Chronopharmacokinetics: implications for drug treatment.
ABSTRACT Nearly all functions of the human body are organized across the 24 hours of the day. This is also true for functions involved in the regulation of pharmacokinetics such as gastric absorption and emptying, gastro-intestinal perfusion, and liver and kidney functions. Several clinical studies, performed in a cross-over design, have provided evidence that the pharmacokinetics of mainly lipophilic drugs can be circadian phase-dependent. These studies show that after oral dosing, peak drug concentration (Cmax) is, in general, higher or time-to-peak (tmax) shorter after morning, compared with evening application. A few studies performed with both immediate-release and sustained-release preparations (isosorbide-5-mononitrate, nifedipine) gave evidence that only the immediate-release formulation displayed circadian time-dependent pharmacokinetics, but not the sustained-release form. Most importantly, pharmacodynamic studies performed in parallel revealed that the effects, as well as the dose-response relationship, can be circadian phase-dependent, an observation which has an impact on pharmacokinetic/pharmacodynamic modelling. Moreover, this can be of relevance because the onset of certain diseases (e.g., bronchial asthma, coronary infarction, angina pectoris, rheumatic complaints) is not randomly distributed across the 24-h scale. In conclusion, there is now convincing evidence that the time-of-day has to be taken into account both in clinical pharmacokinetic and pharmacodynamic studies.
SourceAvailable from: Mohiuddin Ahmed Bhuiyan[Show abstract] [Hide abstract]
ABSTRACT: Pulsatile drug delivery of enalapril maleate is one such system that, by delivering drug at the right time, right place and in right amounts, holds good promises of benefit to the patients suffering from hypertension. The basic design involves the preparation of cross linked hard gelatin capsules using formaldehyde. Then the drug diluent mixtures were prepared and loaded which was separated by using hydrogel plug of polymers of different grades such as HPMC 50 cps, HPMC 100 cps, HPMC K4M, HPMC K15M, HPMC K100M, xanthan gum, carbopol 971 and sodium CMC at different amount (100 and 120 mg). Prepared formulations were subjected to evaluation of various physical parameters and in vitro drug release studies. Dissolution tests were performed using the USP type I basket method at 50 rpm in 6.8 phosphate buffer. From the in vitro dissolution studies it was found that by increasing the amount of polymers, release rate was decreased. Here, 100 mg of HPMC K100M showed 80% drug release in 8 hours whereas 120 mg showed 78.87% drug release in 10 hours. Similar decrease in the release rates were found with the increase of other polymers used in this study. The release data was fitted to various mathematical models such as zero order, first order, Higuchi, Korsmeyer Peppas and Hixson Crowell cube root law. The drug release follows mixed order kinetics and mechanism was found to be non-Fickian diffusion.
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ABSTRACT: Rewar S et al. / JGTPS/ 5(3)- INTRODUCTION: The newer technologies are developing in pharmaceutical field. The most efficacious dosage forms are generated on already existing molecules because many hurdles occur during discovery of the new molecules  . Pulsatile drug delivery system is gaining a lot of interest and attention now a day. Though most delivery system is designed for constant drug release over a prolonged period of time, PDDS are characterized by a programmed drug release, as constant blood level may not always be desirable. These systems have a typical mechanism of delivering the drug rapidly and completely after a lag time  . In traditional days, drug delivery has meant for getting a simple chemical absorbed predictably from the gut or from the site of injection. A second generation drug delivery goal has been the perfection of continuous, constant rate delivery of bioactive agents. However, living organisms are not ''zero-order'' in their requirement or response to drugs. They are predictable resonating dynamic systems, which require different amounts of drug at predictably different times within the circadian cycle which will maximize desired and minimize undesired drug effects  . Modified release dosage forms have a great importance in this regard. Such systems control the release pattern of drug, either with constant or variable rates drug is released with predetermined release rates. However, there are certain conditions for which such a release pattern is not suitable. These conditions demand release of drug after a lag time. This condition can be achieved by Pulsatile drug delivery system which is defined as the rapid and transient release of certain amount of molecules within a short time period immediately after a predetermined off-release period i.e. lag time. A pulse has to be generated in such a way that a complete and rapid drug release is achieved after the lag time so as to match body's circadian rhythms with the release of drugs  . Fig.1: Shows Schematic representation of different drug delivery systems
Article: Chronotherapy: A Review[Show abstract] [Hide abstract]
ABSTRACT: Chronotherapy refers to the use of circadian, ultradian, infradian & seasonal or other rhythmic cycles in the application of therapy. There are number of conditions which show a circadian pattern and advantage could be taken by timing and adjusting the administration of drugs according to the circadian rhythm of the disease. Some of the conditions, which may be significantly benefited, are hypertension, myocardial infarction, bronchial asthma, peptic ulcer, arthritis, duodenal ulcer, diabetes, neurological disorder, cancer and hypercholesterolemia. Chronotherapy can be classified into time controlled systems wherein the drug release is controlled primarily by the delivery system, stimuli induced PDDS in which release is controlled by the stimuli, such as the pH or enzymes present in the intestinal tract or enzymes present in the drug delivery system and externally regulated system where release is programmed by external stimuli like magnetism, ultrasound, electrical effect and irradiation.