Optimum Dose of Once-Daily Oxybutynin Patch in Japanese Patients with Overactive Bladder: A Randomized Double-Blind Trial Versus Placebo.

OBJECTIVE: To evaluate the efficacy, safety, and optimum dose of once-daily oxybutynin patch for overactive bladder. METHODS: A randomized double-blind trial was conducted in patients with overactive bladder symptoms for ≥24 weeks, who received an oxybutynin patch (73.5 or 105 mg) or placebo once daily for 8 weeks. The primary endpoint was the change in the daily frequency of micturition from baseline to the end of study. RESULTS: A total of 579 patients were randomized to the placebo group (n = 164), 73.5 mg oxybutynin patch group (n = 166), and 105 mg oxybutynin patch group (n = 165). The frequency of micturition (mean ± standard deviation) decreased by 1.19 ± 1.80 in the placebo group, 1.87 ± 1.93 in the 73.5 mg group, and 1.80 ± 1.76 in the 105 mg group. Compared with the placebo group, micturition decreased significantly in the 73.5 mg and 105 mg groups (t-test: P = 0.0025 and 0.0039, respectively), while the decrease was similar in both oxybutynin groups. The oxybutynin groups showed significant improvement of urgency, urge incontinence, incontinence, nocturia, mean voided volume, and five or six domains of the King's Health Questionnaire. Dry mouth was noted in 12.1% of the 73.5 mg group and 13.3% of the 105 mg group. Constipation was comparable between the oxybutynin groups and the placebo group. Application site reactions were less frequent in the 73.5 mg group than the 105 mg group. CONCLUSION: The efficacy of oxybutynin patch was confirmed, and the optimum dose for Japanese patients with overactive bladder was 73.5 mg.

Effect of Combination of Low-Frequency Sonophoresis or Electroporation with Iontophoresis on the Mannitol Flux or Electroosmosis through Excised Skin.

In vitro permeation studies of mannitol were conducted across excised hairless mouse skin to determine and compare the enhancing effect of electroporation (EP) or sonophoresis (SP) combined with iontophoresis (IP) on the electroosmotic flow, and to analyze the enhancement mechanism of these combined methods. Mannitol flux was utilized as an index for the electroosmotic flow due to its low molecular weight and no electrorepulsion effect. The combination of SP and IP (SP/IP) resulted in an apparent increase of electroosmotic flow (no effect was sometimes observed by SP/IP), while that of EP and IP (EP/IP) had no synergistic enhancing effect on the electroosmosis. Next, the combined effect of tape-stripping (TS) and IP (TS/IP) was examined in a similar manner to clarify the difference between the SP/IP and EP/IP effects on electroosmosis. When the TS number increased from 0 to 3, the electroosmotic flow increased with the TS number. However, no further increase was observed when the TS number became more than 3, and the flow started to decrease when the TS number became 5. The electric charge of the skin surface was then measured after SP or TS application. When SP was applied, the skin surface charge became much more negative and the electroosmotic flow by SP/IP was markedly increased. Thus, an increase in the electroosmotic flow across the skin during IP application can be obtained not by EP and TS, but by SP. The combined use of SP and IP is a promising means for the enhanced skin delivery of non-electrolyte drugs.

Once-daily oxybutynin patch improves nocturia and sleep quality in Japanese patients with overactive bladder: Post-hoc analysis of a phase III randomized clinical trial.

OBJECTIVES: To investigate the efficacy of a once-daily oxybutynin patch for nocturia, and its influence on sleep quality in patients with overactive bladder. METHODS: We carried out post-hoc analysis of a phase III, randomized, double-blind, comparative study in which an oxybutynin patch was administered once daily for 12 weeks to Japanese patients with overactive bladder. Patients with a baseline mean of one or more episodes of nocturia per night (data from voiding diaries) were analyzed. The mean number of micturitions, mean voided volume per micturition, mean first voided volume at night, mean sleep duration, and hours of undisturbed sleep were compared between the once-daily oxybutynin patch group and the placebo group. All parameters were expressed as the least squares mean values. RESULTS: The analysis included 576 patients. The number of nocturia episodes decreased by 0.66 in the oxybutynin patch group versus 0.51 in the placebo group (P = 0.0249). Also, the voided volume per nocturnal micturition and the first voided volume at night showed a significant increase in the oxybutynin patch group compared with the placebo group (P = 0.0073 and P = 0.0005, respectively). The hours of undisturbed sleep showed significant prolongation by 76.14 min in the oxybutynin patch group versus 56.07 min in the placebo group (P = 0.0257). CONCLUSIONS: Oxybutynin patch treatment reduces the number of nocturia episodes and prolongs the hours of undisturbed sleep, thus improving sleep quality and sleep-related quality of life in patients with overactive bladder.

Elimination of ketoprofen from the stratum corneum after topical administration with ketoprofen formulations in human subjects.

PURPOSE: To assess the drug concentrations and elimination rate of ketoprofen in the stratum corneum following topical administration of two different formulations in human subjects for reference in the risk management of photocontact dermatitis caused by topical ketoprofen. METHODS: Ketoprofen tape and gel were used as test formulations. The stratum corneum at the application sites was removed by tape-stripping at scheduled times after removal of the formulations. The ketoprofen concentration in the stratum corneum was determined by liquid chromatography with tandem mass spectrometry. RESULTS: The ketoprofen concentration in the stratum corneum decreased and the elimination half-life in the stratum corneum was comparable between tape and gel after removal of the test formulations. The ketoprofen concentration in the stratum corneum decreased more rapidly after the subjects took a shower. Ketoprofen was not detected in the stratum corneum adjacent to the tape application sites. CONCLUSIONS: Ketoprofen in the stratum corneum appears to reach the lower limit of quantitation (0.005 µg) 12-16 days after removal of tape or gel. This period is similar to that recommended for avoiding ultraviolet light after removal of topical ketoprofen formulations in the Summary of Product Characteristics for topical ketoprofen in the European Union.

Efficacy and safety of once-daily oxybutynin patch versus placebo and propiverine in Japanese patients with overactive bladder: A randomized double-blind trial.

OBJECTIVES: To evaluate the efficacy and safety of once-daily oxybutynin patch therapy for overactive bladder. METHODS: A randomized double-blind trial was carried out in patients with overactive bladder syndrome, who received an oxybutynin patch, propiverine (20 mg) or placebo once daily for 12 weeks. The primary efficacy end-point was the change of the mean daily number of micturitions in week 12. RESULTS: A total of 1530 patients were randomized to receive the oxybutynin patch (573), propiverine (576) or placebo (381). The change of the mean daily frequency of micturition from baseline in the full analysis set was -1.89 ± 2.04 with the oxybutynin patch, which was significantly higher than with placebo (-1.44 ± 2.23) (P = 0.0015). The difference of the mean change in the mean daily number of micturitions between the oxybutynin patch and propiverine groups showed a 95% confidence interval of -0.28 to 0.21, and the upper limit of this interval was below the predefined non-inferiority margin of 0.37, showing non-inferiority of the oxybutynin patch to propiverine. The incidence of dry mouth and constipation was higher with propiverine than with the oxybutynin patch or placebo. Application site dermatitis was more frequent with the oxybutynin patch (31.8%) than with propiverine (5.9%) or placebo (5.2%), but the dermatitis was generally mild. CONCLUSION: This trial shows the efficacy of the new once-daily oxybutynin patch for overactive bladder. Despite a higher rate of dermatitis with the oxybutynin patch, dry mouth and constipation occurs less often than during treatment with propiverine.

[Recent trend of transdermal drug delivery system development].

The potential of transdermal drug delivery systems has been demonstrated in recent years with the approval of several medicines for use by patients who are unable to use conventional dosage routes, like oral administration or injection. To enhance the TDDS (Transdermal Drug Delivery System) potential to include other drug candidates, many researchers have been exploring enhancement approaches to increase the permeability of various drugs through the skin. Recently, physical enhancement systems are being reported as having big potential by many researchers. In particular, iontophoresis is a very attractive way of delivering ionized drugs by the application of an electric field to the skin. This has been marketed with some topical and systemic drugs (lidocaine and fentanyl). Sonophoresis is also an attractive method to deliver a drug through the skin using ultrasound. Besides these technologies, various physical approaches are under study. Such technologies can be expected to deliver not only small MW compounds but also macromolecules like peptides. In this article, after looking back through the history of TDDS development, I would like to summarize with new physical and chemical approaches and outline of the new trend of TDDS development with those enhancement system.

Effect of electroporation and pH on the iontophoretic transdermal delivery of human insulin.

The synergistic effect of electroporation (EP) and iontophoresis (IP) on the in vivo percutaneous absorption of human insulin was evaluated in rats. Passive diffusion and IP alone (0.4 mA/cm(2)) resulted in almost no skin permeation of insulin at pH 7, whereas EP treatment (150 or 300 V, 10 ms, and 10 pulses) resulted in a high plasma level of insulin and the combined use of EP and IP led to a further increase of the plasma level of insulin compared with that measured after EP alone. Interestingly, a much higher plasma level was observed when the pH of the insulin solution at 7 was increased to 10. One of the reasons was the different aggregation properties of insulin at pH 7 and pH 10. The nonassociation ratio of insulin was significantly higher at pH 10 than at pH 7. Insulin monomers and dimers were observed in addition to the normal form of insulin, hexamer, albeit in low percentages, at pH 10, whereas most of the insulin was in the hexamer form at pH 7. To confirm the influence of the aggregation properties of insulin, the commercially available human insulin analogue insulin lispro was then evaluated. Its skin permeation was found to be extremely high compared to that of conventional human insulin without increasing the solution pH. Marked decreases in blood glucose levels reflecting the increases in the plasma concentration of insulin were also observed after EP/IP treatment. The present study suggests that percutaneous absorption of insulin is synergistically enhanced by a combined use of EP and IP and that altering the aggregation properties of insulin is important to enhance the percutaneous absorption of insulin by IP and/or EP.

Effect of electroporation on the electroosmosis across hairless mouse skin in vitro.

The effect of electroporation on the iontophoresis-produced electroosmosis across the skin was evaluated by measuring the permeability of hairless mouse skin, to mannitol, a non-electrolyte, in vitro. Immediately after electroporation by squared pulses (10 times/s) at 100, 150 or 200 V for 1 ms, anodal iontophoretic permeations were determined at 0.4 mA/cm2 for 4 h. The observed iontophoretic permeability of mannitol was higher with electroporation pretreatment than without pretreatment. The enhanced flux of mannitol induced by electroporation, however, was due to increased passive diffusion. The contribution of convective or osmotic flow caused by anodal iontophoresis on skin permeation of mannitol was decreased by the pretreatment. In addition, osmotic flow was decreased with an increase in the applied voltage for electroporation. In contrast, mannitol flux during cathodal iontophoresis at 0.4 mA/cm2 after 150 or 200 V electroporation was higher than without electroporation as well as anodal iontophoresis, but cathodal iontophoretic flux after electroporation was lower than without iontophoresis. The neutral high-molecular compound dextran rhodamine B was also used as a second model. Anodal iontophoresis alone did not increase skin permeability of the compound. However, electroporation pretreatment before anodal iontophoresis enhanced the skin permeation of dextran rhodamine B, which was due to increased osmotic flow induced by this combination. These results suggest that electroporation decreases the electroosmosis produced by iontophoresis, and that electroporation increases skin permeability to neutral low and high model compounds (mannitol and dextran rhodamine B) probably due to an enlarged permeation pathway. Thus, electroporation affects osmotic flow from the anode to cathode during iontophoresis. Therefore, one has to pay attention to the change in electroosmosis produced by iontophoresis for the combined use of electroporation and iontophoresis to attain a high skin-penetration enhancing effect.

Design and feasibility assessment of topically applied drug formulations for electroporation.

Few studies have been reported on the design of topical formulations consisting of electrodes and active drugs for electroporation as a means to increase skin permeability of the drugs, although many studies were reported for the effect of this physical means using aqueous drug solutions. We, therefore, designed a prototypic reservoir and matrix topical formulations that are suitable for electroporation in the present study. Plate-plate Ag electrodes and sodium diclofenac were used as model electrodes and the drug, respectively. The in vitro skin permeations of the drug obtained from the reservoir and matrix formulations were slightly higher than that from an aqueous suspension. This may be due to slightly higher electric field in the skin barrier for the presently designed formulations than that for the aqueous suspension. The present feasibility test suggests that these reservoirs and matrix formulations are useful prototypic topical formulations for electroporation application to improve the drug permeability through skin.

Prevention of bone loss in ovariectomized rats by pulsatile transdermal iontophoretic administration of human PTH(1-34).

Serum human parathyroid hormone (1-34)[hPTH(1-34)] levels and the anabolic effect of hPTH(1-34) were compared after administration using multiple pulses of iontophoresis or subcutaneous (sc) intermittent injections to ovariectomized (OVX) Sprague Dawley rats. Triple-pulse iontophoretic administration of hPTH(1-34) (doses: 40-400 microg/patch), achieved by repeated 30-min applications of a 0.1 mA/cm(2) current separated by 45-min rest intervals, produced three sharp peaks in the serum hPTH(1-34) level in response to application of the current. Each peak appeared at the end of the 30-min current application period and was proportional to the hPTH(1-34) dose. Compared with once-daily sc injections (7 pulses/week), triple-pulses iontophoretic administered 3 times/week (9 pulses/week) for 4 weeks produced dose-related increases in the bone mineral density (BMD) of the distal 1/3 femur. For the sc administration, the relative BMD values using the vehicle injection as a reference standard for 1, 5, and 25 microg/kg/day were 104, 114, and 121%, respectively. For iontophoretic administration, the relative BMD values using the placebo patch as a reference standard for 40, 120, and 400 microg/patch were 104, 110, and 116%, respectively. The increase in the BMD plotted against the area under the hPTH(1-34) serum level-time curve (AUC) over 1 week resulted in similar straight lines in the 9 pulses/week iontophoretic administration and the 7 pulses/week sc administration groups. The estimated iontophoretic dose giving an equivalent BMD to once-daily sc administration at 5 microg/kg/day was 120 microg/patch. These findings strongly suggest that three iontophoretic pulses administered on alternate days will exert an anabolic effect equivalent to that of daily sc administration at doses giving the same weekly AUC. Furthermore, this method of administering hPTH(1-34) might enable self-medication, a useful advance in the treatment of osteoporosis.