Clinical Bridging From Prefilled Syringe to On-body Injector for Risankizumab in Crohn's Disease.

PURPOSE: This article describes the clinical development bridging strategy and key data to support the marketing application of the risankizumab on-body injection (OBI) system for the treatment of moderately to severely active Crohn's disease (CD), even though the OBI was not evaluated directly in the pivotal Phase III studies in CD. METHODS: Three studies were conducted as part of the clinical bridging strategy. The pilot pharmacokinetics (PK) study was a Phase I, single-dose, 4-arm, open-label, randomized, parallel-group exploratory PK and tolerability study that assessed the effect of rate and volume of administration on the bioavailability (BA) of risankizumab and the extent of injection site-related pain after subcutaneous (SC) administration in healthy subjects. The pivotal BA/bioequivalence (BE) study was a relative BA/BE bridging study in healthy subjects to assess the relative BA of the to-be-marketed risankizumab OBI compared with the prefilled syringe (PFS) used in the Phase III CD studies. The OBI adhesive study was a randomized, open-label, non-drug interventional study in healthy subjects to assess the OBI adhesive effectiveness and skin tolerability at 2 different locations (abdomen and upper thigh) over different periods of time (5 and 30 minutes). FINDINGS: The pilot PK study showed that risankizumab exposures were similar across different rates/volumes of SC administration in healthy subjects, thereby supporting further development of the OBI. Second, a pivotal BA/BE study showed comparability between the OBI and Phase III PFS with bioequivalent risankizumab AUCs and no clinically meaningful difference for Cmax based on the wide therapeutic window of risankizumab. In both studies, no new safety risks were identified. No impact of immunogenicity on PK profile or safety was observed for the OBI. Third, an adhesive OBI (without risankizumab) study showed that there were no differences in adhesion/skin tolerability observed over time (up to 30 minutes) or for location of adhesion, and the OBI device adhesion was well tolerated at both the abdomen and thigh locations. IMPLICATIONS: These results supported the risankizumab OBI presentation approval in CD.

Pharmacokinetic Comparability of Risankizumab Formulations in Prefilled Syringe and Auto-injector for Subcutaneous Injection.

PURPOSE: Risankizumab is a humanized immunoglobulin G1 monoclonal antibody that inhibits the p19 subunit of interleukin 23 from interacting with its receptor for the treatment of moderate to severe plaque psoriasis. The aim of this Phase I biopharmaceutics bridging study was to evaluate the pharmacokinetic comparability, immunogenicity, and tolerability of the risankizumab 90 mg/mL prefilled syringe (PFS) and the risankizumab 150 mg/mL PFS and auto-injector (AI) in healthy subjects. METHODS: Healthy subjects received one 150-mg dose of risankizumab in 1 of 3 ways (226 subjects randomized 3:3:1 to 3 treatment arms): 150 mg/mL by PFS × 1 SC injection, 90 mg/mL by PFS × 2 SC injections, or 150 mg/mL by AI × 1 SC injection, and were followed up for 140 days after dosing for the collection of pharmacokinetic, immunogenicity, and tolerability data. FINDINGS: Risankizumab concentration-time profiles overlapped with comparable pharmacokinetic parameters across all treatment arms, indicating similar pharmacokinetic characteristics. The CIs with both formulations and forms of administration were within the bioequivalence range of 0.80-1.25 across all measures of exposure. The prevalence of treatment-emergent anti-drug antibodies and the percentages of subjects who reported at least 1 treatment-emergent adverse event were comparable across all treatment arms. IMPLICATIONS: Bioequivalence was established between risankizumab 150 mg/mL PFS and 90 mg/mL PFS, and between 150 mg/mL PFS and AI, along with comparable immunogenicity profiles across all 3 treatment arms. Risankizumab 150 mg SC delivered by PFS or AI was well tolerated, with comparable safety profiles across all treatment arms, and no new safety risks were identified.

Dexlansoprazole and Esomeprazole Do Not Affect Bone Homeostasis in Healthy Postmenopausal Women.

BACKGROUND & AIMS: Epidemiological studies have associated proton pump inhibitor (PPI) therapy with osteoporotic fractures, but it is not clear if PPIs directly cause osteoporosis. We evaluated the effect of dexlansoprazole and esomeprazole on bone turnover, bone mineral density (BMD), true fractional calcium absorption (TFCA), serum and urine levels of minerals, and levels of parathyroid hormone (PTH) in healthy postmenopausal women. METHODS: We performed a prospective, multicenter, double-blind study of 115 healthy, postmenopausal women (45 to 75 years of age) from November 4, 2010, through August 7, 2014. Women were randomly assigned to groups given dexlansoprazole (60 mg), esomeprazole (40 mg), or placebo daily for 26 weeks. We measured plasma levels of procollagen type 1 N-terminal propeptide (P1NP) and C-terminal telopeptide of type 1 collagen (CTX) at 0 (baseline), 13, and 26 weeks. Primary outcomes were percent change in P1NP and CTX between weeks 0 and 26. We also measured changes in serum and urine levels of mineral, BMD, PTH (all subjects), and TFCA (n = 30). RESULTS: Between baseline and week 26, there were no significant within-group differences in markers of bone turnover; there was a nonsignificant increase in CTX levels in the dexlansoprazole group (0.12 ng/mL). The esomeprazole and dexlansoprazole groups had significantly increased levels of P1NP (18.2% and 19.2%, respectively) and CTX (22.0% and 27.4%, respectively) at week 26 compared with the placebo group, although these values remained within normal ranges. There were no statistically significant differences between groups in serum or urine levels of minerals, BMD, or PTH at week 26. PPI therapy did not reduce TFCA. CONCLUSIONS: In a prospective study of postmenopausal women, we found significant increases in markers of bone turnover in women given PPI therapy compared with women given placebo, but levels remained within the normal reference range. We found no significant differences among groups in changes in BMD, PTH, serum or urine levels of minerals, or TFCA. Our findings indicate that 26 weeks of treatment with a PPI has no clinically meaningful effects on bone homeostasis. Clinicaltrials.gov no: NCT01216293.

Bioavailability of dexlansoprazole delayed-release capsule granules when administered via nasogastric tube or orally via syringe.

OBJECTIVE: To assess the effect of route of administration on the bioavailability of dexlansoprazole 60 mg delayed-release capsule granules. METHODS: One open-label, Phase I, single-dose, 3-period crossover study was conducted in healthy adults. The bioavailability of Dexilant® (dexlansoprazole) after dexlansoprazole capsule granules were mixed with water and administered via 16 French nasogastric tube or orally via syringe was compared to administration of the intact capsule in the fasted state, swallowed with water. Blood samples were collected before and after dosing to determine dexlansoprazole pharmacokinetic parameter estimates and plasma concentrations. RESULTS: Similar values for area under the plasma concentration-time curve and observed maximum plasma concentration were achieved when the dexlansoprazole 60 mg capsule was administered as the intact capsule or when the granules were mixed with water and administered via nasogastric tube or orally via syringe. The primary endpoints of maximum plasma concentration and area under the plasma concentration-time curve demonstrated bioequivalence when assessing these alternative routes of administration. Most adverse events were rated as mild and were comparable irrespective of administration route. CONCLUSION: Systemic exposure to dexlansoprazole was equivalent regardless of administration route. The dexlansoprazole capsule was well tolerated.

Bioavailability of a dexlansoprazole delayed-release orally disintegrating tablet: effects of food and mode of administration.

BACKGROUND: Dexlansoprazole is a proton pump inhibitor (PPI) approved for use in dual delayed-release capsule and orally disintegrating tablet (ODT) formulations. AIM: To assess effects of food, water, and route of administration on the bioavailability of dexlansoprazole 30-mg ODT. METHODS: Two separate open-label, phase 1, single-dose crossover studies were conducted in healthy adults. In study 1, pharmacokinetic parameters were analyzed in participants receiving dexlansoprazole ODT in a fed or fasted state with and without water. In study 2, the bioavailability of dexlansoprazole after administration via oral syringe or nasogastric (NG) tube, or after swallowing intact with water was compared to ODT administration in the fasted state, swallowed without water. Blood samples for determining dexlansoprazole plasma concentrations and pharmacokinetic parameter estimates were collected before and after dosing. RESULTS: Equivalent values for area under the plasma concentration-time curve (AUC) were observed in the fed and fasted states, but the maximum observed plasma concentration (Cmax) was 38% lower in the fed state; therefore, bioequivalence was not achieved. A water rinse following standard ODT administration decreased dexlansoprazole bioavailability, with lower Cmax and AUC values than when ODT was administered without a water rinse. Bioequivalence was demonstrated when comparing the alternative routes of administration, including via oral syringe or NG tube with standard ODT administration. Unlike with a water rinse, bioequivalence to standard ODT administration (i.e., without water) was demonstrated when swallowing the ODT intact with water. Rates of adverse events were comparable irrespective of administration route in the fasted state (6.7%-9.3%) and were 12% higher in the fed state than in the fasted state. CONCLUSION: The AUC from the dexlansoprazole ODT was equivalent when administered in the fed and fasted states. Equivalent systemic exposure to dexlansoprazole was achieved regardless of the administration route.

Pharmacokinetics and pharmacodynamics of an orally disintegrating tablet formulation of dexlansoprazole.

BACKGROUND: The pharmacokinetics and pharmacodynamics of a novel orally disintegrating tablet (ODT) formulation of delayed-release dexlansoprazole 30 mg was evaluated versus the dexlansoprazole 30 mg capsule in this phase I, open-label, multiple-dose, randomized, two-period crossover study. METHODS: Healthy adults received daily doses of 30 mg dexlansoprazole ODT or 30 mg dexlansoprazole delayed-release capsule for 5 days during two treatment periods, separated by a 7-day washout interval. Blood samples for dexlansoprazole plasma concentrations and intragastric pH measurements were collected through 24 hours postdose on days 1 and 5 of each period. RESULTS: Bioequivalence between the 30 mg ODT and 30 mg capsule dosage forms was demonstrated by the primary endpoints of dexlansoprazole peak concentration (Cmax) and systemic exposure (AUC) values contained within the prespecified 90% confidence interval (CI) range of 0.80-1.25. Additional primary endpoints of intragastric mean pH values and percentage of time with pH > 4 over the 24-hour postdose interval were equivalent for dexlansoprazole ODT and dexlansoprazole capsule. Treatment-emergent adverse events were reported in 23% and 28% of participants receiving the ODT and capsule formulations, respectively. Headache was the most common adverse event in both treatment regimens (5.8% with ODT and 6.0% with capsule). CONCLUSIONS: Administration of dexlansoprazole 30 mg ODT or 30 mg capsule provided equivalent plasma exposure when either was administered as a single dose or as once daily doses for 5 days. Pharmacodynamic equivalence between the two formulations was demonstrated by similar intragastric pH parameters on both day 1 and day 5. No effect of day on dexlansoprazole pharmacokinetics was observed. Dexlansoprazole ODT and dexlansoprazole capsule were both well tolerated.

Bioavailability, safety, and pharmacodynamics of delayed-release dexlansoprazole administered as two 30 mg orally disintegrating tablets or one 60 mg capsule.

BACKGROUND: Dual delayed-release dexlansoprazole is approved for use in adults as a 30 mg orally disintegrating tablet (ODT) or as 30 mg and 60 mg capsules. The pharmacokinetics, pharmacodynamics, and safety profile of two dexlansoprazole 30 mg ODTs were compared with one dexlansoprazole 60 mg capsule in this randomized, phase I, open-label, single-center, multiple-dose, two-period crossover study. METHODS: Participants were randomized in one of two treatment sequences, each comprised two 5-day treatment periods during which two dexlansoprazole 30 mg ODTs or one 60 mg capsule was administered once daily. Pharmacokinetic parameters and the mean intragastric pH profile for the 24-hour period after dosing on days 1 and 5 were described. Adverse events were monitored during study duration and followed up with a phone call 5-10 days after the last dose of study drug. RESULTS: On day 1, peak observed plasma concentration (Cmax) values were similar between two 30 mg ODTs (1047 ng/ml) and one 60 mg capsule (1164 ng/ml). Systemic exposure, measured by the area under the plasma concentration-time curve (AUC), was approximately 25% lower after ODT administration. On day 5, mean pH after daily doses of two 30 mg ODT or one 60 mg capsule was 4.33 and 4.36, respectively; both regimens maintained intragastric pH above 4.0 for 60% of the 24-hour period. Headache was the most commonly reported adverse event (observed in 19.2% of participants); no adverse events leading to study withdrawal occurred. CONCLUSIONS: While systemic exposure (AUC) was 25% lower with ODT, peak concentrations (Cmax) after administration of two dexlansoprazole 30 mg ODTs and one 60 mg capsule were similar. The 24-hour intragastric pH control after administration of two dexlansoprazole 30 mg ODTs was equivalent to one dexlansoprazole 60 mg capsule. Both ODT and capsule were well tolerated.

A thorough QT/QTc study of the effect of fasiglifam, a GPR40 agonist, on cardiac repolarization in healthy adults.

This double-blind, randomized, placebo- and active-controlled, parallel group trial evaluated the potential for multiple-dose fasiglifam to prolong the QT/QTc interval in healthy adults. A total of 280 men and women aged 18-50 years were randomized to receive 14 days of fasiglifam 50 mg (n = 69), fasiglifam 400 mg (n = 70), or placebo (n = 70), or 13 days of placebo followed by single-dose moxifloxacin 400 mg (positive control; n = 71). The primary endpoint was the least square mean difference between fasiglifam and placebo in time-matched change from baseline to last dosing day in QT interval corrected using the Fridericia method (QTcF, calculated as QT/RR(0) (.333) ). For both fasiglifam doses, differences from placebo in QTcF were between -4.9 and 3.0 milliseconds at all postdose time points; maximum upper bounds of the one-sided 95% confidence interval for the difference were 5.7 milliseconds for fasiglifam 50 mg and 2.3 milliseconds for fasiglifam 400 mg, meeting predefined criteria for absence of prolongation. Alternate correction methods (Bazett and Individual) showed similar results. Fasiglifam was well tolerated; no subject withdrew due to an adverse event after receiving fasiglifam. In summary, multiple-dose fasiglifam did not affect cardiac repolarization at therapeutic and supratherapeutic doses and was well tolerated in healthy subjects.

Pharmacokinetics and safety of dexlansoprazole MR in pediatric patients with symptomatic gastroesophageal reflux disease.

OBJECTIVE: To evaluate the safety and pharmacokinetic profile of dexlansoprazole modified-release (MR) capsules in pediatric patients with symptomatic gastroesophageal reflux disease (GERD). METHODS: This Phase I, open-label study enrolled male and female patients (1 to 11 years of age) with GERD. Patients received dexlansoprazole MR 15 mg, 30 mg, or 60 mg (according to weight) once daily for 7 days. Blood samples for the measurement of plasma dexlansoprazole concentrations were collected for 24 hours after the day 7 dose. Dexlansoprazole plasma concentrations and pharmacokinetic parameters were summarized by dose group. Safety assessments included adverse events (AEs), clinical laboratory evaluations, fasting gastrin concentrations, physical examinations, electrocardiograms, and vital signs. RESULTS: Thirty-six patients received study drug (12 per dose group), and 31 had evaluable pharmacokinetic data. There was a significant effect of weight on dose-normalized area under the curve (AUC, P=0.003) and dose-normalized maximum plasma concentration (Cmax) (P=0.013), indicating that for a given dose, dexlansoprazole exposure decreases as body weight increases. After adjusting for body weight, both dexlansoprazole Cmax and AUC increased in an approximately dose-proportional manner with increasing dexlansoprazole dose. A total of ten of 36 patients reported at least one treatment-emergent AE, with most events considered mild in intensity. The most common AEs were vomiting, abdominal pain, diarrhea, and nausea. CONCLUSION: In 1- to 11-year-old patients with symptomatic GERD, weight-adjusted dexlansoprazole AUC and Cmax increased approximately dose-proportionally. However, for a given dose, dexlansoprazole exposure decreased with increasing body weight. Dexlansoprazole MR was well tolerated, and the incidence of AEs did not increase with increasing dose.

Evaluation of the pharmacokinetics and safety of a single oral dose of fasiglifam in subjects with normal or varying degrees of impaired renal function.

INTRODUCTION: Approximately one-third of patients with type 2 diabetes mellitus (T2DM) have concurrent renal impairment. There are limited therapeutic options for these patients. Fasiglifam is a G protein-coupled receptor 40 agonist that was under investigation for the treatment of T2DM. The objective of this study was to evaluate the potential effect of renal impairment on the pharmacokinetics and safety of a single dose of fasiglifam and its metabolite M-1. METHODS: This was a phase I, open-label, parallel-group study. Subjects with varying degrees of renal function received a single oral dose of fasiglifam 50 mg. Blood and urine samples were collected through 168 h postdose. Study endpoints were pharmacokinetic and safety variables. RESULTS: Fifty-three subjects were enrolled. Mean fasiglifam plasma concentrations were higher in subjects with mild renal impairment compared with other groups, but within each renal function cohort, plasma concentrations tended to decrease with decreasing renal function. Regression analyses indicated that fasiglifam exposure decreased and M-1 exposure increased with decreasing renal function. Predicted exposure values at about the midpoint of creatinine clearance for each renal impairment group differed by up to 21% (fasiglifam) and 87% (M-1) from that of the normal renal function group. Hemodialysis had no effect on fasiglifam or M-1 exposure. Fasiglifam renal clearance (CLR) was not affected, but M-1 CLR decreased with increasing impairment. No incidences of hypoglycemia were reported during the study. CONCLUSION: Varying renal function status did not have a significant impact on the clearance of fasiglifam in this study.

Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite exclusion or control of polymorphisms (CYP2C19, ABCB1, PON1), noncompliance, diet, smoking, co-medications (including proton pump inhibitors), and pre-existent variability in platelet function.

OBJECTIVES: This study sought to determine whether known genetic, drug, dietary, compliance, and lifestyle factors affecting clopidogrel absorption and metabolism fully account for the variability in clopidogrel pharmacokinetics and pharmacodynamics. BACKGROUND: Platelet inhibition by clopidogrel is highly variable. Patients with reduced inhibition have increased risk for major adverse cardiovascular events. Identification of factors contributing to clopidogrel's variable response is needed to improve platelet inhibition and reduce risk for cardiovascular events. METHODS: Healthy subjects (n = 160; ages 20 to 53 years; homozygous CYP2C19 extensive metabolizer genotype; no nicotine for 6 weeks, prescription drugs for 4 weeks, over-the-counter drugs for 2 weeks, and no caffeine or alcohol for 72 h; confined; restricted diet) received clopidogrel 75 mg/day for 9 days, at which time clopidogrel pharmacokinetic and pharmacodynamic endpoints were measured. RESULTS: At steady-state, clopidogrel active metabolite (clopidogrel(AM)) pharmacokinetics varied widely between subjects (coefficients of variation [CVs] 33.8% and 40.2% for clopidogrel(AM) area under the time-concentration curve and peak plasma concentration, respectively). On-treatment vasodilator stimulated phosphoprotein P2Y(12) platelet reactivity index (PRI), maximal platelet aggregation (MPA) to adenosine phosphate, and VerifyNow P2Y12 platelet response units (PRU) also varied widely (CVs 32% to 53%). All identified factors together accounted for only 18% of intersubject variation in pharmacokinetic parameters and 32% to 64% of intersubject variation in PRI, MPA, and PRU. High on-treatment platelet reactivity was present in 45% of subjects. CONCLUSIONS: Clopidogrel pharmacokinetics and pharmacodynamics vary widely despite rigorous exclusion or control of known disease, polymorphisms (CYP2C19, CYP3A5, ABCB1, PON1), noncompliance, co-medications, diet, smoking, alcohol, demographics, and pre-treatment platelet hyperreactivity. Thus, as yet unidentified factors contribute to high on-treatment platelet reactivity with its known increased risk of major adverse cardiovascular events. (A Study of the Effects of Multiple Doses of Dexiansoprazole, Lansoprazole, Omeprazole or Esomeprazole on the Pharmacokinetics and Pharmacodynamics of Clopidogrel in Healthy Participants: NCT00942175).

Ultrasonic bioreactor as a platform for studying cellular response.

The need for tissue-engineered constructs as replacement tissue continues to grow as the average age of the world's population increases. However, additional research is required before the efficient production of laboratory-created tissue can be realized. The multitude of parameters that affect cell growth and proliferation is particularly daunting considering that optimized conditions are likely to change as a function of growth. Thus, a generalized research platform is needed in order for quantitative studies to be conducted. In this article, an ultrasonic bioreactor is described for use in studying the response of cells to ultrasonic stimulation. The work is focused on chondrocytes with a long-term view of generating tissue-engineered articular cartilage. Aspects of ultrasound (US) that would negatively affect cells, including temperature and cavitation, are shown to be insignificant for the US protocols used and which cover a wide range of frequencies and pressure amplitudes. The bioreactor is shown to have a positive influence on several factors, including cell proliferation, viability, and gene expression of select chondrocytic markers. Most importantly, we show that a total of 138 unique proteins are differentially expressed on exposure to ultrasonic stimulation, using mass-spectroscopy coupled proteomic analyses. We anticipate that this work will serve as the basis for additional research which will elucidate many of the mechanisms associated with cell response to ultrasonic stimulation.

A randomized, 2-period, crossover design study to assess the effects of dexlansoprazole, lansoprazole, esomeprazole, and omeprazole on the steady-state pharmacokinetics and pharmacodynamics of clopidogrel in healthy volunteers.

OBJECTIVES: The aim of this study was to assess the effects of different proton pump inhibitors (PPIs) on the steady-state pharmacokinetics and pharmacodynamics of clopidogrel. BACKGROUND: Metabolism of clopidogrel requires cytochrome P450s (CYPs), including CYP2C19. However, PPIs may inhibit CYP2C19, potentially reducing the effectiveness of clopidogrel. METHODS: A randomized, open-label, 2-period, crossover study of healthy subjects (n = 160, age 18 to 55 years, homozygous for CYP2C19 extensive metabolizer genotype, confined, standardized diet) was conducted. Clopidogrel 75 mg with or without a PPI (dexlansoprazole 60 mg, lansoprazole 30 mg, esomeprazole 40 mg, or, as a positive control to maximize potential interaction and demonstrate assay sensitivity, omeprazole 80 mg) was given daily for 9 days. Pharmacokinetics and pharmacodynamics were assessed on days 9 and 10. Pharmacodynamic end-points were vasodilator-stimulated phosphoprotein P2Y(12) platelet reactivity index, maximal platelet aggregation to 5 and 20 µmol/l adenosine diphosphate, and VerifyNow P2Y12 platelet response units. RESULTS: Pharmacokinetic and pharmacodynamic responses with omeprazole demonstrated assay sensitivity. The area under the curve for clopidogrel active metabolite decreased significantly with esomeprazole but not with dexlansoprazole or lansoprazole. Similarly, esomeprazole but not dexlansoprazole or lansoprazole significantly reduced the effect of clopidogrel on vasodilator-stimulated phosphoprotein platelet reactivity index. All PPIs decreased the peak plasma concentration of clopidogrel active metabolite (omeprazole > esomeprazole > lansoprazole > dexlansoprazole) and showed a corresponding order of potency for effects on maximal platelet aggregation and platelet response units. CONCLUSIONS: Generation of clopidogrel active metabolite and inhibition of platelet function were reduced less by the coadministration of dexlansoprazole or lansoprazole with clopidogrel than by the coadministration of esomeprazole or omeprazole. These results suggest that the potential of PPIs to attenuate the efficacy of clopidogrel could be minimized by the use of dexlansoprazole or lansoprazole rather than esomeprazole or omeprazole.

Comparator pH study to evaluate the single-dose pharmacodynamics of dual delayed-release dexlansoprazole 60 mg and delayed-release esomeprazole 40 mg.

BACKGROUND: This paper describes a Phase 1, single-center, randomized, open-label, two-period crossover study which compared the pharmacodynamic effects of single doses of dexlansoprazole modified-release 60 mg and esomeprazole 40 mg on 24-hour intragastric pH in healthy adult subjects. METHODS: Forty-four subjects aged 20-54 years were randomized in a 1:1 ratio to two sequence groups defining the order in which they received dexlansoprazole and esomeprazole in periods 1 and 2. Primary pharmacodynamic end points over 24 hours postdose were percentage of time with intragastric pH > 4 and mean pH, and secondary pharmacodynamic end points were percentage of time intragastric pH > 4, and mean pH at 0-12 hours, and at >12-24 hours postdose. Each drug was given after an overnight fast and one hour before breakfast. Continuous pH recording began immediately before dosing through to 24 hours postdose. RESULTS: At 0-24 hours postdose, the mean percentage of time with pH > 4 for dexlansoprazole and esomeprazole was 58% and 48%, respectively; the difference was statistically significant (P = 0.003). The average of mean pH values at 0-24 hours postdose for dexlansoprazole and esomeprazole were 4.3 and 3.7, respectively; the difference was statistically significant (P < 0.001). At >12-24 hours postdose, mean percentage of time with pH > 4 and average of mean pH were greater for dexlansoprazole (60% and 4.5, respectively) compared with esomeprazole (42% and 3.5, respectively); the difference was statistically significant (P < 0.001 for both intervals). At 0-12 hours postdose, the difference in dexlansoprazole and esomeprazole values for the pharmacodynamic end points was not statistically significant. CONCLUSION: For the entire 24-hour postdose period, predominantly resulting from the >12-24-hour postdose interval, the average intragastric pH following a single dose of dexlansoprazole 60 mg was higher compared with that observed following a single dose of esomeprazole 40 mg, and the difference was statistically significant.

Electric field-induced self-assembly of micro- and nanoparticles of various shapes at two-fluid interfaces.

Particle lithography which explores the capability of particles to self-assemble offers an attractive means to manufacture nanostructured materials. Although traditional techniques typically lead to the formation of dense crystals, adjustable non-close-packed crystals are crucial in a number of applications. We have recently proposed a novel method to assemble spherical micro- and nanoparticles into monolayers. The technique consists of trapping particles at a liquid-fluid interface and applying an electric field normal to the interface. Particles rearrange themselves under the influence of interfacial and electrostatic forces to form 2-D hexagonal arrays of long-range order and whose lattice constant depends on the electric field strength and frequency. Furthermore, the existence of an electric field-induced capillary force makes the technique applicable to submicron and nanosized particles. Although spherical particles are often used, non-spherical particles can be beneficial in practice. Here, we review the method, discuss its applicability to particles of various shapes, and present results for particles self-assembly on air-liquid and liquid-liquid interfaces. In the case of non-spherical particles, the self-assembly process, while still taking place, is more complex as particles experience a torque which causes them to rotate relative to one another. This leads to a final arrangement displaying either a dominant orientation or no well-defined orientation. We also discuss the possibility of dislodging the particles from the interface by applying a strong electric field such that the Weber number is of order 1 or larger, a phenomenon which can be utilized to clean particles from liquid-fluid surfaces.

Spontaneous dispersion of particles on liquid surfaces.

When small particles (e.g., flour, pollen, etc.) come in contact with a liquid surface, they immediately disperse. The dispersion can occur so quickly that it appears explosive, especially for small particles on the surface of mobile liquids like water. This explosive dispersion is the consequence of capillary force pulling particles into the interface causing them to accelerate to a relatively large velocity. The maximum velocity increases with decreasing particle size; for nanometer-sized particles (e.g., viruses and proteins), the velocity on an air-water interface can be as large as approximately 47 m/s. We also show that particles oscillate at a relatively high frequency about their floating equilibrium before coming to stop under viscous drag. The observed dispersion is a result of strong repulsive hydrodynamic forces that arise because of these oscillations.

Concentrating particles on drop surfaces using external electric fields.

We propose to use an externally applied uniform electric field to alter the distribution of particles on the surface of a drop immersed in another immiscible liquid. Specifically, we seek to generate well-defined concentrated regions at the drop surface while leaving the rest of the surface particle free. Experiments show that when the dielectric constant of the drop is greater than that of the ambient liquid the particles for which the Clausius-Mossotti factor is positive move along the drop surface to the two poles of the drop. Particles with a negative Clausius-Mossotti factor, on the other hand, move along the drop surface to form a ring near the drop equator. The opposite takes place when the dielectric constant of the drop is smaller than that of the ambient liquid, namely particles for which the Clausius-Mossotti factor is positive form a ring near the equator while those for which such a factor is negative move to the poles. This motion is due to the dielectrophoretic force that acts upon particles because the electric field on the surface of the drop is nonuniform, despite the uniformity of the applied electric field. Experiments also show that when small particles collect at the poles of a deformed drop the electric field needed to break the drop is smaller than without particles. These phenomena could be useful to concentrate particles at a drop surface within well-defined regions (poles and equator), separate two types of particles at the surface of a drop or increase the drop deformation to accelerate drop breakup.