|
|
|
|
|
|
|
erates the drug. In the diffusion-controlled case, the drug is typically dissolved or dispersed in a polymer and released by diffusion. There is currently a silicone-based implant marketed for contraception [47]. Osmotic and swelling-controlled variants of implants are also being developed. For most of these systems, the implant remains intact and removal is relatively simple. There are two main types of chemically-controlled systems: biodegradable and pendant chain. Examples of bioerodible polymers where the polymers degrade by hydrolysis or enzymatic cleavage are: D,L-lactic acid-glycolic acid copolymer (PLGA) [127], polyanhydrides [128], and polyorthoesters [129]. Since the biodegradable system is absorbed over its lifetime, there can be a significant advantage to the patient, but degradation must be reproducible for safety reasons. There are two commercial biodegradable PLGA-based systems for treatment of advanced prostate cancer: 3.6 mg goserelin acetate, an analog of luteinizing hormone releasing hormone, to be released over 28 days [47] and 7.5 mg leuprolide acetate, an analog of gonadotropin releasing hormone, to be released over 28 days [47]. |
|
|
|
|
|
|
|
|
Extensive studies of the degradation of the polymer and its byproducts are required to demonstrate that it is nontoxic, nonimmunogenic, and noncarcinogenic. Long-term safety studies are required. The pharmacokinetics should be extensively characterized in animal models. Obtaining the desired in vivo delivery profile for drugs with narrow therapeutic windows is quite problematic due to burst effects. Delivery in vivo may be governed largely by the surrounding tissue rather than the system. Reproducibility in scale-up and production must be carefully evaluated and has hindered developmental efforts. Removal of solvent can be problematic for PLGA based systems. |
|
|
|
|
|
|
|
|
In pendant chain systems, the drug is chemically bound to the polymer and released by hydrolytic or enzymatic reactions. A spacer group varies the rate of release by controlling the hydrophilicity. The main advantage of these systems is its large capacity for drug (over 80 wt% loading). While bioerodible systems require full toxicological characterization of the polymer once, pendant-chain systems require these studies for every drug and spacer. |
|
|
|
|
|
|
|
|
Acute and chronic inflammation and foreign-body reactions to implants are of great importance [130]. Much fundamental work centers on minimizing protein adsorption [131]. Investigations of the blood compatibility of materials have been adapted to accommodate subcutaneous implants, and similar tests of pathology and durability may be developed. |
|
|
|
|
|
|
|
|
III. Recent Successes and Future Outlook |
|
|
|
|
|
|
|
|
A. Recent Significant Product Introductions |
|
|
|
|
|
|
|
|
During the last few years, several products based on novel drug delivery technologies have been introduced to the marketplace. Among them are Cardiazem |
|
|
|
|
|