Formulation Strategies to Improve Drug Absorption: The Role of Lipid-Based Formulations and Permeation Enhancers

This poster has been presented at the 15th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology, which took place in Prague, Czech Republic.

Formulation Strategies to Improve Drug Absorption: The Role of Lipid-Based Formulations and Permeation Enhancers

Introduction

Lipid-based formulations (LBFs) are a key strategy to enhance oral absorption of poorly soluble and permeable compounds (BCS II–IV), but their development requires predictive in vitro models reflecting gastro-intestinal physiology[1]. Ticagrelor, a BCS IV antiplatelet drug, has low solubility and permeability, making it suitable to evaluate LBFs performance.

Intestinal permeability is usually assessed with Caco-2 monolayers[2], yet they lack physiological features such as mucus, which affects absorption and barrier function. Caco-2/HT29-MTX co-cultures introduce a mucus layer, improving model relevance[3].

This study formulates LBFs using excipients with different functionalities and compares ticagrelor permeability in Caco-2 monolayers versus Caco-2/HT29-MTX (70:30) co-cultures to assess the impact of mucus and how lipid excipients modulate intestinal permeability.

Materials & Methods

Table 1. Lipid-based formulations composition

Cytotoxicity: cytotoxicity studies were conducted to assess the toxicity of the lipid-based formulations. Analyses were performed using a flow cytometer (Attune™ NxT Flow Cytometer, Thermo Fisher Scientific, USA). Briefly, a cell suspension at a density of 5×10⁴ cells per well was seeded in 12-well plates. For each condition, cells were treated with the corresponding sample (pure ticagrelor, placebo, or ticagrelor in LBFs) diluted in Hank’s Balanced Salt Solution (HBSS) for 4 hours at 37 °C.

Permeability: cells were seeded on 12-well Transwell® inserts at 5×10⁴ cells/mL and cultured for 21 days, refreshing medium every two days. Only monolayers with TEER > 500 Ω·cm² (monoculture) or > 300 Ω·cm² (coculture) were used. LBFs were formulated at 80 mg/g and diluted 1:8000 in HBSS before apical addition. Samples were collected at 15, 30, 60, 120, and 180 min and analyzed by LC/MS.

Materials: ticagrelor was obtained from Chanyoo Pharmaceutical Co., Ltd. (Nantong, Jiangsu, China). Tween® 80 was purchased from Sigma-Aldrich (Merck KGaA, Darmstadt, Germany). Labrasol® ALF, Transcutol® HP, Labrafac™ MC60 and Maisine® CC were kindly provided by Gattefossé (Saint-Priest, France).

Results

In both Caco-2 monoculture and Caco-2/HT29-MTX co-culture (Figures 1 and 2), ticagrelor LBFs showed a similar permeability ranking. Pure ticagrelor exhibited low Papp (1.02 × 10-7 cm/s in monoculture, 1.25 × 10-7 cm/s in co-culture).

The Transcutol® HP-only formulation (F5) showed the lowest permeability, reflecting its limited ability to maintain solubilization, despite its solvent capacity. LBFs without permeation enhancers (F3) provided modest improvement, while replacing Tween® 80 with Labrasol® ALF (F4) increased Papp due to Labrasol® ALF permeation-enhancing effect.

Formulations containing only permeation enhancers (F1, F2) showed the greatest improvement: in monoculture, Papp increased 9.4- and 8.4-fold, and in co-culture, 5.2- and 6.6-fold, respectively.

Overall, permeability was lower in the co-culture (Figure 3), however, this difference was not statistically significant and should be interpreted only as an observed trend. This tendency may be related to the patchy mucus layer (Figure 4), which could increase local viscosity and partially limit the diffusion of ticagrelor and LBFs.

Conclusion

• This study is the first to assess ticagrelor LBFs permeability using a Caco-2/HT29-MTX coculture, which better mimics intestinal physiology, and highlights the influence of the mucus layer on apparent permeability.
• Across both models, LBFs enhanced ticagrelor absorption even at low excipient concentration. Conventional solubilizing excipients increased Papp versus the pure API, while dual-functional permeation enhancers produced an additional permeability gain.
• Compared with Caco-2 monocultures, the co-culture generally showed lower permeability, consistent with the diffusional barrier imposed by the mucus layer.

See the full poster on Formulation Strategies to Improve Drug Absorption here

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Source: Gattefossé SAS, Université Clermont Auvergne, Arnaud Bourderi-Cambon, Khaled Fadhlaoui, Manon Rossano, Cédric Miolane, Philippe Caisse, Eric Beyssac, PBP poster: Formulation Strategies to Improve Drug Absorption: The Role of Lipid-Based Formulations and Permeation Enhancers

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