Methods and compositions for disrupting biofilm utilizing chitosan-derivative compounds
Inventors
Baker, Shenda M. • Wiesmann, William P. • Townsend, Stacy Marie
Assignees
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Publication Number
US-11786547-B2
Publication Date
2023-10-17
Expiration Date
Abstract
Described herein are methods of disrupting (e.g., reducing the viscosity of, or dissolving) a preformed biofilm in a subject, the method comprising: administering to the subject an effective amount of a composition comprising a soluble chitosan or derivatized chitosan wherein the soluble chitosan or derivatized chitosan when administered contacts the preformed biofilm, thereby disrupting (e.g., reducing the viscosity of, or dissolving) the preformed biofilm.
Core Innovation
The invention relates to derivatized chitosan comprising a chitosan of formula (I), wherein n is an integer between 20 and 6000 and each R1 is independently selected from hydrogen, acetyl, and a group of formula (II). The derivatized chitosan is characterized by compositional constraints in which at least 25% of the R1 substituents are hydrogen, at least 1% of the R1 substituents are acetyl, and at least 4-30% of the R1 substituents are groups of formula (II), including amino/guanidino-functional groups and guanidine moieties.
The derivatized chitosan is further defined by a molecular weight between 10,000 and 150,000 Da and a polydispersity index (PDI) between 1.5 and 2.5. Related embodiments also describe additional chitosan property ranges including degree of deacetylation (% DDA) and variation in molecular weight intervals, together with optional amino protecting groups such as Boc during synthesis and their removal.
The invention relates to methods of reducing the viscosity of viscous sputum in the respiratory system of a human subject having cystic fibrosis by administering by inhalation a therapeutically effective amount of a composition comprising a derivatized chitosan. The composition disrupts a preformed biofilm in the respiratory system and reduces the viscosity of viscous sputum relative to sputum that has not been contacted with the composition, including embodiments stating at least 50% and at least 80% viscosity reduction.
Claims Coverage
The consolidated claim coverage includes two independent claims directed to inhalation administration of a derivatized chitosan composition for cystic fibrosis sputum viscosity reduction. The inventive features are the formula (I) derivatized chitosan with constrained R1 substituent composition, defined molecular weight and PDI ranges, and the requirement that administration disrupts a preformed biofilm and reduces viscous sputum viscosity versus sputum not contacted with the composition.
Inhalation of derivatized chitosan composition for cystic fibrosis sputum viscosity reduction
Administering by inhalation a therapeutically effective amount of a composition comprising a derivatized chitosan that comprises a chitosan of formula (I), wherein n is an integer between 20 and 6000; each R1 is independently selected from hydrogen, acetyl, and a group of formula (II); at least 25% of R1 substituents are H, at least 1% of R1 substituents are acetyl, and at least 4-30% of R1 substituents are a group of formula (II); the molecular weight is between 10,000 and 150,000 Da; and the polydispersity index (PDI) is between 1.5 and 2.5; wherein upon administration the composition disrupts a preformed biofilm and reduces the viscosity of viscous sputum relative to sputum that has not been contacted with the composition.
Inhalation of formula (I) derivatized chitosan achieving at least 50% viscosity reduction
Administering by inhalation a therapeutically effective amount of a composition comprising a derivatized chitosan of formula (I), with the same R1 substituent constraints and molecular-weight range, wherein upon administration the composition disrupts a preformed biofilm and reduces the viscosity of viscous sputum by at least 50% relative to the sputum that has not been contacted with the composition.
Across the independent claims, the inventive core is an inhalable composition comprising a derivatized chitosan defined by formula (I) and constrained R1 substituent distribution, with specified molecular weight and PDI, where administration disrupts a preformed respiratory biofilm and reduces viscous sputum viscosity versus a non-contact control, including an explicit at-least-50% reduction threshold in one independent claim.
Stated Advantages
Reduces the viscosity of viscous sputum in the respiratory system of a human subject having cystic fibrosis relative to sputum not contacted with the composition.
Disrupts a preformed biofilm in the respiratory system.
Reduces the viscosity of viscous sputum by at least 50% relative to sputum not contacted with the composition, with embodiments stating at least 80%.
Documented Applications
Reducing the viscosity of viscous sputum in the respiratory system of a human subject having cystic fibrosis by inhalation of a derivatized chitosan composition that disrupts a preformed biofilm.
Biofilm disruption in respiratory system contexts associated with viscous sputum.
Treating or preventing gastrointestinal tract infections by reducing biofilm viscosity and/or partial dissolution of biofilm.
Treating or preventing wound infections by reducing biofilm viscosity and/or partial dissolution of biofilm.
Oral, enteral, and topical administration modalities are described for the infection use cases.
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