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US-20260124122-A1 - QUATERNARY AMMONIUM SILANE AQUEOUS HYDROGEL FORMULATIONS

US20260124122A1US 20260124122 A1US20260124122 A1US 20260124122A1US-20260124122-A1

Abstract

Disclosed herein are quaternary ammonium silane aqueous hydrogel formulations, including pharmaceutically acceptable aqueous hydrogel formulations, that provide high aqueous stability to an ammonium silane active moiety, as well as methods of use and manufacture.

Inventors

  • Gary Allred
  • Lany Liebeskind
  • William R. Cast
  • Carl Hilliard

Assignees

  • TOPIKOS SCIENTIFIC, INC.

Dates

Publication Date
20260507
Application Date
20251219

Claims (20)

  1. 1 . An aqueous hydrogel formulation comprising: a) a quaternary ammonium silane compound selected from the group consisting of Formula A-D and Compounds I-XXV; b) a non-ionic gelling agent; c) a non-ionic adhesion agent; d) a non-ionic wetting agent; e) optionally a non-ionic osmotic agent; and f) an aqueous solution; wherein: a is 1, 2, 3, or 4; R 1 is independently at each occurrence selected from the group consisting of C 6 -C 22 alkyl and C 6 -C 22 alkanoyl; R 8 is H or CH 2 OH; R 9 is H or C 1 -C 8 alkyl; X 3 is OH or CH 2 OR 7 ; R 10 , R 11 , and R 12 are independently at each occurrence selected from the group consisting of hydrogen, hydroxyl, CH 2 OR 7 , CON(R 7 ) 2 , COOR 7 , C(O)R 7 , C 1 -C 8 alkyl, C 1 -C 8 hydroxyalkyl, and C 1 -C 8 alkanoyl; R 13 is selected from the group consisting of hydroxyl, CH 2 OR 7 , CON(R 7 ) 2 , COOR 7 , C(O)R 7 , C 1 -C 8 alkyl, C 1 -C 8 hydroxyalkyl, and C 1 -C 8 alkanoyl; R 7 is independently at each occurrence selected from hydrogen, C 1 -C 8 alkyl, C 1 -C 8 hydroxyalkyl, and C 1 -C 8 alkanoyl; X 1 is NR 17 , CH 2 , or C(O); X 4 is selected from the group consisting of hydroxyl, CH 2 OR 7 , CON(R 7 ) 2 , COOR 7 , C(O)R 7 , C 1 -C 8 hydroxyalkyl, and C 1 -C 8 alkanoyl; R 16 is C 1 -C 4 alkyl; R 17 is hydrogen, C 1 -C 8 hydroxyalkyl, or C 1 -C 8 alkanoyl; X − is an anion or is absent if the quaternary amine is balanced with an internal anion; R 32 , R 33 , R 34 , R 22 , R 23 , and R 24 are independently at each occurrence selected from the group consisting of: each R 21 is independently selected from C 1 -C 22 alkyl and C 2 -C 22 alkanoyl; R 28 and R 29 are independently at each occurrence selected from hydrogen, halogen, hydroxyl, N (R 7 ) 2 , CH 2 OR 7 , CON(R 7 ) 2 , COOR 7 , C(O)R 7 , C 1 -C 8 alkyl, C 1 -C 8 hydroxyalkyl, and C 1 -C 8 alkanoyl; X 11 is NR 17 , CH 2 , CHOH, or C(O); X 22 is C 1 -C 8 alkyl or C 1 -C 3 hydroxyalkyl; B + is a cation; and wherein Compounds I-XXV are:
  2. 2 . The aqueous hydrogel formulation of claim 1 , wherein anion X − is selected from methane sulfonate anion and
  3. 3 . The aqueous hydrogel formulation of claim 1 comprising: a) between about 0.1% and 10% (weight/weight) (w/w) of a quaternary ammonium silane compound selected from the group consisting of Formula A-D and Compounds I-XXV; b) between about 0.25% and about 3.0% (w/w) of the non-ionic gelling agent; c) between about 0.025% and about 0.5% (w/w) of the non-ionic adhesion agent; d) between about 0.5% and about 5.0% (w/w) of the non-ionic wetting agent; e) optionally between about 0.5% and about 7.5% (w/w) of the non-ionic osmotic agent; and, f) the aqueous solution.
  4. 4 . The aqueous hydrogel formulation of claim 3 comprising: a) a compound selected from the group consisting of Formula A-D and Compounds I-XXV, wherein the compound is present in the hydrogel formulation at a concentration that results in a trihydroxy-QAS cation present in the hydrogel at between about 0.1% and 5.0% (weight/weight) (w/w) when the compound is fully hydrolyzed, wherein the trihydroxy-QAS cation is of formula wherein r is 1, 2, 3, or 4; R 1 is C 6 -C 22 alkyl or C 6 -C 22 alkanoyl; R** and R*** are independently selected from the group consisting of: i. C 1 -C 4 alkyl; and, ii. C 6 -C 22 alkyl or C 2 -C 22 alkanoyl; b) between about 0.25% and about 3.0% (w/w) of a non-ionic gelling agent; c) between about 0.025% and about 0.5% (w/w) of a non-ionic adhesion agent; d) between about 0.5% and about 5.0% (w/w) of a non-ionic wetting agent; and e) optionally between about 0.5% and about 7.5% (w/w) of a non-ionic osmotic agent.
  5. 5 . The aqueous hydrogel formulation of claim 4 , wherein the aqueous hydrogel formulation does not comprise the non-ionic osmotic agent.
  6. 6 . The aqueous hydrogel formulation of claim 5 , wherein the non-ionic gelling agent is present in a concentration from about 0.5% (w/w) to about 2.0% (w/w).
  7. 7 . The aqueous hydrogel formulation of claim 6 , wherein the non-ionic gelling agent is HPMC.
  8. 8 . The aqueous hydrogel formulation of claim 5 , wherein the non-ionic adhesion agent is present in the amount of between about 0.025% (w/w) and about 0.5% (w/w).
  9. 9 . The aqueous hydrogel formulation of claim 5 , wherein the non-ionic adhesion agent is a poloxamer.
  10. 10 . The aqueous hydrogel formulation of claim 5 , wherein the non-ionic wetting agent is present in a concentration of between about 1.0% (w/w) and 3.0% (w/w).
  11. 11 . The aqueous hydrogel formulation of claim 5 , wherein the non-ionic wetting agent is glycerin.
  12. 12 . The aqueous hydrogel formulation of claim 5 , wherein the aqueous solution is water.
  13. 13 . The aqueous hydrogel formulation of claim 5 , wherein the hydrogel comprises between about 0.25% and about 3% (w/w) trihydroxy-QAS cation of formula:
  14. 14 . The aqueous hydrogel formulation of claim 4 comprising: a. between about 0.3% and about 0.8% (w/w) of a trihydroxy-QAS cation of Formula X that is derived from the complete hydrolysis of a compound in the hydrogel selected from the group consisting of Formula A-D and Compounds I-XXV, or a combination thereof; b. between about 0.8% and about 3.0% (w/w) of a non-ionic gelling agent; c. between about 0.025% to and about 0.40% (w/w) of a non-ionic adhesion agent; d. between about 0.5% and about 4.0% (w/w) of a non-ionic wetting agent; and e. optionally, between about 0.05% and about 0.4% (w/w) of an additional agent.
  15. 15 . The aqueous hydrogel formulation of claim 14 comprising: a. between about 0.3% and about 0.6% (w/w) of a trihydroxy-QAS cation of Formula X that is derived from the complete hydrolysis of Compound XIX; b. between about 0.8% and about 3.0% (w/w) of the non-ionic gelling agent, wherein the non-ionic gelling agent is HPMC; c. between about 0.1% to and about 0.4% (w/w) of the non-ionic adhesion agent, wherein the non-ionic adhesion agent is Poloxamer 407; and d. between about 0.5% and about 4.0% (w/w) of the non-ionic wetting agent, wherein the non-ionic wetting agent is glycerin.
  16. 16 . The aqueous hydrogel formulation of claim 4 comprising: a. between about 0.1% and 5.0% (weight/weight) (w/w) of a trihydroxy-QAS cation of Formula: wherein the hydrogel formulation also comprises as a counterion; b. between about 0.25% and about 3.0% (w/w) of a non-ionic gelling agent; c. between about 0.025% and about 0.5% (w/w) of a non-ionic adhesion agent; d. between about 0.5% and about 5.0% (w/w) of a non-ionic wetting agent; and
  17. 17 . The aqueous hydrogel formulation of claim 16 comprising: a. between about 0.1% and 5.0% (weight/weight) (w/w) of a trihydroxy-QAS cation of Formula: b. between about 0.25% and about 3.0% (w/w) of hydroxypropyl methylcellulose; c. between about 0.025% and about 0.5% (w/w) of Poloxamer 407; and d. between about 0.5% and about 5.0% (w/w) of glycerin.
  18. 18 . The aqueous hydrogel formulation of claim 4 comprising: a. between about 0.1% and 5.0% (weight/weight) (w/w) of a trihydroxy-QAS cation of Formula: b. between about 0.25% and about 3.0% (w/w) of a non-ionic gelling agent; c. between about 0.025% and about 0.5% (w/w) of a non-ionic adhesion agent; and d. between about 0.5% and about 5.0% (w/w) of a non-ionic wetting agent.
  19. 19 . The aqueous hydrogel formulation of claim 14 comprising: a. between about 0.3% and about 0.6% (w/w) of a trihydroxy-QAS cation of Formula X that is derived from the complete hydrolysis of Compound VII; b. between about 0.8% and about 3.0% (w/w) of the non-ionic gelling agent, wherein the non-ionic gelling agent is HPMC; c. between about 0.1% to and about 0.4% (w/w) of the non-ionic adhesion agent, wherein the non-ionic adhesion agent is Poloxamer 407; and d. between about 0.5% and about 4.0% (w/w) of the non-ionic wetting agent, wherein the non-ionic wetting agent is glycerin.
  20. 20 . The aqueous hydrogel formulation of claim 1 , wherein the compound is Compound VIII.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of International Patent Application No. PCT/US2024/050279, filed in U.S. Receiving Office on Oct. 7, 2024, which claims the benefit of U.S. Provisional Application No. 63/543,010, which was filed on Oct. 6, 2023, and U.S. Provisional Application No. 63/547,069, which was filed on Nov. 2, 2023. The entirety of each of these applications is incorporated by reference for all purposes. FIELD OF THE INVENTION This disclosure provides quaternary ammonium silane formulations with enhanced stability useful for reducing, preventing, or inhibiting the growth and development of opportunistic pathogenic microbial organisms (pathogens). The formulations described herein are useful for treating or preventing harmful microbial infections, including polymicrobial infections such as those found in microbial biofilms, on or in a host such as an animal or human. Furthermore, the formulations described herein can be used in an amount sufficient to (a) inhibit the detachment and dissemination of pathogenic cells from extracellular polymeric substances (EPS) of a biofilm; (b) cause a regression of destabilizing overgrowth of pathogenic cells and symbiotic enablers in harmful biofilms; and, (c) inhibit or prevent the attachment and formation of new biofilms by dispersed cells. BACKGROUND OF THE INVENTION Biofilms are structured colonies of various microorganisms, such as bacteria, fungi, and viruses, that live inside of a protective exopolysaccharide matrix responsible for the colony's survival. Biofilms are complex surface attached communities of microorganisms held together by self-produced polymer matrices mainly composed of polysaccharides, secreted proteins, and extracellular DNAs (Tremblay et al., (2013). Method to grow Actinobacillus pleuropneumoniae biofilm on a biotic surface. BMC Vet. Res. 9:213). A biofilm can consist of a single microbial species or a combination of different species of bacteria, protozoa, archaea, algae, filamentous fungi, and yeast that strongly attach to each other and to biotic or abiotic surfaces (Raghupathi et al., (2017)), or at air-liquid interface. Synergistic interactions within a multispecies biofilm enhance individual species protection against grazing by a pelagic protozoan (Front. Microbiol. 8:2649. The ability of microorganisms to develop biofilms has been shown to be an adaptable attribute of microbes (Koczan et al., (2011). Cell surface attachment structures contribute to biofilm formation and xylem colonization by Erwinia amylovora. Appl. Environ. Microbiol. 77, 7031-7039). The formation of biofilm appears to be an evolutionarily-adapted phenomenon that provides microorganisms with strengthened survival mechanisms when compared with individual planktonic cells (Dang and Lovell (2016). Microbial surface colonization and biofilm development in marine environments. Microbiol. Mol. Biol. Rev. 80, 91-138), including enhanced ability to grow in oligotrophic environments (Bowden and Li (1997). Nutritional influences on biofilm development. Adv. Dent. Res. 11, 81-99.), greater access to nutritional resources (Dang and Lovell, 2016), improved survival to biocides (Flemming et al. (2016). Biofilms: an emergent form of bacterial life. Nat. Rev. Microbiol. 14, 563-575), enhanced organism productivity and interactions (Roder et al. (2018). Enhanced bacterial mutualism through an evolved biofilm phenotype. ISME J. 12, 2608-2618), as well as greater environmental stability (Dang and Lovell, 2016). It is readily apparent that biofilms provide novel mechanisms of protection for communities of bacterial species under adverse environmental conditions. Biofilm formation is a complex process and can be described in five main phases: (i) reversible attachment phase, where microbes such as bacteria non-specifically attach to surfaces; (ii) irreversible attachment phase, which involves interaction between microbial cells and a surface using, for example, bacterial adhesins such as fimbriae and lipopolysaccharide (LPS); (iii) production of extracellular polymeric substances (EPS) by the resident microbial cells; (iv) biofilm maturation phase, in which microbe cells synthesize and release signaling molecules to sense the presence of each other, conducing to the formation of microcolony and maturation of biofilms; and (v) dispersal/detachment phase, where the microbial cells depart biofilms and comeback to independent planktonic lifestyle (Muhammad et al., Beyond Risk: Bacterial Biofilms and Their Regulating Approaches. Front. Microbiol. 21 May 2020). The oral cavity is home to over 700 species of microbes, including bacteria, fungi, viruses, and protozoa. Together they form a complex biological system called the oral microbiome (de Jongh, de Vries et al. 2023). Most of these microbes convert from free floating planktonic form into a sessile form to integrate into a surface attached, polymicrobial community encased in a self-produced ex