Compositions and methods of use thereof
Inventors
Baker, Shenda M. • Wiesmann, William P. • Townsend, Stacy Marie
Assignees
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Publication Number
US-11957707-B2
Publication Date
2024-04-16
Expiration Date
Abstract
Described herein are methods for treating or preventing a disease or disorder of the pulmonary system (e.g., cystic fibrosis), respiratory or digestive system in a subject, the methods comprising administering compounds or compositions comprising water soluble polyglucosamine and derivatized polyglucosamine.
Core Innovation
The disclosure describes soluble or derivatized polyglucosamines, particularly poly(acetyl, arginyl) glucosamine (PAAG), characterized by degree of deacetylation, controlled functionalization levels, and composition-defined ranges. The derivatives are characterized by analytical and physicochemical parameters, including infrared spectroscopy for DDA, H-NMR and quantitative elemental analysis for functionalization, and a polydispersity index measured by SEC/MALS, with molecular weight in the kilodalton range.
The PAAG substituent composition is characterized such that at least 25% of R1 substituents are H, at least 1% of R1 substituents are acetyl, and at least 2% of R1 substituents are arginyl-containing substituent(s). A central concept is that entropically driven interactions between a polycation and a polyanion reduce mucus and biofilm viscosity and cohesion, and modulate mucosal glycocalyx cation exchange involving cations such as Na+, Ca2+, and Mg2+.
For Acute Respiratory Distress Syndrome (ARDS), the disclosure includes administering by inhalation an effective amount of a composition comprising a neutral osmol agent and PAAG. The composition is constrained by an osmolality between 150 and 550 mOsmol/kg, and the neutral osmol agent is selected from glycerol, sorbitol, mannitol, xylitol, erythritol, and trehalose.
Claims Coverage
The independent claim coverage centers on inhalation-based prevention or treatment of ARDS using a PAAG composition with a neutral osmol agent. The claims specify PAAG formula and substitution constraints, and composition-level osmolality and neutral osmol agent selection, with dependent claims refining arginine-functionalization, PAAG concentration and dose, molecular weight/polydispersity, nebulizer administration, and an antibacterial agent.
Inhalation treatment or prevention of ARDS with PAAG plus neutral osmol agent
A method for treating or preventing Acute Respiratory Distress Syndrome (ARDS) in a subject by administering by inhalation an effective amount of a composition comprising a neutral osmol agent and poly(acetyl, arginyl) glucosamine (PAAG) having formula (I).
PAAG defined by chain length and R1 substitution constraints
The PAAG comprises formula (I) wherein n is an integer between 20 and 6000; each R1 is independently selected from hydrogen, acetyl, and the arginyl-containing substituent(s); at least 25% of R1 substituents are H, at least 1% of R1 substituents are acetyl, and at least 2% of R1 substituents are the arginyl-containing substituent(s).
Composition osmolality and neutral osmol agent selection
The composition has an osmolality between 150-550 mOsmol/kg and the neutral osmol agent is selected from glycerol, sorbitol, mannitol, xylitol, erythritol, and trehalose.
Arginine-functionalized PAAG at specified percentage range
Using a PAAG characterized by arginine-functionalization at between 20% and 30%.
Administered PAAG dose range
Administering the composition in an amount that provides about 0.2 mg to about 3 mg of PAAG.
PAAG concentration range in the composition
Having PAAG present in the composition at a concentration between 0.1 and 2 mg/ml.
Nebulizer solution composition for inhaled administration
Administering the composition as a nebulizer solution composition for inhaled administration.
Combination with an antibacterial agent
Including and administering an antibacterial agent in the method.
Overall, the claims center on inhaled ARDS treatment or prevention using a PAAG composition constrained by formula (I), defined substitution proportions, and a composition osmolality window of 150-550 mOsmol/kg with a specified neutral osmol agent. Dependent claims further constrain arginine-functionalization, PAAG concentration and administered dose, specify nebulizer-solution inhalation, and optionally add an antibacterial agent.
Stated Advantages
Improves mucociliary clearance and mucociliary transport by reducing mucus/biofilm viscosity and cohesion.
Reduces bacterial attachment/adhesion and bacterial adhesion/colonization.
Reduces inflammatory cytokine secretion.
Reduces mucus viscosity and elasticity and increases airway surface liquid thickness and ciliary beat/mucociliary transport.
Documented Applications
Treating or preventing Acute Respiratory Distress Syndrome (ARDS) by inhalation of a composition comprising a neutral osmol agent and PAAG.
Treating or preventing pulmonary and gastrointestinal mucosal diseases.
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