Antimicrobial compounds, compositions, and uses thereof
Inventors
Sleet, Randolph B. • Kates, Steven A. • Parkinson, Steven
Assignees
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Publication Number
US-10981943-B2
Publication Date
2021-04-20
Expiration Date
Abstract
Antimicrobial compounds and compositions of Formula (I) and methods of use are disclosed.
Core Innovation
The document discloses antimicrobial compounds having Formula (I), including Nu-8, and pharmaceutically acceptable salts. Nu-8 is described as a cytidine analog containing a ribose and two phosphate groups, and the disclosure includes sodium, ammonium, calcium, potassium, magnesium, and cobalt salts, including Nu-8 sodium salt.
The disclosure describes the treatment of infections using antimicrobial compounds while maintaining biological activity and compatibility across selected administration routes. Protonated compound forms and/or less-acidic forms are described as showing unexpectedly high potency and compatibility at pH conditions including pH 3 to pH 5 and pH above about pH 3, and the compounds are described as having activity against slow-growth bacteria.
The disclosure provides pharmaceutical compositions comprising the antimicrobial compounds and pharmaceutically acceptable carriers, excipients, and/or diluents. It also describes methods of treating infections by administering an effective amount of the compound or a pharmaceutically acceptable salt using topical, inhalation, and intravesical routes, including use of an intravesical catheter, and describes multiple or chronic dosing regimens for a range of infection indications.
Claims Coverage
The independently claimed invention is a method of treating an infection by administering an effective amount of a compound having Formula (I), including Nu-8, or a pharmaceutically acceptable salt. The claim set includes six inventive features, with dependent coverage refining administration routes, dosing constraints, regimen characteristics, and salt identity, including a sodium salt.
Treating an infection by administering a compound having Formula (I) or a pharmaceutically acceptable salt
A method comprising administering to a patient an effective amount of a compound having Formula (I) or a pharmaceutically acceptable salt thereof.
Selecting an administration route from a defined set
The method further specifies that the administration route is chosen from a specified list of administration types.
Administering an effective amount in a specified mg/kg range
The method specifies that the administered amount is from about 0.1 to about 1000 milligrams per kilogram of patient body weight.
Multiple-dose regimen over selected maximum time periods
The method specifies that a multiple-dose regimen is administered over a time period selected from specified maximum durations.
Using a sodium salt of the compound
The method further specifies that the pharmaceutically acceptable salt is a sodium salt.
Using a particular sodium salt defined by structure
The method further specifies that the sodium salt is a particular sodium ((2R,3 S,5R)-...)-methyl butyl phosphate compound by structure.
Overall, the claim set is centered on treating infections via administration of a Formula (I) compound, including Nu-8, or its pharmaceutically acceptable salts, with dependent claims narrowing the route of administration, the administered mg/kg range, multiple-dose time periods, and the salt identity to a sodium salt including a specific sodium salt structure.
Stated Advantages
Nu-8 has a higher pH and distinct pKa/solubility relative to the reference compounds.
The document reports bacterial cytological profiling and minimum inhibitory concentration results across pH conditions.
Unexpectedly high potency for protonated or less-acidic forms at pH 3 to pH 5 and pH above about pH 3.
Compatibility with topical, inhalation, and intravesical administration routes.
Activity against slow-growth bacteria.
Documented Applications
Urinary tract infection treatment in mouse and rat models.
In vitro bacterial cytological profiling for bacterial cell viability loss and membrane permeability/cell envelope effects across pH conditions.
Assessment of minimum inhibitory concentration efficacy across incremental pH.
Human treatment modalities explicitly described as tied to Nu-8, including intravesical, inhalational, and topical use, and additional listed human contexts including diabetic foot ulcer, ventilator acquired pneumonia, burn wound, impetigo, otitis externa, and bacterial vaginosis.
Diabetic foot ulcer infection.
Complicated urinary tract infection, including catheter-associated urinary tract infection via intravesical catheter administration.
Lung infections from cystic fibrosis via inhalation administration.
Ventilator acquired pneumonia via inhalation administration.
Burn wound infection.
Otitis externa.
Bacterial vaginosis.
Impetigo.
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