(T1330-03-13) Fabrication and In Vivo Evaluation of 3D Printed Biocompatible Dissolvable Microneedle Patch

Purpose: Microneedles (MNs) are primarily fabricated using multistep polydimtheylsiloxane (PDMS) micromolding method which makes it a batch process and may face reproducibility issues with final product. Lately, MNs have been formulated using a continuous one step process of 3D printing technology. Moreover, it is highly efficient and reproducible technique and can print any design or dimensions of MNs in much less time compared to micromolding approach. Dissolving MNs have been fabricated usingDiphenyl (2,4,6 trimethyl benzoyl) phosphine oxide (TPO) as a photo initiator in combination with PEGDA, polycaprolactone and polyacrylic acid using one step CLIP 3D printing technology. In our previous study, we have also developed DLP printed intelligent MN array (iµNA) usingpoly (ethylene glycol) dimethacrylate (PEGDA) resin containing TPO as a photo initiator and diclofenac sodium as an Active Pharmaceutical Ingredient. However, in a study by Landuyt et al, it has been reported that TPO can cause toxicity in clonal SV 40 large T-antigen transfected human pulp-derived cells (tHPC). Further, a personalized 3D DLP printed MN patch was developed for the subcutaneous delivery of anti-wrinkle small peptide, acetyl hexapeptide 3 (AHP-3) using resin containing polyethylene glycol diacrylate (PEGDA, MW: 700 Da),phenylbis (2,4,6-trimethylbenzoyl) phosphine oxide (BAPO) and vinyl pyrrolidone (VP). However, BAPO has also been reported as a non-biocompatible photo initiator because of its toxic effect on cells. The objective of the present study was to develop and evaluate 3D printed microneedles (MNs) containing Lithium phenyl-2,4,6- trimethylbenzoylphosphinate (LAP) as a photoinitiator to deliver lipophilic active pharmaceutical ingredients (APIs) transdermally for 72 hours (hrs) using quality by design (QbD) and artificial intelligence (AI) algorithms.

Methods: Formlabs Form 2 SLA printer was redesigned using Autodesk fusion 360 software (Fig 1). Resin was formulated using IBU, LAP, poly (ethylene glycol) dimethacrylate 550 (PEGDAMA 550) and distilled water. IBU MN patches were printed using SLA and DLP printing technology. Preliminary screening of LAP concentration, water concentration, exposure time and light intensity was done in the process of IBU MN optimization. IBU MN patch was optimized using three independent variables: LAP concentration (A), water concentration (B) and exposure time (C). Central composite design with 20 run was created and aspect ratio and tip Roc of MNs were measured. Design of Experiment results were validated by Artificial Intelligence (AI) and machine learning algorithms. In vitro release testing (IVRT) and In vitro permeation testing (IVPT) of IBU MNs were also performed. IBU MN patch was then evaluated in in vivo pharmacokinetic studies.

Results: In the present study, dissolvable MN patch of ibuprofen (IBU) as a model drug was successfully fabricated using digital light projector (DLP) printing technology with ~750 μm height, ~250 μm base diameter and tip with radius of curvature (Roc) of ~15 μm (Fig 2). MN patches comprised of IBU, LAP, poly (ethylene glycol) dimethacrylate 550 (PEGDAMA 550) and distilled water were developed using QbD optimization approach and validating using AI and machine learning algorithms. Mechanical strength studies demonstrated that IBU MNs formed pores both on parafilm and human cadaver skin. IBU MNs consisting of 0.23% and 0.49% LAP with 10% water in each showed ~ 2mg/cm²sustained drug permeation at the end of 72 hrs in vitro skin permeation testing studies (IVPT) with flux of ~ 20 μg/ cm²/hr in first 24 hrs. Further, pharmacokinetic (PK) studies conducted in rats for 48 hrs showed ~ 62812.02 ± 11128.39 (ng/ml*hr) of Area under curve (AUC) (0-48hr), 2.66 ± 1.12 h of Tmax and 3717.43 ± 782.25(ng/ml) of Cmax from the IBU MN patch containing 0.23% LAP with no significant difference compared to the patch containing 0.49% LAP (Fig 3).

Conclusion: In conclusion, in the current study, for the first time, biocompatible dissolvable IBU MN patch was successfully fabricated using DLP printing technology to deliver lipophilic API in a sustained manner for 72 hrs in IVPT studies. PK study showed systemic absorption of drug from IBU MNs. These results suggests that various APIs, proteins and peptides can be delivered using DLP printed dissolvable MNs because of its various advantages including its high efficiency, accuracy and reproducibility to print MNs.

Acknowledgements: The research was supported by the National Institute on Minority Health and Health Disparities of National Institutes of Health under Award number U54 MD007582 (U54 RCMI grant) and NSF-CREST Center for Complex Materials Design for Multidimensional Additive Processing (CoManD) award # 1735968.


Fig 1: (A) Redesigned Formlabs Form 2 SLA printer showing significant reduction in the size of build platform and resin tank in the modified printer. (B)Redesigned printer showing modified tank (6cm x 3cm) was fixed inside the large tank 22.5 cm x 18 cm) and the large build platform (15cm x 15 cm) was replaced with small build platform (2cm x 2cm).


Fig. 2: (A) 4 cm2 IBU MN patch after finishing the printing. (B) SEM image of IBU MN patch showing prominent MNs with height of ~ 750 µm height, 350 µm base diameter and 15 µm tip Roc (C) Magnified view of one row of IBU MN array


Fig3. IVPT study showing 0.22% LAP+10% water and 0.49% LAP+10% water showed significantly high cumulative drug permeation at 24, 48 and 72 hrs compared to 0.22% LAP+20% water and 0.49% LAP+20% water. PK study of IBU MN patch on Sprague dawley rats showing no significant effect in systemic absorption of IBU from the IBU MN patches containing 0.23% LAP+10% water and 0.49 % LAP+10 % water.