Optimization, In Vitro, and In Silico Characterization of Theophylline Inhalable Powder Using Raffinose-Amino Acid Combination as Fine Co-Spray-Dried Carriers

Abstract

Background/Objectives: Dry powder inhalation is an attractive research area for development. Therefore, this work aimed to develop inhalable co-spray-dried theophylline (TN) microparticles, utilizing raffinose-amino acid fine carriers intended for asthma therapy. The study addressed enhancing TN's physicochemical and aerodynamic properties to ensure efficient lung deposition. Methods: The process involves spray-drying each formulation's solution using a mini spray drier. A rigorous assessment was conducted on particle size distribution, structural and thermal analysis, morphology study, in vitro and in silico aerodynamic investigation, and aerodynamic particle counter in addition to the solubility, in vitro dissolution, and diffusion of TN. Results: The carriers containing leucine and glycine revealed superior characteristics (mass median aerodynamic diameter (MMAD): 4.6-5 µm, fine particle fraction (FPF): 30.6-35.1%, and amorphous spherical structure) as candidates for further development of TN-DPIs, while arginine was excluded due to intensive aggregation and hygroscopicity, which led to poor aerodynamic performance. TN co-spray-dried samples demonstrated fine micronized particles (D [0.5]: 3.99-5.96 µm) with predominantly amorphous structure (crystallinity index: 24.1-45.2%) and significant solubility enhancement (~19-fold). Formulations containing leucine and leucine-glycine revealed the highest FPF (45.7-47.8%) and in silico lung deposition (39.3-40.1%), rapid in vitro drug release (~100% within 10 min), and improved in vitro diffusion (2.29-2.43-fold), respectively. Moreover, the aerodynamic counter confirmed the development of fine microparticles (mean number particle size = 2.3-2.02 µm). Conclusions: This innovative formulation possesses enhanced physicochemical, morphological, and aerodynamic characteristics of low-dose TN for local asthma treatment and could be applied as a promising carrier for dry powder inhaler development.

Keywords: Andersen cascade impactor; aerodynamic particle counter; dry powder inhaler; glycine; leucine; raffinose; spray-drying; stochastic lung model; theophylline.

Figure 1

Chemical structure and solubility of the utilized raw API and excipients.

Figure 2

The preparation methods of the Rf-based carrier system (A-Carriers screening) and the TN-DPIs (B-TN DPIs), in addition to the spray-drying operational parameters.

Figure 3

The configuration of the horizontal diffusion cells for in vitro permeation study of TN and the characteristics of various parts are illustrated.

Figure 4

Summary of the results of the screened Rf-based carriers. SEM images, particle size, and aerodynamic properties.

Figure 5

Results of solubility analysis of TN, raw drug vs. spray-dried samples in distilled water and SLF.

Figure 6

X-ray diffractograms of raw materials and TN spray-dried samples.

Figure 7

FTIR spectra of raw materials and TN spray-dried samples.

Figure 8

DSC thermograms of raw materials and TN spray-dried samples.

Figure 9

SEM images of TN spray-dried samples and the approximate particle size measured by ImageJ software (D_imageJ).

Figure 10

In vitro aerodynamic performance of the developed TN samples, deposition via Andersen cascade impactor (Inh: Breezhaler + capsule; MA: mouthpiece adaptor; IP: induction port; S: stage; F: filter).

Figure 11

Aerodynamic performance of the developed TN samples. In silico aerodynamic deposition at 5 and 10 s breath hold (E.Th: extrathoracic fraction; T.L: total lung fraction including bronchial and acinar; Ex.h: exhaled fraction).

Figure 12

In vitro dissolution profile of raw-TN, TN-Rf-Lc, and TN-Rf-Lc-Gl2 formulations.

Figure 13

In vitro diffusion profile of raw-TN, TN-Rf-Lc, and TN-Rf-Lc-Gl2 formulations.