Extended-release Capsules Research Articles

An Open-Label Extension Study Assessing the Long-Term Safety and Efficacy of Viloxazine Extended-Release Capsules in Adults with Attention-Deficit/Hyperactivity Disorder.

Viloxazine ER (extended-release capsules; Qelbree®) is a nonstimulant medication that has been approved by the United States Food and Drug Administration (FDA) for treatment of attention-deficit/hyperactivity disorder (ADHD) in children (> 6 years old) and adults. This phase 3 open-label extension to a pivotal phase 3, double-blind trial evaluated the long-term safety and continued efficacy of viloxazine ER in adults with ADHD. This was a multicenter, flexible-dose, open-label extension to a phase III, double-blind, placebo-controlled trial (NCT04016779). Viloxazine ER was initiated at 200 mg/day and adjusted (between 200 and 600 mg/day) to achieve optimal efficacy and tolerability. Trial enrollment was halted temporarily (24 March 2020 to 23 July 2020) due to the coronavirus disease 2019 (COVID-19) pandemic. Participants completing double-blind treatment during that time were offered delayed enrollment upon trial requalification. Safety outcomes were the primary objectives. Secondary objectives were efficacy outcomes, including the ADHD Investigator Symptom Rating Scale (AISRS), and were assessed relative to double-blind baseline (or trial re-entry baseline for those whose enrollment was delayed by the COVID-19 pandemic). Overall, 159 participants (133 immediate and 26 delayed rollover) received viloxazine ER, with a mean exposure of 265 ± 254.9 days. Adverse events (AEs) included (> 10% incidence) insomnia (13.8%), nausea (13.8%), headache (10.7%), and fatigue (10.1%). AEs led to discontinuation for 17.6% of participants [most commonly insomnia (2.5%), nausea (2.5%), and fatigue (1.9%)]. AISRS total score [baseline mean ± standard deviation (SD): 37.9 ± 6.3] improved by the first follow-up visit (-11.4 ± 9.5; week 2) with continued improvement at subsequent visits (last on-study visit: -18.2 ± 11.54). Similar patterns of improvement were seen for other measures of efficacy, including quality of life and executive function. Following initial dose optimization, most participants (73%) used viloxazine ER doses ≥ 400 mg/day, with 36% using doses of 600 mg/day. Long-term viloxazine ER use was well tolerated, with no new long-term safety findings. Improvements in ADHD symptoms and associated measures were sustained throughout trial participation. In total, 73% percent of adult participants in this long-term study used viloxazine ER doses of 400 mg or more during maintenance treatment. Clinicaltrials.gov Identifier: NCT04143217.

Stability-Indicating UV-HPLC Approaches to Estimate Trimetazidine Dihydrochloride in Extended Release Capsule Formulations

Stability-Indicating UV-HPLC Approaches to Estimate Trimetazidine Dihydrochloride in Extended Release Capsule Formulations

Effect of postprandial gastric conditions on in vitro drug release from modified release mesalamine formulations

The effect of gastric prandial conditions on in vitro drug release from oral, locally acting, colon-targeted, mesalamine formulations has not been previously evaluated. In vitro dissolution of four mesalamine formulations were investigated using a USP II paddle apparatus. Fed gastric conditions were simulated under three consecutive phases of milk/buffer at different ratios to simulate changes in physicochemical, gastric composition during food digestion. Drug release was not observed from enteric coated preparations in the fasted state. Under simulative postprandial gastric conditions, however, drug release from Apriso® extended release (ER) capsules was 19 ± 4.7 %. As for Lialda® delayed release (DR) tablets, following two hours of exposure to simulative ileo-colonic media comprising bicarbonate buffer, drug release in the fed and fasted states was 55.7 ± 22.4 % and 12.4 ± 6.4 %, respectively. Significant differences in in vitro dissolution profiles were not observed between fasted and fed conditions for Pentasa® ER capsules and Asacol® HD DR tablets. Published pharmacokinetic data for Apriso and Lialda show higher systemic absorption of mesalamine in fed compared to fasted individuals. Our in vitro data is consistent with these pharmacokinetic findings since fed conditions may give rise to a higher extent of proximal drug release and therefore greater systemic absorption. Furthermore, extent of systemic exposure to mesalamine from Pentasa and Asacol was found not to be affected by food intake. In vitro dissolution studies simulating the gastric prandial state can possibly predict the impact of food on drug release from delayed and sustained release, locally acting formulations.

Pharmacokinetic Bioequivalence and Safety Assessment of Two Venlafaxine Hydrochloride Extended-Release Capsules in Healthy Chinese Subjects Under Fed Conditions: A Randomized, Open-Label, Single-Dose, Crossover Study.

Venlafaxine hydrochloride extended-release (ER) capsules are commonly used to treat depression and anxiety disorders. Evaluation of the bioequivalence of generic formulations with reference products is essential to ensure therapeutic equivalence. The objective of this study was to evaluate the bioequivalence, safety, and tolerability of Chinese-manufactured venlafaxine hydrochloride extended-release capsules compared with USA-manufactured EFFEXOR® XR in healthy Chinese volunteers under fed conditions. A randomized, open-label, single-dose, crossover study was conducted. Subjects were randomly assigned to receive the test formulation (one 150-mg ER capsule manufactured in China) or the reference formulation (one 150-mg ER capsule manufactured in the USA). The bioequivalence of the two drugs was assessed using the area under the plasma concentration-time curve from time zero to the last sampling time (AUC0-t) and the maximum observed concentration (Cmax). A total of 28 subjects were enrolled and randomly assigned to receive a single dose of either the test or reference capsule. All the subjects completed the study and were included in the pharmacokinetic (PK) and safety analyses. The mean AUC0-t and Cmax of venlafaxine and its active metabolite O-desmethylvenlafaxine were comparable between the test and reference products with both parameters close to 100% and the corresponding 90% confidence intervals within the specified 80-125% bioequivalence boundary. Safety was also assessed between the two products and all adverse events (AEs) in this study were mild in severity. Both the test and reference venlafaxine hydrochloride ER capsules were bioequivalent and showed a similar safety and tolerability profile in the population studied. This study was registered at the Drug Clinical Trial Registration and Information Publicity Platform ( http://www.chinadrugtrials.org.cn/index.html ) with registration number CTR20211243, date: June 1, 2021.

The effect of mebeverine in extended-release capsules on intestinal motor function in patients with functional gastrointestinal pathology

Purpose of the study. Evaluation of the clinical effectiveness of combination therapy for FGID with overlap syndrome – gastroesophageal reflux disease (GERD), functional dyspepsia (FD) and irritable bowel syndrome (IBS) using the PPI omeprazole and the myotropic antispasmodic mebeverine hydrochloride in extended-release capsules (Meberin ML, Micro Labs Limited, India) on clinical manifestations and motor-evacuation function of the gastrointestinal tract in patients with FGID with overlap syndrome – GERD, FD with gastric hypersecretion and IBS.Materials and methods. We examined 27 patients with FGID with overlap syndrome of GERD, FD with gastric hypersecretion of hydrochloric acid and IBS.Results and conclusion. It has been established that combination therapy with these drugs for two weeks in 97 % of cases eliminates the clinical symptoms of the syndromes, improves the quality of life of patients, normalizes intestinal motility and myoelectric activity of the gastrointestinal tract.

Unexplained recurrent high fever observed in a depressed adolescent

BackgroundDepressive episodes in adolescents are often accompanied by various physical symptoms, but few studies have explored the association between depression and fever, This case study is the first to report the relationship between unexplained recurrent high fever and depression.Case presentationH is a 15 year old adolescent female currently in junior year. 2 + months ago, H gradually felt depressed after a class change. Around the time, the patient suddenly developed chills with no obvious trigger and fever. H was treated with anti-infective and anti-viral treatments all of which did not show significant improvement. No significant abnormality was seen in any of the related examinations. Considering that the patient’s anxiety, depression and somatic symptoms were obvious during the course of the disease, she was given venlafaxine hydrochloride extended-release capsule 75 mg/d; tandospirone citrate capsule 10 mg Bid; alprazolam tablets 0.4 mg qn to improve mood and sleep; supplemented with transcranial repetitive magnetic stimulation therapy 2 times/d; visible light therapy 1 time/d and psychological counseling once. Over the 6 days of treatment, the patient’s body temperature gradually returned to the normal range and her mood improved significantly.ConclusionDepression should be considered a potential cause of unexplained recurrent fevers in adolescents, even when the temperature is significantly outside the normal range.

Impact of Viloxazine Extended-Release Capsules (Qelbree®) on Select Cytochrome P450 Enzyme Activity and Evaluation of CYP2D6 Genetic Polymorphisms on Viloxazine Pharmacokinetics.

Viloxazine extended-release (ER) [Qelbree®] is a nonstimulant attention-deficit/hyperactivity disorder (ADHD) treatment. In vitro studies suggested potential for viloxazine to inhibit cytochrome450 (CYP) enzymes 1A2, 2B6, 2D6 and 3A4. This clinical study therefore evaluated viloxazine ER effects on index substrates for CYP1A2, 2D6, and 3A4, and secondarily evaluated the impact of CYP2D6 polymorphisms on viloxazine pharmacokinetics. Thirty-seven healthy subjects received a modified Cooperstown cocktail (MCC; caffeine 200mg, dextromethorphan 30mg, midazolam 0.025 mg/kg) on Day 1, viloxazine ER 900 mg/day on Days 3-5, and a combination of viloxazine ER 900 mg and MCC on Day 6. Viloxazine ER effects on MCC substrates were evaluated using analysis of variance. The impact of CYP2D6 genetic polymorphisms on steady-state viloxazine plasma concentrations was evaluated using Student's t test assessing pharmacokinetic parameter differences between poor versus extensive metabolizers. The least squares geometric mean ratio [GMR%] (90% CI) of MCC substrate + viloxazine ER/MCC substrate alone for caffeine maximum concentration (Cmax), area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUCt), and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC∞) was 99.11 (95.84-102.49), 436.15 (398.87-476.92), and 583.35 (262.41-1296.80), respectively; 150.76 (126.03-180.35), 185.76 (155.01-222.61), and 189.71 (160.37-224.42) for dextromethorphan Cmax, AUCt, and AUC∞, respectively; and 112.81 (104.71-121.54), 167.56 (153.05-183.45), and 168.91 (154.38-184.80) for midazolam Cmax, AUCt, and AUC∞, respectively. At steady state, viloxazine least squares GMR (90% CI) for poor/extensive CYP2D6 metabolizers were Cmax 120.70 (102.33-142.37) and area under the plasme concentration-time curve from time 0 to 24 hours (AUC0-24 125.66 (105.36-149.87)). Viloxazine ER is a strong CYP1A2 inhibitor and a weak CYP2D6 and CYP3A4 inhibitor. CYP2D6 polymorphisms did not meaningfully alter the viloxazine ER pharmacokinetic profile.

Lacosamide extended-release capsules are bioequivalent to lacosamide immediate-release tablets: Pharmacokinetic observations and simulations

ObjectivesAssess the bioequivalence of lacosamide extended-release (XR) capsules and immediate-release (IR) tablets and answer real-world clinical questions regarding the use of lacosamide XR. MethodsAn open-label, randomized, two-treatment, two-sequence, oral comparative bioavailability study was conducted to assess the bioequivalence of two lacosamide formulations. Participants were randomized 1:1 to receive lacosamide XR capsules (400 mg once-daily) or IR tablets (200 mg twice-daily) in 1 of 2 sequences over 7-day periods. Primary outcome was the area under the lacosamide concentration-time curve over 24 h at steady-state (AUC0-τ,ss). Secondary outcomes were maximum (Cmax,ss) and minimum concentrations at steady-state (Cmin,ss). Bioequivalence was established when 90% confidence intervals (CIs) for geometric least square means ratios (GLSMs) were between 80% and 125%. Adverse events (AEs) and other safety outcomes were also assessed. Pharmacokinetic simulations, including adherent and partially adherent dosing scenarios with XR and IR formulations, modeled the clinical use of lacosamide XR. ResultsThirty-five healthy adult males were enrolled in the bioequivalence study. After 7 days of study drug, mean AUC0-τ,ss, Cmax,ss, and Cmin,ss values were similar between XR and IR formulations; all 90% CIs for GLSMs were between 80% and 125%. AEs were mild and no serious AEs or other clinically significant safety findings were observed. Pharmacokinetic simulations suggested that partial adherence affected formulations similarly; and the best strategy for switching formulations was to take the morning lacosamide IR dose followed by the evening lacosamide XR dose, as this resulted in the most consistent lacosamide plasma concentrations. ConclusionsOnce-daily lacosamide XR capsules were bioequivalent to twice-daily lacosamide IR tablets. Pharmacokinetic simulations indicated lacosamide XR and IR formulations were similarly affected by partial adherence, though once-daily dosing with lacosamide XR may offer clinical advantages, and formulations can be easily switched. These results support the use of lacosamide XR capsules as a once-daily alternative to lacosamide IR tablets.

Viloxazine: A New Non-Stimulant Treatment for Attention-Deficit/Hyperactivity Disorder (ADHD)


 IntroductionViloxazine is an antidepressant medication classified as an SNRI (serotonin and norepinephrine reuptake inhibitor). In April 2021, it received FDA approval in the United States for the treatment of ADHD in children aged 6 to 17. Subsequently, in May 2022, it was also approved for the treatment of adults with ADHD [1]. Viloxazine, available in extended-release capsules, represents novel non-stimulant medication option for patients with ADHD.Aim of the studyOur aim was to review the viloxazine in the fields of ADHD treatment, summarize current knowledge and analyze the first treatment results.
 
 
 Methods and materialsA review of the literature available in the PubMed database was performed, using the key words: „Viloxazine" ; „ADHD treatment" ; „ADHD”, „attention deficit hyperactivity disorder”, „attention deficit hyperactivity disorder treatment”; „ADHD non-stimulant treatment”; „ADHD non-stimulant”; „ADHD non-stimulant drugs”, „SPN-812”
 
 
 ConclusionViloxazine presents a promising non-stimulant alternative for ADHD treatment with more favorable pharmacokinetics, new way of possible administration and fewer adverse effects, particularly within the cardiovascular system, than other available ADHD medication options. While these findings are encouraging, continual research is imperative to establish the long-term safety profile.

Design and Development of Cyclobenzaprine HCl Sustained Release Pellets by Wurster Coating Method

Background Cyclobenzaprine is structurally related to the tricyclic antidepressants. Cyclobenzaprine may be slightly different than the other musculoskeletal agents because it is believed to decrease skeletal muscle spasm through atropine-like effects directly on the cerebral motor neurons. Cyclobenzaprine may also have analgesic properties that may add to its therapeutic effects. This research encompasses all oral dosage forms and strengths.Objective Even though Cyclobenzaprine HCl tablets are available in market we can formulate pellets because pellets demonstrate good flow properties in the intestine and require less cost for the production of formulation. The main aim of the present study was to produce the extended-release Cyclobenzaprine HCl capsules of 16 hours release to reduce the dosing frequency as a skeletal muscle relaxant when compared with the innovator drug Amrix. Cyclobenzaprine HCL is a muscle relaxant that works on the central nervous system by altering the signals from the brain causing muscle to tighten.Methodology Cyclobenzaprine hydrochloride sustained release SR pellets were prepared by Wurster coating method using different excipients and polymers to release the drug slowly for an extended period of time. The method of preparation of Cyclobenzaprine hydrochloride SR pellets involves two steps drug coating and polymer coating. In the drug coating process the drug was coated in a suspension form on the dummy pellets dried and sieved. Drug coated pellets were coated with SR polymer to form SR pellets. These SR pellets were dried sieved and sent for quality control.Results After 12th hour the percentage drug release from the formulations were 89.6 87.4 85.8 85.6 83.9 75.1 for the formulation containing EC N14 2.5 5 7.5 and EC N50 10 12.5 and 15 respectively. The dissolution profile was shown and the mean dissolution time of pellets was noted to be 6.19 hrs. Formulation F5 was identified to be the most superior formulation.Conclusion Accordingly it can be concluded that the F5 12.5 ww EC N50 is a robust one and the performance is less likely to be affected by the various factors studied. The formulations were subjected to stability studies according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use ICH guidelines for three months which demonstrated all the tested formulations to be stable.

Formulation development and characterization of galantamine hydrobromide extended-release capsules (8mg)

The aim of the present work is to develop extended-release capsules of Galantamine HBr (8mg) and compare them with the reference listed drug (Reminyl or Razadyne). The capsules were prepared using Pelletization technique and evaluated for preformulation characteristics, physical, and chemical parameters. The In-vitro dissolution studies were conducted using USP type II (paddle apparatus) in 900 ml of pH 6.5 phosphate buffer. Among all the formulations, F7 was found to be pharmaceutically equivalent to reference listed drug due to its similarity factor (f2= 96) in drug release profile. The F7 formulation was loaded for stability study and no change was observed, which indicates that the optimized F7 formulation was stable.

Retrospective analysis of the biopharmaceutics characteristics of solid oral Modified-Release drug products in approved US FDA NDAs designated as Extended-Release or Delayed-Release formulations

BackgroundModified Release (MR) orally administered drugs products [Extended-Release (ER) and Delayed-Release (DR)] differ from Immediate-Release (IR) drug products in their drug release site and/or rate to offer therapeutic advantages. It is important to understand the biopharmaceutics factors that determine how a drug works in the gastrointestinal tract and the various pharmacokinetic properties that determine a drug’s rate of absorption and release in the human body. To better understand the biopharmaceutics characteristics of ER and DR drug products, this study retrospectively analyzed submissions approved by the US Food and Drug Administration (FDA), from 2001 to 2021, and their corresponding review documents. This review work is expected to enhance the readers’ understanding regarding the biopharmaceutics properties that supported approval of these products’ ER claims, as per 21 CFR 320.25(f), and DR claims. MethodsA comprehensive search was conducted using the FDA’s internal New Drug Application (NDA) database for ER and DR oral drug products approved between 2001 and 2021. The search yielded 87 ER applications (23 ER capsules and 64 ER tablets) and 21 DR applications (10 DR capsules, 11 DR tablets) for which electronic records were accessible. These products were analyzed for overall drug product design, dosing frequency compared to the reference (if applicable), degree of fluctuation, dissolution method, and alcohol dose-dumping. ResultsOut of 87 total applications for ER drug products that were assessed, 62% of the ER tablets contained a polymer matrix formulation, and hypromellose (HPMC) was used in 50% of these products. 52% of the ER capsules consisted of polymer beads while about half of the DR drug products contained a non-bead formulation with a combination of polymers. The majority of ER drug products were found to have a reduction in dosing frequency and a decrease in the degree of fluctuation when compared to the IR reference product. The 13 ER drug products that exhibited an increase in degree of fluctuation exhibited general and pharmacodynamic benefits, such as reduced dosing frequency and reduced pill burden. The majority of DR formulations were developed to prevent drug degradation in the stomach, followed by to decrease potential stomach irritation, and lastly for localized release in the colon. The majority of ER drug products had 1:1 ratios of dissolution duration compared to dosing frequency (i.e., the majority of ER drug products had a dissolution duration of 24 h and were dosed every 24 h while those with a dissolution duration of 12 h were dosed every 12 h). The majority of ER applications had single-stage dissolution methods while most DR drug products used biphasic dissolution methods. All of the DR dissolution methods incorporated an acid stage of 2 h and a buffer stage with various timeframes. 53% the DR drug products had a ratio of dissolution duration to dosing frequency of 1:4 (e.g. a dissolution duration of 2 h to a dosing frequency of 8 h) or 1:8 (e.g. a dissolution duration of 2 h to a dosing frequency of 16 h). Of the ER tablets and DR drug products, 72% exhibited no alcohol dose-dumping under in vitro testing conditions. ER capsules, however, did not yield similar results—most of which exhibited alcohol induced dose-dumping. Alcohol dose dumping was mitigated by either in vivo studies or warnings on the drug product label. ConclusionThe results of this study help the reader understand the design, characteristics, and pharmacological advantages of the ER and DR drug products for patient benefit; as well as the regulations governing the FDA’s assessment of ER claims.

A convolution-based in vitro-in vivo correlation model for methylphenidate hydrochloride delayed-release and extended-release capsule.

Delayed-release and extended-release methylphenidate hydrochloride (JORNAY PM®) is a novel capsule formulation of methylphenidate hydrochloride, used to treat attention deficit hyperactivity disorder in patients 6 years and older. In this paper, we develop a Level A invitro-in vivo correlation (IVIVC) model for extended-release methylphenidate hydrochloride to support post-approval manufacturing changes by evaluating a point-to-point correlation between the fraction of drug dissolved invitro and the fraction of drug absorbed invivo. Dissolution data from an invitro study of three different release formulations: fast, medium, and slow, and pharmacokinetic data from two invivo studies were used to develop an IVIVC model using a convolution-based approach. The time-course of the drug concentration resulting from an arbitrary dose was considered as a function of the invivo drug absorption and the disposition and elimination processes defined by the unit impulse response function using the convolution integral. An IVIVC was incorporated in the model due to the temporal difference seen in the scatterplots of the estimated fraction of drug absorbed invivo and the fraction of drug dissolved invitro and Levy plots. Finally, the IVIVC model was subjected to evaluation of internal predictability. This IVIVC model can be used to predict invivo profiles for different invitro profiles of extended-release methylphenidate hydrochloride.

Oxycodone Extended-Release Capsule Utilization for Pain Management in a Cancer Palliative Care Clinic: A Retrospective Review

Xtampza ER™, an oxycodone extended-release capsule (OERC), was the first long-acting opioid to feature abuse-deterrent properties and various routes of administration without pharmacokinetic alterations. The primary objective of this study was to evaluate changes in reported pain scores after initiation of or rotation to OERC from a previous opioid. Baseline scores were from patients’ outpatient visits immediately before starting OERC and were compared to those at the next two follow-up visits. Secondary objectives identified variables that influenced pain scores. Methods included screening for cancer patients with outpatient OERC prescriptions seen in the palliative care clinic. Eighty-two charts were reviewed with 66 included. Overall mean pain scores at both follow-ups were lower than those at baseline (–0.7 ± 2.1; −1.1 ± 2.4). Results were statistically significant between first and second-reported pain scores versus baseline (p = 0.009; 0.012) but clinically insignificant, defined as a ≥ 2-point change in numeric pain scores. Most patients discontinued OERC at the first or second follow-up (35; 53%), and 12.1% of patients who started OERC were prescribed OERC at the end of the study. There were no significant variables identified to influence pain scores either statistically or clinically. Further studies are needed to determine the long-term efficacy and safety in cancer palliative-care patients.

The effects of once-daily opicapone 50 mg on the pharmacokinetics of levodopa administered as carbidopa/levodopa extended-release capsules: an open-label study

The effects of once-daily opicapone 50 mg on the pharmacokinetics of levodopa administered as carbidopa/levodopa extended-release capsules: an open-label study

Evaluating the Release of Different Commercial Orally Modified Niacin Formulations In Vitro.

To evaluate the release profile of different modified-release oral formulations of niacin, such as immediate-release (IR) powder and tablets, timed-release (TR) caplets, extended-release (ER) capsules, and controlled-release (CR) tablets, to assure their defined release pattern and correlate this release with their matrix polymers. Niacin is used to manage hyperlipidemia by reducing cutaneous flushing and hepatotoxicity adverse events. The release profiles of different types of modified-release dosage forms depend on the types of coating materials (polymers) used in the matrix formation. Although different types of niacin formulations exist, none of the niacin dissolution profiles have been evaluated and compared in the literature. Four commercial orally modified-release niacin brands were collected from a local CVS pharmacy retail store, in Miami, FL, USA. The in vitro release study was conducted in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF) conditions. The results of the release patterns of four niacin-modified dosage forms (IR, ER, TR, and CR) were aligned with their release definitions. However, the CR dosage form did not follow an ideal release pattern. The release rate of niacin in vitro was pH dependent, which was confirmed by the similarity factor (f2) results. All the f2 comparison values were below 50 in both the SIF and SGF media, while all the comparisons were below the f2 values for all brands in the SIF media.

Methylphenidate Superior Efficacy Dosing Schedule: Three Hour Schedule for Immediate Release Tablets and Six Hour Schedule for Extended-Release Capsules

Background: Methylphenidate Hydrochloride is used mostly for treating Attention Deficit and Hyperactivity Disorder and Narcolepsy. It is available in Immediate Release tablets, liquids, extended-release doses, and transdermal patches. Clinicians instruct patients to take Immediate Release tablets four hours apart or eight to nine hours after an extended-release dose. Four-hour dosing has been used for decades while many patients complain of a “roller coaster” of symptoms stopping and returning several times each day. Four-hour dosing is inaccurate because Immediate Release tablets are effective for two to three hours. Methods: The “roller coaster” was addressed with information from a 2014 to 2022 research program and from analyzing over 400 Dopamine deficiency articles. Results: The four-hour Immediate Release schedule and the eight-to-nine-hour extended-release schedule are inaccurate for research and treatment. Four-hour dosing causes two hours of non-efficacy during transitions between doses. The eight-to-nine-hour schedule causes three to four hours of non-efficacy during transitions. Three-hour and six-hour schedules sustain efficacy across and between sequential doses. Conclusion: Under four-hour dosing, soon after hour-three a patient’s plasma concentration drops below and stays below the efficacy threshold for an hour and forty-five minutes. The loss of efficacy occurs during every transition from one dose to the next. Under four-hour dosing, patients who take four sequential doses experience 205 minutes of loss of efficacy every two hours three times every day, totaling 615 minutes per day. To the best knowledge of this author, he is the first person to find three-hour dosing stops the roller coaster. Efficacy occurs during transitions because dose-onset adds plasma concentration at the same rate that termination loses plasma concentration. Sequential doses taken at hour-3 combine into a level that stays above the efficacy threshold. When sequential doses are taken sometime after hour-3, the termination-dose drops below the efficacy-threshold and the sequential onset-dose does not create enough plasma concentration to bring a terminating plasma concentration to a higher level. Proper timing is critical for patients to receive high quality benefits of Methylphenidate. Three-hour dosing matches the biochemistry of Methylphenidate and enables high quality benefits.

Preparation of Sustained Release Formulation of Verapamil Hydrochloride Using Ion Exchange Resins.

The purpose of this investigation was to formulate and evaluate the interaction between cation exchange resins and verapamil hydrochloride. The uptake studies were conducted using the rotating bottle apparatus. The Langmuir-like equation was applied to the experimental data and the maximum drug loading was determined from the Langmuir-like parameters. The drug-resin complexes were evaluated using XRD, SEM, and particle size analysis. Release studies were performed using USP dissolution apparatus 2. The resin with the lowest percentage of cross-linking had the highest uptake capacity. The percent increase in particle size due to complexation was found to be associated with drug loading; the highest drug loading had the highest increase in particle size. The X-ray diffraction patterns of the resins and the drug-resin complexes showed that they were both amorphous. The maximum drug release was approximately 40% when conventional dissolution testing was used. Results showed that sink conditions could not be maintained using conventional dissolution methods. Maximum drug release increased dramatically by increasing the volume of samples withdrawn and fresh dissolution medium added. Excellent correlation was obtained between sample volume and drug release rate with an R-value of 0.988. Particle diffusion-controlled model and film diffusion-controlled model were both applied to the experimental data. The results indicated that the rate-limiting step is the diffusion of the exchanging cations through the liquid film. The modified release formulation was prepared successfully and correlated very well with the USP monograph for verapamil hydrochloride extended release capsules.

Adult attention deficit hyperactivity disorder: a comprehensive review.

Attention deficit hyperactivity disorder (ADHD) is a common childhood disorder, with only 2-3% prevalence into adulthood. The epidemiology and proposed causes of ADHD are multifactorial, including genetic, prenatal and environmental influences. The diagnosis of ADHD is often complicated by masking coping mechanisms, an overlap of symptoms with other, more commonly diagnosed disorders. Traditionally, it has been treated with stimulant medications. Non-stimulant options often target norepinephrine and dopamine regulation and are preferred in cases of comorbid substance use disorder, anxiety and other complicating factors, due to an improved side-effect profile and patient preference. They include atomoxetine and viloxazine. The latter, Viloxazine, in the form of extended-release capsules, is the first novel, non-stimulant option approved for adults with ADHD, in the past two decades. Its therapeutic effects are predominantly produced by its action as a norepinephrine reuptake inhibitor and may also modulate the serotonergic system. Viloxazine is relatively safe and effective in treating other disorders such as depression, anxiety, epilepsy and substance use disorder. Its pharmacokinetics includes metabolization by CYP enzymes. As antiepileptics inhibit CYP1A2, therefore, a special consideration would be needed, when co-administering with anti-epileptic drugs. Similarly, individuals with liver or cardiovascular disease and a personal or family history of bipolar disorder require close monitoring, while on this medication. A thorough review of the history, mechanism of action, pharmacokinetics and drug-drug interactions has been presented here, with special attention on treatment in adults with comorbid conditions. This study conducted an all-language literature search on Medline, Cochrane, Embase, and Google Scholar until December 2022. The following search strings and Medical Subject Headings (MeSH) terms were used: "Viloxazine," "ADHD," "Stimulants," and "adult ADHD." We explored the literature on the growing knowledge of Viloxazine. A thorough review of the history, mechanism of action, pharmacokinetics, and drug-drug interactions are reviewed here with special attention on treatment in adults with comorbid conditions.

Effects of Viloxazine ER (Qelbree®) on Weight and Height Trajectories: Interim Results From a Long-term, Open-Label Extension Trial in Pediatric ADHD

AbstractIntroductionStimulant medications and the norepinephrine reuptake inhibitor, atomoxetine, contain warnings regarding potential for slowing of growth (weight and height) in children and recommend monitoring of growth when using these medications for pediatric ADHD. Viloxazine ER (viloxazine extended-release capsules; Qelbree®), is a nonstimulant medication, FDA-approved for ADHD in adults and children (≥6 years of age). Viloxazine ER has pharmacologic differences from other approved ADHD medications and might not affect growth in the same manner as other therapies. A safety analysis was conducted to determine viloxazine ER effects on growth and weight trajectories in pediatric ADHD patients with long-term use.MethodsData were evaluated from five DBPC, phase 2 and 3 clinical trials and an ongoing long-term, open-label extension (OLE) trial (NCT02736656). Viloxazine ER doses during the trials ranged from 100–400 mg/day (age 6–11 yrs) or 100–600 mg/day (age 12–17 yrs). Height and weight were evaluated pretreatment in both DB and OLE every 3 months during the OLE, and converted into percentile values and corresponding z-scores using Centers for Disease Control (CDC) normal growth curves to evaluate growth trajectories. The incidence of weight- and growth-related adverse events (AEs) terms were also evaluated.ResultsAt the time of data cut (31 July 2019), 1097 subjects had received at least one dose of viloxazine ER in the OLE (66% male, mean (SD) age 10.8 (3.06), 59% age 6–11, mean (SD) BMI 18.8 (3.42) kg/m2, height 146.7 (17.46) cm, weight 42.1 (16.01) kg. During the OLE, mean (SE) z-scores for height and weight were between -1 and 1 for all timepoints, indicating growth measures within a normal range compared with expected values. Similar results were observed when weight and height were analyzed by sex and by age categories. Growth data were available for 338 subjects at 12 months. Among these subjects, the mean (SD) change from baseline in weight-for-age z-score was -0.2 (0.5) and height-for-age z-score was -0.14 (1.1). Adverse events relevant to weight and growth in the DB trials (incidence ≥ 1%) included (viloxazine ER [100–600 mg/day] n=1117 vs. placebo n=487): decreased appetite (8.1% vs. 0.8%), nausea (5.1% vs. 2.7%), vomiting (4.7% vs. 1.4%), weight increase (0.4% vs. 1.2%) and weight decrease (1.3% vs. 0.4%), and increased appetite (0.2% vs. 1.2%). During the OLE weight-and growth-related AEs reported for ≥ 1% of subjects were: decreased appetite 5.8%, vomiting 2.7%, nausea 2.4%, weight decreased 2.3%, and weight increased 2.0%.ConclusionsOver time, pediatric subjects taking viloxazine ER, on average, maintained normal weight and height relative to the CDC’s child growth charts. However, because Qelbree may affect weight, it is recommended that healthcare providers check patient weight before starting and while using viloxazine ER.FundingSupernus Pharmaceuticals, Inc.