3. 3.1.

Sustained-Release Dosage Forms Introduction

Apart from the effectiveness, safety and purity of the active ingredients embedded in modern dosage forms, the pharmaceutical concept of the latter is becoming increasingly important. Very early on, due consideration has to be given to their pharmacokinetics in order to obtain that specific release profile which guarantees optimum therapeutic efficiency. Controlled release of the actives from oral dosage forms with poly(meth)acrylates can be achieved in many different ways. Enclosing drugs in diffusion-controlled membranes is an important basic principle of controlled time release. Combining neutral, permeable polymers with anionic soluble types permits realization of various release mechanisms, while paying due regard to the physicochemical properties of the drug. The techniques are briefly described and demonstrated hereafter. 3.1.1 Matrix Tablets Matrix tablets are easy to manufacture by direct compression of EUDRAGIT powders such as EUDRAGIT S 100 and EUDRAGIT RS PO. The required polymer quantities are between 10 and 50% of the tablet weight. They are mixed with the actives in a dry state. The release is determined by the type and quantity of poly(meth)acrylate powder. This concept is particularly suitable for low-dose drugs. Other hydrophilic or hydrophobic excipients may be added to influence the release profile by diffusion or erosion. Our figure on page 117 shows the influence of increasing quantities of EUDRAGIT S 100 powder on the liberation of theophylline according to McGinity [14]. The release rate rises in gastric fluid above pH 7, since the polymer substance dissolves at this point. Higher tableting pressures often increase the delaying action only slightly.

Figure 10

Drug release from theophylline matrix tablets with EUDRAGIT S 100

100

[ %] active release

75 [

50

25

3 Time [h]
10% S 100

without EUDRAGIT

5% S 100

15% S 100

Compressional force 120 - 140 N In vitro release according to the USP

Matrix tablets via wet granulation can be manufactured with aqueous polymer dispersions according to conventional methods. EUDRAGIT L 30 D-55 and EUDRAGIT NE 30 D provide granules with good compressive properties. In this case, too, the release of the acti ve slows down with increasing polymer content. The delaying action of the incorporated polymers is much more pronounced than in direct compression. Wet granulation is particularly suitable for high-dose, readily watersoluble actives. The dependence of the release profile on the compressional force has to be examined from case to case. In this application, polymethacrylates perform the dual function of delaying matrix former and binder. For this reason, addition of further excipients to increase the strength of compressed tablets is rarely required. Release of active ingredients from matrix tablets in digestive fluids initially occurs preferentially by diffusion through pores, whereas subsequently the tablets are required to erode and disintegrate slowly. The kinetics often follows the laws described by Higuchi [25]. Important influencing factors are the particle size, the dose and solubility of the drug, the type and quantity of the matrix former as well as the porosity and disintegration behavior of the tablets. Pores at the surface, through which the active diffuses particularly quickly in the initial phase, can be closed with thin retarding films. This is achieved with as little as 1 -2 mg of dry polymer substance/cm. These films lower the dose that is set free within the first two hours, but they do not noticeably affect the further release of the active [3]. In these cases, too, disintegration of the spent tablets should be aimed at.

3.1.2

Multiparticulate Dosage Forms

More expensive to manufacture and develop, but also more reliable in their biopharmaceutical behavior, are oral dosage forms containing actives divided into many individual units, so-called subunits. Upon ingestion, the particles mix with the chyme, pass the pylorus at the stomach exit unhindered and spread over a large section of the intestinal tract. Enclosed particles behave like small diffusion cells. As long as undissolved drug is present in the core, its release occurs at a constant rate, i.e. according to a zero-order reaction. Once the entire drug load of the diffusion cell is dissolved, however, release follows a first-order reaction. According to Higuchi, release from matrix particles occurs proportionally to t, i.e. fast at the beginning and then ever more slowly. On many occasions, the in vitro and in vivo release behavior of multiparticulate dosage forms is not noticeably influenced by the movement and quantity of digestive fluids. Owing to the large number of individual particles, fluctuations in the milieu of the digestive tract and the overall release profile frequently also compensate each other. For this reason, bioavailability and the desired release rate for maintenance of the requisite blood level are much more reliably achieved than with monolithic dosage forms. Plain film-coated tablets with their delicately thin film coats are to be rejected as too risky for sustained release over several hours.Using fluidized beds, spherical microtablets, compact granules or uniformly shaped and mechanically stable active crystals can easily be enclosed in film coatings that are either permeable or partially soluble. The most expedient size range for the particles is 0.2 to 1.2 mm. Depending on the overall surface area of the core material and the solubility of the drug, about 5 to 25% dry polymer substance, calculated on drug, is required to achieve a coating with a delaying action over 5 to 7 hours.

Figure 11

Release of active from coated potassium chloride crystals

[%] active released 120 100 80 60 40 20 0 0 1 2 3 4 Time [h] 5 6 7 5 % polymer 6 % polymer 7% polymer 8% polymer 14% polymer

Coating with aqueous dispersion EUDRAGIT NE 30 D Particles 0.3 - 0.8 mm in size, applied by fluidized bed process

The above figure illustrates the controlled drug release from potassium chloride crystals coated with increasing quantities of EUDRAGIT NE 30 D. Other polymethacrylate dispersions suitable for sustained-release coatings are EUDRAGIT RL 30 D and EUDRAGIT RS 30 D, which can be mixed to influence the permeability of film coatings in a controlled manner. Coated particles for controlled drug release are usually filled into hard gelatin capsules. They can, however, also be easily swallowed from a spoon or in larger quantities by other means. The following section deals with the compression of coated particles. Compression of coated particles When coated particles are directly compressed to tablets, a large number of coatings tear during the process. However, the damaged films immediately form a matrix structure, which usually slows down release of the active ingredient. On the other hand, if the film coatings are sufficiently stable and flexible and the mechanical stress to which the particles are exposed is reduced by incorporation of fillers, binders and disintegrants, controlled-release particles can be compressed to rapidly disintegrating sustained-release tablets with most of the coatings remaining intact. We have found that after adding 20 to 50% easily compressible excipients, coated particles ranging from 0.2 to 0.1 mm in size can be converted to tablets that disintegrate within a few minutes but show largely the same release behavior as uncompressed particles.

This concept, however, requires accurate adjustment of the physicochemical parameters of core material, coating formulation and tableting excipients. The film coatings, for example, must be sufficiently elastic to survive the mechanical stress of compression unharmed. The excipients added to the outer phase must be easily compressible, must fill up the interstices between the particles in the tablet mass and keep the particles apart to prevent the coatings from fusing. The following diagram (Fig. 12) compares the release kinetics of theophylline pellets coated with 12% dry substance of EUDRAGIT RL 30 D and EUDRAGIT RS 30 D (4:6) with the release kinetics of tablets produced from these pellets which disintegrate within less than 5 minutes. Further excipients are Avicel PH 102, corn starch and magnesium stearate [25], which make up a total of 45%. Figure 12

Rapidly disintegrating tablets from coated theophylline tablets

coating with 12% dry polymer substance of EUDRAGIT RL 30 D/RS 30 D 4:6
[%] release 100 80 60 40 20 0

5 Time [hrs]

Disintegrating tablets

Coated pellets

3.1.3

Possible Combinations of Coating Media

Different methods and coating agents can be combined to achieve a specific release profile. When various active ingredients are put together in one dosage form, they often have to be prepared individually or sealed against each other. Where separate coating of active particles is possible, nearly any desired mixture can be filled into capsules and each active liberated according to need. The desired effect can often also be achieved by a multilayer structure in which the drug to be released in the stomach is incorporated in the outer coating layer, for example, and the one intended for safe passage through the stomach in the enteric-coated core. Sustained-release coatings may be composed of permeable and enteric la yers. Another possibility is mixing different EUDRAGIT solutions or aqueous dispersions.

If the permeability of coatings decreases as a result of the varying solubility of actives at increasing pH values, the permeable grades EUDRAGIT RL/RS can be combined with the gastroresistant, enterosoluble polymers EUDRAGIT L/S. The latter are then dissolved from the coating film in the intestine and make up for the moderate solubility of the actives in this environment. [27,28]. In summary, it may be stated that numerous methods are available today for obtaining release profiles that are tailored both to the nature of the active substance and to the therapeutic needs as far as site and time of release are concerned. Although we have only mentioned a few of very many possible combinations, we hope to have shown that controlled development of dosage forms in careful observance of the physicochemical, pharmacokinetic and pharmacological properties of the active ingredients can noticeably enhance the effect and compatibility of medication. 3.1.4 Testing of Dosage Forms with Modified Drug Release

Health authorities worldwide demand in vitro release testing of the final product for all individually administered solid oral dosage forms. If the pharmacopeial monographs do not stipulate certain procedures, or if these procedures cannot be applied, the empirical findings, the equipment and the methods used have to be described in detail. For dosage forms with modified drug release the results of in vitro release testing are of crucial importance. In the development phase, testing for drug release provides a selection of suitable control principles as well as information on storage stability. At the production stage, consistent bioavailability must be ensured. Very early on, a reliable relationship has to be established between in vitro and in vivo results, in order to expose therapeutically relevant discrepancies first between different formulations and later also between production batches. This correlation is most likely if the test conditions are in close proximity to the physiological circumstances. Various physiological factors may exert an influence on the dissolution and release of active ingredients from pharmaceutical dosage forms. Examples are the quantity and pH value of digestive fluids, the residence time of the drug in the different sections of the digestive tract as well as the viscosity and degree of thickening of the chyme. Apart from the release pattern of the dosage form, it is the absorption, distribution, metabolization and excretion - possibly depending on concentration - that influence the in vivo drug concentration at the site of action. Release of the active is one prerequisite for its bioavailability, but not the sole determining factor. Dosage forms which appear to be identical in vitro may show completely different behavior in vivo. Even if the more or less standardized in vitro methods described in the pharmacopeial monographs are used, the correlation between in vivo and in vitro results must be confirmed from case to case.

A test method correlated with in vivo data only applies to the formulation tested. Any change in the qualitative and quantitative composition, or in the processing method, may impair or indeed eliminate the correlation. A verified in vitro test method for drug release should be a reliable tool for exposing differences in biopharmaceutical quality as a result of processing technique and for ensuring product uniformity. Test apparatus The test apparatus and procedures described in the USP 23 and EP have been largely adopted by the pharmacopeias of other countries. The basket and paddlestirring elements are widely used, and their marginal conditions usually allow adequate scope for adaptation to drug properties and individual formulations. Ph.Eur. DAC now also describes a flow-through cell (method V. 5.4) which has proved useful where sink conditions must be observed and is a suitable alternative for other reasons. Test fluids For testing drug release, you should use the test fluids that come closest to physiological conditions. These are normally aqueous buffer solutions. Whether or not the addition of enzymes helps to adjust bodily conditions depends on the composition of the dosage form or the delayed-release principles on which it is based. Additions of surfactants and organic solvents are unacceptable, unless their presence is demonstrably the only possibility of revealing physiologically relevant properties and batch-to-batch variations. Water, 0.1 M hydrochloric acid as well as buffer solutions in special cases are used for establishing disintegration times of tablets and capsules. Test fluids for determining drug release from enteric and delayed-release dosage forms are described in USP XXI under <724>. For the latter, wa ter is usually not suitable as a test fluid, because many adsorption, swelling and diffusion processes occur very differently in electrolytic solutions than in pure water. Release tests with enteric dosage forms are first conducted in 0.1 M hydrochloric acid within 1 to 2 hours and then continued in buffer solution pH 6.8. The starting medium, 0.1 M hydrochloric acid, is either rebuffered to pH 6.8 within 2 hours after adding trisodium phosphate solution or is replaced with a pre-prepared phosphate buffer solution. USP 23 contains several monographs for preparations with modified drug release, which also specify the test fluids to be used.

It is very important to test the drug release from delayed-action dosage forms at varying pH values, at least in the development phase, so as to find out about the influence of pH and utilize it in a controlled manner where necessary. The ionic strength may also exert an influence on drug release. As natural digestive fluids are isotonic, it makes sense to use isotonic buffer solutions for testing. Isotonic phosphate buffers are listed in Hager's handbook. The 0.1-0.2 M phosphate buffers mentioned in the USP and other pharmacopeias are mostly suitable. Test conditions Temperature: 37 1C according to the USP. Movement: The monographs in USP 23 normally specify a stirring speed of 100 rpm for Apparatus 1 (rotating basket) and of 50 rpm for Apparatus 2 (paddle). While care must be taken not to generate excessive mechanical stress by stirring, the speed should, however, be adequate to prevent diffusion processes in the test fluid. When testing pellets, the stirring rate must be increased to prevent agglomeration. Validation of the speed level is strongly recommended. Volume of test fluid: Normally, the test for drug release is required to be performed under sink conditions, i.e. the drug concentration should not exceed 10% of the saturation concentration for the duration of the test [20]. At the usual test fluid volumes of 900 to 1000 mL, maintenance of sink conditions may be a problem with high-dose or low-solubility substances. In such cases it is better to use a flow-through cell in which the overall fluid quantity can be increased with ease by changing the flow rate. The so-called half-change method according to Mnzel [23] causes a multiplication of the liquid volume in standard equipment, since half of the buffer solution is replenished with fresh solution at hourly intervals. This method simulates the natural course of events in the body, such as absorption of active ingredient, addition of fresh digestive fluid and gradual increase in pH, and provides a copious amount of test fluid for analysis of the drug released. However, since it involves a considerable amount of manual work and is difficult to automatize, it is rarely used today. Besides, modern methods are available for determining drug release also from small sample quantities. Specifications The specifications for preparations not acknowledged by the USP monographs, or for tests in countries in which the USP is not recognized, can be derived from in vitro drug release profiles verified in vivo.

The established correlation between in vivo and in vitro results should then provide the basis for fixing the upper and lower limits of release rates. The regulatory principles of the health authorities contain detailed recommendations to this effect. Under <724>, the USP presents Acceptance Tables for enteric-coated preparations tested in 0.1 M hydrochloric acid and phosphate buffer pH 6.8. The average percentage of drug dissolved in 0.1 M hydrochloric acid within 2 hours must not be more than 10% of labelled content. After adjustment to pH 6.8 and operating the apparatus for - usually - 45 minutes, the average amount of active ingredient dissolved (Q) must be tha t specified in the individual monographs.

Our technical advice on the uses of our materials is given without obligation. The buyer is responsible for the application and processing of our products and is also liable for observing any third-party rights. Technical data concerning our products are typical values. = registered trademark. EUDRAGIT = reg. Trademark of Rhm GmbH, Darmstadt