Sustained-Release Bupropion Overdose: A Case Report

Bupropion is an atypical antidepressant with a unique aminoketone structure similar to amphetamines. A narrow therapeutic margin is evident from observational studies that show seizure activity with doses of 400-600 mg or higher. A 38-year old woman took an overdose of 6 grams of bupropion with 110 grams of alcohol. She presented to the Emergency Department with agitation, visual hallucinations and myoclonus of the upper limbs; eyes spontaneously open with isochoric and light reactive pupils with horizontal nystagmus; afebrile, normotensive (121/63 mm Hg) and tachycardic (120 beats/minute). The electrocardiogram revealed a sinus tachycardia with prolonged QT interval (QT/QTc: 0.46/ 0.537) and a QRS complex length in the upper limit of normal. Arterial blood gases revealed metabolic acidosis (pH = 7.16) with increased anion-gap (value=18). She developed mal epilepticus needing thiopental induced coma and Intensive Care Unit (ICU) admission. She suffered prolonged symptoms including seizures before fully recovering. The narrow therapeutic range and the increasing use in the treatment of smoking cessation boosted the number of intentional and unintentional poisoning by this drug. Previous reports of bupropion overdose almost all involve the immediate release formulation. There are some reports of overdose with sustained-release formulation, but there is limited information on its spectrum of toxicity

Development and optimization of a novel sustained-release dextran tablet formulation for propranolol hydrochloride

A novel oral controlled delivery system for propranolol hydrochloride (PPL) was developed and optimized. The in vitro dissolution profiles of sustained-release matrix tablets of racemic PPL were determined and compared with the United States Pharmacopeia (USP) tolerance specifications for Propranolol Hydrochloride Extended-Release Capsules. The influence of matrix forming agents (native dextran, hydroxypropyl methylcellulose (HPMC), cetyl alcohol) and binary mixtures of them on PPL release in vitro was investigated. A central composite design was applied to the optimization of a sustained-release tablet formulation. The sustained-release matrix tablets with good physical, mechanical and technological properties were obtained with a matrix excipient:PPL ratio of 60:40 (w/w), with a dextran:HPMC ratio of 4:1 (w/w) and with a cetyl alcohol amount of 15% (w/w). A comparative kinetic study of the present matrix tablets and commercial SUMIAL RETARD capsules (Spain) was established. The value for the similarity factor (f2 = 69.6) suggested that the dissolution profile of the present two sustained-release oral dosage forms are similar. Higuchi (diffusion) and Hixon–Crowell (erosion) kinetic profiles were achieved and this codependent mechanism of drug release was established

Wurster fluidised bed coating of microparticles: Towards scalable production of oral sustained-release liquid medicines for patients with swallowing difficulties

© 2019 The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Suspension of microparticles in an easy-to-swallow liquid is one approach to develop sustained-release formulations for children and patients with swallowing difficulties. However, to date production of sustained-release microparticles at the industrial scale has proven to be challenging. The aim of this investigation was to develop an innovative concept in coating sustained-release microparticles using industrial scalable Wurster fluidised bed to produce oral liquid suspensions. Microcrystalline cellulose cores (particle size < 150 µm) were coated with Eudragit® NM 30 D and Eudragit® RS/RL 30 D aqueous dispersions using a fluidised bed coater. A novel approach of periodic addition of a small quantity (0.1% w/w) of dry powder glidant, magnesium stearate, to the coating chamber via an external port was applied throughout the coating process. This method significantly increased coating production yield from less than 50% to up to 99% compared to conventional coating process without the dry powder glidant. Powder rheology tests showed that dry powder glidants increased the tapped density and decreased the cohesive index of coated microparticles. Reproducible microencapsulation of a highly water-soluble drug, metoprolol succinate, was achieved, yielding coated microparticles less than 200 µm in size with 20-hour sustained drug release, suitable for use in liquid suspensions. The robust, scalable technology presented in this study offers an important solution to the long-standing challenges of formulating sustained-release dosage forms suitable for children and older people with swallowing difficulties.Peer reviewedFinal Published versio

Ionically cross-linked alginate hydrogels as drug delivery systems for analgesics in broiler chickens : thesis presented in partial fulfilment of the requirement for the degree of Masters of Science in Chemistry at Massey University, Palmerston North, Manawatu, New Zealand

Treating birds with analgesic drugs requires continuous injections of near lethal concentrations to maintain the therapeutic dose in the blood plasma. This is due to birds having higher metabolic rates than mammals. Therefore, there is a need to develop drug delivery systems that can control and slow down the release of analgesics in birds. This study was designed to analyse the sustained release of the model analgesics, sodium salicylate and sodium aspirin, from ionically cross-linked alginate hydrogels, in in vitro and in vivo experiments using broiler chickens as the model bird. Analgesic loaded hydrogels separated into two layers, unlike the homogeneous blank hydrogels. This was labelled as the separation effect. Swelling studies indicated the absence of the insoluble cross-linked alginate material in the hydrogels where the separation effect occurred, with most of the hydrogels dissolving back into the medium. The highest equilibrium swelling percentage achieved in the loaded hydrogels was 68 %. In comparison, the highest equilibrium swelling percentage in the blank hydrogels was 622 %. In vitro drug release profiles showed that the hydrogels released up to 100% of the sodium salicylate within 3.33 hours. In contrast, the hydrogels containing sodium aspirin released only 35 % of the encapsulated drug. Hydrogels containing a drug concentration of 150 mg/mL were injected into the model birds at a dose rate of 150 mg/Kg. No chicken reacted negatively to the hydrogel injection. In vivo results indicate sustained release of the model analgesic from the hydrogels compared to the release from the aqueous solutions of the drug. The effective concentration for an analgesic effect of sodium salicylate was maintained by the group injected with an aqueous solution of sodium salicylate 18 hours after the injection. The groups injected with the hydrogel with the maximum calcium chloride content saw the largest sustained release, with the plasma concentration of sodium salicylate remaining over the effective concentration for up to 36 hours after the injection. Keywords: Sodium salicylate, sodium aspirin, hydrogel, analgesia, sustained release, broiler chicken

Continuous direct compression as manufacturing platform for sustained release tablets

This study presents a framework for process and product development on a continuous direct compression manufacturing platform. A challenging sustained release formulation with high content of a poorly flowing low density drug was selected. Two HPMC grades were evaluated as matrix former: standard Methocel CR and directly compressible Methocel DC2. The feeding behavior of each formulation component was investigated by deriving feed factor profiles. The maximum feed factor was used to estimate the drive command and depended strongly upon the density of the material. Furthermore, the shape of the feed factor profile allowed definition of a customized refill regime for each material. Inline NIRs was used to estimate the residence time distribution (RTD) in the mixer and monitor blend uniformity. Tablet content and weight variability were determined as additional measures of mixing performance. For Methocel CR, the best axial mixing (i.e. feeder fluctuation dampening) was achieved when an impeller with high number of radial mixing blades operated at low speed. However, the variability in tablet weight and content uniformity deteriorated under this condition. One can therefore conclude that balancing axial mixing with tablet quality is critical for Methocel CR. However, reformulating with the direct compressible Methocel DC2 as matrix former improved tablet quality vastly. Furthermore, both process and product were significantly more robust to changes in process and design variables. This observation underpins the importance of flowability during continuous blending and die-filling. At the compaction stage, blends with Methocel CR showed better tabletability driven by a higher compressibility as the smaller CR particles have a higher bonding area. However, tablets of similar strength were achieved using Methocel DC2 by targeting equal porosity. Compaction pressure impacted tablet properties and dissolution. Hence controlling thickness during continuous manufacturing of sustained release tablets was crucial to ensure reproducible dissolution. (C) 2017 Elsevier B.V. All rights reserved

Sustained Release of Topical Anesthetics

A composition and method to alleviate oral mucosal discomfort and irritation in an orthodontic patient. A wax matrix containing less that 15% analgesic/anesthetic agent such as benzocaine and excipients enhanced and extended release of the analgesic/anesthetic agent compared to known art formulations. The composition exhibited desirable aesthetic properties, was easy to apply, and the relatively lower concentration of active agent provided enhanced safety

Niacin-induced clotting factor synthesis deficiency with coagulopathy

Although coagulopathy is a well-known complication of severe niacin- induced hepatotoxic reaction, it is not found in patients with minimal aminotransferase level elevations. Three patients with significant clotting factor synthesis deficiency and coagulopathy (prothrombin times, >1.5 times control) from sustained-release niacin had only mild aminotransferase level elevations (1.5 to 2.0 times normal). In each case, protein deficiency, coagulopathy, and aminotransferase level elevation resolved promptly after withdrawal of niacin therapy. In one case, this syndrome recurred after rechallenge with sustained-release niacin, whereas the coagulopathy did not recur in a second patient rechallenged with crystalline niacin. Deficiency in protein synthesis, including coagulation factors, and coagulopathy are unrecognized complications of sustained-release niacin therapy. These cases indicate the need to measure prothrombin times routinely in patients who develop even mild aminotransferase level elevation while receiving sustained- release niacin therapy. These data are important in light of the increasing use of sustained-release niacin in the treatment of patients with lipid disorders

Formulation and Development of Bilayer Floating Tablet of Nifedipine using surface solid dispersion technique

The aim of the present work was to develop formulation of Nifedipine in the form of bilayer floating sustained release tablet. Bilayer consist of a two layers, immediate release layer and second sustained release layer, compressed in single unit dosage form. Immediate release layer contains surface solid dispersion of Nifedipine and Floating sustained release layer also contain surface solid dispersion of Nifedipine by using HPMC K100M and HPMC K15M as sustained release polymer. Nifedipine is an antihypertensive drug. Surface solid dispersion of Nifedipine was prepared by solvent evaporation method with different super disintegrant as a polymer for improvement of solubility resulting in improved bioavailability. In the present study Nifedipine bilayer floating controlled release tablet were prepared with the help of direct compression method, using sodium bicarbonate and citric acid which generate gas upon contact with gastric fluid. Immediate release layer releases the drug immediately and floating sustained release layer floats on gastric fluid for upto12 hours and releases the drug in sustained manner, subsequently it prolongs duration of action. The tablets were evaluated for various physical parameters, buoyancy studies, dissolution studies and drug released mechanisms. The batch number F5 formulation showed minimum disintegration time of immediate release layer (24 sec) and gave maximum swelling index of the sustained release layer (82.8%) and also maximum drug release duration of Nifedipine spread over 12 hours

SUSTAINED RELEASE ITOPRIDE HYDROCHLORIDE MATRIX TABLET

Oral route gets the highest priority for thedelivery of the drug as well as better patient compliance incase of self delivery dosage formulation. The aim ofpresent investigation was undertaken with the objective offormulating sustain release formulation of Itopridehydrochloride for oral drug delivery. Itopride hydrochlorideis highly water soluble prokinetic drug.Hydroxypropylmethylcellulose K4M (lower viscositygrade) and K100M (higher viscosity grade) were used as amatrix forming agents to control the release of drug. HPMCK4M and HPMC K100M were used individually as well asin combination with different proportion in the preparationof the Sustained release formulation. 32 factorial designswere applied to the polymer concentration that affects thedrug release profile. Reduced equation for drug release at2hr,6hr,and10hrwere22 1 2 1 Q 37.644 5.41X 3.25X 2.017X ,26 1 2 1 Q 72.367 8.05X 4.4X 3.75X ,and10 1 1 2 90.844 5.8 2.633 2.8 2 Q X X X Xrespectively. Optimized batch F019 shows good tabletproperties like hardness(7-9kg/cm2), thickness(4.48mm),friability(0.024%),assay(99.3%) and nearly similar drugrelease profile to the targeted reference drug release profileand it was indicated by similarity factor (f2=86.04)