(T1430-01-01) 3-D Printed Rapidly Disintegrating Oral Films for Targeted Delivery of Aspirin in the Brain for Ischemic Stroke

Purpose: Stroke is one of the leading causes of death and disability. In the United States alone, more than 795,000 people experience a stroke every year, of which 87% are ischemic strokes, and 25% of the cases are due to the recurrence of stroke cases. Aspirin, a versatile small-molecule drug with irreversible non-selective COX-1 and COX-2 inhibition, at low doses, alone or in combination, is approved for the secondary prevention of acute non-cardioembolic ischemic stroke and transient ischemic stroke conditions. Due to its ability to induce anti-inflammatory and antiplatelet aggregation effects soon after an acute event, it is recommended for patients who have already had an ischemic stroke or transient ischemic attack (TIA), as they are at high risk for stroke recurrence. It is widely explored in dual antiplatelet therapies in conjunction with other selective COX inhibitors like Clopidogrel for ischemic stroke interventions and prevention of neurodegenerative diseases. Currently, Aspirin is being delivered via oral and intravenous (IV) routes, which come with several shortcomings, including the lower ability of Aspirin to cross the blood-brain barrier (BBB) and severe systemic side effects like gastric bleeding, thus increasing the risk of comorbidities in critically ill and comatose patients. Therefore, there is a need to develop a brain-targeted drug delivery system for Aspirin to increase its penetrance into the brain tissue, further increasing its local potency and reducing systemic side effects. The primary objective of this project proposal is to develop and test a brain-targeted nanoparticle delivery system for Aspirin and its administration using pain-free drug administration strategies such as nasal drops (intranasal) and oral dissolving films (buccal) to enhance convenience in non-responsive patients.

Methods: The formulation of ODFs involved the use of various biodegradable polymers. The photo-initiator, Diphenyl phosphine oxide, was used to initiate the UV crosslinking reaction. G-code was created for printing the ODF using CELLINK INKREDIBLE plus® 3D bioprinter. The ODFs of the lead formulation were printed and crosslinked under UV light with an intensity of 405 nm for film formation. The ODF formulation was printed in an in-lab prepared mold. This mold was prepared using the SYLGARD 186 silicone elastomer kit of two polymers. The base (10 parts) was combined with the curing agent (1 part). After the final mixture was stirred for 20 min, the mixture was placed onto the lid of a 96-well plate. Finally, the 96-well plate was placed directly on top of the lid where the mixture of bases A and B was located. Then, this 96-well plate was placed in the desiccator overnight. Blank ODFs (only polymers) and Aspirin NPs ODFs, were characterized. The average diameter of the ODFs was 0.43 mm, which is an appropriate size for a mice in-vivo model. Once the thin film is placed in the buccal cavity, an optimal ODF should allow the film-forming polymers to disintegrate quickly, releasing the BSA Aspirin nanoparticles. The average disintegration time was 2.4 minutes, indicating a quick disintegration time, leading to a quicker dispensing of the drug-loaded NP. The pH of the buccal mucosa is approximately 6.5-7.2. The pH of the aspirin-NPs loaded ODFs is within the neutral range, indicating that the ODF formulation was suitable for the buccal mucosa.

Results: The physiochemical characterization of 3D-printed oral dissolving films was evaluated based on various parameters. The weight variation was recorded as 8.43 ± 0.74 mg for the blank polymer film, 10.73 ± 0.46 mg for the blank MP film, and 10.86 ± 0.28 mg for the aspirin-loaded MP film. The diameter was consistently 0.4 mm for all film types, while the thickness was 0.33 ± 0.10 mm for the blank polymer and 0.47 ± 0.24 mm and 0.47 ± 0.26 mm for the blank MP and aspirin MP films, respectively. The disintegration time increased slightly with the inclusion of active components, showing values of 1.38 ± 0.29 minutes for the blank polymer, 2.24 ± 0.24 minutes for the blank MP, and 2.38 ± 0.28 minutes for the aspirin MP film. The pH of the films remained neutral to slightly alkaline, with a pH of 7.5 for both the blank polymer and aspirin MP films, while the blank MP film exhibited a pH of 8. These results highlight the uniformity, quick disintegration, and neutral pH profile of the films, suggesting their potential suitability for oral administration.

Conclusion: We successfully formulated and characterized 3D-printed oral dissolving films (ODFs) for the targeted delivery of aspirin to the brain. These ODFs are designed to facilitate the delivery of nanoparticulate formulations, supporting the hypothesized improvement in targeted drug delivery and therapeutic outcomes. Additionally, by exploring non-traditional, pain-free routes of administration, this proof-of-concept study provides a foundation to evaluate and compare the effectiveness of nanoparticle-based formulations delivered through these innovative methods.

References: 1. Ugwoke, M.I.; Verbeke, N.; Kinget, R. The Biopharmaceutical Aspects of Nasal Mucoadhesive Drug Delivery. J. Pharm. Pharmacol. 2010, 53, 3–21, doi:10.1211/0022357011775145.
2. Pacheco, M.S.; Barbieri, D.; Da Silva, C.F.; De Moraes, M.A. A Review on Orally Disintegrating Films (ODFs) Made from Natural Polymers Such as Pullulan, Maltodextrin, Starch, and Others. Int. J. Biol. Macromol. 2021, 178, 504–513, doi:10.1016/j.ijbiomac.2021.02.180.

Table 1 Physiochemical characterization of ODFs