Profiling in vitro drug release from subcutaneous implants: a review of current status and potential implications on drug product development

Abstract

This review presents current methods and strategies for studying the release characteristics of drugs from subcutaneous implant dosage forms. Implants are dosage forms that are subcutaneously placed with the aid of surgery or a hypodermic needle, and are designed to release drugs over a prolonged period of time. In most cases, the objective of a release test is to identify sufficiently discriminatory procedures that in turn would provide data to set meaningful specifications. Additional information obtained from successful in vitro-in vivo correlations (IVIVC) and accelerated drug release tests are extremely useful during drug product development.Although several workers have employed different methods to monitor drug release from these dosage forms, the use of the compendial Apparatus 4 (flow-through) device has been recommended in a publication on FIP/AAPS Guidelines for drug release testing of modified release dosage forms. However, most of method development with this device has focused on oral immediate or controlled release dosage forms and little published information is available on implants. Two recent reports on workshops provide useful information on methods to evaluate drug release from controlled-release parenterals such as implants, including IVIVC and accelerated release testing. Details on such studies, however, are generally not found in the literature; possibly because of the high proprietary value of methodologies for establishing release specifications of implant dosage forms. This article reviews the current status of methodologies used in the investigation of drug release from subcutaneous implants with an emphasis on mechanistic, product development and regulatory perspectives.

Safe and Sustained Vaginal Delivery of Pyrimidinedione HIV-1 Inhibitors from Polyurethane Intravaginal Rings

“…Although utilization of sink conditions does in fact classify the device type-the most common being time dependent (matrix devices) or time independent (reservoir devices)-it seldom reflects in vivo pharmacokinetics. This and other studies utilizing novel delivery platforms have shown a disparity between in vitro release under sink conditions and in vivo release, particularly for poorly water soluble compounds, which constitute the majority of antiretrovirals being developed as microbicides (20,42). With hydrophobic compounds such as the PYDs, achieving sink conditions requires large volumes of aqueous release medium (up to hundreds of milliliters per day) and/or a high concentration of surfactants or organic solvents to increase the API's solubility in the medium.…”

Polymeric implants of diclofenac for site specific and prolonged drug delivery for use in orthopedic or arthritic patients.

“…The tremendous release of drug ensures the degradation of polymer that can be seen in release profile in the form of sigmoidal curve. Surfacedegrading approach and bulk-degrading approach are the two subcategories of the degradation-controlled mechanism [23,24]. Further studies are needed to be performed in animals followed by the clinical study to validate the effectiveness of the prepared implants.…”

Regulatory Issues and Challenges Associated with the Development of Performance Specifications for Modified Release Parenteral Products

“…Accelerated release for implants and microspheres may be accomplished via modifi cations of temperature, solvent, ionic strength, pH, agitation rate, or the addition of surfactants or enzymes [ 54 ] . However, in each case, such changes could potentially alter the mechanism of drug release.…”

“…Iyer [ 54 ] provided a list of considerations for the development of product specifi cations and in vitro rest methods. Based upon the discussions provided in this chapter, we can add to that list.…”