VOLUME 22 : NUMBER 4 : August 1999
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The use of extended-release products offers some potential advantages in patient convenience/compliance and therapeutic outcomes. However, the range of drugs for which clinically significant advantages have been shown is limited. Prescribers and pharmacists should be aware of the costs of these products and have a knowledge of their clinical use in selected patient groups. In some instances, the formulation is probably serving a marketing objective rather than a clinical objective.
Key words: formulation, pharmacokinetics.
Aust Prescr 1999;22:88-90
Drug products designed to reduce the frequency of dosing by modifying the rate of drug absorption have been available for many years. Early modified-release products were often intramuscular/subcutaneous injections of suspensions of insoluble drug complexes, e.g. procaine penicillin, protamine zinc insulin, insulin zinc suspensions or injections of the drug in oil, e.g. fluphenazine decanoate. Advances in technology have resulted in novel oral modified-release dosage forms.
Many terms are used to describe modified-release products including extended-release, prolonged-release, controlled-release, controlled-delivery, slow-release and sustained-release. These preparations, by definition, have a reduced rate of release of active substance. In general, these terms are interchangeable.
Delayed-release products are modified-release, but by definition are not extended-release. They involve the release of discrete amount(s) of drug some time after drug administration, e.g. enteric-coated products, and exhibit a lag time during which little or no absorption occurs.
While a number of such modified-release products are available as both prescription and over-the-counter drugs, only a limited number have been shown to offer a therapeutic advantage. Many of the formulations appear to have been developed to extend patents or to create a marketing advantage over conventional-release products, rather than because of clinical advantage.
Extended-release products offer 3 potential benefits:
sustained blood levels
attenuation of adverse effects
Theoretical drug concentration profile following multiple dosing of a drug as an immediate-release form every 8 hours ( – ) and as an extended-release form once every 24 hours (---).
Sustained blood levels
The size and frequency of dosing is determined by the pharmacodynamic and pharmacokinetic properties of the drug. The slower the rate of absorption, the less the blood concentrations fluctuate within a dosing interval. This enables higher doses to be given less frequently. For drugs with relatively short half-lives, the use of extended-release products may maintain therapeutic concentrations over prolonged periods (Fig. 1).
Attenuation of adverse effects
With conventional dosage forms, high peak blood concentrations may be reached soon after administration with possible adverse effects related to the transiently high concentration. An example is hypotension in patients taking rapid-release nifedipine products. The use of an extended-release product avoids the high initial blood concentrations which cause the sudden reduction in blood pressure and other significant haemodynamic changes such as reflex tachycardia.1,2 Another example is the transient nausea at sub-toxic concentrations which results from the local irritation caused by high intestinal concentrations of some conventional-release products such as theophylline.
Improved patient compliance
Drugs with short half-lives often need to be given at frequent intervals to maintain blood concentrations within the therapeutic range. There is an inverse correlation between the frequency of dosing and patient compliance. A reduction in the number of daily doses offered by extended-release products has the potential to improve compliance.3 However, this advantage probably only occurs when conventional formulations need to be given 3 or more times a day.
For many controlled-release products, the release rate can be altered by various factors including food and the rate of transit through the gut. There may be some differences in the release rate from one dose to another, but these have been minimised by modern formulations.
Extended-release products contain a higher drug load and thus any loss of integrity of the release characteristics of the dosage form has potential problems. While some extended-release products can be divided to provide half-doses (Table 1), others should only be taken whole (Table 2). Modified-release products should never be crushed or chewed as the slow-release characteristics may be lost and toxicity may result. This is particularly important in patients unable to swallow whole tablets, a problem commonly affecting the elderly. The larger size of extended-release products may cause difficulties in ingestion or transit through the gut. These problems may result in some drugs, e.g. Slow-K, causing local tissue damage in patients who have a pathological or drug-induced reduction in gut motility.
Which drugs are suitable for extended-release formulations?
The extent of fluctuation in drug concentration at steady state is determined by the relative magnitude of the elimination half-life and the dosing interval. If a drug is given at an interval equal to the elimination half-life, there is a two-fold difference between the maximum and minimum concentrations at steady state.
For drugs with short half-lives and with a clear relationship between concentration and response, it will be necessary to dose at regular, frequent intervals in order to maintain the concentration within the therapeutic range. Higher doses at less frequent intervals will result in higher peak concentrations with the possibility of toxicity. For some drugs with wide margins of safety, this approach may be satisfactory, e.g. amoxycillin has a half-life of approximately one hour, but a dosage frequency of 8 hours. This means that very large fluctuations will occur within a dosing interval, but, in view of the low toxicity of this drug, no difficulty with this approach is encountered provided the concentrations are above the minimum effective concentration during the dosing interval. On the contrary, clinical efficacy may be enhanced by the transiently high bactericidal concentration of the antibiotic e.g. aminoglycosides.
Conversely, drugs with long half-lives can be given at less frequent intervals. There is generally no advantage in formulating these drugs as extended-release formulations unless a rapid rate of change of concentration during the absorptive phase is responsible for transient adverse effects. The pharmacological effect of some drugs with short half-lives is sustained by various mechanisms:
the drug binds to the tissues e.g. tissue-bound ACE inhibitors. For these drugs, less frequent dosing is needed even though the drug may have a short half-life
the drugs have irreversible effects e.g. the inhibition of platelet cyclo-oxygenase by aspirin
the relationship between response and plasma/blood concentrations is relatively flat or if the dose given results in concentrations which are in the plateau region of the dose-response relationship e.g. thiazides in hypertension
the drug is metabolised to pharmacologically active metabolite(s) which are more slowly cleared than the parent drug e.g. quinapril, trandolapril, venlafaxine.
Extended-release tablets which can be broken, but not crushed or chewed
Types of extended-release products
In these systems, there is a water-insoluble polymer which controls the flow of water and the subsequent egress of dissolved drug from the dosage form. Both diffusional and dissolution processes are involved. In `reservoir' devices, a core of drug is coated with the polymer and, in `matrix' systems, the drug is dispensed throughout the matrix. Cellulose derivatives are commonly used in the reservoir types, while the matrix material may be plastics, e.g. methylacrylate-methyl methacrylate, polyvinyl chloride, hydrophilic polymers such as cellulose derivatives or fatty compounds including carnauba wax. Examples of this type of formulation include Plendil ER, Agon SR, Kapanol and Slow-K.
In these products, the rate of dissolution of the drug (and thereby availability for absorption) is controlled by slowly soluble polymers or by micro encapsulation. Once the coating is dissolved, the drug becomes available for dissolution. By varying the thicknesses of the coat and its composition, the rate of drug release can be controlled. Some preparations contain a fraction of the total dose as an immediate-release component to provide a pulse dose soon after administration. The pellet dosage forms of diffusion- or dissolution-controlled products can be encapsulated or prepared as a tablet. These products should not be chewed as the coating may be damaged. One of the advantages of encapsulated pelleted products is that the onset of absorption is less sensitive to stomach emptying. The entrance of the pellets into the small intestine (where the majority of drug absorption occurs) is usually more uniform than with non-disintegrating extended-release tablet formulations. An example of this type of product is Fefol.
Extended-release tablets which should not be broken, crushed or chewed
The release of drug from these products is controlled by the erosion rate of a carrier matrix. The rate of release is determined by the rate of erosion. An example of this formulation is Sinemet CR. With this product, some patients may experience a later onset of effect after the morning dose, compared to conventional levodopa tablets, because of the delayed release of the drug.
Osmotic pump systems
The rate of release of drug in these products is determined by the constant inflow of water across a semipermeable membrane into a reservoir which contains an osmotic agent. The drug is either mixed with the agent or is located in a reservoir. The dosage form contains a small hole from which dissolved drug is pumped at a rate determined by the rate of entrance of water due to osmotic pressure. The rate of release is constant and can be controlled within tight limits yielding relatively constant blood concentrations. The advantage of this type of product is that the constant release is unaltered by the environment of the gastrointestinal tract and relies simply on the passage of water into the dosage form. The rate of release can be modified by altering the osmotic agent and the size of the hole. An example of this type of product is Adalat Oros.
Ion exchange resins
Some drugs can be bound to ion exchange resins and, when ingested, the release of drug is determined by the ionic environment within the gastrointestinal tract. Examples of this type of product are Duromine containing the basic drug phentermine complexed onto an anionic resin, and MS Contin suspension which uses a polystyrene sulphonate resin.
Switching to extended-release products
Where a prescriber wishes to transfer a patient from an immediate-release to an extended-release product, generally the equivalent total daily dose should be the same. In some cases, an effective response may be achieved with a lower dose of the extended-release product. In view of the complexity of extended-release products and the potential for greater variability, both inter- and intra-subject, patients should be monitored to ensure that the anticipated benefit of switching to such products is actually obtained.
A wide range of drugs is now formulated in a variety of different oral extended-release dosage forms. However, only those which result in a significant reduction in dose frequency and/or a reduction in toxicity resulting from high concentrations in the blood or gastrointestinal tract are likely to improve therapeutic outcomes.
Birkett DJ. Pharmacokinetics made easy. Sydney: McGraw Hill; 1998.
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