Antiviral compositions
Inventors
Foster, Alison J. • Long, James • Rannard, Steven P. • Wang, Dong • Duncalf, David J. • Owen, Andrew
Assignees
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Publication Number
US-9820939-B2
Publication Date
2017-11-21
Expiration Date
Abstract
The present invention provides a composition and an antiviral drug preparation, each comprising at least one water-insoluble antiviral drug and at least one water-soluble carrier material, wherein the water-insoluble antiviral drug is dispersed through the water-soluble carrier material in nano-disperse form. The present invention further provides processes for preparing the compositions and drug preparations, and also aqueous nano-dispersions obtained by combining water and the compositions.
Core Innovation
The invention relates to antiviral and especially antiretroviral compositions and drug preparations in which a water-insoluble antiviral drug is dispersed through a water-soluble carrier material in nano-disperse form. The compositions are substantially solvent-free and are characterized by nano-dispersion particle sizes, including z-average particle size values below defined limits. The disclosure defines water-insoluble antiviral drugs by solubility thresholds and provides water-soluble carrier material criteria for selecting carriers suitable for nano-dispersion formation.
A process is described for obtaining the substantially solvent-free nano-dispersions by forming an emulsion comprising a solution of the water-insoluble antiviral drug in a water-immiscible solvent and a solution of the water-soluble carrier material in an aqueous solvent, or by providing a single-phase solution comprising a non-aqueous solvent, an aqueous solvent, a water-soluble carrier material dissolved in the mixture, and the water-insoluble antiviral drug dissolved in the mixture but not in the aqueous solvent alone. The emulsion or single-phase solution is spray-dried or freeze-dried to remove the aqueous solvent and the water-immiscible solvent, producing a nano-dispersion of the antiviral drug in the carrier material.
The disclosure identifies carrier-material options including water-soluble polymers, water-soluble surfactants, water-soluble inorganic materials, and water-soluble sugars, and includes preferred non-crosslinked polymer selections. It also enumerates antiviral and antiretroviral drug classes suitable for the compositions, with specific named examples including saquinavir, efavirenz, lopinavir, and ritonavir, among others. Performance rationales and testing are described, including in vitro Caco-2 permeability of nano-dispersed saquinavir relative to dissolved saquinavir, and the disclosure reports similar or improved permeability with an example indicating efflux bypass.
Claims Coverage
The independent claims cover a substantially solvent-free nano-dispersion composition of a water-insoluble antiviral drug in a water-soluble carrier, and a process for forming it. The inventive features include nano-disperse dispersion in specified carrier classes, formation through an emulsion or single-phase solution, and spray-drying or freeze-drying to remove solvents, together with dependent claim features that narrow particle size, drug solubility, carrier selection, solvent selection, and antiviral selection.
Substantially solvent-free nano-dispersion of a water-insoluble antiviral drug in a water-soluble carrier
A substantially solvent-free composition consisting of at least one water-insoluble antiviral drug and at least one water-soluble carrier material, wherein the water-insoluble antiviral drug is dispersed through the water-soluble carrier material in nano-disperse form, with the water-soluble carrier material selected from water-soluble inorganic materials, water-soluble surfactants, water-soluble polymers, water-soluble sugars and mixtures thereof, and wherein the water-insoluble antiviral drug does not comprise darunavir.
Emulsion or single-phase solution followed by spray-drying or freeze-drying to remove solvents
A process comprising forming an emulsion comprising a solution of the water-insoluble antiviral drug in a water-immiscible solvent and a solution of the water-soluble carrier material in an aqueous solvent, or providing a single-phase solution comprising at least one non-aqueous solvent, an aqueous solvent, a water-soluble carrier material dissolved in the mixture, and a water-insoluble antiviral drug dissolved in the mixture but not alone, and spray-drying or freeze-drying the emulsion or single-phase solution to remove the aqueous solvent and the water-immiscible solvent to obtain the substantially solvent-free composition comprising a nano-dispersion of the antiviral drug in the carrier material.
Nano-dispersion particle size constraint
The nano-dispersed form of the water-insoluble antiviral drug in an aqueous nano-dispersion has a z-average particle size below 1000 nm.
Water solubility threshold defining the water-insoluble antiviral drug
A substantially solvent-free composition in which the water-insoluble antiviral drug has a water solubility of less than 10 g/L at 25°C as described in the disclosure.
Specified water-soluble polymeric carrier selection
A substantially solvent-free composition where the water-soluble polymeric carrier material is selected from polyvinylalcohol, poly(ethylene glycol), polyvinylpyrrolidone, poly(2-ethyl-2-oxazaline), hydroxypropylcellulose, hydroxypropylmethylcellulose, alginates, and mixtures thereof.
Selected non-aqueous solvent options for emulsion formation
A substantially solvent-free composition where the non-aqueous solvent is chosen from chloroform, toluene, cyclohexane, ethyl acetate, dichloromethane, or mixtures thereof.
Selected protease inhibitor list for narrowing the antiviral drug selection
A substantially solvent-free composition where the protease inhibitor is selected from amprenavir, atazanavir, boceprevir, fosamprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir, or mixtures thereof.
Overall, the claim coverage centers on a substantially solvent-free composition with a water-insoluble antiviral drug dispersed in nano-disperse form through a selected water-soluble carrier, together with a defined process route using an emulsion or single-phase solution followed by spray-drying or freeze-drying. Dependent claim features narrow the invention by constraining nano-dispersion particle size, defining water-insolubility via a water solubility threshold, selecting specific water-soluble polymers and non-aqueous solvents, and limiting antiviral selection through named lists including protease inhibitors and a darunavir exclusion.
Stated Advantages
Rapid dispersion in water is described as a performance rationale.
Potentially clear dispersions are described.
Improved PK/bioavailability metrics are described.
In vitro Caco-2 testing indicates nano-particulate formulations show similar or improved permeability versus dissolved drug, with an example indicating efflux bypass.
Documented Applications
Antiviral, especially antiretroviral, drug preparations formulated as substantially solvent-free nano-dispersions of water-insoluble antiviral drugs in water-soluble carrier materials.
In vitro Caco-2 permeability testing of nano-dispersed saquinavir versus dissolved saquinavir using a transwell permeability model.
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