VOLUME 11 NUMBER 4, 2000 Contents: Modified-release preparations Modified-release preparations With the ever increasing number of modified-release SUMMARY preparations on the market, the debate continues as to * The use of a modified-release (m/r) preparation cannot whether these products actually fulfil a clinical need be justified unless it offers clear clinical advantages or are merely premium priced over, often less expensive, conventional-release line-extensions to encourage preparations. brand name prescribing. * M/R preparations may be prescribed to: The recent NHS performance • reduce the dosing frequency and improve patient 1 indicators document has once compliance; again highlighted modified- release (m/r) preparations as • reduce fluctuations (peaks and troughs) in drug an area where there is often plasma concentrations, in order to reduce unnecessary prescribing. concentration-related side-effects or improve M/R preparations tend to be effectiveness; relatively expensive and in • control the site of drug delivery in the many cases, the clinical need could be met by a cheaper gastrointestinal tract. alternative. This Bulletin * There is little good quality evidence to suggest that discusses the various factors that need to be taken into once daily dosing has a clear clinical advantage over account when deciding if an twice daily dosing. Missing a once daily dose can result m/r preparation is appropriate. in long periods of subtherapeutic plasma concentrations. Therefore, twice daily dosing may be What is modified-release? preferred in patients known to miss doses. * Prescribers should always consider whether an The term modified-release defines preparations that have been m/r preparation is clinically justified. For those designed in such a way that the limited situations where this is the case, prescribing by rate or place at which the brand ensures the correct preparation is dispensed. active ingredients are released Brand name prescribing is particularly important for 2 has been modified. This is an theophylline nifedipine all encompassing term that the m/r preparations of , and BNF now uses to cover prepara- diltiazem, as there is concern over the clinical tions such as sustained-release, implications of switching between inequivalent controlled-release and delayed- preparations. release. Although theoretically covered by m/r, the BNF has * In general, m/r preparations should be reserved for retained the separate term specific patients where there is a problem with enteric coated. compliance, effectiveness or side-effects which these The sole use of the term preparations could help overcome. modified-release is helpful to simplify the confusing terminol- ogy. However, its use conceals The MeReC Bulletin is produced the differences between the drug delivery systems, which by the NHS for the NHS may be defined as: MeReC Bulletin Volume 11, Number 4, 2000 13 • Sustained-release - the drug is released slowly at a rate gov- Pharmaceutical modification The rate of drug release is reduced by increasing particle size or forming insoluble erned by the delivery system.3 crystals e.g. Tegretol Retard or Adalat Retard. • Controlled-release - the drug is released at a constant rate Coated pellets Drug pellets are coated with a slowly dissolving polymer of varying thickness for and plasma concentrations varied release. The pellets can either be compressed into a tablet or put in a gelatin after administration do not capsule e.g. Fenbid, Slo-Phyllin or Inderal-LA. vary with time.3 Insoluble matrix • Delayed-release - the drug The drug is dispersed within an insoluble porous matrix. As fluid enters the matrix, is released at a time other the drug is dissolved and diffuses out slowly e.g. Slow-K, Imdur or Betaloc-SA. than immediately after Eroding matrix 3 administration i.e. the site The drug is dispersed within a soluble matrix. As the matrix is eroded, the drug is of release is controlled. slowly released e.g. MST Continus or Phyllocontin Continus. Osmotic pump There are many mechanisms by The drug and an osmotic agent are enclosed by a semipermeable membrane. As which drug release from a prepar- water is drawn into the tablet, dissolved drug is released in a controlled way through ation can be modified (see table 1). a laser-drilled hole e.g. Volmax, Adalat LA. pH sensitive coating The formulation is coated with a polymer of pH dependent solubility for site specific Why prescribe a modified-release delivery. This can either avoid drug release in the stomach (enteric coating) e.g. preparation? Nu-Seals Aspirin, or specifically deliver drug to the colon e.g. Asacol. Table 1. Some mechanisms of modified drug release M/R preparations may be prescribed to: manufacturers. However, this concentration-related side-effects, • reduce the dosing frequency and can have drawbacks. Patients particularly for rapidly absorbed improve patient compliance; may forget that a dose has drugs such as nifedipine.14 • reduce fluctuations (peaks and already been taken and repeat it Minimising the trough may troughs) in drug plasma con- later in the day.11 They may also improve effectiveness, for example centrations, in order to reduce miss a dose completely. Missing in maintaining 24-hour blood concentration-related side- a dose is a particular problem pressure control with certain effects or improve effectiveness; with a once daily preparation antihypertensive agents.15 • control the site of drug delivery as it can result in long periods in the gastrointestinal (GI) tract. where drug plasma concentra- M/R preparations are often tions are subtherapeutic. Twice used for drugs with a narrow Generally, the use of an m/r daily dosing may, therefore, therapeutic index, such as preparation cannot be justified be preferred, especially if the theophylline and lithium. This unless it offers clear clinical patient is known to miss doses.12 may help to maintain the plasma advantages over, often less concentration within the limits of expensive, conventional-release There are many reasons for effectiveness and toxicity.13 preparations. noncompliance. Polypharmacy is often a factor11 and the number of drugs should be reviewed and Controlling the site of delivery Improving patient compliance reduced to a minimum before considering m/r preparations. M/R preparations can be By slowing the rate of drug Patients’ understanding of their developed to deliver a drug to a release, m/r preparations allow condition and treatment should specific site in the GI tract. For drugs with short half-lives to be also be addressed if compliance example, enteric coated prepara- administered less frequently. It is is a problem. tions direct delivery to the small generally well accepted that, for intestine, preventing drug release the majority of patients, reducing in the stomach. This aims to the dosing frequency to once or Reducing fluctuations in drug either protect the stomach from twice daily improves compliance.4 plasma concentrations the drug, or protect the drug from the degrading environment of the However, there is little good By slowing the rate of drug stomach. Other preparations, quality evidence to suggest that release, and hence absorption, such as those containing once daily dosing has a clear m/r preparations aim to provide aminosalicylates for inflammatory clinical advantage over twice close to constant plasma concen- bowel disease, are formulated daily dosing. Most studies have trations over a prolonged period to allow site specific delivery to shown that compliance is either of time.13 the colon or small intestine to the same, or slightly improved, exert local effects. with a once daily preparation.5-11 Levelling out the plasma profile Whilst this improvement has can be advantageous, but only reached statistical significance in for drugs where there is a close Which drugs are suitable as m/r some studies,10-11 its clinical correlation between plasma preparations? significance is less clear. concentration and either therapeutic effect or toxicity. Apart from formulations that The ‘once a day is best’ belief Reducing high peak plasma control the site of drug delivery, is heavily promoted by concentrations can reduce most m/r preparations slow the 14 MeReC Bulletin Volume 11, Number 4, 2000 rate of drug release. To ensure Conventional-release characteristics. Therefore, maximum absorption from these carbamazepine is often bioequivalence cannot be as- preparations, it is essential that prescribed three or four times a sumed and all m/r preparations the drug is well absorbed day for epilepsy. M/R prepara- are licensed by brand name. throughout the entire GI tract. tions allow twice daily dosing and Drugs which are absorbed only at may also reduce the incidence of Switching between m/r specific sites, such as iron16, folic dose-related side-effects.16,19 preparations of drugs with a acid and vitamin B12, are not narrow therapeutic index may suitable as m/r preparations.13 have serious clinical conse- What are the problems with m/r quences. Therefore, both the Drugs with a narrow therapeutic preparations? Royal Pharmaceutical Society and index, those which are rapidly the BNF recommend brand name absorbed, and those with a The release of a drug from an prescribing for m/r theophylline short duration of action are m/r preparation is dependent (or aminophylline) prepara- often formulated into m/r on changes in GI transit time. In tions.16,20 This is also advisable for preparations. Drugs with a patients with ‘GI hurry’ some of all formulations of lithium. long duration of action, such the dose may be lost if the prep- as amitriptyline, do not need to aration passes through the body Brand name prescribing is also be given frequently and an m/r before drug release is complete. recommended for m/r preparation is unnecessary. Conversely, if the transit time is preparations of nifedipine and delayed, excessive release of the longer-acting diltiazem16,20 It is also important to consider drug or ‘dose dumping’ can where numerous formulations whether the therapeutic area occur.