Low density, good flowability cyclodextrin-raffinose binary carrier for dry powder inhaler: anti-hygroscopicity and aerosolization performance enhancement

ABSTRACT

Background: The hygroscopicity of raffinose carrier for dry powder inhaler (DPI) was the main obstacle for its further application. Hygroscopicity-induced agglomeration would cause deterioration of aerosolization performance of raffinose, undermining the delivery efficiency.

Methods: Cyclodextrin-raffinose binary carriers (CRBCs) were produced by spray-drying so as to surmount the above issue. Physicochemical attributes and formation mechanism of CRBCs were explored in detail. The flow property of CRBCs was examined by FT4 Powder Rheometer. Hygroscopicity of CRBCs was elucidated by dynamic vapor sorption study. Aerosolization performance was evaluated by in vitro deposition profile and in vivo pharmacokinetic profile of CRBC based DPI formulations.

Results: The optimal formulation of CRBC (R₄) was proven to possess anti-hygroscopicity and aerosolization performance enhancement properties. Concisely, the moisture uptake of R₄ was c.a. 5% which was far lower than spray-dried raffinose (R₀, c.a. 65%). R₄ exhibited a high fine particle fraction value of 70.56 ± 0.61% and it was 3.75-fold against R₀. The pulmonary and plasmatic bioavailability of R₄ were significantly higher than R₀ (p < 0.05).

Conclusion: CRBC with anti-hygroscopicity and aerosolization performance enhancement properties was a promising approach for pulmonary drug delivery, which could provide new possibilities to the application of hygroscopic carriers for DPI.

KEYWORDS:

• Dry powder inhaler
• carrier
• density
• flowability
• anti-hygroscopicity
• aerosolization performance

Acknowledgments

The authors greatly appreciate the funding by National Science Foundation of China under Grant No. 81673375 and No. 81703431; by Sun Yat-Sen University under Grant No. 16ykpy23; Science and Technology Foundation Guangzhou under Grant No. 201509030006. Besides, the authors would like to thank the help in the FT4 instrument and data analysis from Freeman Technology Ltd.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. A reviewer on this manuscript has disclosed that they have participated in consulting, advisory boards, speaker panels, or received travel reimbursement for Amphastar, AstraZeneca, Mylan, Novartis, Oriel, Pearl, Sunovion, Teva, and Theravance. The same reviewer has also conducted multicenter clinical research trials for approximately 40 pharmaceutical companies.

Author contribution

Z. Zhao conducted the experiments and revised the manuscript. Z. Huang analyzed the data and wrote the paper. X. Zhang analyzed the data and helped to design the study. Y. Huang helped to design the study and revised the manuscript. Y. Cui, C. Ma and G. Wang helped to conduct the experiments. T. Freeman and X. Lu were responsible for the design, experiment, and analysis of FT4 tests. X. Pan and C. Wu designed and supervised the study and proofread the manuscript.

Supplementary data

Supplemental data for this article can be accessed here.

Additional information

Funding

This paper was funded by the National Natural Science Foundation of China (81673375; 81703431), the Science and Technology Foundation Guangzhou (201509030006), and Sun Yat-sen University (16ykpy23).