(M1030-01-04) Development of Extrusion-Based 3D Printed Hydrophilic Polymeric Transdermal Films of Pramipexole Dihydrochloride for Parkinson’s disease

Purpose: 3D printing has been revolutionizing the pharmaceutical industry as it enables the construction of diverse pharmaceutical formulations with flexibility in geometric shapes and patterns. 3D printing is an additive manufacturing technology that is classified into different types based on the principle involved and extrusion-based 3D printing is one such platform which has gained significant importance in pharmaceutical industry. Developing 3D printed films for transdermal delivery of drugs offers noteworthy advantages in comparison to conventional transdermal patches as 3D printing allows for incorporation of different polymers, enables control over release rates, facilitates a complete solvent-free environment and a provides a continuous manufacturing platform devoid the use of heat. Parkinson’s disease (PD) is the second most common neurodegenerative disease that has approximately 10 million cases worldwide. Pramipexole dihydrochloride (PPXCL) (logP: 1.76, MW: 284.24g/mol) is a dopamine agonist which triggers the secretion of dopamine. It is used for treating PD and is taken orally as tablets (0.375-4.5 mg). PD severely compromises the quality of life and is more prevalent amongst the elderly population who are most likely to be affected with other concomitant conditions. Being on multiple therapies further challenges patient compliance and adds to the pill burden. Thus, in this project we aimed to assess the feasibility of using different grades of polymers for developing 3D printed films that can be used as a three-day transdermal film for managing PD.

Methods: In vitro permeation testing (IVPT) studies were performed using vertical Franz diffusion cells across dermatomed porcine ear skin. To assess the barrier integrity of the skin, transepithelial electrical resistance (TEER) was measured. The passive permeation of PPXCL was studied using a 2% solution of PPXCL in 1X phosphate buffered saline (PBS) and receptor samples were collected at predetermined time points for up to 72 hours and analyzed using a validated RP-HPLC method. The choice of the primary film-forming agent was done by assessing different grades of polyvinyl alcohol (PVA; EMPROVE® exp Ph Eur, USP, JPE) having varied molecular weights (PVA 3-82, PVA 8-88, PVA 18-88, PVA 26-88 and PVA 40-88). Plastoid® was chosen as the hydrophilic adhesive and glycerin was chosen as the plasticizer. The grade and percentage of PVA for formulating the film was optimized. Azone, transcutol and dimethyl sulfoxide (DMSO) were screened as chemical enhancers. Polymeric solutions were prepared by dissolving PVA in water at 90 °C. Plastoid® was prepared using Eudragit E100, lauric acid and adipic acid. PVA solution, Plastoid® and glycerin were mixed post which 2% PPXCL was loaded and kept for mixing overnight in a rotary shaker. The polymeric blends were assessed based on various parameters such as the extent of drug loading, extrudability from 3D printer nozzle, adhesiveness, and rheological properties. F8 and F13 were chosen for 3D printing drug loaded films. Printing parameters such as nozzle diameter, printing speed, printbed temperature, infill pattern and printing pressure were optimized. The 3D printed films were air-dried overnight and their drug content and weight uniformity were assessed. IVPT was performed using these films across dermatomed porcine skin (Figure 1). The effect of the chosen polymer grade and chemical enhancer on permeation was assessed by performing statistical analysis using one-way ANOVA analysis.

Results: All polymeric blends were found to be shear thinning systems and had varying viscosities. Polymeric blends made with high molecular weight PVA enabled increased drug loading, were more adhesive and had better printability. Thus, F8 and F13 films were chosen as prototypes for IVPT (Figure 2). An increase in transdermal permeation of PPXCL was observed in both cases, from drug loaded films and from films with chemical enhancers. 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) 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 (Figure 3).

Conclusion: 3D printed polymeric hydrophilic adhesive films of PPXCL were developed and characterized. The effect of incorporating different grades of polymers and chemical enhancers was assessed.

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.
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Steps involved in development of 3D printed polymeric films


Formulation matrix and its properties


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