Highly dispersible powders, compositions and methods for preparation
Inventors
Ohtake, Satoshi • Saxena, Atul • Truong-Le, Vu
Assignees
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Publication Number
US-9072783-B2
Publication Date
2015-07-07
Expiration Date
Abstract
A method for the selection of pharmaceutically acceptable excipients that allow for the production of highly dispersible powders produced by spray drying.
Core Innovation
The disclosed invention relates to pharmaceutically acceptable dispersible spray-dried powders engineered to improve aerosol properties. The approach selects pharmaceutically acceptable excipients for their hydrophobicity using the Kyte-Doolittle hydropathy index and/or the water-to-vapor transfer free energy. The engineered powders are intended to achieve improved dispersion characterized by fine particle distribution and mass median aerodynamic diameter.
In particular, the invention provides dispersible powders comprising gallium and a hydrophobic monomeric amino acid excipient. The excipient is defined as monomeric amino acids only, selected to be more hydrophobic than alanine according to the Kyte-Doolittle index. Incorporation of more hydrophobic amino acids into gallium citrate/sodium citrate solutions is described as improving aerosol dispersion compared with powders without such amino acids.
The disclosed compositions and embodiments include dispersible powders containing gallium salts and hydrophobic monomeric amino acids, with spray drying and other drying modes noted for powder production. Experimental correlations are described between hydropathy and aerosol performance metrics such as FPD<3.3 μm and MMAD. Stability data over long-term storage are also described, supporting the performance of the dispersible powders.
Claims Coverage
The relevant independent claims define pharmaceutically acceptable dispersible powders and specify key inventive features: gallium with hydrophobic monomeric amino acid excipients defined by hydrophobicity relative to alanine (Kyte-Doolittle index), monomeric-only amino acids, specific excipient mass ranges, and aerosol performance thresholds.
Hydrophobic monomeric amino-acid excipient with gallium-based dispersible powder
A pharmaceutically acceptable dispersible powder comprising gallium and a hydrophobic monomeric amino acid excipient that is more hydrophobic than alanine, according to the Kyte-Doolittle index, wherein the powder only contains amino acids in monomeric form.
Excipient mass fraction and particle-performance requirements
A pharmaceutically acceptable dispersible powder wherein the mass of the excipient is 15%-25% of the mass of the powder, and wherein the fine particle distribution (FPD) of the powder that is under 3.3 microns is greater than 30% or wherein the mass median aerodynamic diameter (MMAD) of the powder is under 10 microns.
Leucine-defined monomeric amino-acid powder with tighter excipient range
A pharmaceutically acceptable dispersible powder comprising monomeric leucine, wherein the mass of the leucine is at least 20.5% the mass of the powder and 22% or less than the mass of the powder, wherein the powder only contains amino acids in monomeric form, and wherein the fine particle distribution (FPD) of the powder that is under 3.3 microns is greater than 30% or wherein the mass median aerodynamic diameter (MMAD) of the powder is under 10 microns.
Non-leucine hydrophobic monomeric amino-acid excipient for dispersible powder
A pharmaceutically acceptable dispersible powder comprising a monomeric amino acid hydrophobic excipient, other than leucine, that is more hydrophobic than alanine, according to the Kyte-Doolittle index, wherein the powder only contains amino acids in monomeric form.
Across the independent claims, the coverage centers on dispersible powders containing gallium and hydrophobic monomeric amino acids selected by Kyte-Doolittle hydropathy relative to alanine, with monomeric-only amino acids and defined excipient mass percentages. The powders further require aerosol dispersion performance, expressed as FPD<3.3 μm >30% or MMAD <10 μm, with an additional leucine-specific embodiment using a narrower excipient mass range.
Stated Advantages
Improved aerosol dispersion, associated with increased fine particle distribution (FPD<3.3 μm) and reduced MMAD compared with powders without the more hydrophobic amino acids.
Documented Applications
Formulation of pharmaceutically acceptable dispersible powders using spray drying and other drying modes for producing dispersible pharmaceutical powder compositions.
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