapy for overactive bladder (OAB). Transdermal administration of oxybutynin minimizes plasma concentrations of the active metabolite N-desethyloxybutynin (N-DEO), which can have anticholinergic adverse effects. OBJECTIVES: In four phase I studies, we separately assessed the effects of OTG application site selection on oxybutynin bioavailability (site-to-site study); the effects of post-application showering on oxybutynin steady-state pharmacokinetics (showering study); the effects of sunscreen application on oxybutynin absorption (sunscreen study); and the person-to-person transfer of oxybutynin through skin-to-skin contact at the application site (transference study). METHODS: All four studies were open-label, randomized, phase I studies. The site-to-site and showering studies involved repeated administration of OTG to establish steady-state plasma concentrations of oxybutynin and N-DEO; the other two studies involved single doses. Clinical visits were required for pharmacokinetic sampling, supervision of OTG self-application on pharmacokinetic sampling days, showering, sunscreen application and transference experiments. The study included healthy subjects aged 18-45 years. Subjects with conditions requiring medical therapy or interfering with the application of OTG or the interpretation of pharmacokinetic results were excluded. Participants applied OTG (1 g containing oxybutynin chloride 10%, 1.14 mL/dose) once daily to the abdomen, upper arm/shoulder or thigh. Showering occurred 1-6 hours after dosing. Sunscreen was applied 30 minutes before or after OTG application. Abdomen-to-abdomen contact with movement for 15 minutes between treated and untreated participants was conducted 1 hour after dosing. Time points of serial blood sampling for pharmacokinetic analyses varied among studies. Plasma concentrations of oxybutynin and N-DEO (except transference study) were measured. Bioequivalence was tested with ANOVA models for log(e)-transformed plasma exposure (area under the plasma concentration-time curve [AUC]) and maximum plasma concentration (C(max)) to generate 90% confidence intervals (CIs). RESULTS: Oxybutynin and N-DEO exposures (AUCs) from time zero to 24 hours (AUC(24)) were similar for the three application sites, with N-DEO/oxybutynin mean AUC(24) ratios of approximately 0.9. The 90% CIs for thigh-to-abdomen ratios of oxybutynin AUC(24) (0.93, 1.23) and C(max) (0.85, 1.16) were within the interval required for bioequivalence (0.8, 1.25); the other application site ratios for oxybutynin had boundaries slightly outside this interval. Showering 1-6 hours and sunscreen application 30 minutes before or after OTG application had minor effects on oxybutynin concentrations. After vigorous skin contact between treated and untreated participants at the application site, the mean ± SD AUC from time zero to 48 hours (AUC(48)) of oxybutynin in 12 untreated participants was 29.8 ± 24.5 ng · h/mL, approximately one-quarter of the exposures generally seen in subjects treated with a single dose of OTG. Oxybutynin AUC(48) after clothing-to-skin contact was undetectable in 12 of 14 untreated participants and very low (mean ± SD 0.4 ± 0.8 ng · h/mL) in two untreated female participants. CONCLUSION: The bioavailability of oxybutynin and its pharmacokinetic profile are not greatly affected by application site selection, post-application showering or sunscreen use shortly before or after dosing with OTG. Oxybutynin transference to untreated persons is essentially prevented by avoiding direct skin-to-skin contact with the application site.

A comprehensive non-clinical evaluation of the CNS penetration potential of antimuscarinic agents for the treatment of overactive bladder.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: This study provides antimuscarinic agents for overactive bladder (OAB) display variable association with side effects mediated by the central nervous system (CNS), which may be of particular concern in the elderly. Adverse effects on CNS functioning are related to muscarinic receptor subtype selectivity and the ability of the agent to cross the blood-brain barrier, where P-gp plays a role in limiting permeability. WHAT THIS STUDY ADDS: This study provides a parallel investigation of CNS penetration of antimuscarinic OAB agents in vivo and assessment of physical properties and permeability in cell monolayers in vitro. It adds further understanding of the roles of passive transcellular permeability and P-gp in determining CNS penetration of antimuscarinic OAB agents. It also enables a comparison of CNS side-effect profiles of OAB agents with preclinical CNS penetration data. AIMS: To assess and compare the mechanisms of central nervous system (CNS) penetration of antimuscarinic overactive bladder (OAB) agents. METHODS: Physical properties were computed or compiled from the literature. Rats were administered 5-hydroxymethyl tolterodine (HMT), darifenacin, oxybutynin, solifenacin, tolterodine or trospium subcutaneously. At 1 h postdose, plasma, brain and cerebrospinal fluid (CSF) concentrations were determined using LC-MS/MS assays. Brain and plasma protein binding were determined in vitro. Permeability in the presence and absence of the efflux transporter P-glycoprotein (P-gp) was assessed in RRCK and MDCK-MDR1 transwell assays. RESULTS: Oxybutynin displayed extensive CNS penetration, with brain:plasma ratios (B:P), unbound brain:unbound plasma ratios (Kp,free) and CSF:free plasma ratios each >1. Tolterodine (B:P = 2.95, Kp,free = 0.23 and CSF:free plasma = 0.16) and solifenacin (B:P = 3.04, Kp,free = 0.28 and CSF:free plasma = 1.41) showed significant CNS penetration but with some restriction from CNS as indicated by Kp,free values significantly <1. 5-HMT, darifenacin and trospium displayed much lower B:P (0.03-0.16), Kp,free (0.01-0.04) and CSF:free plasma (0.004-0.06), consistent with poor CNS penetration. Permeability in RRCK cells was low for trospium (0.63 × 10(-6) cm s(-1) ), moderate for 5-HMT (11.7 × 10(-6) cm s(-1) ) and high for darifenacin, solifenacin, tolterodine and oxybutynin (21.5-38.2 × 10(-6) cm s(-1) ). In MDCK-MDR1 cells 5-HMT, darifenacin and trospium, were P-gp substrates, whereas oxybutynin, solifenacin and tolterodine were not P-gp substrates. CONCLUSIONS: Brain penetration was low for antimuscarinics that are P-gp substrates (5-HMT, darifenacin and trospium), and significant for those that are not P-gp substrates (oxybutynin, solifenacin and tolterodine). CNS adverse events reported in randomized controlled clinical trials show general alignment with the preclinical data described in this study.

Oxybutynin topical and transdermal formulations: an update.

Oxybutynin, an antimuscarinic agent, is well established for the treatment of overactive bladder (OAB) and is the gold standard for the treatment of severe neurogenic bladder. Although oral oxybutynin is effective in relieving the urinary symptoms of OAB, medication adherence is low at least in part because of substantial anticholinergic adverse effects. The poor anticholinergic tolerability has been attributed to high circulating levels of N-desethyloxybutynin (DEO), a pharmacologically active product of presystemic metabolism of oral oxybutynin in the liver and gastrointestinal tract. Transdermal formulations of oxybutynin avoid first-pass metabolism and thereby produce lower DEO plasma concentrations. Oxybutynin chloride topical gel (OTG) (Gelnique(R), Watson Pharmaceuticals, Corona, CA, USA), a new gel-based transdermal formulation of oxybutynin, was approved by the U.S. Food and Drug Administration in January 2009. Results of a placebo-controlled U.S. phase III study demonstrated that OTG is efficacious in relieving symptoms of OAB and is associated with a low incidence of anticholinergic adverse events. Patients may find that OTG, with its excellent efficacy, convenient once-daily application and outstanding tolerability profile, is a valuable alternative to oral antimuscarinic agents for the treatment of OAB.

Estimating skin permeability from physicochemical characteristics of drugs: a comparison between conventional models and an in vivo-based approach.

This study evaluates the correlation of some widely used skin permeability predictive models with a recently proposed empirical model based on human in vivo dermatopharmacokinetic data. Drug fluxes through the skin have been calculated using in vitro- and in vivo-based models, and observed in vivo data, and the values compared. Most in vitro-based models underestimate the in vivo data by 1-100-fold. The discrepancy between observed data and prediction reaches the maximum (1000-10,000-fold underestimation) for nicotine (with the smallest molecular weight and logK(oct)), nitroglycerin (with the largest number of hydrogen bond acceptor groups), and for oxybutynin (with the largest molecular weight and logK(oct)) where there was a 1000-fold flux overestimation. However, most models correlated well with the in vivo data and the in vivo-based model (p<0.05). The vehicle effect and using non-steady state in vivo data in the flux calculations partly account for the observed discrepancies between predicted and observed values. Nevertheless, these results reveal the need for further refinement of skin permeability predictive equations, using the steady state in vivo data, and consideration of formulation effect.

The effect of drug concentration on solvent activity in silicone membranes.

The effects of supersaturated formulations on drug permeation through artificial and biological membranes have been reported by a number of research groups. However, little information is known about solvent permeation from these supersaturated formulations, and in particular the effect of high drug concentrations and degree of saturation (DS) on solvent activity. The aim of this study was to determine the effect of the DS of a model drug, oxybutynin, on solvent and drug permeation. Supersaturated residues of oxybutynin in propylene glycol (PG) or (octyl salicylate) OSAL were prepared by the solvent evaporation method. In both formulations a high percentage (25%, v/v) of solvent was used in order to avoid solvent depletion. Permeation of PG and OSAL through silicone was monitored by GC and HPLC, respectively. All OSAL formulations permeated to a higher extent than PG formulations. A decrease in OSAL permeation with 5 DS formulations was observed in comparison with 1 DS or 2 DS formulations, indicating a decrease in solvent activity with drug concentration. In addition, the drug transport from the 5 DS formulation of OSAL was higher than the 1 and 2 DS formulations but lower than predicted. Based on both solvent and drug permeation, this suggests that the low drug permeation observed with 5 DS resulted from a decrease in solvent thermodynamic activity rather than a decrease in solute activity as a result of drug crystallisation. Using PG formulations, the PG permeation remained unaffected with the DS of the formulation, up to 5 DS.

Transdermal oxybutynin.

*Oxybutynin inhibits contraction of the detrusor muscle in the overactive bladder by binding to muscarinic M(3) receptors and blocking acetylcholinergic activation. *The transdermal oxybutynin system, applied twice weekly, delivers continuous oxybutynin over a 96-hour patch wear period. The transdermal route of administration avoids the extensive first-pass metabolism of oxybutynin to its active metabolite, N-desethyloxybutynin. *In two well designed trials in patients with overactive bladder, transdermal oxybutynin 3.9 mg/day decreased the number of incontinence episodes and increased average voided volume to a significantly greater extent than placebo. Urinary frequency was improved to a significantly greater extent with transdermal oxybutynin than with placebo in one trial but not the other. *There was no significant difference between transdermal oxybutynin and extended-release oral tolterodine for any of these endpoints. *Health-related quality-of-life improvements with transdermal oxybutynin were shown in patients with overactive bladder in the open-label MATRIX trial, as demonstrated by significant improvements in all domains of the King's Health Questionnaire. *Transdermal oxybutynin is generally well tolerated in patients with overactive bladder. The majority of patients who discontinued transdermal oxybutynin treatment in two pivotal trials did so because of application-site reactions. However, none discontinued treatment because of dry mouth.