Sharad Mangal1, Haichen Nie2, Rongkun Xu1,3, Rui Guo1, Alex Cavallaro4, Dmitry Zemlyanov5, Qi Tony Zhou6. 1. Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana, 47907, USA. 2. Teva Pharmaceuticals, 145 Brandywine Pkwy, West Chester, Pennsylvania, 19380, USA. 3. Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, Liaoning, 110016, China. 4. Future Industries Institute, University of South Australia, Mawson Lakes, SA, 5095, Australia. 5. Birck Nanotechnology Center, Purdue University, 1205 West State Street, West Lafayette, Indiana, 47907, USA. 6. Department of Industrial and Physical Pharmacy, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, Indiana, 47907, USA. tonyzhou@purdue.edu.
Abstract
PURPOSE: Inhalation therapy is popular to treat lower respiratory tract infections. Azithromycin is effective against some bacteria that cause respiratory tract infections; but it has poor water solubility that may limit its efficacy when administrated as inhalation therapy. In this study, dry powder inhaler formulations were developed by co-spray drying azithromycin with L-leucine with a purpose to improve dissolution. METHODS: The produced powder formulations were characterized regarding particle size, morphology, surface composition and in-vitro aerosolization performance. Effects of L-leucine on the solubility and in-vitro dissolution of azithromycin were also evaluated. RESULTS: The spray dried azithromycin alone formulation exhibited a satisfactory aerosol performance with a fine particle fraction (FPF) of 62.5 ± 4.1%. Addition of L-leucine in the formulation resulted in no significant change in particle morphology and FPF, which can be attributed to enrichment of azithromycin on the surfaces of composite particles. Importantly, compared with the spray-dried amorphous azithromycin alone powder, the co-spray dried powder formulations of azithromycin and L-leucine demonstrated a substantially enhanced in-vitro dissolution rate. Such enhanced dissolution of azithromycin could be attributed to the formation of composite system and the acidic microenvironment around azithromycin molecules created by the dissolution of acidic L-leucine in the co-spray dried powder. Fourier transform infrared spectroscopic data showed intermolecular interactions between azithromycin and L-leucine in the co-spray dried formulations. CONCLUSIONS: We developed the dry powder formulations with satisfactory aerosol performance and enhanced dissolution for a poorly water soluble weak base, azithromycin, by co-spray drying with an amino acid, L-leucine.
PURPOSE: Inhalation therapy is popular to treat lower respiratory tract infections. Azithromycin is effective against some bacteria that cause respiratory tract infections; but it has poor water solubility that may limit its efficacy when administrated as inhalation therapy. In this study, dry powder inhaler formulations were developed by co-spray drying azithromycin with L-leucine with a purpose to improve dissolution. METHODS: The produced powder formulations were characterized regarding particle size, morphology, surface composition and in-vitro aerosolization performance. Effects of L-leucine on the solubility and in-vitro dissolution of azithromycin were also evaluated. RESULTS: The spray dried azithromycin alone formulation exhibited a satisfactory aerosol performance with a fine particle fraction (FPF) of 62.5 ± 4.1%. Addition of L-leucine in the formulation resulted in no significant change in particle morphology and FPF, which can be attributed to enrichment of azithromycin on the surfaces of composite particles. Importantly, compared with the spray-dried amorphous azithromycin alone powder, the co-spray dried powder formulations of azithromycin and L-leucine demonstrated a substantially enhanced in-vitro dissolution rate. Such enhanced dissolution of azithromycin could be attributed to the formation of composite system and the acidic microenvironment around azithromycin molecules created by the dissolution of acidic L-leucine in the co-spray dried powder. Fourier transform infrared spectroscopic data showed intermolecular interactions between azithromycin and L-leucine in the co-spray dried formulations. CONCLUSIONS: We developed the dry powder formulations with satisfactory aerosol performance and enhanced dissolution for a poorly water soluble weak base, azithromycin, by co-spray drying with an amino acid, L-leucine.
Authors: Qi Tony Zhou; John A Denman; Thomas Gengenbach; Shyamal Das; Li Qu; Hailong Zhang; Ian Larson; Peter J Stewart; David A V Morton Journal: J Pharm Sci Date: 2011-03-31 Impact factor: 3.534
Authors: Paul M Young; Rania O Salama; Bing Zhu; Gary Phillips; John Crapper; Hak-Kim Chan; Daniela Traini Journal: Drug Dev Ind Pharm Date: 2014-05-09 Impact factor: 3.225