(M0930-08-51) Design and Evaluation of 3D Printed Hydrophilic Transdermal Films of Pramipexole Dihydrochloride Using PVA Variants

Purpose: 3D printing has emerged as a transformative technology in the pharmaceutical industry, enabling the fabrication of diverse drug formulations with customizable geometric designs and patterns. Among various 3D printing techniques, extrusion-based 3D printing has gained significant traction due to its suitability for pharmaceutical applications. In particular, the development of 3D printed films for transdermal drug delivery offers distinct advantages over conventional transdermal patches. These include the ability to incorporate multiple polymers, precise control over drug release profiles, solvent-free processing, and a heat-free, continuous manufacturing platform. Parkinson’s disease (PD), the second most common neurodegenerative disorder, affects approximately 10 million people worldwide. Pramipexole dihydrochloride (PPXCL) (logP: 1.76, MW: 284.24 g/mol), a dopamine agonist, is commonly prescribed for PD management in oral tablet form (0.375–4.5 mg). PD predominantly affects the elderly, who often deal with multiple comorbidities, resulting in polypharmacy and reduced medication adherence. This project explores the feasibility of utilizing various grades of polymers to fabricate 3D printed transdermal films designed for sustained, three-day drug delivery of PPXCL. Such a system aims to improve patient compliance by minimizing pill burden and offering a non-invasive, controlled-release therapeutic alternative for PD management.

Methods: Formulation development involved identifying the optimal film-forming agent, for which various grades of polyvinyl alcohol (PVA; EMPROVE® exp Ph Eur, USP, JPE) with differing molecular weights and hydrolysis percentage—PVA 3-82, 8-88, 18-88, 26-88, and 40-88—were screened. Plastoid® (composed of Eudragit E100, lauric acid, and adipic acid) was selected as the hydrophilic adhesive, and glycerin was used as a plasticizer. Polymeric solutions were prepared by dissolving PVA in water at 90 °C. Plastoid® and glycerin were subsequently incorporated, followed by the addition of 2% PPXCL. The resulting polymeric blends were mixed overnight using a rotary shaker to ensure homogeneity. Printing parameters such as nozzle diameter, print speed, bed temperature, infill pattern, and extrusion pressure were optimized for consistent film formation (Figure 1). These blends were evaluated for key formulation parameters, including drug loading capacity, extrudability through the 3D printer nozzle, adhesiveness, and maintenance of shape integrity upon printing (Table 1). Among the tested formulations, F8, F11 and F13 demonstrated optimal characteristics and were selected for in vitro permeation testing (IVPT) along with a 2% PPXCL solution in 1X PBS as the passive group. IVPT was conducted using vertical Franz diffusion cells with dermatomed porcine ear skin as the model membrane. To ensure skin barrier integrity, transepithelial electrical resistance (TEER) measurements were taken prior to the studies. Receptor samples were collected at predetermined intervals over a 72-hour period and analyzed using a validated RP-HPLC method. Azone, Transcutol®, and dimethyl sulfoxide (DMSO) were evaluated as potential chemical permeation enhancers and incorporated in the films. Subsequently the best-suited film as per IVPT results was characterized for weight uniformity, texture analysis and drug content. The influence of polymer grade and chemical enhancers on drug permeation was statistically evaluated using one-way ANOVA and suitable statistical test.

Results: Polymeric blends formulated with high molecular weight PVA demonstrated enhanced drug loading capacity, improved adhesiveness, and superior printability. Based on these characteristics, formulations F8, F11, and F13 representing PVA grades 18-88, 26-88, and 40-88, respectively were selected as the most suitable candidates for in vitro permeation testing (IVPT) (Table 1). A notable increase in transdermal permeation of PPXCL was observed from both the drug-loaded films and the formulations containing chemical permeation enhancers, when compared to the passive control group. The passive permeation of PPXCL from PBS as vehicle was 13.60±3.89 µg/cm² and a significant increase was seen in permeation from the 3D printed films F8 (37.88 ±3.05 µg/cm²), F11 (51.64 ±3.08 µg/cm² and F13 (83.22 ±8.06 µg/cm²). Upon incorporation of chemical enhancers into the F13 films, azone (584.92 ± 24.83 µg/sq.cm) and DMSO (368.14 ± 14.24 µg/sq.cm) further significantly enhanced the permeation and exploring the combination of DMSO and azone further enhanced the permeation (1298.70 ±181.99 µg/cm²) (Figure 2). Combination of chemical enhancers was done to assess improvement in lag time associated with delivery.

Conclusion: 3D printed polymeric hydrophilic adhesive films containing PPXCL were successfully developed and characterized. The impact of incorporating various polymer grades and chemical permeation enhancers on the film properties and drug permeation performance was systematically evaluated.

References: [1] S. Abdella, F. Afinjuomo, Y. Song, R. Upton, S. Garg, 3D printed bilayer mucoadhesive buccal film of estradiol: Impact of design on film properties, release kinetics and predicted in vivo performance, Int J Pharm 628 (2022). https://doi.org/10.1016/J.IJPHARM.2022.122324.
[2] M.D. Muñoz, H. Castán, M.A. Ruiz, M.E. Morales, Design, development and characterization of transdermal patch of methadone, J Drug Deliv Sci Technol 42 (2017) 255–260. https://doi.org/10.1016/J.JDDST.2017.04.011.
[3] C. Padula, S. Nicoli, P. Colombo, P. Santi, Single-layer transdermal film containing lidocaine: Modulation of drug release, European Journal of Pharmaceutics and Biopharmaceutics 66 (2007) 422–428. https://doi.org/10.1016/J.EJPB.2006.11.014.


Figure 1: Steps involved in development of 3D printed polymeric films


Table 1: Formulation matrix and its properties


Figure 2: IVPT results showing A) Total amount of PPXCL delivered in receptor from PBS vehicle and 3D printed films F8, F11 and F13. B) Total amount of PPXCL delivered in receptor from F13 films incorporated with chemical enhancers transcutol, Azone and DMSO and combination (DMSO + azone).