Oral Extended-release Formulation Research Articles

Gepirone (Exxua) for depression.

The FDA has approved an oral extended-release formulation of gepirone (Exxua – Fabre-Kramer), a selective 5-HT1A receptor agonist, for treatment of major depressive disorder (MDD) in adults. Gepirone was originally developed decades ago for treatment of anxiety and depression, but it was not approved by the FDA for such use. Gepirone is structurally related to buspirone, which is FDA-approved for treatment of anxiety.

Can in vitro/in silico tools improve colonic concentration estimations for oral extended-release formulations? A case study with upadacitinib

Upadacitinib, classified as a highly soluble drug, is commercially marketed as RINVOQ®, a modified-release formulation incorporating hydroxypropyl methylcellulose as a matrix system to target extended release throughout the gastrointestinal (GI) tract. Our study aimed to explore how drug release will occur throughout the GI tract using a plethora of in vitro and in silico tools. We built a Physiologically-Based Pharmacokinetic (PBPK) model in GastroPlus™ to predict the systemic concentrations of the drug when administered using in vitro dissolution profiles as input to drive luminal dissolution. A series of in vitro dissolution experiments were gathered using the USP Apparatus I, III and IV in presence of biorelevant media, simulating both fasted and fed state conditions. A key outcome from the current study was to establish an in vitro-in vivo correlation (IVIVC) between (i) the dissolution profiles obtained from the USP I, III and IV methods and (ii) the fraction absorbed of drug as deconvoluted from the plasma concentration-time profile of the drug. When linking the fraction dissolved as measured in the USP IV model, a Level A IVIVC was established. Moreover, when using the different dissolution profiles as input for PBPK modeling, it was also observed that predictions for plasma Cmax and AUC were most accurate for USP IV compared to the other models (based on predicted versus observed ratios). Furthermore, the PBPK model has the utility to extract the predicted concentrations at the level of the colon which can be of utmost interest when working with specific in vitro assays.

Review of Extended Drug Delivery Oral Formulations

Generally maximum times applied route for administration of drugs is oral only. The drugs that are given orally but are having smaller half-life and great dosing rate of recurrence are very promising methodology is oral extended release drug delivery system. In this system, frequency of dosing diminishes or moderates for assured drugs through slow release of drug over an extended time period. Extended release drug delivery system can affect by different physicochemical and biological properties. The present review contains brief–up on innumerable oral extended release formulation methodologies.

Abstract P318: INDOLE-3 ACETIC ACID: A NOVEL DUAL-ACTION INHIBITOR OF THE ENDOTHELIN SYSTEM FOR TREATING HYPERTENSION

Elevated levels of endothelin-1 (ET-1) stimulate potent vasoconstriction, free radical production, oxidative stress, and vascular inflammation, which are often present in salt-sensitive hypertension, pulmonary hypertension, drug-resistant hypertension, and hypertension among African Americans. There is currently no known drug that simultaneously targets both ET-1 receptors (ETRs) and the ET-1 synthesizing enzyme ECE-1, even though dual targeting of the ET system could lead to a new generation of drug molecules with improved therapeutic outcome. Using an integrated in vitro, in vivo and in silico approaches, here we report the discovery of indole-3 acetic acid (IAA) as an inhibitor of both ET-1 receptors and ECE-1. IAA is produced in the human body via tryptophan metabolism by gut microbiota. Our data demonstrates that IAA concentration-dependently inhibits ET-1-evoked vasoconstriction in rat resistance mesenteric arteries and ET-1-stimulated reactive oxygen species (ROS) production in smooth muscle cells (SMCs). Furthermore, IAA suppresses ET-1-induced endothelial cell (EC) activation, adhesion molecule overexpression, and leukocyte adhesion. IAA inhibits ET-1-stimulated, ET A R- and ET B R-mediated increases in [Ca 2+ ] i . Intriguingly, IAA produces a concentration-dependent inhibition of purified human ECE-1. Treatment of Dahl salt-sensitive (DSS) hypertensive rats, a model of augmented ET-1 signaling, with an oral extended-release formulation of IAA significantly inhibits blood pressure elevation in high-salt diet-fed (HSD) DSS rats. IAA-treated DSS arteries show intact acetylcholine- and sodium nitroprusside-induced vasodilation, suggesting that IAA preserves endothelial and smooth muscle function, respectively. IAA treatment also prevents arterial remodeling, oxidative stress, and kidney dysfunction in HSD DSS rats. Overall, our study identifies IAA as the first-in-class dual-action inhibitor of ETRs and ECE-1, which produces profound antihypertensive effect in vivo. IAA could also be therapeutically useful for other cardiovascular diseases in which ET-1 signaling is implicated.

An overview on fundamentals of immediate release drug delivery system

Tablet is most popular among all dosage forms today because of its convenience, ease of administration, greater flexibility in dosage form design, ease of production, and low cost and non-invasive therapy. Formulation of tablets requires API along with excipients. Excipients include lubricants, diluents, binders, glidants, disintegrants, sweetening agents, flavoring agents, etc. Recent trends indicate that multi-particulate drug delivery systems are suitable for achieving extended-release oral formulation with a low risk of dose dumping, mixing flexibility to attain difference release patterns, and reproducible and short gastric residence time. Modern technology in immediate-release tablets, such as novel granulation techniques and electrostatic dry powder coating techniques, are prevalent nowadays. Recently, the immediate-release formulation has been similar to various sustained-release formulations that are currently readily attainable.

Nanostructured lipid carrier for bioactive rice bran gamma-oryzanol

The current work presents the development of a nanostructured lipid carrier (NLC) as a colloidal encapsulation and controlled release system for bioactive γ-oryzanol (GO) from rice bran oil. GO-loaded NLC (GO-NLC) were prepared using rice bran oil GO via a hot homogenisation method with sunflower oil (liquid lipid) and stearic acid (solid lipid) as the encapsulating lipid matrix, and rice bran phospholipids and Tween 80 as stabilisers. Fabricated GO-NLC had a 95% encapsulation efficiency with a spherical ‘yolk–shell’ morphology and a 143 nm mean particle diameter. A 60-day storage stability study showed that GO-NLC had high GO retention (>90%) at ambient temperature in light and dark conditions. In vitro release studies demonstrated that GO can be released from GO-NLC via different modes: slow controlled release into simulated intestinal fluid, following the Korsmeyer-Peppas model, and rapidly into a surfactant solution (Tween 80), following first-order release kinetics. Lastly, in vitro studies showed encapsulation of GO in NLCs afforded an 18-fold increase in free radical-scavenging activity, a two-fold increase in hyaluronidase-inhibitory, and a 200-fold improvement in anti-inflammatory activity. These suggest that GO-NLC is a suitable GO delivery system, which can either perform as an oral extended-release formulation or a rapid-release, surfactant triggered system, with improved health-promoting bioactivities.

Viloxazine in the Management of CNS Disorders: A Historical Overview and Current Status.

Viloxazine has a long history of clinical use in Europe as an antidepressant, and has recently been repurposed into an extended-release form for the treatment of attention-deficit/hyperactivity disorder in the USA. An immediate-release formulation was approved for the treatment of depression in the UK in 1974, and was subsequently marketed there and in several European countries for 30 years with no major safety concerns. In contrast to first-generation antidepressants (e.g., tricyclic antidepressants, monoamine oxidase inhibitors), viloxazine was associated with a relatively low risk for cardiotoxicity. Gastrointestinal symptoms were the most commonly reported side effects. The therapeutic effects of viloxazine are thought to be primarily the result of its action as a norepinephrine reuptake inhibitor, although in vitro and preclinical in vivo animal data suggest that viloxazine may also impact the serotoninergic system. This review summarizes the evolving knowledge of viloxazine based on information from previously published preclinical and clinical investigations, and acquired unpublished historical study reports from both open-label and blinded controlled clinical trials. We review the chemical properties, mechanism of action, safety, and tolerability across these studies, and discuss the contemporary rationale for the development of this agent as an extended-release oral formulation for the treatment of attention-deficit/hyperactivity disorder.

Prediction of in vivo performance of oral extended release formulations prior to clinical evaluation: A case study for enteric coated polymeric beads formulation

To reduce cost and time for product development, an ideal strategy for the development of oral extended release (ER) product is to identify the desired formulation with minimum needsfor clinical evaluation. The aim of this work was to demonstrate the feasibility of adopting a “prediction-then-validation” strategy for the development of oral ER formulations. Instead of the traditional approach using multiple ER formulations for IVIVC development, an enteric-coated fast release formulation was successfully utilized for the development of a biopredictive tool to estimate the drug release from enteric coated polymeric ER formulations in the intestine. A TS1 (time scale factor between Tvitro and Tvivo equals to 1) system was designed and developed, based on which the in vivo pharmacokinetic (PK) performance of ER formulations in dog and in human were well predicted prior to in vivo evaluations. The model further passed a posteriori validation using the criteria for level A IVIVC and, as designed, provided a Tscale value of 1 for the IVIVC model.

A Review Extended Release Oral Drug Delivery System and Multiparticulate Drug Delivery Systems (MDDS)

The extended release product will optimize therapeutic effect and safety of a drug at the same time improving the patient convenience and compliance. By incorporating the dose for 24 hrs into one tablet/capsule from which the drug is released slowly. The concept of multiple unit dosage form was initially introduced in the early 1950’s.These forms play a major role in the design of solid dosage form processes because of their unique properties and the flexibility found in their manufacture. These forms can be defined as oral dosage forms consisting of a multiplicity of small discrete units, each exhibiting some desired characteristics. The release of drug from pellets depends on a variety of factors including the carrier used to form pellets and the amount of drug contained in them. Consequently, pellets provide tremendous opportunities for designing new controlled and extended release oral formulations, thus extending the frontier of future pharmaceutical development. The possible mechanism for drug release includes solution/diffusion through the continuous polymer phase or plasticizer channels, diffusion through aqueous pores and osmotically driven release through aqueous pores. To distinguish between these mechanisms, the release rate was studied as a function of coating thickness, plasticizer content and osmotic pressure in the dissolution medium.

Safety and efficacy of extended release ketamine tablets in patients with treatment-resistant depression and anxiety: open label pilot study.

Background:Ketamine’s defining side effects are dissociation and increased blood pressure/heart rate. An oral formulation with delayed absorption could minimize these effects. We recently reported safety and tolerability data for an extended release ketamine tablet in healthy volunteers.Methods:To assess safety, tolerability, efficacy, and pharmacokinetics of an extended release oral ketamine tablet in patients with treatment-resistant depression/anxiety. This was a multiple dose open-label flexible dose uncontrolled study in seven patients with treatment-resistant depression/anxiety, who had all previously demonstrated mood improvement to subcutaneous ketamine. Assessments included ratings of anxiety, depression and dissociation, safety and tolerability, and blood samples for ketamine pharmacokinetics and brain-derived neurotrophic factor (BDNF) concentrations.Results:Improvements in anxiety and depression ratings occurred gradually over 96 h; all patients had >50% improvements in mood ratings. Ketamine was safe and well tolerated, with no changes in vital signs, and a single brief report of dissociation. Ketamine may induce its own metabolism, as the ratio of norketamine to ketamine increased out to 96 h. Serum BDNF concentrations did not change during the study.Conclusion:Ketamine’s safety/tolerability may be improved with an extended release oral formulation. Onset of mood improvement is slightly delayed compared with parenteral dosing. These data support the further development of extended release ketamine tablets for treatment of resistant depression and anxiety disorders.

Formulation and Development of Sustained Release Pellets of Nifedipine by Fluidized Bed Processor

Recently, extended release pharmaceutical products became a very useful tool in medical practice, offering a wide range of actual and perceived advantages to the patients. Oral drug delivery is the most preferred route for the various drug molecules among all other routes of drug delivery, because ease of administration which lead to better patient compliance. So, oral extended release drug delivery system becomes a very promising approach for those drugs that are given orally but having the shorter half-life and high dosing frequency. Extended release is also providing promising way to decrease the side effect of drug by preventing the fluctuation of the therapeutic concentration of the drug in the body. Recent trends indicate that multiparticulates drug delivery systems are especially suitable for achieving extended release oral formulations with low risk of dose dumping, flexibility of blending to attain different release patterns as well as reproducible and short gastric residence time. Development of Nifedipine Sustained Release pellets by Fluidized Bed Processing technology. The different trials were formulated and evaluated for its percent Cumulative drug release, percent Swelling index and scanning electron microscopy. The release of drug from pellets depends on a variety of factors including the carrier used to form pellets and the amount of drug contained in them. In these, trial 2 is Shows better results Such as, percent Cumulative Drug Release is 84.34%, and Scanning Electron Microscopy study shows Pellets uniformities and Spherical shape particle's also less Agglomeration.

Combined site-specific release retardant mini-matrix tablets (C-SSRRMT) for extended oral delivery of dexketoprofen trometamol: in vitro evaluation and single versus multiple doses pharmacokinetic study in human volunteers

Development of extended release oral formulations of dexketoprofen trometamol (DT), a rapidly eliminated drug with high solubility, poses a great challenge especially when a portion of the dose is to be absorbed from the colon. In this study, site-specific release-retardant mini-matrix tablets (SSRRMTs) were developed and functionally coated with pH-responsive materials to achieve a site-specific delivery of DT at the duodenojejunal (DSRRMT) and ileocecal (ISRRMT) regions. Stomach-specific coated mini-tablets (SSCMTs) were manufactured for immediate release of about 16% of the daily dose of DT in the stomach. The SSCMT, DSRRMT, and ISRRMT were combined into a solid dosage form (C-SSRRMT tablets or capsules) to achieve the required linear release profile for once daily administration of DT. The SSRRMT and C-SSRRMT formulations were evaluated for the physical properties, in vitro-disintegration and in vitro dissolution and proved to be consistent with the pharmacopeial specifications. The in vitro release profiles of both C-SSRRMT tablets and capsules showed a constant release rate of about 6 mg/h and were similar to that of the theoretical target linear release profile. The pharmacokinetic study using human volunteers showed the bioequivalence of a single oral dose of C-SSRRMT capsules compared to three-successive oral doses of the immediate release market tablets with less ups and downs in the drug levels. The C-SSRRMT capsules formulation, may therefore, constitute an advance in the extended oral delivery of DT without the lack of efficacy and the adverse events frequently encountered in multiple daily dosing of the immediate release tablets.

Robustness of barrier membrane coated metoprolol tartrate matrix tablets: Drug release evaluation under physiologically relevant in vitro conditions

Robust in vitro drug release behavior is an important feature of extended release (ER) hydrophilic matrix formulations for accurate prediction of in vivo drug release. In this study, ER hydrophilic matrix tablets of metoprolol tartrate were formulated using a high viscosity grade of hypromellose as a rate-limiting polymer. Expectedly, this formulation showed an undesirable initial burst release followed by controlled drug release. Application of a barrier membrane (BM) coating of ethylcellulose with a pore former (hypromellose) resulted in the elimination of the burst effect. The aim of this study was to investigate the robustness of in vitro metoprolol release from BM-coated hydrophilic matrix tablets by simulating the physicochemical properties of gastrointestinal fluids and mechanical stress in the fasted- and fed state human gastrointestinal (GI) tract. Uncoated and BM-coated matrices were subjected to various dissolution studies simulating the varying pH conditions and additional physicochemical parameters, and the mechanical stress that can be caused by GI motility during both fasted and fed state GI passage. The BM-coated formulation showed robust drug release without an initial burst in all test scenarios. BM-coated matrix formulations thus represent a very promising approach for obtaining a highly controlled and robust drug release from oral ER formulations.

Efficacy of oral trazodone slow release following intravenous administration in depressed patients: a naturalistic study.

Up to date, no studies in literature assessed the efficacy of a treatment schedule including i.v. trazodone followed by its oral administration. In light of this lack of evidence, the aim of the present study was to evaluate the efficacy and tolerability of trazodone, administered first i.v. and then orally in a sample of Major Depressive Disorder (MDD) patients. Thirty four patients underwent i.v. administration of trazodone (75-100 mg in 250 mL of saline) for 1 week. During the second week, oral extended-release formulation (150-300 mg per day) was added to the i.v. administration. Finally, extended-release trazodone was orally administration at doses of 150-300 mg per day. Psychometric scales were performed at baseline (T0), after 2 weeks (T1), 6 weeks (T2), after 3 months (T3), and 6 months (T4). The total sample included 34 subjects (14 males and 20 females). There was a statistically significant decrease in Hamilton Depression Rating Scale total scores from T0 to T1 (t=9.06; df=33), from T1 to T2 (t=4.96; df=29), from T2 to T3 (t=4.08; df=19), and from T3 to T4 (t=2.25; df=19); in Hamilton Anxiety Rating Scale total scores from T0 to T1 (t=8.79; df=33) and from T1 to T2 (t=5.61; df=29); in Montgomery-Asberg Depression Rating Scale total scores from T0 to T1 (t=9.30; df=33), from T1 to T2 (t=5.69; df=29), and from T2 to T3 (t=3.16; df=19). This finding confirms previous results on depression with concomitant anxiety symptoms: focusing on trazodone prolonged-release formulation, available data documented its efficacy in MDD.

Opana-Induced Renal and Hepatic Injury: A Case Report and Review

A 34-year-old Caucasian female presented with headache, fatigue, mild abdominal pain, and dehydration. She admitted to intravenous abuse of 'melted' Opana ER tablets (extended-release oral formulation of oxymorphone hydrochloride). Noted clinical signs included tachycardia, tachypnea, and trace peripheral edema. Abnormal laboratory tests included low creatinine clearance, hemoglobin, hematocrit, and platelet. Histological studies of hepatorenal biopsies showed evidence of severe active thrombotic microangiopathy (TMA) involving the arterioles and small arteries of the kidney and scattered portal and lobular granulomata and hepatic vascular changes involving the hepatic artery branches in some portal tract. To our knowledge of the published English literature, this is probably the first case report of Opana induced thrombotic microangiopathy (TMA) with evidence of histological involvement to both the kidney and the liver.

Piribedil for the Treatment of Motor and Non-motor Symptoms of Parkinson Disease.

Dopamine agonists are well-established symptomatic medications for treating early and advanced Parkinson disease (PD). Piribedil was one of the first agonists to be marketed (1969) and is widely used as an extended-release oral formulation in European, Latin-American, and Asian countries. Piribedil acts as a non-ergot partial dopamine D2/D3-selective agonist, blocks alpha2-adrenoreceptors and has minimal effects on serotoninergic, cholinergic, and histaminergic receptors. Animal models support the efficacy of piribedil to improve parkinsonian motor symptoms with a lower propensity than levodopa to induce dyskinesia. In PD patients, randomized double-blind studies show that piribedil (150-300mg/day, three times daily) is superior to placebo in improving motor disability in early PD patients. Based on such evidence, piribedil was considered in the last Movement Disorder Society Evidence-Based Medicine review as "efficacious" and "clinically useful" for the symptomatic treatment of PD, either as monotherapy or in conjunction with levodopa, in non-fluctuating early PD patients. This effect appears comparable to what is known from other D2 agonists. However, randomized controlled trials are not available to assess the effect of piribedil in managing levodopa-induced motor complications. Pilot clinical studies suggest that piribedil may improve non-motor symptoms, such as apathy, but confirmatory trials are needed. The tolerability and safety profile of piribedil fits with that of the class of dopaminergic agonists. As for other non-ergot agonists, pneumo-pulmonary, retroperitoneal, and valvular fibrotic side effects are not a concern with piribedil. The original combination of piribedil D2 dopaminergic and alpha-2 adrenergic properties deserve further investigations to better understand its antiparkinsonian profile.

PND31 - Cost-Effectiveness Analysis of Ipx066 In advanced Parkinson’s Disease

Parkinson’s disease (PD) is a progressive disease associated with substantial economic and societal burden. Immediate-release (IR) carbidopa-levodopa (CD-LD) is the gold standard in treatment for advanced PD patients. However, effectiveness of IR CD-LD diminishes with long-term treatment and is associated with increased “off” time (re-emergence of PD symptoms) and the advent of motor complications. CD-LD plus entacapone (CL+E) has produced some clinical improvement over IR CD-LD alone. IPX066 is an extended-release oral formulation of CD-LD designed to address some of the limitations of IR CD-LD by rapidly attaining and maintaining therapeutic LD concentrations for a prolonged duration. The aim of the study was to evaluate the comparative cost-effectiveness of IPX066 against CL+E. A Markov model was developed comparing IPX066 with branded and generic CL+E in the US market. Health states included ≤ 25% “off” time, > 25% “off” time, and dead. The model simulated a hypothetical patient’s progression over a 5-year period through these health states, with a 6-month Markov cycle length. Outcomes evaluated were total direct costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICER). Dosing and efficacy data from a Phase 3 study comparing IPX066 and CL+E, average wholesale acquisition drug costs (RedBook), and published literature were utilized for this evaluation. Non-2014 costs were inflated to reflect the 2014 value using the medical component of the Consumer Price Index. The discount rate employed was 3%. IPX066 was dominant over both branded and generic CL+E therapies, with ICERs of (-$166,044) and (-$75,920), respectively. On average, patients who received IPX066 experienced a 5.1% increase in QALYs (2.90) compared with patients who did not receive IPX066 (2.76). IPX066 dominated the other two therapies throughout multiple sensitivity analyses, driven largely by improved effectiveness of IPX066. IPX066 is likely to be a cost-effective therapy in patients with advanced PD.

Pharmacokinetics of an oral extended-release formulation of doxycycline hyclate containing acrylic acid and polymethacrylate in dogs.

To determine the pharmacokinetics of doxycycline hyclate administered orally in the form of experimental formulations with different proportions of acrylic acid-polymethacrylate-based matrices. 30 healthy adult dogs. In a crossover study, dogs were randomly assigned (in groups of 10) to receive a single oral dose (20 mg/kg) of doxycycline hyclate without excipients (control) or extended-release formulations (ERFs) containing doxycycline, acrylic acid polymer, and polymethacrylate in the following proportions: 1:0.5:0.0075 (ERF1) or 1:1:0.015 (ERF2). Serum concentrations of doxycycline were determined for pharmacokinetic analysis before and at several intervals after each treatment. Following oral administration to the study dogs, each ERF resulted in therapeutic serum doxycycline concentrations for 48 hours, whereas the control treatment resulted in therapeutic serum doxycycline concentrations for only 24 hours. All pharmacokinetic parameters for ERF1 and ERF2 were significantly different; however, findings for ERF1 did not differ significantly from those for the control treatment. Results indicated that both ERFs containing doxycycline, acrylic acid polymer, and polymethacrylate had an adequate pharmacokinetic-pharmacodynamic relationship for a time-dependent drug and a longer release time than doxycycline alone following oral administration in dogs. Given the minimum effective serum doxycycline concentration of 0.26 μg/mL, a dose interval of 48 hours can be achieved for each tested ERF. This minimum inhibitory concentration has the potential to be effective against several susceptible bacteria involved in important infections in dogs. Treatment of dogs with either ERF may have several benefits over treatment with doxycycline alone.

Use of IVIVC in the Development of Oral Extended-Release Formulations: A Personal Perspective

Use of IVIVC in the Development of Oral Extended-Release Formulations: A Personal Perspective

O-001 Budesonide MMX® 9 mg for Inducing Remission in Patients With Mild-to-Moderate Ulcerative Colitis Not Adequately Controlled With Oral 5-ASAs

Budesonide MMX® (B-MMX) is a once-daily, extended release oral formulation designed to provide targeted delivery of budesonide throughout the colon. Previous post-hoc analyses of randomized, controlled studies of B-MMX monotherapy suggested that it was effective for induction of remission of mildly to moderately active UC in patients with or without prior 5-ASA use. Here we present data from a prospectively designed, randomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of B-MMX in patients experiencing an active UC flare despite treatment with an oral 5-ASA. Patients with mildly to moderately active UC (UCDAI ≥4 and ≤10) inadequately controlled with oral 5-ASA monotherapy were randomized 1:1 to add once-daily B-MMX 9 mg or placebo (PBO) for 8 weeks to their existing 5-ASA. Patients were required to be on a stable, therapeutic dose of an oral 5-ASA (e.g., mesalamine ≥2.4 g/day or equivalent dose of another 5-ASA) throughout the study. Patients who increased their 5-ASA dose or administered other UC therapies were considered non-responders. The primary efficacy endpoint was combined clinical and endoscopic remission at Week 8, as defined by a UCDAI score of ≤1, with subscores of 0 for rectal bleeding, stool frequency and mucosal appearance. Secondary and exploratory endpoints assessed clinical remission (rectal bleeding and stool frequency subscores = 0), endoscopic remission (mucosal appearance subscore = 0) and histological healing (histological activity grade = 0, as assessed via central reading). Missing data were handled using a worst case imputation scheme, in which patients with missing data were considered non-responders. Adverse events (AEs) were assessed throughout the study. Of 510 patients enrolled, 458 (230 B-MMX, 228 PBO) were included in the intent-to-treat population (46% female, mean age: 44.5), which excluded patients with normal baseline mucosal histology or infectious colitis. Combined clinical and endoscopic remission was achieved in a greater percentage of B-MMX-treated patients than PBO-treated patients (13% versus 7.5%, P = 0.0488, worst case analysis). This treatment effect was driven primarily by the mucosal appearance subscore. On this measure, a greater percentage of B-MMX-treated patients than PBO-treated patients achieved a score of 0 (20% versus 12.3%, P = 0.0248), indicative of endoscopic remission. B-MMX also induced histological healing in a greater percentage of patients than placebo (27% versus 17.5%, P = 0.0155). Overall, 31.8% and 27.1% of patients treated with B-MMX or placebo reported an AE, and the majority were mild or moderate in severity. Study discontinuation due to AEs occurred in 4.7% and 3.5% of the B-MMX and placebo groups, respectively. In patients experiencing an active flare of UC despite baseline oral 5-ASA therapy, adding B-MMX 9 mg was significantly more effective than placebo at inducing combined clinical and endoscopic remission as well as histological healing. B-MMX was generally well-tolerated when given in combination with an oral 5-ASA.