WO2023086877A1 - Nouvelles compositions et méthodes thérapeutiques - Google Patents

Nouvelles compositions et méthodes thérapeutiques Download PDF

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WO2023086877A1
WO2023086877A1 PCT/US2022/079624 US2022079624W WO2023086877A1 WO 2023086877 A1 WO2023086877 A1 WO 2023086877A1 US 2022079624 W US2022079624 W US 2022079624W WO 2023086877 A1 WO2023086877 A1 WO 2023086877A1
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compound
composition
compounds
formula
ocular
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Suchismita ACHARYA
Sumita Behera
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Ayuvis Research Inc
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Ayuvis Research Inc
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Priority to EP22893836.1A priority Critical patent/EP4429673A4/fr
Priority to AU2022383860A priority patent/AU2022383860A1/en
Priority to CA3237508A priority patent/CA3237508A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof

Definitions

  • the present invention is directed to novel products, variants, pharmaceutically acceptable salts and prodrugs thereof, and medical use of such compounds for the treatment and/or management of sepsis, septicemia, septic shock, peritonitis, skin and soft tissue infections, ocular infection, ocular inflammation, ocular angiogenesis, rheumatoid arthritis (RA), atherosclerosis, inflammatory bowel diseases (IBD), necrotizing enterocolitis, asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome, acute lung injury, bacterial and viral pneumonia, chronic lung injury, acute kidney injury, chronic kidney injury, fibrosis, fever syndromes, cachexia, psoriasis, autoimmune diseases, cardiac diseases, retinoblastoma, cancer and/or any disorder associated with inflammation, immunomodulation and microbial infection.
  • oxygenation/ventilation strategies optimization of fluid/vasopressor use, early goal-directed therapy
  • (2) targeting bacterial virulence factors i.e. antiendotoxin antibodies, endotoxin removal columns
  • targeting host response factors i.e. corticosteroids, anticytokine drugs, anticoagulants.
  • current therapies are not completely effective in patients with sepsis and septic shock. These therapies are even less effective in immunocompromised and older patients.
  • HAP Hospital-acquired pneumonia
  • NV-HAP non-ventilator HAP
  • VAP ventilator-associated pneumonia
  • HAP occurs at a rate of 4-50 cases per 1,000 admissions in community hospitals and general medical wards, and 120-220 cases per 1,000 ICU admissions 1 , accounting for >50% of the antibiotics prescribed in ICUs, and resulting in 33-50% mortality 2 .
  • PAP aeruginosa- associated pneumonia
  • MDR multi- drug resistant
  • CAP Community acquired pneumonia
  • aeruginosa infects about 75% of patients with cystic fibrosis aged 25-35 years; the mucoid form of the infection has a poor prognosis.
  • This infection has been treated traditionally by combination of fluoroquinolone and aminoglycoside antibiotics such as ciprofloxacin and colistin, in combination with meropenem, as P. aeruginosa is developing resistant to ⁇ -lactam antibiotics 10 .
  • a new generation ⁇ -lactam antibiotic cefepime seems more effective against P. aeruginosa; however, increasing incidence of antimicrobial resistance 11 has led to a serious restriction in treatment options for P. aeruginosa infections.
  • aeruginosa has been reported to be responsible for the pathogenesis of acute organ injury and sepsis by provoking host inflammatory responses and inducing systemic inflammatory syndromes 15 .
  • the innate immune system plays a critical role in battling the bacterial infection, strategic targeting of the host together with an appropriate antimicrobial treatment of the pathogen(s) by rational combination therapy may suppress antibacterial resistance, lead to resolution of antimicrobial-resistant infections, and mitigate the damages caused by an overt inflammatory response, thereby overcoming some of the impediments to antibiotic therapies.
  • ARDS Acute Respiratory Distress Syndrome
  • ARDS is a severe form of respiratory failure, leading to other organ failure, sepsis/death that develops in association with a variety of insults including massive hemorrhage, systemic infection, inhalation of noxious agents, bacterial infections, burns and blast trauma and has an overall mortality of 30-40%. It is estimated that 200,000 individuals develop ARDS each year in the United States (Rubenfeld, Caldwell et al. 2005, Villar, Blanco et al. 2016). One of the major complications of trauma-based morbidity in military combat is the development of ARDS, occurring in 8- 82% of selected patient populations.
  • BPD Bronchopulmonary dysplasia
  • BPD the single costliest complication of hospitalization during infancy
  • an average cost per discharge of $116,000 (Russell, Green et al. 2007).
  • BPD is associated with significant pulmonary and neurodevelopmental sequelae that continue to have health ramifications into adulthood (Bhandari and Bhandari 2011, Natarajan, Pappas et al.2012, Bhandari and McGrath-Morrow 2013, Raju, Buist et al.2017). It is thus important to understand the long-term consequences of BPD, as they are likely to have a significant impact on treatment and cost and application of health care during the lifetime of those born prematurely.
  • the pathologic hallmarks of BPD include: hyperoxia-induced pulmonary inflammation (Bhandari 2014, Balany and Bhandari 2015, Harijith and Bhandari 2016), increased cell death (Li, Choo-Wing et al. 2011, Choo-Wing R 2013, Sureshbabu, Syed et al. 2015, Sureshbabu, Syed et al. 2016), dysregulated angiogenic factors (Bhandari, Choo-Wing et al.2008, Sun H 2013, Sun H 2013, Syed, Choo-Wing et al. 2016) culminating in impaired alveolarization and dysregulated vascularization of the lung (Balany and Bhandari 2015).
  • Respiratory distress syndrome RDS
  • hyperoxia exposure is common antecedents of BPD.
  • the current standard-of-care therapeutic approach to treat RDS in premature neonates is exogenous surfactant and supplemental oxygen, however, there is no specific and effective method of prevention or treatment of BPD (Bhandari 2014).
  • NICHD/NHLBI National Institute of Child Health and Human Development/National Heart, Lung and Blood Institute
  • the identification of potential drugs to target BPD in preterm infants has been categorized as a “research priority” (McEvoy, Jain et al. 2014).
  • IL-10 primarily produced by T-helper 2 cells, B cells, monocytes, macrophages and keratinocytes is known to reduce the synthesis of pro-inflammatory cytokines and terminate inflammatory responses (Moore, Rousset et al.1991). Low levels of IL-10 are found in patients with transfusion-related ALI (Kapur, Kim et al. 2017). Importantly, treatment with IL-10 alleviated lung injury induced by ischemia–reperfusion, lipopolysaccharide (LPS) (Bi, Wang et al.2008), bleomycin and ozone; absence of endogenous IL-10 enhanced ALI induced by carrageenan.
  • LPS lipopolysaccharide
  • CD163 is released in the circulation in its soluble form, sCD163, via cleavage of the extracellular domain by matrix metalloproteases (MMPs) following oxidative stress (Timmermann and Högger 2005) or via activation of TLR4 after inflammatory stimuli (Weaver, Pioli et al. 2007, Zhi, Gao et al. 2017) and used as a biomarker for injury/inflammation.
  • MMPs matrix metalloproteases
  • sCD163 protects monocytes from hyperactivation during bacterial infections by dampening the secretion of the proinflammatory cytokines TNF ⁇ , IL ⁇ 1 ⁇ , IL ⁇ 6 and IL ⁇ 8 (Kneidl, Löffler et al. 2012) and endocytosing inflammatory neutrophils, and excess hemoglobin/haptoglobin complexes, so possesses phagocytic activity in clearing cell debris.
  • the inflammation may be caused by mechanical ventilation or gram- negative bacterial or polymicrobial infections.
  • the compounds find use in the treatment of bacterial lung infection induced pneumonia, chronic lung injury induced bronchopulmonary dysplasia in pre-term infants, sepsis and severe sepsis, SIRS and septic shock.
  • the compounds find use for treating inflammatory disorders, such as age- related macular degeneration (AMD) and retinopathy of prematurity pathogenesis.
  • AMD age- related macular degeneration
  • retinopathy of prematurity pathogenesis retinopathy of prematurity pathogenesis.
  • Such inflammatory conditions include, but are not limited to, ocular inflammatory diseases and choroidal neovascularization.
  • Compounds of the present invention have been unexpectedly found to possess superior anti- inflammatory activity in inhibiting inflammatory biomarkers such as TNF- ⁇ , IL-1 ⁇ and IL-6 in LPS induced human mononuclear cell assay and producing anti-inflammatory cytokine IL-10.
  • Compounds of present invention protected mice from both lethal gram-negative sepsis against Escherichia coli, polymicrobial sepsis in a cecal ligation and puncture model and P. aeruginosa induced lung pneumonia.
  • the present disclosure provides methods of inhibiting inflammatory biomarkers such as, but not limited to, TNF- ⁇ , IL-1 ⁇ and IL-6 in LPS induced human mononuclear cell assay by administering the compounds disclosed herein to a patient in need thereof.
  • the present disclosure provides methods of protecting mice from lethal gram-negative sepsis against Escherichia coli and Pseudomonas aeruginosa by administering the compounds disclosed herein to a patient in need thereof.
  • Compounds of the present invention have also been unexpectedly found to possess broad spectrum antimicrobial activity against both gram positive (methicillin susceptible Staphylococcus aureus and methicillin resistant Staphylococcus aureus), gram negative (E.
  • the present disclosure provides methods of treating infection caused by both gram positive (methicillin susceptible Staphylococcus aureus and methicillin resistant Staphylococcus aureus), gram negative (E. Coli, P. Aeruginosa, A, Baumannii, K. Pneumonia) bacteria as well as fungus (C. Albicans) by administering compounds disclosed herein to a patient in need thereof.
  • Compounds of the present invention have also been unexpectedly found to inhibit and eradicate biofilm formed by S. aureus.
  • the present disclosure provides methods of inhibiting or eradicating biofilm formed by a microorganism, such as but not limited to S. aureus by contacting a surface with compounds disclosed herein.
  • Compounds of present invention also demonstrated superior in vivo efficacy in protecting mice against cecal ligation and puncture (CLP) induced death and organ dysfunction.
  • CLP cecal ligation and puncture
  • Compounds of the present invention have also been unexpectedly found to possess superior activity against HMGB1 induced inflammation in mouse macrophages and reduced VEGF expression in retinal pigmental epithelial cells (ARPE-19) and daily intraperitoneal injection of the compound was able to reduce the average size of choroidal neovascularization (CNV) lesions to about 60% of those in control mice treated with vehicle only.
  • CNV choroidal neovascularization
  • an aspect of the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to Formula (I), or a pharmaceutically acceptable salt thereof:
  • R H, C(O)R 1 , alkyl, benzyl, substituted benzyl;
  • R 1 CH 3 , alkyl, piperidine nitroxyl, or biotin;
  • R 2 H, C(O)R 1 , C(S)NR 1 or aceloxy alkyl carbamate of the following formula:
  • R 2 C(O)OCHR 3 OC(O)OR 4 , piperidine nitroxyl, or fluorescein isothiocyanate (FITC);
  • R 3 H, CH 3 , C 2 H 5 , isopropyl;
  • R 4 substituted alkyl group;
  • X H, O, NH, or S and
  • the composition is formulated a sterile, injectable aqueous or oleaginous suspension.
  • the composition is formulated as a sterile topical gel, ointment or aqueous spray.
  • the composition further comprises an anti-inflammatory agent, an antimicrobial agent, or both.
  • the compound of Formula (I) is further defined as:
  • an aspect of the present disclosure relates to a method of treating at least one of sepsis, septicemia, septic shock, peritonitis, skin and soft tissue infections, ocular infection, ocular inflammation, ocular angiogenesis, rheumatoid arthritis (RA), atherosclerosis, inflammatory bowel diseases (IBD), necrotizing enterocolitis, asthma
  • the step of administering comprises providing a pharmaceutical compound comprising about 5.0 mg to about 100 mg of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof to a patient in need thereof, whereby the patient is treated.
  • the step of administering comprises administering the pharmaceutical composition comprising about 10.0 mg to about 1000 mg of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof to a patient in need thereof, whereby the patient is treated.
  • an aspect of the present disclosure relates to a composition
  • the composition is formulated a sterile, injectable aqueous or oleaginous suspension.
  • the composition is formulated as a sterile topical ocular solution.
  • the compound is selected from at least one of: .
  • an aspect of the present disclosure relates to a method of treating ocular angiogenesis, ocular inflammation which comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition according to claim 13, or a pharmaceutically acceptable salt thereof, whereby said subject is treated.
  • the compounds are selected from at least one of compounds 38 to 44:
  • the present invention includes compounds for the treatment of sepsis, septicemia, septic shock, peritonitis, skin and soft tissue infections, ocular infection, ocular inflammation, ocular angiogenesis, rheumatoid arthritis (RA), atherosclerosis, inflammatory bowel diseases (IBD), necrotizing enterocolitis, asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome, acute lung injury, bacterial and viral pneumonia, chronic lung injury, acute kidney injury, chronic kidney injury, fibrosis, fever syndromes, cachexia, psoriasis, autoimmune diseases, cardiac diseases, retinoblastoma, cancer and/or any disorder associated with inflammation, immunomodulation and microbial infection.
  • FIG.1 is a graph showing a graph with anti-pseudomonal activity of compounds 1 and 4 in mouse lungs by decreasing bacterial CFUs.
  • FIG.2 is a graph showing the phagocytosis and intracellular bacteria killing activity of compound 4 in human monocyte derived macrophages model.
  • FIG. 3 is a table showing the synergistic and additive activity of bacteria killing activity by compound 4 in combination with standard of care antibiotics.
  • FIG.4 showing prevention of chronic lung injury by compounds 4 in juvenile mouse BPD model after intraperitonial dosing.
  • FIG.5 showing the clean genotoxicity profile of compounds 1, 4, 34 and 42 in bacteria mutation and in vitro micronucleus studies.
  • FIG.5 showing the clean genotoxicity profile of compounds 1, 4, 34 and 42 in bacteria mutation and in vitro micronucleus studies.
  • FIG.6 showing affinity for hERG channel binding of compounds 1, 34 and 42 in HEK293 cell assay.
  • FIG.7 showing no off targets activities of compounds 4 and 42 in Eurofin’s 87 receptor, enzyme, ion channel assay.
  • FIG.8 showing no off targets activities of compounds 4 and 42 in Eurofin’s 87 receptor, enzyme, ion channel assay.
  • FIGS.9A and 9B showing pharmacokinetic profile of compounds 1 in adult rats after intravenous dosing.
  • FIG.10 is a graph showing binding of compound 11 to mouse spleen derived monocytes in a dose dependent manner.
  • FIG.11 is a graph showing binding of compound 11 to the TLR4 present in mouse spleen derived monocytes in a dose dependent manner.
  • FIG. 12 is a graph showing binding of compound 11 to the CD163 receptor present in mouse spleen derived monocytes in a dose dependent manner.
  • FIGS. 13A and 13B are micrographs showing no treatment and bioavailability of compound 26 in mouse lung after intranasal administration of the nanosuspension formulation.
  • FIG.14 is a graph showing the results of an evaluation of the TLR4 modulator compound 31 of the present invention in a mouse endotoxemia sepsis model and illustrates that compound 31 protected mice from lethal gram-negative sepsis against E. coli at a dose of 10mg/kg.
  • FIGS.15A to 15D are graphs showing the results of an evaluation of the TLR4/CD163 modulators AVR-25 (compound 34) AVR-45 (compound 39), AVR-48 (compound 42) and compound 43 of the present invention in a cecal ligation and puncture (CLP) model and illustrates that all the compounds protected mice from CLP induced polymicrobial sepsis and death.
  • FIGS.15A to 15D are graphs showing the results of an evaluation of the TLR4/CD163 modulators AVR-25 (compound 34) AVR-45 (compound 39), AVR-48 (compound 42) and compound 43 of the present invention in a cecal ligation and puncture (C
  • FIG. 16A to 16C are the histopathology score of major organs which demonstrates that, on treatment of compounds 34 and 44, the compounds of present invention reversed the major pathological changes and tissues resembled to sham group.
  • FIG. 17 demonstrated that compound 34 of present invention effectively down regulates the inflammatory cytokines in vivo in CLP mice.
  • FIG. 18 demonstrates that an evaluation of the TLR4 modulating compound 32 of the present invention in a lased induced CNV mouse model for wet AMD. Compound 32 decreased the choroidal neovascularization ⁇ 60% as compared to the positive control.
  • FIG. 19 demonstrates that compounds of present invention (31, and 32) decreased HMGB1 induced VEGF production in ARPE-19 cell.
  • FIG.20 demonstrates that compounds of present invention inhibit HMGB1 induced production of inflammatory mediator (TNF- ⁇ ) in mouse bone marrow derived macrophages.
  • FIG.21 demonstrates that compounds of present invention inhibit HMGB1 induced production of inflammatory mediators (TNF- ⁇ , i-NOS) and upregulate M2 biomarker CXCR4 in mouse macrophages.
  • FIGS. 22A, 22B, 22C and 22D demonstrate that compounds of present invention inhibited LPS induced production of inflammatory mediators in human blood cells.
  • FIG. 23A, 23B, 23C, 23D and 23E demonstrate that compounds of present invention produce anti-inflammatory cytokine IL-10 in human blood cells.
  • FIG. 24 demonstrates that compounds of present invention decrease LPS induced sCD163 level in human blood cells.
  • FIG. 25 demonstrates that compounds of present invention have broad-spectrum antimicrobial activity.
  • FIG.26 demonstrates that compounds of present invention inhibited biofilm formation.
  • FIG.27 demonstrates that the broad-spectrum antimicrobial activity of the compounds of present invention is via disruption of cell membrane.
  • FIGS.28A and 28B demonstrate that compounds of present invention do not bind to the plasma serum protein.
  • FIG.29 shows the synthetic scheme for preparing compound 4 and analogs.
  • FIG.30 shows the synthetic scheme for preparing compound 42.
  • FIG.31 provides the synthetic scheme for preparing compound 11.
  • FIG.32 provides the synthetic scheme for preparing compound 35 and 37.
  • LPS lipopolysachharide
  • TLR4 signaling receptor Toll Like Receptor 4
  • some investigators are seeking to develop antagonists that block either activation through TLRs or downstream signaling pathways that inhibit the storm of inflammatory molecules.
  • TLR4 inhibitor has the potential to balance the immune response and not suppress the immunity which is critical for development of secondary infection during sepsis.
  • an anti-inflammatory intervention such as corticosteroids may reduce the toxic effects of the inflammatory response but may also compromise effective host protection from the infection, especially in geriatric and immunocompromised patients.
  • the compounds of present innovation are small molecules that can synergistically inhibit inflammation, increase phagocytosis of bacteria, decrease microbial infection.
  • the compounds of current invention decrease the bacterial CFUs via binding to TLR4 and CD163 receptors activating the phagocytic pathway and decreasing inflammation with therapeutic potential to treat sepsis, septicemia and septic shock, ARDS, bacterial and viral pneumonia without compromising the immunity.
  • the compounds and compositions of the present invention can be used to treat at least one of sepsis, septicemia, septic shock, peritonitis, skin and soft tissue infections, ocular infection, ocular inflammation, ocular angiogenesis, rheumatoid arthritis (RA), atherosclerosis, inflammatory bowel diseases (IBD), necrotizing enterocolitis, asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome, acute lung injury, bacterial and viral pneumonia, chronic lung injury, acute kidney injury, chronic kidney injury, fibrosis, fever syndromes, cachexia, psoriasis, autoimmune diseases, cardiac diseases, retinoblastoma, cancer, disorder associated with inflammation, immunomodulation or microbial infections.
  • sepsis septicemia
  • septic shock peritonitis
  • skin and soft tissue infections ocular infection, ocular inflammation, ocular angiogenesis, rheumatoid arthritis (RA), atherosclerosis, inflammatory bowel diseases
  • TLR4 signaling is also essential for survival in acute lung injury induced by virulent P. aeruginosa type III secretory toxins found in multi-drug resistance (MDR) strains. Thus, it is required to maintain a balance between inflammation and resolution
  • MDR multi-drug resistance
  • the compounds of present invention bind to TLR4 in such a way that there is selective activation of the target cell so that there is increase in expression of the important anti-inflammatory cytokine IL-10.
  • the anti-inflammatory cytokine IL-10 is an important endogenous regulator of chemokine expression in acute lung inflammation.
  • Posterior segment neovascular ocular diseases as exemplified by proliferative diabetic retinopathy (PDR), exudative age-related macular degeneration (AMD) and retinopathy of prematurity (ROP), are a growing and huge health threat which require new effective therapies.
  • PDR proliferative diabetic retinopathy
  • AMD exudative age-related macular degeneration
  • ROP retinopathy of prematurity
  • Retinal neovascularization associated with PDR is the leading cause of blindness in working age adults.
  • Choroidal neovascularization (CNV) is responsible for 200,000 new cases of exudative AMD each year in the US rendering this neovascular pathology the leading cause of legal blindness in non-third world nations.
  • TLR4 Toll Like Receptor
  • TLR4 could contribute to the pathogenesis of AMD by multiple mechanisms such as release of TNF- ⁇ , interleukin-1 ⁇ , and other pro-inflammatory mediators.
  • TLR4 activation suppresses Wnt signaling, leading to reduced growth factor expression, secretion, and increased photoreceptor death in response to oxidative stress as well as can also lead to oxidative damage of photoreceptor outer segments.
  • TLR4 has a direct effect on several inflammation-related signaling pathways including MAPK, NF ⁇ - ⁇ and Jak1/Stat1 and shown to mediate neuronal toxicity through caspase-3, neuronal iNOS and ERK1/2, JNK1/2 and p38.
  • TLR4-mediated microglial activation by endogenous photoreceptor proteins in retinal inflammation can aggravate retinal cell death.
  • release of high-mobility group box-1 in ischemic neural tissue has been shown to initiate TLR4-dependent responses that contribute to retinal neovascularization [He et al, Arteriosclerosis, Thrombosis, and Vascular Biology.2013;33:330-338].
  • the compounds of present innovation are small molecules that can synergistically inhibit angiogenesis, inflammation and accelerate phagocytosis with therapeutic potential to treat AMD.
  • angiogenesis a smallmolecule that can synergistically inhibit angiogenesis, inflammation and accelerate phagocytosis with therapeutic potential to treat AMD.
  • TLR4 antagonist for inhibiting inflammation and angiogenesis for ocular indications such as dry/wet AMD, diabetic retinopathy, or any chronic ocular inflammation.
  • Compounds 34 demonstrated high efficacy in protecting organ dysfunction and death of mice in a cecal ligation and puncture (CLP) model of sepsis at 10mg/kg on intravenous (IV) dosing and downregulated inflammatory cytokines such as TNF- ⁇ , IL-1 ⁇ and IL-6 in a statistically significant manner. Compound 34 also reduced both acute and chronic lung injuries in mouse models via IP injection.
  • CLP cecal ligation and puncture
  • IV intravenous
  • Compound 34 also reduced both acute and chronic lung injuries in mouse models via IP injection.
  • Compounds of the present invention (34) can be synthesized using reported procedure as describe in Mohamed R. E et al, Carbohydrate research, 2001, 331, 129-142. [0077] Accordingly, the compounds find use as anti-inflammatory compounds.
  • Compounds of the present invention (35-38) can be synthesized using the synthesis schemes illustrated in FIG.31 in conjunction with knowledge available in the art.
  • Compounds of the present invention (38-44) have shown to inhibit LPS induced inflammation biomarkers (TNF- ⁇ , IL-1 ⁇ and IL-10.
  • Compound 39, 42 and 43 also showed broad spectrum antimicrobial activity against gram-negative, gram-positive bacteria as well fungus. Compound 39 and 43 unexpectedly inhibited biofilm formation by MSSA and MRSA. Compounds 39, 42 and 43 demonstrated high survival, organ protection in CLP mice model of sepsis when administered intravenously (10mg/kg dose). Accordingly, compounds as described herein find use as anti-inflammatory molecules in some embodiments. In some embodiments the compounds are anti-infective or antimicrobial.
  • n 0-1
  • R benzyl, substituted benzyl
  • R 1 COCH 3
  • R 2 cyclohexyl, p-nitro phenyl, piperidine nitroxy, piperidine-N-hydroxyl, p-methoxy phenyl.
  • Compounds of the present invention have shown to inhibit LPS induced inflammation biomarkers (TNF- ⁇ , IL-1 ⁇ and IL-6) in human monocytes and upregulated IL-10.
  • Compounds 49 also showed broad spectrum antimicrobial activity against gram-negative, gram-positive bacteria as well fungus.
  • Compounds 49 unexpectedly inhibited biofilm inhibition by MSSA and MRSA.
  • Compound 49 demonstrated high survival, organ protection in CLP mice model of sepsis when administered intravenously (5.0 mg/kg dose).
  • Compounds of the present invention can be synthesized using the synthesis schemes illustrated in FIG.30- 31 developed by us in conjunction with knowledge available in the art.
  • certain embodiments comprise pharmaceutically acceptable salts of compounds according to the present invention.
  • compositions comprise, but are not limited to, soluble or dispersible forms of compounds according to the present invention that are suitable for treatment of disease without undue undesirable effects such as allergic reactions or toxicity.
  • Representative pharmaceutically acceptable salts include, but are not limited to, acid addition salts such as acetate, citrate, benzoate, lactate, or phosphate and basic addition salts such as lithium, sodium, potassium, or aluminum.
  • FORMULATIONS [0084]
  • the compounds of the present disclosure are incorporated into parenteral formulations.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, and intra-arterial injections with a variety of infusion techniques.
  • Intra-arterial and intravenous injection as used herein includes administration through catheters. Preferred for certain indications are methods of administration that allow rapid access to the tissue or organ being treated, such as intravenous injections for the treatment of endotoxemia or sepsis.
  • the compounds of the present disclosure will be administered in dosages which will provide suitable inhibition of LPS activation of target cells; generally, these dosages are, preferably between 50- 3000 mg/patient, or from 100-2500 mg/patient or from 200-2000 mg/patient or from 500-1000 mg/patient or from 750-1000 mg/patient, more preferably, between 500-750 mg/patient and most preferably, between 250-500 mg/patient.
  • compositions containing the active ingredient may be in any form suitable for the intended method of administration.
  • Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadeaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate).
  • a suspending agent such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethyl cellulose, sodium alginate, polyvinylpyrrolidone, gum
  • the aqueous suspension may also contain one or more preservative such as ethyl of n-propyl p-hydroxybenzoate.
  • the pharmaceutical compositions of the invention are preferably in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenteral-acceptable diluent or solvent, such as a solution in 1,3- butanediol or prepared as a lyophilized powder.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid may likewise be used in the preparation of injectables.
  • the formulation comprises PLA or PLGA microparticles and may be further mixed with Na 2 HPO 4 , hydroxypropyl methylcellulose, polysorbate 80, sodium chloride, and/or edentate disodium.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders of the kind previously described.
  • compositions of the present disclosure also contain from about 80% to about 99.5%, preferably from about 90 or 95% to about 98.5% of a compatible non-aqueous pharmaceutically acceptable topical vehicle.
  • compositions of the present invention may contain up to about 5% water without significant adverse effects on the formation of the desired gels.
  • non-aqueous vehicle components include (but are not limited to) short chain alcohols and ketones and emollients, such as hydrocarbon oils and waxes, lanolin and lanolin derivatives, silicone oils, monoglyceride, diglyceride, and triglyceride esters, fatty alcohols, alkyl and alkenyl esters of fatty acids, alkyl and alkenyl diesters of dicarboxylic acids, polyhydric alcohols and their ether and ester derivatives; wax esters and beeswax derivatives.
  • Preferred vehicles incorporate methanol, ethanol, n-propanol, isopropanol, butanol, polypropylene glycol, polyethylene glycol and mixtures of these components.
  • Particularly preferred vehicles include ethanol, n-propanol and butanol, especially ethanol.
  • These preferred solvents may also be combined with other components, such as diisopropyl sebacate, isopropyl myristate, methyl laurate, silicone, glycerine and mixtures of these components, to provide non-aqueous vehicles which are also useful in the present invention. Of these additional components, diisopropyl sebacate is especially useful.
  • compositions of the present invention may additionally contain, at their art-established usage levels, compatible adjunct components conventionally used in the formulation of topical pharmaceutical compositions.
  • adjunct components may include, but are not limited to, pharmaceutically-active materials (such as supplementary antimicrobial or anti-inflammatory ingredients, e.g., steroids) or ingredients used to enhance the formulation itself (such as excipients, dyes, perfumes, skin penetration enhancers, stabilizers, preservatives, and antioxidants).
  • compositions of the present invention permit the formation of gels without requiring the presence of conventional gelling agents, such agents are preferably not included.
  • examples of such agents include the pharmaceutically-acceptable acidic carboxy polymers, such as the Carbopol compounds commercially available from B. F. Goodrich Chemicals, Cleveland, Ohio.
  • the gel-form compositions of the present invention may be formulated by the conventional mixing of the components described above. Gel formation takes place within from about 2 minutes to about 16 hours after mixing, depending upon the components utilized.
  • the cream, lotion or gel packaged in a common trigger spray container will be firmly adhered to the area of interest as a regular cream does after it is sprayed out from the container.
  • the present disclosure provides a pharmaceutical non-aerosol spray composition for topical application, which comprises the compounds as described herein alone or in combination.
  • the compounds are present in an amount in the range of 0.1% to 20% or in some embodiments from 1 to 15% by weight, or in some embodiments from 2 to 10% by weight of cream, lotion or gel.
  • the compounds used in the present invention can be incorporated into a neutral hydrophilic matrix cream, lotion or gel.
  • the cream or lotion matrix for topical application is characterized by polyoxyethylene alkyl ethers.
  • the gel is characterized by high molecular weight polymer of cross-linked acrylic acid.
  • Polyoxyethylene alkyl ethers are non- ionic surfactants widely used in pharmaceutical topical formulations and cosmetics primarily as emulsifying agents for water-in-oil and oil- in-water emulsions. It is characterized in this invention as a base for non-aerosol trigger sprayable cream or lotion.
  • Cross-linked acrylic acid polymer (Carbomer) employed to form the gel is another object of this invention.
  • a particularly suitable base for non-aerosol spray is therefore a cream or lotion containing from 1 to 25% of polyoxyethylene alkyl ethers, 3 to 40% of humectant and 0.1 to 1% of preservative or preservatives and the balance to 100% being purified water.
  • the polyoxyethylene alkyl ether can be one or any combination selected from the group consisting of polyoxyl 20 cetostearyl ether (Atlas G-3713) , poloxyl 2 cetyl ether (ceteth-2) , poloxyl 10 cetyl ether (ceteth-10) , poloxyl 20 cetyl ether (ceteth-20) , poloxyl 4 lauryl cetyl ether (laureth-4) , poloxyl 23 lauryl cetyl ether (laureth-23) , poloxyl 2 oleyl ether (oleth-2) , poloxyl 10 oleyl ether (oleth-10) , poloxyl 20 oleyl ether (oleth-20) , poloxyl 2 stearyl ether (steareth-2) , poloxyl 10 stearyl ether (steareth-10) , poloxyl 20 stearyl ether (steareth-20)
  • Suitable humectant can be one or any combination selected from the group consisting of propylene glycol, polyethylene glycol, sorbitol or glycerine.
  • Suitable preservative is one or any combination selected from the group consisting of methylparaben, propylparaben, benzyl alcohol, benzoic acid, sodium benzoate, sorbic acid and its salt or phenylethyl alcohol.
  • Another suitable base for non-aerosol spray is a gel containing from 0.1 to 2.0% of Carbomer, 0.1 to 1% of alkaline solution, 3 to 40% of humectant and 0.1 to 1% of preservative or preservative as and the balance to 100% being purified water.
  • Carbomer can be one or any combination selected from the group consisting of Carbomer 934, Carbomer 940 or Carbomer 941.
  • the suitable humectant, preservative and purified water for the gel are same as that in the case or cream or lotion.
  • Other sprayable formulations are described in US Pre-Grant Publication US2005/00255048, which is expressly incorporated herein by reference.
  • Ophthalmic formulation topical and intravitreal dosing:
  • the compound of the invention will typically be a small percentage of the total ophthalmic composition.
  • the compound of the invention will typically be at least 0.01 w/v %, more typically at least 0.1 w/v % and even more typically at least 0.5 w/v % of the ophthalmic composition.
  • the compound of the invention will also typically be no greater than 5.0 w/v %, even more typically no greater that 3.0 w/v % and even more typically no greater than 1.5 w/v % of the ophthalmic composition.
  • the ophthalmic composition will also typically include a suitable ophthalmic vehicle for delivery of the compound to the eye. It is contemplated that the ophthalmic composition may be configured for topical or intravitreal application to the eye and the ophthalmic vehicle will likely be different depending upon the manner of application.
  • the ophthalmic composition be aqueous and include a substantial amount of water.
  • the composition will include at least 30 w/v %, more typically at least 80 w/v % and even more typically at least 90 w/v % water (e.g., purified water).
  • the ophthalmic compositions may include only or consist essentially of water and compound of the invention.
  • PLGA or PLA macroparticle formulation of the compound of invention will be used as described by Shelke etal [Drug Deliv Transl Res. 2011, (1): 76–90].
  • the ophthalmic composition could include other ingredients as well such as Na 2 HPO 4 , hydroxypropyl methylcellulose, polysorbate 80, sodium chloride, and edentate disodium.
  • the vehicle be only or consist essentially of water for a topical application, particularly if that topical application is performed shortly after water is combined with the test compound or the composition is packaged in a manner to prevent contamination.
  • the ophthalmic composition is to be applied as a multi-dose ophthalmic composition over an extended period of time (e.g., as drops from an eye-dropper once, twice, thrice or more per day for multiple days)
  • the ophthalmic composition will likely include additional ingredients such as antimicrobial or preservative agents or systems, surfactants, buffering agents, tonicity agents, anti-oxidants, viscosity-modifying agents any combinations thereof or the like.
  • the compositions of the present invention typically include antimicrobial agent.
  • Potential antimicrobial agents include, without limitation, hydrogen peroxide, chlorine containing preservatives such as benzalkonium chloride or others.
  • the composition of the present invention is entirely or substantially free of any non-polymeric quaternary anti- microbial agents such as benzalkonium chloride (BAK).
  • Most preferred antimicrobial agent in the pharmaceutical composition includes polymeric quaternary ammonium compound.
  • the phrase “substantially free of” as it refers to an ingredient of the ophthalmic composition means that it is contemplated that the ophthalmic composition can be either entirely devoid of that particular ingredient or includes only a nominal amount of that particular ingredient.
  • the polymeric quaternary ammonium compounds useful in the compositions of the present invention are those which have an antimicrobial effect and which are ophthalmically acceptable.
  • Preferred compounds of this type are described in U.S. Pat. Nos. 3,931,319; 4,027,020; 4,407,791; 4,525,346; 4,836,986; 5,037,647 and 5,300,287; and PCT application WO 91/09523 (Dziabo et al.), which are expressly incorporated herein by reference.
  • the most preferred polymeric ammonium compound is polyquaternium 1, otherwise known as POLYQUADTM or ONAMERMTM with a number average molecular weight between 2,000 to 30,000. Preferably, the number average molecular weight is between 3,000 to 14,000.
  • the polymeric quaternary ammonium compounds are generally used in the suspensions of the present invention in an amount that is greater than about 0.00001 w/v %, more typically greater than about 0.0003 w/v % and even more typically greater than about 0.0007 w/v % of the suspension. Moreover, the polymeric quaternary ammonium compounds are generally used in the compositions of the present invention in an amount that is less than about 3 w/v %, more typically less than about 0.003 w/v % and even more typically less than about 0.0015 w/v % of the composition.
  • the antimicrobial agent of the composition of the present invention can additionally or alternatively include an antimicrobial system such as a borate/polyol complex system.
  • an antimicrobial system such as a borate/polyol complex system.
  • borate shall refer to boric acid, salts of boric acid, borate derivatives and other pharmaceutically acceptable borates, or combinations thereof. Most suitable are: boric acid, sodium borate, potassium borate, calcium borate, magnesium borate, manganese borate, and other such borate salts. Borate interacts with polyols, such as glycerol, propylene glycol, sorbitol and mannitol, to form borate polyol complexes.
  • polyols such as glycerol, propylene glycol, sorbitol and mannitol
  • polyol includes any compound having at least one hydroxyl group on each of two adjacent carbon atoms that are not in trans configuration relative to each other.
  • the polyols can be linear or cyclic, substituted or unsubstituted, or mixtures thereof, so long as the resultant complex is water soluble and pharmaceutically acceptable. Examples of such compounds include: sugars, sugar alcohols, sugar acids and uronic acids.
  • Preferred polyols are sugars, sugar alcohols and sugar acids, including, but not limited to: mannitol, glycerin, xylitol, sorbitol and propylene glycol.
  • the borate/polyol complex antimicrobial system i.e., the borate and polyol together
  • the borate to polyol ratio (weight to weight ratio) in the composition is typically between 1 to 1 and 1 to 10 and more typically is between 1 to 2 and 1 to 4 (e.g., about 1 to 3).
  • Tyloxapol, polysorbate-80 and polyoxyl hydrogenated castor oil are preferred surfactants.
  • Tyloxapol is a highly preferred surfactant.
  • the surfactant is typically present in a concentration that is at least 0.01 w/v %, more typically at least 0.025 w/v % and even possibly at least 0.1 w/v % of the composition and also typically is less than 5 w/v %, more typically less than 2.0 w/v % and even possibly less than 1.0 w/v % of the composition.
  • compositions of the present invention that are to be used for topical applications are typically formulated so as to be compatible with the eye.
  • the ophthalmic compositions intended for direct application to the eye will be formulated so as to have a pH and tonicity that are compatible with the eye.
  • the compositions will typically have a pH in the range of 4 to 9, preferably 5.5 to 8.5, and most preferably 5.5 to 8.0. Particularly desired pH ranges are 6.0 to 7.8 and more specifically 6.4 to 7.6.
  • the compositions will have an osmolality of 200 to 400 or 450 milliosmoles per kilogram (mOsm/kg), more preferably 240 to 360 mOsm/kg.
  • compositions of the present invention are multi-dose ophthalmic compositions, for example, where the composition is in an eye dropper and can be administered as one or more drops once, twice, thrice or more times per day, topically to the eye.
  • the compositions preferably have sufficient antimicrobial activity to allow the compositions to satisfy the USP preservative efficacy requirements, as well as other preservative efficacy standards for aqueous pharmaceutical compositions.
  • preservative efficacy standards for multi-dose ophthalmic solutions in the U.S, and other countries/regions are set forth in the following table: Preservative Efficacy Test (“PET”) Criteria (Log Order Reduction of Microbial Inoculum Over Time) B acteria Fungi A reduction of 1 log (90%), USP 27 The compositions must demonstrate by day 7; 3 logs (99.9%) by over the entire test period, which means day 14; and no increase no increases of 0.5 logs or greater, after day 14 relative to the initial inoculum. Japan 3 logs by 14 days; and no No increase from initial count at 14 and i ncrease from day 14 28 days through day 28. Ph. Eur.
  • B A reduction of 1 log at 24 A reduction of 1 log (90%) by day 14, hours; 3 logs by day 7; and and no increase thereafter no increase thereafter
  • FDA/ISO A reduction of 3 logs from No increase higher than the initial value 14730 initial challenge at day 14; at day 14, and no increase higher than and a reduction of 3 logs the day 14 rechallenge count through f rom rechallenge day 28.
  • the methods comprise administering to a patient in need thereof an effective amount of the antimicrobial and anti-inflammatory compositions described herein such that the disease or disorder is treated.
  • the medical use of such compounds will be for the treatment and/or management of sepsis, neonatal sepsis, septicemia, septic shock, burn and wounds, infective endocarditis, biofilm inhibition, ocular infection, ocular inflammation, ocular angiogenesis, diabetic retinopathy, retinopathy of prematurity, uveitis, rheumatoid arthritis (RA), atherosclerosis, inflammatory bowel diseases (IBD), asthma, acute respiratory distress syndrome, chronic obstructive pulmonary disease, bronchopulmonary dysplasia, fever syndromes, cachexia, psoriasis, autoimmune diseases, cardiac diseases, retinoblastoma, cancer, acute and chronic kidney injury and/or any disorder associated with inflammation, immunomodulation and microbial infection.
  • EXAMPLE 1 In vitro and in vivo efficacy: The compounds of invention reduced CFUs of Pseudomonas aeruginosa bacteria in mouse lungs, increased phagocytotic activity in human macrophages and demonstrated synergistic activities with standard of care antibiotics.
  • FIG. 3 Checkerboard MIC assay of Compound 4 + different SoC antibiotic combinations using gram-negative (P. aeruginosa, A.
  • FIG.4 is a graph that shows the effect of intranasal PLGA nanosuspension of compound 4 (20 ⁇ M, at day P2 and P4) on normoxia (21% O 2 , room air, RA, P0-P14), and BPD mouse pups (100% O 2 , P0-P4, then P4-P14 at 21% O 2 ).
  • RA pups all the compounds were safe to use with no significant change in chord lengths (CL), an indicator of lung injury.
  • CL chord lengths
  • N 4-5. ****p ⁇ 0.0001.
  • One-way ANOVA Dunnett's multiple comparisons test.
  • EXAMPLE 3 In vitro genotoxicity, hERG channel and off target binding effect of the compounds of present inventions. [0125] FIG. 5: Ames bacterial reverse mutation test was conducted at Covance Inc, Harrogate, UK according to their screening protocol in the absence and presence of S- 9 (Jemnitz, Veres et al. 2004).
  • Treatments of compounds 1, 4, 34 and 42 were conducted in strains TA 98 and TA100 (Salmonella typhimurium) in the absence and presence of metabolic activation system S-9 (Molecular Toxicology Incorporated, USA) from male Sprague-Dawley rats induced with Aroclor 1254 added as a 5% mix to the test system.
  • the cultures were incubated at 37 ⁇ 1°C to provide a working culture of approximately 108 to 109 cells/mL, which was confirmed by either viability plating or optical density (OD) assessment at 650 nm. Revertant counts per well and the mean number of revertants (per well) were calculated for each treatment and strain.
  • FIG.5 also shows an alternative to measuring structural aberrations in mitotic cells is to measure micronuclei in human peripheral blood lymphocytes.
  • Cytochalasin B (Cyto-B), if added to the cultures, inhibits cytokinesis (cell division) but not karyokinesis (nuclear division) resulting in the formation of binucleate cells (Fenech and Morley 1985). If micronuclei are counted in binucleate cells, then a measurement of micronucleus induction resulting from cell division can be obtained. In the absence of S- 9 activation, no statistically significant increases in MNBN cells were observed for any concentration of compounds 1, 4, 34 and 42 were analyzed.
  • FIGS.7 and 8 This study was conducted at Eurofins to establish the potential compounds 4 and 42 to interact with 87 different off-target receptors, ion channels, transporters, and enzymes.
  • FIGS. 11 and 12 Cells were incubated at 4 o C for 1 hr followed by incubation with biotinylated compound 11 along with monocyte markers. Then the cells were probed with appropriate fluorescence coupled streptavidin (for anti-human TLR4 and CD163 antibodies) and analyzed by FACS.
  • FIGS.13A and 13B Compound 26 with FITC group as fluorescence marker was encapsulated in PLGA and delivered as IN (20 ⁇ M) suspension to mouse pups. Cryosections of the control mouse lungs show the absence of the drug (no fluorescence) and presence of compound 26 with fluorescence.
  • RA room air
  • FITC fluorescein isothiocyanate
  • PLGA poly D, L-lactic-co-glycolic acid
  • Scale bar 100 ⁇ m, N 2.
  • FIGS. 16A to 16C are the histopathology score of major organs which demonstrates that, on treatment of compounds 34 and 44, the compounds of present invention reversed the major pathological changes and tissues resembled to sham group.
  • EXAMPLE 7 Compounds were tested for inhibiting the production of inflammatory mediators in human peripheral blood mononuclear cells. [0139] FIGS.
  • Compound 32 and 34 (10 ⁇ M) were found to be more potent than chitohexaose, (Compound 31) (10 ⁇ M) in terms of percentage of inhibition of LPS mediated induction of inflammatory cytokines (LPS vs Chtx p ⁇ 0.001 whereas LPS vs compound 32 or 34 p ⁇ 0.0001).
  • the protocol was followed as described [Panda etal, PLoS Pathog 2012, 8, e1002717].
  • Human mononuclear cells were stimulated with LPS along with the series of compounds (10 ⁇ M) for 48 h. TNF- ⁇ , IL-1 ⁇ , Il-6 in culture supernatants were quantified according to the manufacturer’s instruction.
  • EXAMPLE 8 Compounds 31, 32, and 35 inhibits LPS induced production of inflammatory mediator (TNF- ⁇ ) in mouse bone marrow derived macrophages.
  • FIG. 20 Bone marrow derived mouse macrophages were treated with 100 ⁇ M of the test compounds for 8 hours. Pro-inflammatory cytokines such as TNF- ⁇ protein level was measured by real- time RT-PCR. LPS treatment (10 ng/ml) was used as positive control.
  • FIG. 21 The expressions of TNF- ⁇ and iNOS were both inhibited by compound 35 in macrophages.
  • CXCR4 an M2 macrophage marker, was upregulated by 35, suggesting potential effects on microphage polarization suggesting immune modulating activity.
  • Bone derived macrophages from mouse were treated with HMGB1 for 8 hours, with or without 100 ⁇ M of compound 35.
  • FIGS. 23A to 23E Interleukin 10 (IL-10) is a cytokine with potent anti-inflammatory properties that plays a central role in limiting host immune response to pathogens, thereby preventing damage to the host and maintaining normal tissue homeostasis. Dysregulation of IL-10 is associated with enhanced immunopathology in response to infection as well as increased risk for development of many autoimmune diseases.
  • FIGS.23 B-E showed the increase in IL-10 with other analogs 34, 39, 43 and 42 when treated for 48h and ELISA measurement done with cell lysates.
  • EXAMPLE 11 Compounds of present invention decreases the LPS induced soluble CD163 (sCD163) in cell supernatants after 24 h as measured by ELISA showing decreased inflammation.
  • FIG.24 demonstrates that compounds of present invention decrease LPS induced sCD163 level in human blood cells.
  • EXAMPLE 12 Chitohexaose (Compound 31) protected mouse from lethal gram-negative sepsis against E. Coli.
  • EXAMPLE 14 Histopathology score of organ tissues post-CLP mice.
  • H/E Hematoxylin Eosin staining of different organs of Sham, CLP and compounds 34 or 42 treated mice were done.
  • EXAMPLE 16 Compounds of present invention have broad-spectrum antimicrobial activity.
  • the compounds were screened against selected gram negativee (E. Coli, P. Aeruginosa, A, Baumannii, K. Pneumonia), gram positive (MRSA) as well as fungus (C. Albicans) mostly found in burn and septic wounds. Most of them showed antimicrobial activity with MIC 90 of 50-200 mg/L (FIG.25).
  • MIC Minimum Inhibitory Concentrations
  • CLSI Clinical Laboratory Standards Institute
  • test and control compounds have been dissolved in DMSO, diluted to proper concentrations and added to 96-well microdilution trays.
  • Brain Heart Infusion Broth (BHI) was used for studies with bacterial strains such as S. aureus, E. coli, P. aeruginosa, K. pneumoniae, A. baumannii and Candida albicans.
  • the CBD produces 96 equivalent biofilms for the assay of antibiotic susceptibilities by the standard 96-well technology. Susceptibility to a standard group of compounds and antibiotics was determined for National Committee for Clinical Laboratory Standards (NCCLS) as described previously.
  • NCCLS National Committee for Clinical Laboratory Standards
  • EXAMPLE 18 The broad-spectrum antimicrobial activity of the compounds of present invention is via disruption of cell membrane.
  • the effects of the AVR compounds on exponentially growing MRSA and membrane integrity were evaluated.
  • EXAMPLE 19 Compounds of present invention do not bind to the plasma serum protein.
  • One of the major difficulties in designing systemic, oral or topical drug candidate is their poor plasma/tissue bioavailability due to binding of the drug to the plasma serum protein.
  • Cytotoxicity and therapeutic index were also evaluated by exposing to NIH 3T3 mouse fibroblast cell lines (ATCC, Manassas, VA) to antibiotic colistin and AVR compounds for 24 h, followed by an MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide, Thermo Fischer, MA] assay as described previously.
  • MTT 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide, Thermo Fischer, MA] assay as described previously.
  • the cytotoxicity for all the AVR compounds in NIH 3T3 mouse fibroblast cell line is shown in FIG. 25, indicating that AVR compounds selectively inhibit the growth of MRSA without compromising the growth of fibroblast cells which are critical in wound healing process and has >4 fold therapeutic index for compounds 39 and 43.
  • EXAMPLE 21 Compounds 31 and 32 decreased VEGF production in ARPE-19 cell.
  • the RPE Central to photoreceptor survival and function, the RPE is the major source of the angiogenic factor VEGF and therefore plays a central role in the modulation and progression of choroidal neovascularization [Spilsbury et al, The American Journal of Pathology 2000, 157, 135-144; Betts et al, ISRN Ophthalmology 2011, 2011, 184295] leading to AMD.
  • HMGB1 an endogenous ligand for TLR4
  • ARPE-19 showed that compounds 31 and 32 (50 ⁇ g/mL) effectively reduced the HMGB1 induced VEGF production in ARPE-19 cells in a statistically significant manner (p ⁇ 0.01).
  • 2 ⁇ 10 5 ARPE-19 cells were seeded in 24 well plate for 24 h in full medium containing 10% serum following which they were maintained for additional 24 h with serum free medium.
  • Cells were treated with 0 ⁇ g/mL (medium) or 100ng/mL of HMGB1 along with or without of 50 ⁇ g/mL of test compounds for 24 h.
  • Supernatant was collected and assayed using human VEGF ELISA kit from Peprotech according to manufacturer’s instructions.
  • RPE cells are located adjacent to choroidal capillaries and other major ocular vasculatures.
  • Laser CNV was induced in C57BL/6 (10-12 weeks) mice using an Iridex Oculight GL 532nm diode laser (Mountain View, CA) connected to the Micron IV fundus imaging system using a laser injector (Phoenix Research Laboratories, Pleasanton, CA).
  • the parameters used to reproducibly obtain successful laser spots were: 350 mW, 75 msec, and 50 ⁇ m spot size.
  • Four laser spots were applied; 2-3 disc diameters from the optic nerve.
  • Compounds 32, and chitotriose and BSS were administered by IP injection once daily, and was started one day before laser and continued for 10 days after laser.
  • mouse eyes were examined by fundus fluorescein angiography and/or optical coherence tomography (OCT) to visualize the CNV lesions.
  • OCT optical coherence tomography
  • animals were sacrificed, and RPE/choroid/sclera flat mounts were prepared and stained with both FITC-conjugated isolectin B4 and anti-ICAM-2 antibody to quantitatively measure the size of CNV.
  • p-Pinacoloneboronatephenyl 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy- ⁇ -D-glucopyranoside B A solution of 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy- ⁇ -D-glucopyranosyl chloride A (5.0g, 13.67 mmol), tetrabutylammonium hydrogen sulfate (4.65g, 13.67 mmol), and 4-(4, 4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)phenol (3.15 g, 1.05 equiv.) in a mixture of CH 2 Cl 2 (100 mL) and 1N NaOH (50 mL) was stirred vigorously for 1 h.
  • p-Pinacoloneboronatephenyl 2-acetamido-2-deoxy- ⁇ -D-glucopyranoside 4 The above p- Pinacoloneboronatephenyl 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy- ⁇ -D-glucopyranoside B (2.45g, 4.45 mmol) was suspended in dry MeOH (70 mL) and methanolic solution of NaOMe (1M solution, 4.25 equivalent) was added and the mixture was stirred at RT until dissolution was complete (15 min). Dowex 50WX2-200 (5g, previously washed in methanol) was added and removed by filtration after 15 min. The solution was evaporated in vacuo to dryness.
  • p-Boronic acid phenyl 2-acetamido-2-deoxy- ⁇ -D-glucopyranoside 7 The above compound p- pinacoloneboronatephenyl 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy- ⁇ -D-glucopyranoside B (1.5g, 2.73 mmol) in acetone/H 2 O (4:1) was treated with NaIO 4 (2.5 equiv.), NH 4 OAc (1.5 equiv) and was stirred at RT for 24 hrs. pH of the reaction mixture was adjusted to 3 by adding 1N HCl and stirred for additional 30mins.
  • the azide intermediate F was converted to intermediate amine G by using standard azide to amine reduction procedure using TPP, H 2 O by stirring at 23 o C overnight.
  • This intermediate product G was then coupled with commercially available NH-succinamide- Biotin using 1.5 equivalents of EDCI, DIPEA and catalytic amount of HOBt to give 91% yield of compound 11 after column purification.
  • the structure of compound 11 was confirmed by both 1 HNMR and MS.
  • Topical/intravitreal formulation [0197] The table below represents exemplary ranges for a topical or intravitreal ophthalmic composition according to the present invention: 44 [0198] EXAMPLE-25. Injectable Formulation. [0199] The table below represents exemplary ranges for an intravenous (IV) composition according to the present invention: The compound of the invention is dissolved in most of the water (35° 40° C.) and the pH adjusted to between 6.5 and 7.4 with the hydrochloric acid or the sodium hydroxide as appropriate. The batch is then made up to volume with water and filtered through a sterile micropore filter into a sterile 10 mL amber glass vial (type 1) and sealed with sterile closures and over seals.
  • IV intravenous
  • EXAMPLE-26 The tables below represent exemplary ranges for topical gel, lotion and spray compositions according to the present invention.
  • Oral Formulations The composition of the present invention is typically administered in admixture with suitable pharmaceutical salts, buffers, diluents, extenders, excipients and/or carriers (collectively referred to herein as a pharmaceutically acceptable carrier or carrier materials) selected based on the intended form of administration and as consistent with conventional pharmaceutical practices. Depending on the best location for administration, the composition may be formulated to provide, e.g., maximum and/or consistent dosing for the particular form for oral, rectal, topical, intravenous injection or parenteral administration.
  • compositions may be administered alone, it will generally be provided in a stable salt form mixed with a pharmaceutically acceptable carrier.
  • the carrier may be solid or liquid, depending on the type and/or location of administration selected.
  • the composition may be included in a tablet.
  • Tablets may contain, e.g., suitable binders, lubricants, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents and/or melting agents.
  • oral administration may be in a dosage unit form of a tablet, gelcap, caplet or capsule, the active drug component being combined with an non-toxic, pharmaceutically acceptable, inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol,mixtures thereof, and the like.
  • Suitable binders for use with the present invention include: starch, gelatin, natural sugars (e.g., glucose or beta-lactose), corn sweeteners, natural and synthetic gums (e.g., acacia, tragacanth or sodium alginate), carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants for use with the invention may include: sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, mixtures thereof, and the like.
  • Disintegrators may include: starch, methyl cellulose, agar, bentonite, xanthan gum, mixtures thereof, and the like.
  • the composition may be administered in the form of liposome delivery systems, e.g., small unilamellar vesicles, large unilamallar vesicles, and multilamellar vesicles, whether charged or uncharged.
  • Liposomes may include one or more: phospholipids (e.g., cholesterol), stearylamine and/or phosphatidylcholines, mixtures thereof, and the like.
  • the composition may also be coupled to one or more soluble, biodegradable, bioacceptable polymers as drug carriers or as a prodrug.
  • Such polymers may include: polyvinylpyrrolidone, pyran copolymer, polyhydroxylpropylmethacrylamide-phenol, polyhydroxyethylasparta-midephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues, mixtures thereof, and the like.
  • composition may be coupled one or more biodegradable polymers to achieve controlled release of the composition
  • biodegradable polymers for use with the present invention include: polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels, mixtures thereof, and the like.
  • gelatin capsules may include the composition and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like.
  • diluents may be used to make compressed tablets. Both tablets and capsules may be manufactured as immediate- release, mixed-release or sustained-release formulations to provide for a range of release of medication over a period of minutes to hours.
  • Compressed tablets may be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere.
  • An enteric coating may be used to provide selective disintegration in, e.g., the gastrointestinal tract.
  • the oral drug components may be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
  • liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents, mixtures thereof, and the like.
  • suitable solvents for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents, mixtures thereof, and the like.
  • Liquid dosage forms for oral administration may also include coloring and flavoring agents that increase patient acceptance and therefore compliance with a dosing regimen.
  • water, a suitable oil, saline, aqueous dextrose (e.g., glucose, lactose and related sugar solutions) and glycols (e.g., propylene glycol or polyethylene glycols) may be used as suitable carriers for parenteral solutions.
  • Solutions for parenteral administration include generally, a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffering salts.
  • Antioxidizing agents such as sodium bisulfite, sodium sulfite and/or ascorbic acid, either alone or in combination, are suitable stabilizing agents.
  • Citric acid and its salts and sodium EDTA may also be included to increase stability.
  • parenteral solutions may include pharmaceutically acceptable preservatives, e.g., benzalkonium chloride, methyl- or propyl-paraben, and/or chlorobutanol. Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field, relevant portions incorporated herein by reference.
  • the composition may also be delivered as an intranasal form via use of a suitable intranasal vehicle.
  • a suitable intranasal vehicle for direct delivery to the nasal passages, sinuses, mouth, throat, esophagous, tachea, lungs and alveoli, the composition may also be delivered as an intranasal form via use of a suitable intranasal vehicle.
  • the composition may be delivered using lotions, creams, oils, elixirs, serums, transdermal skin patches and the like, as are well known to those of ordinary skill in that art.
  • Parenteral and intravenous forms may also include pharmaceutically acceptable salts and/or minerals and other materials to make them compatible with the type of injection or delivery system chosen, e.g., a buffered, isotonic solution.
  • Capsules may be prepared by filling standard two-piece hard gelatin capsules each with 10 to 500 milligrams of powdered active ingredient, 5 to 150 milligrams of lactose, 5 to 50 milligrams of cellulose and 6 milligrams magnesium stearate.
  • Soft Gelatin Capsules A mixture of active ingredient is dissolved in a digestible oil such as soybean oil, cottonseed oil or olive oil. The active ingredient is prepared and injected by using a positive displacement pump into gelatin to form soft gelatin capsules containing, e.g., 100-500 milligrams of the active ingredient.
  • Tablets A large number of tablets are prepared by conventional procedures so that the dosage unit was 100-500 milligrams of active ingredient, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 50-275 milligrams of microcrystalline cellulose, 11 milligrams of starch and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.
  • Tablets may contain suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and melting agents.
  • suitable liquid dosage forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules.
  • Such liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, thickeners, and melting agents.
  • Oral dosage forms optionally contain flavorants and coloring agents.
  • Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.
  • effervescent tablet To provide an effervescent tablet appropriate amounts of, e.g., monosodium citrate and sodium bicarbonate, are blended together and then roller compacted, in the absence of water, to form flakes that are then crushed to give granulates. The granulates are then combined with the active ingredient, drug and/or salt thereof, conventional beading or filling agents and, optionally, sweeteners, flavors and lubricants.
  • injectable solution A parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in deionized water and mixed with, e.g., up to 10% by volume propylene glycol and water.
  • the solution is made isotonic with sodium chloride and sterilized using, e.g., ultrafiltration.
  • Suspension An aqueous suspension is prepared for oral administration so that each 5 ml contain 100 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 ml of vanillin.
  • the active ingredient is compressed into a hardness in the range 6 to 12 Kp.
  • the hardness of the final tablets is influenced by the linear roller compaction strength used in preparing the granulates, which are influenced by the particle size of, e.g., the monosodium hydrogen carbonate and sodium hydrogen carbonate. For smaller particle sizes, a linear roller compaction strength of about 15 to 20 KN/cm may be used.
  • the table below represents exemplary ranges for an oral suspension composition according to the present invention: The compound of the invention is accurately weighed and was transferred in 5-mL centrifuge tubes and the corresponding volume of each tested vehicle (shown in the table) was then added to reach 5 mg/mL as maximal solubility target concentration.
  • Cream or lotion formulation The table below represents exemplary ranges for cream or lotion composition according to the present invention: dissolve the methyl paraben in about 80% of total amount of propylene glycol. Add the poloxyl 2 cetyl ether into this solution with agitation. In a separate processing container mix the 20% of the propylene glycol, part of the purified water and 10.0 g of compound 15 to form a uniform suspension. Gradually add the suspension into the first processing container with moderate stirring until a homogenous, soft, white cream is obtained Pass the cream through a colloid mill and bring the mass of the batch to the targeted quantity. [0221] Non-aerosol spray formulation.
  • an aspect of the present disclosure relates to a pharmaceutical composition
  • a pharmaceutical composition comprising, consisting essentially of, or consisting of: a compound according to Formula (I), or a pharmaceutically acceptable salt thereof:
  • R H, C(O)R 1 , alkyl, benzyl, substituted benzyl;
  • R 1 CH 3 , alkyl, piperidine nitroxyl, or biotin;
  • R 2 H, C(O)R 1 , C(S)NR 1 or aceloxy alkyl carbamate of the following formula:
  • R 2 C(O)OCHR 3 OC(O)OR 4 , piperidine nitroxyl, or fluorescein isothiocyanate (FITC);
  • R 3 H, CH 3 , C 2 H 5 , isopropyl;
  • R 4 substituted alkyl group;
  • X H, O, NH, or S and is linked to the anomeric carbon via R stereochemistry (beta anomer) at a
  • the composition is formulated a sterile, injectable aqueous or oleaginous suspension.
  • the composition is formulated as a sterile topical gel, ointment or aqueous spray.
  • the composition further comprises an anti-inflammatory agent, an antimicrobial agent, or both.
  • the compound of Formula (I) is further defined as compounds having any one of the formulas 1 to 10.
  • an aspect of the present disclosure relates to a method of treating at least one of sepsis, septicemia, septic shock, peritonitis, skin and soft tissue infections, ocular infection, ocular inflammation, ocular angiogenesis, rheumatoid arthritis (RA), atherosclerosis, inflammatory bowel diseases (IBD), necrotizing enterocolitis, asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome, acute lung injury, bacterial and viral pneumonia, chronic lung injury, acute kidney injury, chronic kidney injury, fibrosis, fever syndromes, cachexia, psoriasis, autoimmune diseases, cardiac diseases, retinoblastoma, cancer, disorder associated with inflammation, immunomodulation or microbial infections which comprises, consists essentially of, or consists of: administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition of Formula (I), or a pharmaceutically acceptable salt thereof, whereby the subject is treated.
  • a pharmaceutical composition of Formula (I) or
  • the step of administering comprises providing a pharmaceutical compound comprising about 5.0 mg to about 100 mg of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof to a patient in need thereof, whereby the patient is treated.
  • the step of administering comprises administering the pharmaceutical composition comprising about 10.0 mg to about 1000 mg of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof to a patient in need thereof, whereby the patient is treated.
  • an aspect of the present disclosure relates to a composition
  • the composition is formulated a sterile, injectable aqueous or oleaginous suspension.
  • the composition is formulated as a sterile topical ocular solution.
  • the compound is selected from those of Formula 45 to 53.
  • an aspect of the present disclosure relates to a method of treating ocular angiogenesis, ocular inflammation which comprises administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition according to claim 13, or a pharmaceutically acceptable salt thereof, whereby said subject is treated.
  • the compounds are selected from at least one of compounds 38 to 44.
  • the present invention includes compounds for the treatment of sepsis, septicemia, septic shock, peritonitis, skin and soft tissue infections, ocular infection, ocular inflammation, ocular angiogenesis, rheumatoid arthritis (RA), atherosclerosis, inflammatory bowel diseases (IBD), necrotizing enterocolitis, asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome, acute lung injury, bacterial and viral pneumonia, chronic lung injury, acute kidney injury, chronic kidney injury, fibrosis, fever syndromes, cachexia, psoriasis, autoimmune diseases, cardiac diseases, retinoblastoma, cancer and/or any disorder associated with inflammation, immunomodulation and microbial infection.
  • the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.
  • “comprising” may be replaced with “consisting essentially of” or “consisting of”.
  • the phrase “consisting essentially of” requires the specified integer(s) or steps as well as those that do not materially affect the character or function of the claimed invention.
  • the term “consisting” is used to indicate the presence of the recited integer (e.g., a feature, an element, a characteristic, a property, a method/process step or a limitation) or group of integers (e.g., feature(s), element(s), characteristic(s), propertie(s), method/process steps or limitation(s)) only.
  • the term “or combinations thereof” as used herein refers to all permutations and combinations of the listed items preceding the term.
  • A, B, C, or combinations thereof is intended to include at least one of: A, B, C, AB, AC, BC, or ABC, and if order is important in a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB.
  • expressly included are combinations that contain repeats of one or more item or term, such as BB, AAA, AB, BBC, AAABCCCC, CBBAAA, CABABB, and so forth.
  • BB BB
  • AAA AAA
  • AB BBC
  • AAABCCCCCC CBBAAA
  • CABABB CABABB
  • words of approximation such as, without limitation, “about”, “substantial” or “substantially” refers to a condition that when so modified is understood to not necessarily be absolute or perfect but would be considered close enough to those of ordinary skill in the art to warrant designating the condition as being present.
  • the extent to which the description may vary will depend on how great a change can be instituted and still have one of ordinary skilled in the art recognize the modified feature as still having the required characteristics and capabilities of the unmodified feature.
  • a numerical value herein that is modified by a word of approximation such as “about” may vary from the stated value by at least ⁇ 1, 2, 3, 4, 5, 6, 7, 10, 12 or 15%.
  • compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.

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Abstract

La présente invention concerne de nouveaux produits, variantes, sels pharmaceutiquement acceptables et promédicaments correspondants, ainsi que l'utilisation médicale de tels composés pour le traitement et/ou la gestion de la sepsie, de la septicémie, du choc septique, de la péritonite, des infections de la peau et des tissus mous, de l'infection oculaire, de l'inflammation oculaire, de l'angiogenèse oculaire, de la polyarthrite rhumatoïde (PR), de l'athérosclérose, des maladies intestinales inflammatoires (AII), de l'entérocolite nécrosante, de l'asthme, de la bronchopneumopathie chronique obstructive, du syndrome de détresse respiratoire aiguë, des lésions pulmonaires aiguës, de la pneumonie bactérienne et virale, des lésions pulmonaires chroniques, des lésions rénales aigües, des lésions rénales chroniques, de la fibrose, des syndromes de la fièvre, de la cachexie, du psoriasis, des maladies auto-immunes, des maladies cardiaques, du rétinoblastome, du cancer et/ou de tout trouble associé à une inflammation, à une immunomodulation et à une infection microbienne.
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US4696919A (en) * 1983-10-13 1987-09-29 Chugai Seiyaku Kabushiki Kaisha Method of preventing and treating obesity
US20140193368A1 (en) * 1999-08-17 2014-07-10 Immunopath Profile, Inc. Pluripotent therapeutic compositions and uses thereof
US20200022995A1 (en) * 2018-07-02 2020-01-23 Ayuvis Research, Inc. Novel Immunodulating Small Molecules

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JP2019513137A (ja) * 2016-03-30 2019-05-23 アユヴィス リサーチ インク．Ａｙｕｖｉｓ Ｒｅｓｅａｒｃｈ， Ｉｎｃ． 新規組成物及び治療方法
US12440471B2 (en) * 2021-07-30 2025-10-14 Ayuvis Research, Inc. Compositions and methods for the treatment of bronchopulmonary dysplasia (BPD) and BPD-associated pulmonary hypertension

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US4696919A (en) * 1983-10-13 1987-09-29 Chugai Seiyaku Kabushiki Kaisha Method of preventing and treating obesity
US20140193368A1 (en) * 1999-08-17 2014-07-10 Immunopath Profile, Inc. Pluripotent therapeutic compositions and uses thereof
US20200022995A1 (en) * 2018-07-02 2020-01-23 Ayuvis Research, Inc. Novel Immunodulating Small Molecules

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Title
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VACHHARAJANI VIDULA, VITAL SHANTEL: "Obesity and Sepsis", J INTENSIVE CARE MED, vol. 21, no. 5, 1 September 2006 (2006-09-01), pages 287 - 295, XP093067920, ISSN: 0885-0666, DOI: 10.1177/0885066606290670 *

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