Drug release implant

Figure 10.6 Concentration profiles after implantation of a spherical drug-releasing implant, (a) Solid lines represented the transient solution to Equation 10-20 with the following parameter values D = 4 x 10 cm /s ...

PHAs are made from renewable sources such as sugarcane, one of the most significant and traditional Brazilian feedstocks, as well as from other renewable sources such as starch, vegetable oils etc. Their applications range from packaging to disposables and applications in the medical field (matrices for slow drug release, implants, artificial tissues, patterns and suture wire) due to their biocompatibility. These hiopolymers are similar to plastics produced from petroleum and can be laminated, molded and injected easily. Also, they are fully biodegradable in a period of six months to a year. ... 

FIGURE 11.2 Concentration profiles after implantation of a spherical drug-releasing implant. (Panel a, Transient) Solid lines represent the transient solution to Equation 11.12 (i.e.. Equation 11.13) with the following parameter values D = 4 x 10 cm /sec R = 0.032 cm k = 1.9 x 10 sec (t / = 1 h). The dashed line represents the steady-state solution (i.e., Equation 11.15) for the same parameters. (Panel b, Steady-state) Solid lines in this plot represent Equation 11.15 with the following parameters D = 4 x 10 cm /sec R = 0.032 cm. Each curve represents the steady-state concentration profile for drugs with different elimination half-lives in the brain, corresponding to different dimensionless moduli, / = 10 min (/ = 1.7) 1 h (0.7) 34 h (0.12) ... 

Recently, Tsakala et al. (90) formulated pyrimethamine systems based on several lactide/glycolide polymers. These studies were conducted with both microspheres (solvent evaporation process) and implants (melt extrusion process). In vitro studies indicated that pyrimethamine-loaded implants exhibited apparent zero-order release kinetics in aqueous buffer whereas the microspheres showed an initial high burst and considerably more rapid drug release. In vivo studies in berghi infected mice confirmed that the microspheres did not have adequate duration of release for practical application. However, the implants offer promise for future clinical work as more than 3 months protection was observed in animals. 

A ketene acetal-terminated prepolymer was first prepared from 2 eq of the diketene acetal 3,9-bis(ethylidene-2,4,8,10-tetraoxaspiro-[5,5]undecane) and 1 eq of the diol 3-raethyl-l,5-pentanediol and. then 30 wt% levonorgestrel, 7 wt% Mg(OH)2j and a 30 mole% excess of 1,2,6-hexanetriol mixed into the prepolymer. This mixture was then extruded into rods and cured. Erosion and drug release from these devices was studied by implanting the rod-shaped devices subcutaneously into rabbits, explanting at various time intervals, and measuring weight loss and residual drug (15). 

Implants are small, sterile cylinders of dmg, inserted beneath the skin or into muscle hssue to provide slow absorption and prolonged achon therapy. This is principally based on the fact that such dmgs, invariably hormones, are almost insoluble in water and yet the implant provides a rate of dissoluhon sufficient for a therapeuhc effect. The British Pharmacopoeia (1993) describes one implant, testosterone. The United States National Formulary (1990) also ineludes oestradiol. Implants are made fiom the pure drug into tablet form by compression or fusion. No other ingredient can be included sinee this may be insoluble or toxie or, most importantly, may influence the rate of drug release. 

Ethylene vinyl acetate has also found major applications in drug delivery. These copolymers used in drug release normally contain 30-50 wt% of vinyl acetate. They have been commercialized by the Alza Corporation for the delivery of pilocarpine over a one-week period (Ocusert) and the delivery of progesterone for over one year in the form of an intrauterine device (Progestasert). Ethylene vinyl acetate has also been evaluated for the release of macromolecules such as proteins. The release of proteins form these polymers is by a porous diffusion and the pore structure can be used to control the rate of release (3). Similar nonbiodegradable polymers such as the polyurethanes, polyethylenes, polytetrafluoroethylene and poly(methyl methacrylate) have also been used to deliver a variety of different pharmaceutical agents usually as implants or removal devices. 

In order to design such an efficient and effective device, one must understand the mechanisms by which drug is transported in the ocular interior. One issue debated in the literature for some time has been the relative importance of transport by passive diffusion versus that facilitated by the flow of fluid in the vitreous (see, e.g., Ref. 226). To predict the geometric distribution even at steady state of drug released from an implant or an intravitreal injection, one must appreciate which of these mechanisms is at work or, as appropriate, their relative balance. 

A pharmacotectonics concept was illustrated by researchers, in which drug-delivery systems were arranged spatially in tissues to shape concentration fields for potent agents. NGF-releasing implants placed within 1-2 mm of the treatment site enhanced the biological function of cellular targets, whereas identical implants placed mm from the target site of treatment produced no beneficial effect (Mahoney and Saltzman, 1999). Because of some limitations with controlled delivery systems, alternatives such as encapsulation of cells that secrete these factors are discussed in the next section. 

This book is a companion volume to Pharmaceutical Technology Controlled Drug Release, Volume 1, edited by M.H.Rubinstein and published in 1987. It focused on the different types of polymeric materials used in controlled release. This book extends these concepts to include drug properties, design and optimization, coating, the effect of food and pharmacokinetics. It also reflects the growing interest in biodegradable polymers in oral and topical formulations and the use of sterile implants. 

Dissolution kinetics was studied under sink conditions by placing one implant in varying volumes (usually 100 ml) of phosphate buffer pH 7.4, while agitating in a horizontally shaking water bath (50 1 rev/min) at 37 1°C. Samples were withdrawn at varying time intervals for a duration of 21 days (an estimate of the expected duration of clinical use) and the amount of tobramycin sulphate released was determined spectrophotometrically. Equal volumes of fresh medium were added to replace aliquots removed for assay and the amount of drug release was corrected for dilution. Triplicate measurements were performed for each batch of implants prepared. 

Studies using smaller implants of 2.9 mm diameter indicated statistically significant differences in the two rate constants (Table 2) and extent of drug released from the implant in comparison with implants of mean diameter 6.2 mm. This could be attributed to an increase in surface area per unit volume of the smaller implant. 

Both in vitro and in vivo results indicate that drug release is incomplete and poorly controlled from implants prepared at the drugxamer ratio used clinically. 

The two principal implants that release levonorgestrel, i.e. the six-capsule Norplant and the two-rod Jadelle are considered by authoritative reviewers to have essentially equal rates of drug release, pregnancy, and adverse events over 5 years of use (1). 

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