(M1430-06-36) Self-Micellizing Dry Powder Inhaler System for Cyclosporine A Using Sodium Stearate

Purpose: The purpose of this study was to develop a dry powder inhaler (DPI) formulation of cyclosporine A (CSA) for localized pulmonary delivery. CSA is a poorly water-soluble immunosuppressant characterized by a relatively long half-life (5–18 hours) and a short Tmax (1–2 hours), making it a promising therapeutic candidate for chronic pulmonary diseases such as idiopathic pulmonary fibrosis (IPF). However, due to its low aqueous solubility, formulation optimization is essential to achieve efficient pulmonary delivery. DPI formulations offer several advantages, including rapid onset of action, avoidance of first-pass metabolism, reduced dosing frequency and amount, and minimized systemic side effects, making them well suited for the pulmonary delivery of drugs like CSA. In this study, various excipients including sodium stearate (NaSt), mannitol, magnesium stearate (MgSt), and sodium chloride (NaCl) were screened to evaluate their ability to enhance CSA solubility and suitability for inhalable formulation development.

Methods: Twelve CSA DPI formulations were prepared by spray drying ethanolic CSA solutions mixed with various excipients (NaSt, mannitol, MgSt, NaCl). The feed solution (2% w/v solids) was spray-dried at 80 °C using a blower flow of 0.3 m³/min and atomizing pressure of 100 kPa. Each excipient was evaluated based on its effects on spray drying yield, drug content, aqueous solubility, in vitro dissolution, and aerodynamic performance. Based on these screening results, sodium stearate (NaSt) was selected as the optimal excipient. The aqueous solubility of CSA in each formulation was determined by adding excess drug to distilled water (DW) and shaking at 37 °C for 24 hours, followed by centrifugation and quantification of the supernatant. The aerodynamic performance of the CSA formulations was assessed using an Andersen Cascade Impactor (ACI). In this test, 20 mg of powder was loaded, and air was drawn through the impactor at a flow rate of 28.3 L/min. The deposition profile across stages (from stage 0 to stage 7 and filter) was used to calculate emitted dose (ED), fine particle fraction (FPF), mass median aerodynamic diameter (MMAD), and fine particle dose (FPD). In vitro dissolution studies were conducted using the Franz cell diffusion method. The dissolution medium consisted of pH 7.4 PBS (0.01 M) supplemented with 1% Tween 80, and the membrane filter used was 0.8 μm cellulose. Each donor chamber contained 18 mg of formulation, and the receptor chamber was maintained at 37 °C. Samples were collected at 15, 30, 60, 120, and 180 minutes to evaluate the drug release profile. The resulting powders were also characterized by scanning electron microscopy (SEM) for particle morphology and X-ray diffraction (XRD) for crystallinity. SEM and transmission electron microscopy (TEM) were further used to confirm micelle formation behavior in the receptor medium after dissolution.

Results: CSA-10 was identified as the optimal formulation. Formulations containing magnesium stearate (CSA-7 to CSA-9) exhibited low drug content due to poor solubilization, whereas CSA-10, containing sodium stearate, showed enhanced aqueous solubility and favorable drug loading. SEM images confirmed the formation of discrete spherical particles (~2–5 μm) with minimal aggregation in CSA-10, suitable for pulmonary delivery. XRD analysis demonstrated significantly reduced crystallinity in CSA-10 compared to raw CSA and the physical mixture, indicating partial amorphization achieved through spray drying. In vitro dissolution studies revealed that CSA-10 achieved a significantly higher release (44.8% at 180 min) compared to raw CSA (~5%) and other formulations (~9%), attributed to in situ micelle formation by NaSt. SEM/TEM analysis of the receptor medium confirmed micelle-like nanostructures ( < 100 nm) formed exclusively in CSA-10. Aerosolization tests indicated that CSA-10 had the highest emitted dose (88.22%) and respirable MMAD (3.45–3.87 μm), although its FPF (70.48%) was lower than CSA-1 and CSA-4 (~90%). Despite a slightly lower FPD (4.14 mg vs. 4.78 mg for CSA-4), CSA-10 maintained effective pulmonary delivery due to superior solubility.

Conclusion: CSA-10, incorporating sodium stearate as a self-micellizing agent, effectively enhances the solubility, dissolution, and aerosol performance of cyclosporine A. Sodium stearate spontaneously forms micelles above its critical micelle concentration (CMC) via hydrophobic self-assembly of its long alkyl chains, enabling efficient dispersion and stabilization of poorly water-soluble drugs in aqueous environments such as pulmonary fluids. Despite a modest reduction in FPF, CSA-10’s high emitted dose and rapid, sustained drug release via in situ micellization make it a promising formulation for localized pulmonary drug delivery. This strategy avoids first-pass metabolism, reduces dosing frequency, and minimizes systemic side effects, offering a viable solution for chronic respiratory diseases requiring long-term immunomodulation.

References: 1. Fu LW, Yang LY, Chen WP, Lin CY. Cyclosporin pharmacokinetics following administration of capsules and Neoral in paediatric patients with lupus nephritis. Br J Clin Pharmacol. 1997 Aug;44(2):125-7
2. Juarez MM, Chan AL, Norris AG, Morrissey BM, Albertson TE. Acute exacerbation of idiopathic pulmonary fibrosis—a review of current and novel pharmacotherapies. J Thorac Dis 2015;7(3):499-519
3. Takei R, Arita M, Tokioka F, Tachibana H, Tokumasu H, Ishida T. Cyclosporin A in idiopathic chronic fibrosing interstitial pneumonia without idiopathic pulmonary fibrosis. J Thorac Dis 2018;10(12):6695-6701
4. Aso S, Matsui H, Fushimi K, Yasunaga H. Effect of cyclosporine A on mortality after acute exacerbation of idiopathic pulmonary fibrosis. J Thorac Dis 2018;10(9):5275-5282
5.Wu, P., Liu, G., Li, X.et al.Effects of CMC and Micelle Formation on the Removal of Sodium Benzoate or Sodium Stearate in a Sodium Aluminate Solution.JOM72, 263–269 (2020).


Twelve CSA DPI formulations were prepared by spray drying


Physicochemical Properties


In vitro evaluation