Aqueous suspension formulation comprising 4-(4-(4-(((3R,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluoro-phenyl)tetrahydrofuran-3-yl)methoxy)-3-methylphenyl) or a pharmaceutically acceptable salt thereof
Inventors
COLLEY, Thomas Christopher • Ito, Kazuhiro • Strong, Peter • Sunose, Mihiro • MCCONVILLE, MATTHEW
Assignees
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Publication Number
US-10513511-B2
Publication Date
2019-12-24
Expiration Date
Abstract
The invention relates to aqueous suspension formulations of compounds, as defined in the specification and as represented by the compound of formula (I): and to their use in therapy.
Core Innovation
The invention relates to an aqueous suspension formulation comprising a compound of formula (I), 4-(4-(4-(((3R,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methoxy)-3-methylphenyl)piperazin-1-yl)-N-(2-hydroxycyclohexyl)benzamide, or a pharmaceutically acceptable salt thereof. The formulation supports stereoisomer selection for Compound (I), including Compounds (Ia) and (Ib), and is described as suitable for topical administration to the nose or lung.
The document links the formulation to therapeutic activity against mycoses, including Aspergillus fumigatus and azole-resistant Aspergillus. Biological evaluation reports planktonic growth inhibition, bronchial epithelial infection models, and human alveolar bilayer invasion, with galactomannan as a biological readout.
In vivo evaluation is described in immunocompromised neutropenic mice with therapeutic and prophylactic efficacy. Outcomes reported include lung fungal burden reduction, reduction of serum and BALF galactomannan, reduction of lung Aspergillus DNA, inhibition of cytokines IL-6 and TNFα, reduced body weight loss, and combination effects with azoles including posaconazole.
Claims Coverage
The independent claim is directed to an aqueous suspension formulation comprising a specified compound of formula (I) or a pharmaceutically acceptable salt, with five principal inventive features reflected across the claims.
Aqueous suspension formulation with compound of formula (I)
An aqueous suspension formulation comprising a compound of formula (I), 4-(4-(4-(((3R,5R)-5-((1H-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methoxy)-3-methylphenyl)piperazin-1-yl)-N-(2-hydroxycyclohexyl)benzamide, or a pharmaceutically acceptable salt thereof.
Stereoisomer selection for compound of formula (I)
The aqueous suspension includes the compound of formula (I) as a stereoisomer selected from Compounds (Ia) and (Ib), or a pharmaceutically acceptable salt of either stereoisomer.
Topical administration to the nose or lung
The aqueous suspension is administered topically to the nose or lung.
Finely divided suspension with D50 particle size range
The aqueous suspension defines the compound of formula (I) in a finely divided form having a D50 particle size of 0.5–10 µm.
Excipients and optional additional active ingredient
The aqueous suspension further includes one or more excipients selected from buffers, tonicity adjusting agents, pH adjusting agents, viscosity modifiers, surfactants, and co-solvents, and may include a second or additional active ingredient selected from azole antifungal agents, amphotericin B, an echinocandin, or an inhibitor of 3-hydroxy-3-methyl-glutaryl-CoA reductase.
The claim coverage centers on an aqueous suspension comprising the specified compound of formula (I), with stereoisomer selection, topical delivery to the nose or lung, a D50 particle-size constraint, and optional excipients and co-active antifungal or related agents.
Stated Advantages
Potent antifungal agent activity against Aspergillus fumigatus, including azole-resistant strains, demonstrated in planktonic, bronchial epithelial infection, and human alveolar bilayer invasion models.
In vivo therapeutic and prophylactic efficacy in immunocompromised neutropenic mice, including lung fungal burden reduction and reductions in serum and BALF galactomannan.
Reduction of lung Aspergillus DNA and inhibition of cytokines IL-6 and TNFα, together with reduced body weight loss.
Combination therapy with posaconazole produces sustained or synergistic inhibition reflected by longer DFB50 versus monotherapy.
Documented Applications
Antifungal treatment and/or prevention of mycosis caused by fungi, including Aspergillus fumigatus and azole-resistant mycoses.
Use in infection/invasion biological models including bronchial epithelial infection and human alveolar bilayer invasion, with galactomannan readouts.
Intranasal administration in immunocompromised neutropenic mice with therapeutic and prophylactic efficacy measured by lung fungal burden, serum and BALF galactomannan, and lung Aspergillus DNA.
Combination therapy with posaconazole, with inhibition assessed by longer DFB50 versus monotherapy.
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