Subdermal implants for controlled release of small molecule drugs

Abstract

Long-acting subdermal implants have emerged as a promising platform for drug delivery, providing controlled/sustained therapeutic effects over months to years when implanted beneath the skin. This thesis investigates the development, optimization, and evaluation of subdermal implant platforms designed to deliver small molecule therapeutic agents over extended periods, addressing the issues of patient compliance associated with conventional drug delivery methods such as oral administration. The key aim of this PhD project is to develop subdermal implants capable of providing long-term controlled release of two small molecule drugs at targeted therapeutic doses: dapivirine (DPV), a non-nucleoside reverse transcriptase inhibitor (NNRTI) for HIV-1 pre-exposure prophylaxis (PrEP); and cholecalciferol (vitamin D3), to alleviate widespread vitamin D deficiency.

These subdermal implants were developed using thermosetting silicone elastomers—the polymer previously used in marketed subdermal implants such as Norplant®, Jadelle®, and Sino-implant (II) ®, as well as the in the monthly DPV vaginal ring developed through collaboration between our research group at Queen’s University Belfast and the International Partnership for Microbicides (IPM). The subdermal implants were manufactured using several methods: (i) injecting the drug-containing silicone elastomer mix or liquid Kolliphor EL into the commercially available medical grade silicone tubing to create reservoir-type implants; (ii) injecting the drug-containing silicone elastomer mix into mold—polyvinyl chloride (PVC) sleeving—to create matrix-type implants; (iii) using a dip-coating method to apply a thin drug-free silicone elastomer film to the surface of matrix-type implants to create reservoir-type implants.

The development of the DPV subdermal implant aimed to investigate how various parameters modulate drug release rates and to formulate implants that deliver the required DPV dose. In vitro release testing evaluated factors such as drug loadings, implant dimensions (drug-loaded core and non-medicated rate-controlling membrane), implant types (reservoir-type and matrix-type), implant designs (solid core and liquid core), and testing parameters (release medium volume) that impact on the drug release rates. The results demonstrated that DPV release from the reservoir-type implant with a constant activity source followed zero-order release kinetics, with the release rate modifiable by adjusting the thickness of the rate-controlling membrane and the surface area of the drug-loaded core. Increasing drug loading in the core could extend the implant’s duration with minimal effect on the DPV release rate. For the reservoir-type DPV implant with a non-constant activity source using liquid Kolliphor EL as a solubilising agent, the DPV release rate correlated with drug loading but gradually decreased as the DPV concentration in the core declined. DPV release from the matrix-type implant followed the Higuchi model under permeation-controlled conditions but shifted to zero-order release kinetics under conditions of inadequate agitation and/or non-sink release medium (dissolution-controlled mechanism).

In developing the vitamin D3 subdermal implant, the primary challenge was stabilizing vitamin D3 to prevent its degradation within the implant. To address this, antioxidants were incorporated into liquid Kolliphor EL-based implants, and the impacts of different antioxidant types and quantities on vitamin D3 release and stabilization were evaluated. The results suggested that achieving the desired vitamin D3 delivery dose with optimal stability required the antioxidant to have sufficient potency and efficacy without being rapidly released or depleted alongside vitamin D3. Additionally, a cocrystal of vitamin D3, known for its enhanced stability, was synthesized and used as a surrogate for pure vitamin D3 in silicone elastomer-based implants. The release profile of vitamin D3 from these cocrystal-incorporated implants was also assessed, and the drug release mechanisms were thoroughly investigated to guide further formulation optimization.

Comprehensive mechanical studies were conducted using several testing methods, including Shore (durometer) hardness testing, three-point bend testing, and tensile testing, to evaluate the impact of implant dimensions, silicone elastomer types, drug types and loadings on the mechanical properties of the implants developed in this thesis. These studies provided insights into how these parameters affect the mechanical properties of the subdermal implant device, with the aim of guiding further implant development and optimization to achieve optimal mechanical strength and flexibility, preventing implant fracture during insertion, removal, or while in situ.

The studies presented in this thesis are encouraging for the future subdermal implant platforms for other small molecule drugs targeting chronic indications.

Date of Award	Dec 2024
Original language	English
Awarding Institution	Queen's University Belfast
Supervisor	Peter Boyd (Supervisor) & Karl Malcolm (Supervisor)