Formulations Sustained-release

Improvements in asthma treatment include the development of more effective, safer formulations of known dmgs. The aerosol adrninistration of P2-agonists or corticosteroids results in a decrease in side effects. Also, the use of reUable sustained release formulations has revolutionized the use of oral xanthines which have a very narrow therapeutic index (see Controlled release technology). For many individuals, asthma symptoms tend to worsen at night and the inhaled bronchodilatots do not usually last through an entire night s sleep (26,27). 

Common side effects of theophylline therapy include headache, dyspepsia, and nausea. More serious side effects such as lethal seizures or cardiac arrythmias can occur if blood levels are too high. Many derivatives of theophylline have been prepared in an effort to discover an analogue without these limitations (60,61). However, the most universal solution has resulted from the development of reHable sustained release formulations. This technology limits the peaks and valleys in semm blood levels that occur with frequent dosing of immediate release formulations. ControUed release addresses the problems inherent in a dmg which is rapidly metabolized but which is toxic at levels ( >20 7g/mL) that are only slightly higher than the therapeutically efficacious ones (10—20 p.g/mL). Furthermore, such once-a-day formulations taken just before bedtime have proven especially beneficial in the control of nocturnal asthma (27,50,62). 

A. Yacobi and E. Halpetin-Walega, eds.. Oral Sustained Release Formulations Design and Evaluation, Pergamon Press, New York, 1988. 

Takahara J, Takayama K, Nagai T. Multi-objective simultaneous optimization technique based on an artificial neural network in sustained release formulations. 

Zupancic Bozic D, Vrecar F, Kozjek F. Optimization of diclofenac sodium dissolution from sustained release formulations using an artificial neural network. Eur... 

Adverse Effects The most common adverse effects are gastrointestinal upset, tremor, and polyuria,30 which are dose-related. Nausea, dyspepsia, and diarrhea can be minimized by coadministration with food, use of sustained-release formulations, and giving smaller doses more frequently to reduce the amount of drug in the gastrointestinal tract at a given time. Tremor is present in up to 50% of patients. In addition to the approaches above, low-dose P-blocker therapy such as propranolol 20 to 60 mg/day often reduces the tremor. 

In addition, biodegradable nanoparticles for sustained release formulations to improve site-specific drug delivery has also been reviewed [98]. 

Infants and children older than 1 year of age are considered to be very efficient metabolizers of drugs and may actually require larger doses than those predicted by weight adjustment of adult doses or shorter dosing intervals [33], On the basis of metabolic activity, sustained-release formulations would appear to be ideal for children 1-10 years old, if bioavailability issues prove not to be problematic. The ability to clear drugs in critically ill children may be severely compromised therefore, dosing in this subgroup of patients requires careful titration [34]. 

Short-acting nifedipine may rarely cause an increase in the frequency, intensity, and duration of angina in association with acute hypotension. This effect may be obviated by using sustained-released formulations of nifedipine or other dihydropyridines. Other side effects of dihydropyridines include dizziness, flushing, headache, gingival hyperplasia, and peripheral edema. Side effects due to vasodilation such as dizziness, flushing, head-... 

Sustained-release formulation available. fiFDA approved for prevention of migraine. cDaily or prolonged use limited by potential toxicity. 

Wilson CG, Washington N, Greaves JL, Kamali F, Rees JA, Sempik AK, Lampard JF. Bimodal release of ibuprofen in a sustained-release formulation—a scintigraphic and pharmacokinetic open study in healthy volunteers under different conditions of food-intake. Int J Pharm 1989 50 155—161. 

Yuasa H, Torimoto M, Tomei S, Watanabe J (2000) Carrier-mediated drug transport in the colon implications in designing drugs for sustained release formulations. Millennial World Congress of Pharmaceutical Sciences, San Francisco, California, USA, Abstracts p 77... 

Entacapone can be combined with the immediate- and sustained-release formulations of levodopa/carbidopa. 

Psychosis or mania Antidepressants can precipitate manic episodes in bipolar disorder patients during the depressed phase of their illness and may activate latent psychosis in other susceptible individuals. The sustained-release formulation of bupropion is expected to pose similar risks. There were no reports of activation of psychosis or mania in clinical trials conducted in nondepressed smokers. 

Al-Shareef AH, Buss DC, Allen EM, Routledge PA. The efficacy of charcoal and sorhitol (alone and in combination) on plasma theophyfhne concentrations after sustain-release formulation. Human Expt Toxicol 1990 9 179-82. 

Sustained-release formulations can produce stable serum concentrations with once or twice daily dosage. Therapeutic effects occur at blood levels > 5 mg/1, and side effects increase considerably at levels > 15 mg/1. Smoking, alcohol, anticonvulsants, and rifampicin induce the drug-metabolizing enzyme system in liver and reduce the half-life of theophylline. On the other hand, heart and liver failure, sustained fever, old age and drugs such as cimeti-dine, ciprofloxacin, and oral contraceptives reduce theophylline clearance and thereby increase serum concentrations. 

FIA was used to optimise sampling from a tablet dissolution apparatus in order to determine the rate of release of iron (II) from a sustained release formulation. The dissolution medium was automatically sampled at 30-minute intervals and the 100/rl aliquots of medium were mixed with the iron complexing agent ferrozine, diluted and then passed into a spectrophotometric detector. The system was microprocessor controlled thus enabling unattended sampling of the dissolution medium for a prolonged period."... 

To help avoid nitrate tolerance, clinicians should employ the smallest effective dose and administer the compound infrequently. A daily nitrate-free period is also recommended, particularly with use of the transdermal patches or ointment. A better understanding of the pharmacokinetic profile achieved with these sustained-release formulations should result in more effective dosing regimens. 

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