SUSTAINED RELEASE HORMONAL PREPARATIONS (1970)

ABSTRACT By convention, drug potency is a relationship between the administered dose and the biologic response. Drug availability to the organism is a function of a dosage form or formulation, »drug delivery system« and its metabolic fate, »drug removal system«. The most obvious way to obtain a greater drug effect is to increase dosage. However, this has a disadvantage in that the level might persist beyond the time for the next dosage and consequently lead to a drug buildup. Anything which leads to a decline in the effective level may cause a failure of the response. Divided dosage decreases these variations and should lead to improved drug efficiency. We have postulated that this could be achieved by a sustained-release parenteral implant which represents an infinite number of daily divided doses ( Rudel 1968). Two types of sustained release preparations were studied. A prolonged release, and a marked increase in biological effectiveness can be achieved by either enclosing a steroid in a membrane permeable to it, or by admixing the steroid to a biologically inert lipid substance. Polydimethylsiloxane was found to be a suitable polymer readily permeable to steroids. The release in vitro followed Fick's law, permeation being proportional to surface area and inversely proportionate to membrane thickness. Limited experience indicates that this is not the case in vivo . When implanted in experimental animals absorption was increased by increasing the surface area regardless of membrane thickness. By monitoring radioactivity excreted in urine and faeces it was shown that absorption of steroids from either type of implant was not steady. Possibly encapsulation noted with either type of implant was a contributory factor, even though no inflammatory reaction was noted. An important feature of a sustained release form was the demonstration of increased biological effectiveness, and of therapeutic index. Several steroid hormones released from implants were considerably more efficient than when the same compounds were given in a conventional, once-a-day subcutaneous injection or oral administration. Accumulation of a drug and/or of its metabolites was markedly decreased in many tissues when a sustained release form was used in contrast to an oral administration. The low uptake of the active priciple and/or of its metabolites in various tissues of animals treated with a sustained release form shows that such implants may act as an »arteficial gland«, the rate of release being nearer to the biological requirement. Possibly many drugs delivered in this manner may exhibit fewer »side effects«. The main difference between polydimethylsiloxane and lipid implants is the rigidity of geometrical shape of the former and constantly diminishing area of the latter. Under optimal conditions, as yet to be achieved, polymer implants could be expected to release the same amounts of an active principle through most of its life. After the implant has been exhausted, an empty hull of foreign material is left embedded in the tissue. A lipid implant, on the other hand, may release continuously diminishing amounts, but will be absorbed by the tissue.