Characterisation of Drug Delivery Efficacy Using Microstructure-Assisted Application of a Range of APIs.

Polymer-based solid microstructures (MSts) have the potential to significantly increase the quantity and range of drugs that can be administered across the skin. MSt arrays are used to demonstrate their capacity to bypass the skin barrier and enhance permeability by creating microchannels through the stratum corneum, in a minimally invasive manner. This study is designed to demonstrate the ability of MSts to exceed the current boundaries for transdermal delivery of compounds with different molecular weights, partition coefficients, acid dissociation constants, melting points, and water solubilities. In vitro permeation of a range of selected molecules, including acetyl salicylic acid (aspirin), galantamine, selegiline hydrochloride (Sel-HCl), insulin, caffeine, hydrocortisone (HC), hydrocortisone 21-hemisuccinate sodium salt (HC-HS) and bovine serum albumin (BSA) has been studied across excised porcine skin with and without poke and patch application of MSts. Permeation of the molecules was monitored using Franz diffusion cells over 24 h. MSts significantly increased the permeation of all selected molecules up to 40 times, compared to topical applications of the molecules without MSts. The greatest increase in permeation was observed for caffeine with 70 ± 8% permeation and the lowest enhancement was observed for HC with a 2.4 ± 1.3% increase in permeation. The highest obtained flux was BSA (8133 ± 1365 µg/cm2/h) and the lowest flux observed for HC (11 ± 4 µg/cm2/h). BSA and HC also showed the highest (16,275 ± 3078 µg) and the lowest (73 ± 47 µg) permeation amount after 24 h respectively. MSt-treated skin exhibits greatly increased permeation. The molecule parameters (size, acid dissociation constant, partition coefficient and solubility)-traditional hurdles associated with passive diffusion through intact skin-are overcome using MSt skin treatment.

Demographic and Clinical Characteristics of Patients With Type 2 Diabetes Mellitus Initiating Dipeptidyl Peptidase 4 Inhibitors: A Retrospective Study of UK General Practice.

PURPOSE: The majority of people with type 2 diabetes mellitus (T2DM) will develop chronic kidney disease in their lifetime. Because most dipeptidyl peptidase (DPP)-4 inhibitors require dose adjustment in patients with T2DM and renal impairment, we aimed to understand how these treatments are prescribed in UK clinical practice, and to determine whether recommended dose adjustments are being made at initial prescription. METHODS: This retrospective, descriptive cohort study analyzed data from the Clinical Practice Research Datalink (CPRD). Patients of interest were those with T2DM and renal impairment initiated on a DPP-4 inhibitor between 2014 and 2015. Patients under 40 years of age and with type 1 diabetes were excluded. Descriptive statistics were calculated for baseline demographic and clinical characteristics, and the study protocol was approved by the Independent Scientific Advisory Committee for Medicines and Healthcare products Regulatory Agency database research. FINDINGS: A total of 3425 patients diagnosed with T2DM and renal impairment and initiated on a DPP-4 inhibitor were identified. The percentages of patients prescribed the high dose of saxagliptin, alogliptin,sitagliptin, and vildagliptin were 48%, 43%, 41%, and 27%, respectively, which is not recommended given their renal dysfunction. These are conservative estimates, as they do not include patients with severe renal impairment on sitagliptin and alogliptin, whose doses should be further reduced. No patients were prescribed an inappropriately high dose of linagliptin, as there is no requirement for dose adjustment in patients with renal impairment. IMPLICATIONS: In this study, a considerable number of patients with T2DM and renal impairment were prescribed an inappropriately high dose of saxagliptin, alogliptin, sitagliptin, or vildagliptin for their level of renal impairment at treatment initiation. This prescribing could have been due to the complexity of different dosing requirements, or a lack of awareness of the need for dose adjustment of most DPP-4 inhibitors in patients with renal impairment. Linagliptin may be used in patients with moderate or severe renal impairment without dose adjustment.

Efficacy of simplified bladder training in patients with overactive bladder receiving a solifenacin flexible-dose regimen: results from a randomized study.

OBJECTIVE: To compare the efficacy of flexible-dose solifenacin 5/10 mg with and without simplified bladder training in patients with overactive bladder (OAB) syndrome. PATIENTS AND METHODS: SOLAR (SOLifenacin Alone and with simplified bladder Re-training) was a multicentre, prospective, randomized, parallel-group, open-label study in patients with OAB. After a 2-week, single-blind, placebo run-in, 643 patients were randomized to treatment with either solifenacin 5 mg once daily (od) alone (323) or 5 mg od combined with simplified bladder training (320) for 8 weeks. At week 8, patients in both groups could request a dose increase to solifenacin 10 mg od for the remaining 8 weeks of the study. The primary efficacy endpoint was the change from baseline in the mean number of micturitions/24 h after 8 weeks. Secondary efficacy measures were the change in micturition frequency and other voiding diary variables at week 16. Patient-reported outcomes were also assessed, including patient Perception of Bladder Condition, Incontinence Quality of Life, and Treatment Satisfaction using a visual analogue scale score; tolerability was also assessed. RESULTS: Solifenacin given alone was effective in improving all measures of OAB evaluated in the study. When simplified bladder training was used combined with solifenacin there was a further significant improvement in micturition frequency at week 8, and this difference was maintained through to week 16. The use of simplified bladder training with solifenacin also significantly improved treatment satisfaction at week 16 over the responses to solifenacin given alone. There was no significant difference between the treatment groups at week 16 in urgency, incontinence or other secondary variables measured. The most common adverse event reported was dry mouth in both treatment groups; there was a low rate of discontinuation due to adverse events in the total study group. CONCLUSION: Combined treatment with solifenacin and simplified bladder training was more effective than solifenacin alone in reducing micturition frequency at weeks 8 and 16, and improving treatment satisfaction at week 16 in patients with OAB. Simplified bladder training did not improve on the benefits of solifenacin alone in the symptoms of urgency or incontinence.

Exploratory pilot study assessing the risk of cognitive impairment or sedation in the elderly following single doses of solifenacin 10 mg.

OBJECTIVES: To assess the cognitive effects of single doses of solifenacin 10 mg compared with placebo (primary objective) and oxybutynin immediate release (IR) 10 mg (secondary objective) in elderly subjects. METHODS: Single-centre, randomised, double-blind, placebo-controlled study in 12 healthy elderly volunteers, with three crossover periods separated by two 14-day washout periods. Each sequence consisted of a single dose of solifenacin 10 mg in one period, oxybutynin IR 10 mg in another and placebo in another. Aspects of attention, information processing, working memory, episodic memory and self-rated mood and alertness were tested using the validated Cognitive Drug Research computerised assessment system. RESULTS: There was no evidence from absolute mean values or changes from baseline to suggest that solifenacin 10 mg impaired cognition or self-ratings of mood and alertness versus placebo. Post-hoc ANCOVA showed no statistically significant cognitive deterioration with solifenacin versus placebo, when measured at a time point closest to the probable C(max) of solifenacin. Oxybutynin was associated with statistically significant impairments in several measures of cognitive function at a time point corresponding with its probable C(max). CONCLUSION: In this pilot study, single 10 mg doses of solifenacin did not show any clear propensity to impair cognitive function in a healthy elderly population.

Solifenacin in the treatment of urgency and other symptoms of overactive bladder: results from a randomized, double-blind, placebo-controlled, rising-dose trial.

OBJECTIVES: To examine the effects of the antimuscarinic agent solifenacin on urinary urgency, using a range of novel and established outcome measures, as urgency is the principal symptom of the overactive bladder syndrome (OAB). PATIENTS AND METHODS: The study (SUNRISE, solifenacin in the treatment of urgency symptoms of OAB in a rising dose, randomized, placebo-controlled, double-blind, efficacy trial) was a randomized, double-blind, 16-week, placebo-controlled, multicentre study of solifenacin 5/10 mg in 863 patients with symptoms of OAB for > or = 3 months. The primary efficacy variable was the change from baseline to endpoint in the number of episodes of severe urgency with or without urgency incontinence per 24 h, as measured using the Patient Perception of Intensity of Urgency Scale, grade 3 + 4. Secondary efficacy variables included patient-reported outcomes for bladder condition, urgency bother and treatment satisfaction. A 3-day voiding diary was used to record micturition frequency and episodes of urgency and incontinence. A 7-day diary was used to assess speed of onset of effect. RESULTS: Solifenacin 5/10 mg was significantly more effective than placebo in reducing the mean number of episodes of severe urgency with or without incontinence per 24 h from baseline to endpoint (-2.6 vs -1.8, P < 0.001). There were also statistically significant differences in favour of solifenacin 5/10 mg over placebo for all secondary variables measured at endpoint, including patient-reported outcomes. There was a significant improvement in urgency as early as day 3 of treatment. Treatmente-mergent adverse events with solifenacin 5/10 mg were mainly mild or moderate in severity, and only led to discontinuation in 3.6% of patients. CONCLUSION: Solifenacin significantly reduced the number of urgency episodes and the extent of urgency bother, and was well tolerated; it was effective as early as day 3 of treatment.

A cost-utility analysis of once daily solifenacin compared to tolterodine in the treatment of overactive bladder syndrome.

OBJECTIVE: To evaluate the cost-utility of solifenacin, a new generation antimuscarinic, compared with tolterodine in the treatment of overactive bladder syndrome (OAB), from the perspective of the UK National Health Service (NHS). RESEARCH DESIGN AND METHODS: A 1-year Markov model was constructed using data from a 12-week, randomised, double-blind study that compared flexible dosing with solifenacin (5 mg and 10 mg) with tolterodine (IR 2 mg bd/ER 4 mg) in adults with OAB. The model incorporated five discrete health states that were based on disease severity (micturitions/day and incontinence episodes/day). A 'drop out' state was also used in the model to account for patients that discontinued treatment in the first year. UK-specific costs for drug treatment and pad use as well as utilities were assigned to each health state. RESULTS: Solifenacin was a less costly and more effective treatment strategy compared with tolterodine. During the course of 1 year, the estimated cost per patient was pound509 for patients treated with solifenacin and pound526 for those given tolterodine, a cost saving of pound17 per patient. Treatment with solifenacin was also associated with a small incremental gain of 0.004 quality-adjusted-life-years (QALYs) over tolterodine. Sensitivity analysis suggests that the incremental cost effectiveness of solifenacin relative to tolterodine does not appear to exceed pound30 000/QALY with even large variations in key model parameters. CONCLUSION: Flexible dosing with solifenacin is likely to be cost-effective versus tolterodine in the treatment of OAB. Further studies are needed to confirm these results.

A randomized double-blind placebo-controlled multicentre study to explore the efficacy and safety of tamsulosin and tolterodine in women with overactive bladder syndrome.

OBJECTIVES: To evaluate the efficacy of tamsulosin oral-controlled absorption system (OCAS) vs placebo in overactive bladder (OAB), to evaluate the safety and tolerability of once-daily dosing with tamsulosin OCAS, and to compare the efficacy and safety with tolterodine extended-release (ER). PATIENTS AND METHODS: A parallel-group, multicentre, multinational study was conducted with a single-blind placebo run-in period of 2 weeks, followed by a randomized, double-blind, double-dummy active and placebo-controlled treatment period of 6 weeks; women (aged 18-70 years) with symptoms of OAB for >/= 3 months were recruited. Women were randomized to receive one of four doses of tamsulosin OCAS (0.25, 0.5, 1.0 or 1.5 mg), 4 mg of tolterodine ER, or placebo once daily for 6 weeks. The primary efficacy variable was the change in the mean number of voids/24 h. Secondary efficacy variables included change from baseline in; mean volume voided per void, mean number of incontinence episodes/24 h, mean number of urgency episodes/24 h and in quality of life (QoL), as assessed using the Kings Health Questionnaire (KHQ). RESULTS: Overall, 364 women were randomized; the primary efficacy analysis showed that the difference from placebo in the mean number of voids/24 h was not statistically significant for tamsulosin OCAS 1.5 mg (P = 0.189). There was no statistically significant difference for tolterodine ER 4 mg vs placebo in the mean number of voids/24 h (P = 0.353). Similarly, for the secondary outcome variables there was no statistically significant difference between tamsulosin and placebo. Although women taking tolterodine ER 4 mg had a consistently greater increase in mean voided volume/void and consistent decreases in incontinence episodes/24 h, urgency episodes/24 h and episodes of nocturia/24 h, this was not statistically significant. There was no significant improvement in QoL scores across the treatment groups. Tamsulosin OCAS was well tolerated and the proportion of women discontinuing because of adverse events was low (4.7%). CONCLUSION: Tamsulosin is not effective for treating OAB in women and the evidence from this study does not support its use on an empirical basis.

Treatment outcomes in the STAR study: a subanalysis of solifenacin 5 mg and tolterodine ER 4 mg.

OBJECTIVE: To compare OAB symptom outcomes following initial randomised treatment with solifenacin 5 mg or tolterodine ER 4 mg at the 4-week clinic-visit and again at 12 weeks for patients choosing to remain on this treatment dose from 4 weeks. METHODS: A prospective, double blind, double-dummy, two-arm, parallel-group, 12-week study (The STAR study) was conducted to compare the efficacy and safety of solifenacin 5/10 mg and tolterodine extended release (ER) 4 mg in OAB patients. RESULTS: At 4 weeks mean improvements in OAB symptoms, including urgency, frequency (primary variable), incontinence and nocturia, were larger in patients randomised to solifenacin 5 mg; with the difference for incontinence being statistically significant (mean reduction in incontinence episodes/24 hrs in the solifenacin group of -1.30 vs. -0.90 (p=0.0181); the mean result for solifenacin 5 mg amounted to a 44% additional improvement.) There was an associated significant reduction in pad use (reduced by -1.21 vs. -0.80; p=0.0089); the mean result for solifenacin 5 mg amounted to a 51% additional improvement over that of tolterodine ER 4 mg. For patients choosing to remain on these treatments improvements in favour of solifenacin were maintained at study end (12-weeks). Treatments were well tolerated. CONCLUSIONS: Within 4 weeks solifenacin 5mg was statistically significantly better than tolterodine ER 4 mg in improving incontinence and reducing incontinence pad use. Differences in efficacy in favour of solifenacin 5 mg were maintained from 4 weeks for the duration of the study for patients choosing to remain on their starting dose.