A Reactive Prodrug Ink Formulation Strategy for Inkjet 3D Printing of Controlled Release Dosage Forms and Implants

Yinfeng He,Richard J M Hague,Gustavo F Trindade,Giuseppe Mantovani,Ricky D Wildman,Shaban Khaled,Christopher J Tuck,Derek J Irvine,Felicity R A J Rose,Ruggero Foralosso,Alexander Ilchev,Laura Ruiz‐Cantu,Clive J Roberts,Elizabeth A Clark

doi:10.1002/adtp.201900187

Abstract

AbstractA strategy for creating tuneable 3D printed drug delivery devices is proposed. 3D printing offers the opportunity for improved compliance and patient treatment outcomes through personalization, but bottlenecks include finding formulations that provide a choice of drug loading and release rate, that are tuneable, and avoid the need for surgical removal. The suggested solution is to exploit 3D inkjet printing freedoms. A reactive prodrug is used that can polymerize into drug‐attached macromolecules during 3D printing and by tuning the hydrophilicity, hydrolysis can be facilitated or hindered, which in turn controls drug release. To demonstrate this approach, ibuprofen is attached to 2‐hydroxyethyl acrylate through a cleavable ester bond, formulated for inkjet 3D printing, and then printed to produce a solid dosage form. This allows a much higher loading than is usually achievable—in this case up to 58 wt%. Of equal importance, the 3D inkjet printing freedoms mean that the drug delivery device is highly tuneable: by selection of spacer monomers to adjust the hydrophilicity; through geometry; by spatially varying the components. Consequently, hierarchical release systems are created bespoke, from the molecular to macro. This approach represents a new paradigm for the formulation of printable inks for drug‐loaded medical devices.

Highlights

Introduction lio of3D printing techniques that are available for fabricating solid dosage forms and implants
Our approach has a number of elements that provide advantages over commonly used formulating strategies: First, we are able to achieve ink formulations that can hold up 58 w/w% drug loading and are amenable to IJ3DP processing; second, through the tuning of the ink formulation we have demonstrated that manipulation of the release profile of the printed product is possible; third, as the drug is released, the polymer backbone structure dissolves avoiding the necessity for surgical removal
Schematic of the approach used to prepare a reactive prodrug for ink formulation development. a) The selected drug candidate was grafted to a reactive monomer by a degradable covalent bond and prepared into inkjet printable formulations by mixing with additives that can tune the release speed;[37,38] The developed formulation was inkjet-printed and polymerized in situ by UV photo-polymerization to form a solid 3D structure; b) Molecular structures of ibuprofen, hydroxyethyl acrylate, and synthesized reactive prodrug; c) Bespoke tablets with a spatially varying drug distribution fabricated with multi-material IJ3DP

Summary

Introduction

Introduction lio of3D printing techniques that are available for fabricating solid dosage forms and implants. We demonstrate the design of a reactive prodrug using a low viscosity reactive linker which contains two side groups (Figure 1a); one of which can form a temporary bond with the target drug molecules, while the other side group is able to polymerize to form solid structures during the IJ3DP process.

Results

Conclusion