CONTROLLED RELEASE TECHNOLOGY 1 INTRODUCTION

Controlled drug delivery is the phasing of d rug adm inistration for a condition so that the optimal am ount of drug is given in the tim e required. The use of spherical particles for pharm aceutical dosage forms is dated by historical interest in the hand - rolled pill, O 'C onnor and Schwartz, (1989). Spherical granules flow freely and pack uniform ly and are therefore suitable for producing controlled release pellets of the m ultiple unit dosage form. M ultiple unit dosage form s spread out uniformly in the gastrointestinal tract. This results in a m ore reproducible drug absorption and reduces local irritation com pared to single unit dosage forms. A num ber of oral solid dosage form s are produced m ainly in the form of coated pellets (Mehta, 1986), w ith a low surface to volume ratio and good flow characteristics that can be filled into gelatin capsules or com pressed into tablets. The advantages of these dosage forms include; highly reproducible transit through the gastrointestinal tract and as they are w idely distributed over a large surface area the risk of dam age to the intestinal m ucosa is m inim ised. The optim um d ru g th erap eu tic concentration is m aintained w ith m inim um blood fluctuation and reproducible release rates over extended tim e p eriods m ay be

obtained. These drug delivery systems are particularly suitable for drugs w ith short half lives. A wide range of drugs w ith short half- lives, in clu d in g p ro p ran o lo l, in d o m eth acin , th eo p h y llin e an d nitroglycerin have been form ulated by this m ethod. Pellets are usually coated for aesthetic reasons, enteric release, taste m asking, stability or to control release of the active ingredient (Deasy, 1984). The m atrix and reservoir systems are the m ost com m only u sed m ethods in controlling drug release.

M ost controlled release system s are classified (Lee an d Robinson, 1978) into a num ber of different types, either chemically co n tro lled system s or diffusion controlled. D iffusion co n tro lled system s m ay be further classified into m em brane reservoir and m atrix systems, including porous inert matrix tablets, eroding m atrix tablets, tablets w ith a diffusion controlling m em brane and swellable hydrophilic matrices. A spherical pellet which is sm ooth and dense has a m inim um surface area per u n it volum e an d can be characterized by its diameter. Most of these sustained release pellets em ploy dissolution as the rate lim iting step as a d ru g w ith slow dissolution is inherently sustained. To achieve optim um therapeutic effects it is often desirable to have zero o rd er d ru g release. M em brane reservoir systems, where the drug core is su rro u n d ed by a rate - controlling membrane, are often employed for this purpose. A n u m ber of m ethods involve coating individual particles or granules w ith a slowly dissolving outer layer. By varying the thickness of the coat it is possible to control the release, as the time required for the coat to dissolve is a function of its thickness and aqueous solubility.

1.2.2 MATRIX TYPE SYSTEMS

M atrix type system s utilize conventional pharm aceutical techniques and are relatively simple to m anufacture. Release of a d ru g from the dosage form m ay be controlled by the rate of penetration of the dissolution fluid into the insoluble matrix. The d ru g is usually com pressed w ith some sort of slowly dissolving carrier an d the porosity and tortuosity of the m atrix will affect the rate of d rug release as will the drug solubility. The d rug release rate decreases w ith time in a matrix form ulation due to the increased diffusional

distance and decreased surface area available. Matrix system s usually show first order release behaviour w ith a continually dim inishing release rate. This is a result of the increasing diffusional resistance an d decreasing area at the penetrating diffusion front as m atrix diffusion proceeds. Higuchi (1961), derived an equation to describe d ru g release from a porous (granular) m atrix system w hich stays intact during dissolution (no swelling or erosion);

Q = [ D e/T ( 2A - eCg ) Cs t] V2

w here Q = w eight in grams of drug released per unit surface area, D = diffusion coefficient of drug in the release m edium , e = porosity of the m atrix, T = tortuosity of the matrix, C§ = solubility of the dru g in the release m edium and A = concentration of dru g in the tablet. Therefore, to achieve zero order release from a matrix, one needs to select a geom etry that compensates for the increase in diffusional distance with a corresponding increase in surface area available. This square root of time relationship has become the accepted standard in evaluating drug release from inert matrices. A plot of the am ount of d ru g released versus the square root of time should be linear if the the d ru g release from the m atrix is diffusion controlled. This assum es that a pseudo steady state is m aintained, that perfect sink conditions apply and excess solute is present, d ru g particles are sm aller than those in the matrix, the diffusion coefficient rem ains constant and that there is no interaction betw een the d ru g and the m atrix. In practice the diffusion of a d ru g often occurs in com bination w ith a swelling or erosion process and this complicates the release m odel. H opfenberg (1976), describes the release from erodible slabs, cylinders and spheres, w here surface erosion is the only factor allowing drug release to occur. Lee (1984) describes the release from an erodible or swellable polym er m atrix in the presence of m o v in g boundaries. The sw ellable system has also been investigated by a w ide num ber of other w orkers including, Peppas and Korsmeyer (1987) and Ranga and Devi (1988).

A n u m b er of reta rd an t m aterials are u sed in m atrix form ulations, either insoluble or hydrophilic types. The d ru g is em bedded in a matrix core of the retardant. Many different polym ers, w axes, gum s and clays have been rep o rted in the literatu re as reta rd an t materials. The choice of dru g and retard an t m aterial will affect the rate and mechanism of drug release from the device. D rug d iffu sio n th ro u g h polym ers is affected by m orphological and structural characteristics of the polymer.

1.2.3 EXTRUSION/SPHERONIZATION

The preparation of spherical pellets w ith a high d ru g content m ay be achieved by extrusion- spheronization, as described by Conine and H adley (1970) and Reynolds (1970). Extrusion is defined (Fielden an d N ew ton, 1992) as the process of form ing a raw m aterial into a p ro d u c t of uniform shape and density, by forcing it th ro u g h an oriface or die under controlled conditions. The processing sequence involves dry blending of the pow ders with the active ingredient, w et g ran u latio n of the mass, extrusion and subsequent spheronization and drying of the pellets formed (Figure 1.3). The process has diverse applications in a range of industries. Extrusion is a continuous process and the force required to extrude is d ep en d en t on the rheological properties of the extrudate and the die itself. A dvantages of the m ethod for preparing pellets include; regularity of pellet shape, uniform ity of size, a smooth surface and good flow properties. A good extrusion mixture consists of a cohesive and suitably plastic m ass, which is non-adhesive to both the equipm ent used and itself.

Extrusion is m ainly classified into system s u n d er tem perature control or sem isolid systems w hereby solvents are a d d ed to the m aterials to alter the consistency of the mix. The various types of extruders have the common feature of forcing the extrudate through a n arro w die. The different types are discussed below. Com m ercial extruders include the screw feed extruders, the gravity extruder and the prefilled type i.e. the ram extruder.