(T1530-05-31) A Novel Dissolution Model to Study the Release and Uptake of Oral Lymphotropic Drug Products

Purpose: The design of candidate lymphotropic formulations is meticulously tailored to facilitate their preferential uptake by the intestinal lymphatics, providing an alternative absorption pathway in contrast to the enteric-portal route. However, conventional dissolution tests, while indispensable for assessing drug quality and performance in specified media, lack the ability to predict their absorption via the portal pathway or their subsequent circulation within the lymphatic system. To address this critical knowledge gap, our study endeavors to develop an innovative first-generation dissolution model. This model aims to investigate the dynamics of release and uptake exhibited by orally administered lymphotropic drug formulations, while simultaneously exploring and elucidating key formulation challenges.

Methods: Dissolution tests were condcuted on three commercially available lymphotropic drug products: Terbinafina (Laboratorio), APO-TERBINAFINE (Apotex), and Lamisil (Novartis). These tests were performed using modified USP Apparatus II and IV, which incorporated a lymphatic compartment to simulate lymphatic uptake. To create the lymphatic space, a dialysis bag with a molecular weight cut-off (MWCO) of 12-14kD and a width of 45 mm was utilized, holding 5 ml of Intralipid®. Intralipid® serves as an artificial chylomicron, representing lymph-carrying lipoproteins formed by enterocytes that facilitate drug transport through the lymphatics. Standard dissolution conditions were applied to evaluate drug release in various media. Samples were collected at different time intervals, up to 60 minutes, and subsequently filtered through 0.2µ nylon filters before being injected into HPLC vials for analysis. Drug samples from the lymphatic vicinity samples were treated with acetonitrile before their filtration and HPLC analysis.

Results: Our experimental setup allowed us to assess both the rate and extent of drug release into simulated biological fluids and lymphatic fluid simultaneously, enabling a comprehensive analysis of release profiles over time. The percentage of drug dissolved at different time points demonstrated notable variations among the three products, as depicted in Table 1. Apoterbinafine showed the lowest release in both models with the modified USP IV being able to impart better distinction between products. The variation in performance was attributed to the excipients utilized in the tested products. In general, the lymphatic uptake profile of the products closely mirrored their blood release profile.

Conclusion: Our research findings demonstrated the effectiveness of the developed lymphatic-focused methodology and dissolution models in evaluating formulations and identifying factors that may influence chylomicron uptake. It is essential to establish robust pharmaceutical lymphotropic performance testing methods that can keep up with the growing complexity of pharmaceutical products. The proposed model offers valuable insights for assessing formulation and manufacturing processes and has the potential to contribute to the development of in-vitro bioequivalence guidelines specifically tailored for lymphotropic formulations.

References: 1. Yousef M, Silva D, Bou-Chacra N, Davies N, Löbenberg R. The Lymphatic System: A Sometimes Forgotten Compartment in Pharmaceutical Sciences. Journal of Pharmacy and Pharmaceutical Sciences, 2021; 24: 533-547.
2. Yousef M, Park C, Le T, Bou-Chacra N, Davies N, Löbenberg R. Simulated Lymphatic Fluid for In-vitro Assessment in Pharmaceutical Development. Dissolution Technologies, 2022; 29(2): 86-93.
3. Yousef M, Davies NM, Löbenberg R. Development of Novel In-vitro Model to Study Lymphatic Uptake of Drugs Following Oral Administration. J Pharm Pharm Sci, 2021; 24: 50s.

Table 1. Results of performance of the three terbinafine products in modified dissolution apparatus for lymphotropic performance testing