(T1430-07-45) Development of Inhalable Tadalafil Formulations for the Treatment of Pulmonary Hypertension

Purpose: Pulmonary hypertension is one of the complex disease conditions that can cause severe morbidity and mortality. Tadalafil is one of the effective drugs that can treat pulmonary hypertension, however, exhibits poor solubility. The purpose of this study is to develop and evaluate inhalable formulations of tadalafil for treating pulmonary hypertension by improving the poor aqueous solubility thereby increasing the bioavailability of Tadalafil.

Methods: Various solubilizing techniques were developed to improve the solubility of Tadalafil, including β-cyclodextrins (βCD, HP-βCD, SBE-βCD), Self-Nanoemulsifying Drug Delivery Systems (SNEDDS), cinnamon oil-based nano emulsions, and cosolvents. Two optimized formulations were prepared based on the appearance/transparency, stability, and solubility. Tadalafil nano emulsion (CO44) was prepared using the mixture of Caproyl 90, Labrasol and Transcutol. Tadalafil solution (Transcutol formulation) was prepared using Transcutol as a cosolvent. These formulations were further tested for their aerosol performance using the LC Sprit Nebulizer. The delivered dose testing was performed using a Copley BRS 1100 Breath Simulator in accordance with USP < 1601 > (adult profile). Droplet size distribution was determined by a laser diffraction method using a Malvern SprayTec instrument equipped with inhalation cell, and aerodynamic particle size distribution (APSD) was determined by using a cooled Next Generation Impactor (NGI) at 15 LPM as per USP < 1601 >.

Results: The use of cyclodextrins (solubility of Tadalafil < 0.5mg/ml) as solubilizer/complexing agent did not result in adequate solubility to achieve the target dose of 10 mg whereas nano emulsion using Capryol oil, cinnamon oil nano emulsion and use of Transcutol as cosolvent have improved the solubility significantly. However, the cinnamon oil nano emulsion showed high viscosity and suffered from phase separation. Hence, based on adequate solubility and stability, CO44 (Tadalafil nano emulsion 2.5 mg/ml) and Transcutol (Tadalafil solution 5mg/ml) formulations were chosen as optimized formulations and further studies were conducted. CO44 formulation achieved a delivered dose of 10.2 ± 1.0 mg (n=3), while the Transcutol formulation has delivered dose of 6.1 ± 0.2 mg (n=3). Figure 2 shows a graph representing the percentage drug deposited on each stage of the NGI. The mass median aerodynamic diameter (MMAD) and fine particle fraction (FPF) of the nebulized formulations were determined using a NGI and calculated using Copleys CITDAS software. The MMAD of CO44 formulation was found to be 3.49 ± 0.25 µm (n=3) with fine particle fraction of 65.28 ± 4.28 % (n=3) whereas Transcutol formulation has MMAD of 4.19 ± 0.16 µm and FPF of 56.85 ± 2.04 %. DSD data as shown in figure 3 indicate that both formulations have fine droplets and well correlate with the MMAD values obtained by NGI. D50 of CO44 formulation was found to be 2.61± 0.02 µm and D50 of Transcutol formulation was found to be 3.54 ± 0.14 µm.

Conclusion: In summary, both the CO44 and Transcutol formulations provided sufficient solubility and stability to enable effective nebulized delivery of Tadalafil. The MMAD and FPF values suggest that both formulations are suitable for deep lung deposition. DD and DSD results support their potential for pulmonary delivery, warranting further in vivo evaluation.

References: Ali HS, Ahmed SA, Alqurshi AA, Alalawi AM, Shehata AM, Alahmadi YM. Tadalafil-loaded self-nanoemulsifying chewable tablets for improved bioavailability: Design, in vitro, and in vivo testing. Pharmaceutics. 2022 Sep 12;14(9):1927.

Acknowledgements: The authors declare no conflict of interest.


Figure1. Delivered dose of nebulized Tadalafil formulations determined using Breathing simulator with adult breathing profile. Data presented as Mean ± Sd, (n=3).


Figure 2. In vitro aerosol deposition profile of nebulized formulations of Tadalafil represented as % total drug deposited on each stage of the NGI at 15 LPM. Data presented as mean ± SD, n=3.


Figure 3. Droplet size distribution of nebulized Tadalafil formulations determined by Spraytec represented as cumulative size distribution. CO44 formulation (black) and Transcutol formulation (red).