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

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

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 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

Widening use of dexamethasone implant for the treatment of macular edema

Sustained-release intravitreal 0.7 mg dexamethasone (DEX) implant is approved in Europe for the treatment of macular edema related to diabetic retinopathy, branch retinal vein occlusion, central retinal vein occlusion, and non-infectious uveitis. The implant is formulated in a biodegradable copolymer to release the active ingredient within the vitreous chamber for up to 6 months after an intravitreal injection, allowing a prolonged interval of efficacy between injections with a good safety profile. Various other ocular pathologies with inflammatory etio­pathogeneses associated with macular edema have been treated by DEX implant, including neovascular age-related macular degeneration, Irvine–Gass syndrome, vasoproliferative retinal tumors, retinal telangiectasia, Coats’ disease, radiation maculopathy, retinitis pigmentosa, and macular edema secondary to scleral buckling and pars plana vitrectomy. We undertook a review to provide a comprehensive collection of all of the diseases that benefit from the use of the sustained-release DEX implant, alone or in combination with concomitant therapies. A MEDLINE search revealed lack of randomized controlled trials related to these indications. Therefore we included and analyzed all available studies (retrospective and prospective, com­parative and non-comparative, randomized and nonrandomized, single center and multicenter, and case report). There are reports in the literature of the use of DEX implant across a range of macular edema-related pathologies, with their clinical experience supporting the use of DEX implant on a case-by-case basis with the aim of improving patient outcomes in many macular pathologies. As many of the reported macular pathologies are difficult to treat, a new treat­ment option that has a beneficial influence on the clinical course of the disease may be useful in clinical practice

Formulation of Dipyridamole Sustained Release Tablet Using Floating System

Dipyridamole is a drug for prevention of postoperative thromboembolic complication of heart valve replacement and long term therapy of angina&nbsp;pectoris will be well absorbed in stomach. To maintain therapeutic plasma concentration in long time and to increase bioavalaibility is needed a sustained release dosage form having the long residence time in the stomach. The objective of this research was to make floating sustained release tablet of dipyridamole conforming to the requirement that was&nbsp;set up by dipyridamol therapeutic concentration. Tablets were made by wet granulation method using aquadest as a liquid binder, HPMC K4M, Ac-di-sol, Avicel PH 102, talk, and Mg stearat. Dissolution assay was carried out using type 2 release tester at rotation speed of 50 rpm in medium 900 mL HCl 0.1 N at 37 &plusmn; 0.5 &deg;C for 8 hours. The formulation containing of 50 mg dipirydamole, HPMC K4M (30%), Ac-di-sol (20%), Avicel PH 102 (37%), talk (2%), and Mg stearat (1%) released 59.61 &plusmn; 6.73% and 89.34 &plusmn; 5.87% of dipyridamole respectively after 4 and 8 hours that conformed to the requirement

Effects of low dose morphine on perceived sleep quality in patients with refractory breathlessness : a hypothesis generating study

© 2015 Asian Pacific Society of Respirology. Background and objective The management of chronic refractory breathlessness is one of the indications for regular low-dose (≤30 mg/24 h) oral sustained release morphine. Morphine may disrupt sleep in some conditions and improve sleep quality in others. This study aimed to determine any signal of regular, low-dose morphine on perceived sleep disruption due to breathlessness and perceived sleep quality. Methods This is a secondary analysis of data from 38 participants with refractory breathlessness (30 male; 33 with COPD) aged 76 ± 0.9 years who completed a double-blind, randomized, placebo-controlled, cross-over study in which they received 20 mg oral sustained release morphine daily and placebo for 4 days each. Participant ratings of sleep disruption due to breathlessness and perceived sleep quality were obtained daily throughout the 8-day trial. Results Perceived sleep disruption due to breathlessness over the 4-day period ranged between 13% and 32% of participants for placebo and 13% and 26% for morphine, decreasing by each day of the study during the morphine arm. Most participants reported 'very good' or 'quite good' sleep throughout the trial and were less likely to perceive poor sleep quality during the morphine arm (odds ratio = 0.55, 95% confidence interval: 0.34-0.88, P = 0.01). Participants who reported decreased breathlessness during the 4 days on morphine were also likely to report improved sleep quality with morphine (P = 0.039). Conclusion Four days of low-dose morphine improved perceived sleep quality in elderly participants with refractory breathlessness. Regular low-dose morphine targeted to reduce refractory breathlessness may yield associated benefits by reducing sleep disruption and improving sleep quality

An oral multiparticulate, modified-release, hydrocortisone replacement therapy that provides physiological cortisol exposure

Objective It is not possible with current hydrocortisone replacement to mimic the diurnal cortisol profile in patients with adrenal insufficiency. Previous attempts with modified-release technology were unsuccessful. Our objective was to develop hydrocortisone formulations that recreate the diurnal cortisol profile using multiparticulate technology. Design and Measurements Screening by in vitro dissolution profiles, pharmacokinetic (PK) testing in dexamethasone-suppressed dogs and humans, and comparison with a reference population. Setting Field laboratories and clinical research facility. Results Formulations were generated using an enteric (delayed release) design configuration with an extended (sustained release) dissolution profile. In vitro dissolution confirmed delayed and sustained hydrocortisone release. However, in dogs and humans, sustained release resulted in reduced bioavailability. A formulation, DIURF-006, was developed that maintained delayed release but omitted the sustained-release functionality. PK characterization of DIURF-006 showed that, despite absence of a sustained-release component, absorption was sufficiently sustained to deliver extended hydrocortisone absorption. In dexamethasone-suppressed volunteers (n = 16) receiving a twice-daily ‘toothbrush’ regimen (20 mg at 23:00 h and 10 mg at 07:00 h), DIURF-006 gave a similar cortisol profile to physiological cortisol levels: DIURF-006 vs physiological, Geomean AUC 5610 vs 4706 h * nmol/l, Geomean Cmax 665 vs 594 nmol/l and Median Tmax 8·5 h vs clock time 08:12 h for peak cortisol. The relative bioavailability of DIURF-006 vs hydrocortisone was 89%, and cortisol levels increased linearly with doses between 5 and 30 mg. Conclusion A multiparticulate oral hydrocortisone formulation with only an enteric coat provides delayed and sustained absorption and when given in a ‘toothbrush’ regimen provides physiological cortisol exposure