Impact of product design parameters on in vitro release from intrauterine systems

Abstract

Polydimethylsiloxane (PDMS)-based levonorgestrel intrauterine systems (LNG-IUSs) contain a large amount of potent LNG, and therefore it is important to understand the impact of product design parameters on the in vitro and in vivo performance to ensure safety and efficacy, as well as to avoid serious side effects resulting from dose dumping. LNG-IUS is a complex drug-device combination product, and its formulation design, requires consideration of additional factors such as device configuration and dimensions, in addition to formulation and processing parameters. In this study, ten qualitatively (Q1) and quantitatively (Q2) equivalent LNG-IUSs were manufactured with differences in source (supplier) and dimensions (i.e., thickness) of the outer membrane, drug particle size, dimensions of the drug reservoir (i.e., inner diameter), as well as configuration of the entire IUS. A real-time in vitro release testing method was developed for the LNG-IUSs. In addition, an accelerated release testing method was developed using hydro-alcoholic media in order to reduce the time associated with formulation design. Source variations and thickness of their outer membranes had a great impact on the in vitro drug release from the LNG-IUSs. It was demonstrated that the thicker the outer membrane, the slower the drug release rate. The physicochemical properties of the outer membranes obtained from different sources were characterized to understand their impact on the in vitro drug release of the LNG-IUSs. The composition and mechanical strength may play a role in differences in drug release. The LNG-IUS formulation prepared with the larger drug particle size showed a slightly slower daily release rate. The drug release rates from the compositionally equivalent LNG-IUSs linearly correlated to the surface area of the corresponding drug reservoirs. Another factor that affected the drug release rate was the configuration of the entire IUS. It was shown that the placement of the outer membrane was significant, i.e. whether the ends of the drug reservoir were covered or not. It is important to note that real-time release showed zero-order release kinetics over the test period of approximately 900 days. The current study provides a comprehensive understanding of the impact of product design parameters on the in vitro drug release of LNG-IUSs. In addition, the developed real-time and accelerated release testing methods showed good discriminatory ability for compositionally equivalent LNG-IUSs prepared using different product design parameters.

Keywords: In vitro drug release; Levonorgestrel; Polydimethylsiloxane; Product design; Source variation; USP apparatus 2.