(496c) Rapid on-Site Manufacturing Approach with 3DP Capsules: Delayed Burst Release for Regional Absorption

A critical gap existing in our first-to-human strategy is the ability to evaluate complex dosage forms under the on-site formulation (OSF) strategy. We propose to use 3D printing (3DP) to fill this gap by enabling OSF with custom dosage forms using this flexible, high quality, highly reproducible, rapid, and material sparing approach. The 3DP platform has the potential to enable project teams to gain a better understanding of the complex in vitro-in vivo relationships across different drug release mechanisms through accelerated pharmacokinetic screening clinical trials during or immediately following Phase I, and potentially diminish a portion of the decade-long timing from molecule patent to commercialization. Specifically, human regional absorption and permeation is difficult to determine in early clinical phases. The models we use today for calculating regional permeation in the GI tract are largely based on datasets collected in the last few decades using one of two approaches: 1) a double lumen or triple lumen catheter system, or 2) either a single or double tube-balloon system, where the tube would be fed through the intestinal tract and the balloons would be inflated to isolate a portion of the intestines during the study. Both methods are invasive and not feasible as a routine study in humans. An oral delivery system has been developed by Medimetrics called IntelliCap, which is capable of investigating regional absorption; however, this technology is proprietary and therefore may not be cost effective to use for routine studies.

A Hyrel 3D System 30M printer along with various modular heads were purchased from Hyrel 3D, whose heads were modified or custom designed to be able to print new polymer filaments that are semi-brittle, soft, or flexible, or a combination thereof, or to be capable of injecting fluids with viscosities between 20-3000 cP for a single-click print-and-fill dosage form. In this presentation, the development of a set of capsule formulations for delayed burst release with controlled timing is shown to facilitate regional absorption studies on new active pharmaceutical ingredients. By manipulating the thickness of the capsule walls, the onset of release can be controlled. Due to the swelling behavior of PVA, it was discovered that the mechanical properties were critical for robust formulations due to delamination failure that would occur if the layer-layer weld during the printing process was not sufficiently strong. It was also found that fillings containing a large fraction of swellable materials, such as water, affected the physical stability of the formulations. As a first step to enable robust formulations, finite element analysis was used to understand the effect of water-containing drug fillings on the dissolvable capsule shell, and the shell geometry was optimized to reduce swelling stresses that may cause delamination in- vitro or vivo. Second, software techniques were developed, called zoning, to print capsules with no functional defects. Additionally, due to the nature of the 3DP process, in vitro analysis revealed a unique anisotropic dissolution behavior. Custom USP2 hanging baskets were designed and manufactured via 3DP for orientation control during dissolution. Lastly, an in vivo (beagle dogs) study was run using two 3DP capsule formulations and an immediate release compacted tablet as a control, and found a good in vitro – in vivo relationship.