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WO2024180569A1 - Suspension de nébulisation aqueuse synergique pour la gestion de troubles respiratoires infectieux et processus de préparation - Google Patents

Suspension de nébulisation aqueuse synergique pour la gestion de troubles respiratoires infectieux et processus de préparation Download PDF

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WO2024180569A1
WO2024180569A1 PCT/IN2024/050213 IN2024050213W WO2024180569A1 WO 2024180569 A1 WO2024180569 A1 WO 2024180569A1 IN 2024050213 W IN2024050213 W IN 2024050213W WO 2024180569 A1 WO2024180569 A1 WO 2024180569A1
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suspension
acid
aqueous
nebulization
tuberculosis
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Ajaykumar Balraj Kanduri
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    • 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
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/10—Carbonates; Bicarbonates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/18—Iodine; Compounds thereof
    • 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
    • A61K9/10—Dispersions; Emulsions

Definitions

  • the present disclosure relates to non-antibiotic formulation towards management of infectious respiratory disorders. More specifically, the present disclosure is directed to a synergistic aqueous nebulization suspension comprising active ingredients that synergistically show activity against infectious diseases that affect the respiratory system, and to a process of preparation thereof.
  • Tuberculosis is an airborne respiratory infectious disease caused by Mycobacterium tuberculosis. Although primarily a pulmonary pathogen, M. tuberculosis can cause disease in almost any part of the body. Infection with M. tuberculosis can evolve from containment in the host, in which the bacteria are isolated within granulomas (latent TB infection), to a contagious state, in which the patient shows symptoms that can include cough, fever, night sweats and weight loss. Only active pulmonary TB is contagious. In many low-income and middle-income countries, TB continues to be a major cause of morbidity and mortality, and drug- resistant TB is a major concern in many countries.
  • MDR Multidrug-resistant
  • XDR extensively drug resistant Tuberculosis
  • XXDR strains are resistant to all first and second-line drugs. More recently, a new category of M. tuberculosis strains not yet recognized by the WHO have been identified in Italy, India and Iran, and named totally drug-resistant TB (TDR-TB) for being resistant to all tested antibiotics plus some of the ones currently in the discovery pipeline. The emergence of these potentially incurable strains stresses the urgent need to develop new drug regimens and/or alternative anti-TB strategies to combat these superbugs.
  • COVID-19 denoted as first most infectious and deadliest disease in the world.
  • SARS-CoV Middle East respiratory syndrome
  • SARS-CoV-2 reported and identified in late 2019, is the third beta-coronavirus probably originated from bats and, over time, accumulated mutations that gave it the capacity for zoonotic transmission.
  • Multidrug-resistant (MDR), Extensively drug resistant (XDR), Extremely drug resistant (XXDR) and totally drug resistant (TDR) tuberculosis might be the results of frequent genetic mutation occurred due to long term use of antibiotics, steroids, immunosuppressants, and a weakened host immunity.
  • the existing treatment regimen includes all-oral and injectable antibiotics which are delivered minimum 6 months to 12 months or may be longer than that. While using multiple drugs at a time, even if the synergism is observed the adverse drug interaction cannot be declined. Also, oral drugs comparatively take longer time for metabolism and to act at target organ and target pathogen specific mechanism.
  • the present discovery adopted neither oral nor invasive (injectable) but the inhalation or nebulization route which is target organ specific (lung) and target pathogen specific (M. tuberculosis). Also, the formulation developed is not categorized as an antibiotic but contains natural inorganic elements and organic substrates.
  • Nebulization delivery initiates its mechanism of action quickly, safely and effectively. Nebulization delivery system can be easily adopted by children, adults, seniors as well as pregnant and lactating women as compare to oral or invasive route.
  • CA2700534 discloses the method of administering an aerosolized anti-infective, such as a glycopeptide, to the respiratory system of a patient.
  • a ratio of an amount of the glycopeptide, such as vancomycin, delivered to the pulmonary system of the patient in a 24-hour period to a minimum inhibitory amount for the target organ for the same period is about 2 or more.
  • a system to introduce aerosolized medicament to a patient may include a humidifier coupled to an inspiratory limb of a ventilator circuit wye, where the humidifier supplies heated and humidified air to the patient, and an endotracheal tube having a proximal end coupled to a distal end of the ventilator circuit wye.
  • the system may also include a nebulizer coupled to the endotracheal tube, where the nebulizer generates the aerosolized medicament.
  • US20220323489 discloses systems and methods for treating drug resistant pneumonia and tuberculosis using hypochlorous acid (HOG).
  • HOG hypochlorous acid
  • This prior art relates to nebulizing HOG as a method of treating drug resistant bacteria, in particular, bacterial pneumonia pathogens (i.e., Streptococcus pneumoniae) and Mycobacterium tuberculosis bacteria.
  • the nebulized HOG solution may be approximately 180 parts per million (PPM) of the aqueous solution and have a pH of less than 6.
  • AU2012258488 discloses a method of administering an aerosolized anti-infective, such as a glycopeptide, to the respiratory system of a patient.
  • a ratio of an amount of the glycopeptide, such as vancomycin, delivered to the pulmonary system of the patient in a 24-hour period to a minimum inhibitory amount for the target organ for the same period is about 2 or more.
  • a system to introduce aerosolized medicament to a patient may include a humidifier coupled to an inspiratory limb of a ventilator circuit wye, where the humidifier supplies heated and humidified air to the patient, and an endotracheal tube having a proximal end coupled to a distal end of the ventilator circuit wye.
  • the system may also include a nebulizer coupled to the endotracheal tube, where the nebulizer generates the aerosolized medicament.
  • the chemical composition of marine aerosol is an important environmental cue for the development of non-antibiotic formulation towards elimination of infectious respiratory disorders including but not limited to tuberculosis and SARS-CoV-2 (CO VID-19).
  • a synergistic nebulization formula containing natural cation, anion, organic acids and metal nanoparticle with specific pH and ionic strength may act as potent antimicrobial and antiviral therapy.
  • the synergistic mechanism including physical damage with nanometals, altering cellular environment with ion-channel blockers and excessive accumulation of toxic organic metabolites in pathogens may help complete elimination from host. This discovery tried to adopt non-antibiotic, natural formulation and methodology to overcome limitations of existing technologies with optimum efficacy and safety.
  • It is another object of the present disclosure to provide a synergistic aqueous nebulization suspension containing natural cation, anion, organic acids and metal nanoparticle with specific pH and ionic strength may act as potent antimicrobial and antiviral therapy.
  • aspects of the present disclosure provides a synergistic aqueous nebulization suspension comprising active ingredients that synergistically show activity against infectious diseases, such as bacterial infections, viral infections, fungal infections, protozoan infections that affect the respiratory system.
  • the present disclosure also provides a process for the preparation of such composition and its use.
  • the present invention provides a synergistic aqueous nebulization suspension containing natural cation, anion, organic acids and metal nanoparticle with specific pH and ionic strength may act as potent antimicrobial and antiviral therapy.
  • the present invention provides a synergistic aqueous nebulization suspension comprising a combination of Sodium Chloride (NaCl), Magnesium Sulphate (MgSo4), Calcium bicarbonate [Ca(HCO3)2], Potassium Chloride (KC1), Iodine (12) / Hypoiodous acid, Aluminium Nanoparticle (Gamma A12O3) having Particle size 5-50nm, Glyoxylic acid, Malonic acid, Succinic acid in a therapeutically effective amount.
  • NaCl Sodium Chloride
  • MgSo4 Magnesium Sulphate
  • Ca(HCO3)2 Calcium bicarbonate
  • KC1 Potassium Chloride
  • Iodine (12) / Hypoiodous acid Aluminium Nanoparticle (Gamma A12O3) having Particle size 5-50nm, Glyoxylic acid, Malonic acid, Succinic acid in a therapeutically effective amount.
  • the pH value of the synergistic aqueous nebulization suspension may be adjusted if necessary to pH 3 to 9.
  • the pH of the synergistic aqueous nebulization suspension is between 4.5 and 6.5 for use against bacterial infections; and between 8 and 9 for use against viral infections.
  • the present invention provides a synergistic aqueous nebulization suspension comprising: 100-250mM of Sodium Chloride (NaCl), 75-125mM of Magnesium Sulphate (MgSo4), 8-12mM of Calcium bicarbonate [Ca(HCO3)2], 20-30mM of Potassium Chloride (KC1), 15-25mM of Iodine (12) / Hypoiodous acid, 1-1 Opg / L of Aluminium Nanoparticle (Gamma A12O3) having Particle size 5-50nm, 50-125mM of Glyoxylic acid, 5-25mM of Malonic acid, and 5-20mM of succinic acid.
  • the present disclosure is directed to a process for preparing a synergistic aqueous nebulization suspension for use in the treatment of microbial infections, which comprises the steps of: a) dissolving Sodium Chloride (NaCl), Magnesium Sulphate (MgSo4), Calcium bicarbonate [Ca(HCO3)2], Potassium Chloride (KC1), Iodine (12) / Hypoiodous acid, Aluminium Nanoparticle (Gamma A12O3) having Particle size 5-50 nm, Glyoxylic acid, Malonic acid and Succinic acid in the aqueous solvent to form a suspension; b) adding a pH modifying agent to the solution of step a) to adjust pH 3 to 9; and c) adding water to the solution of step b) to reach a predetermined total volume and homogenizing the resulting suspension to obtain the synergistic aqueous nebulization suspension.
  • NaCl sodium Chloride
  • MgSo4 Magnes
  • the present disclosure is directed to a process for preparing a synergistic aqueous nebulization suspension for use in the treatment of microbial infections, which comprises the steps of: a) dissolving, based on the total volume of the composition, 100-250mM of Sodium Chloride (NaCl), 75-125mM of Magnesium Sulphate (MgSo4), 8-12mM of Calcium bicarbonate [Ca(HCO3)2], 20-30mM of Potassium Chloride (KC1), 15-25mM of Iodine (12) / Hypoiodous acid, l-10pg / L of Aluminium Nanoparticle (Gamma A12O3) having Particle size 5-50nm, 50- 125mM of Glyoxylic acid, 5-25mM of Malonic acid, and 5-20mM of succinic acid in the aqueous solvent to form a solution; b) adding a pH modifying agent to the solution of step a) to adjust
  • the present disclosure provides a method for treating bacterial or viral infection in a human subject, comprising administering the synergistic aqueous nebulization suspension by nebulizer to the human subject a unit dose of the synergistic aqueous nebulization suspension comprising 1 ml to 5 ml of the aqueous composition containing 100-250mM of Sodium Chloride (NaCl), 75-125mM of Magnesium Sulphate (MgSo4), 8-12mM of Calcium bicarbonate [Ca(HCO3)2], 20-30mM of Potassium Chloride (KC1), 15-25mM of Iodine (12) / Hypoiodous acid, l-10pg / L of Aluminium Nanoparticle (Gamma A12O3) having Particle size 5-50nm, 50- 125mM of Glyoxylic acid, 5-25mM of Malonic acid, and 5-20mM of succinic acid.
  • KC1 Potassium Chloride
  • Figure 1 Location for future healthcare centers or rehabilitation centers at coastal regions free from anthropogenic emissions
  • FIG. 5 MGIT 960 tubes of TBS, MDR and XDR (C, T12, T22 and T33)
  • terapéuticaally effective amount refers to an amount of a formulation or component, effective in producing the desired therapeutic response in a particular patient (subject) suffering from a disease or disorder.
  • the present invention provides a pharmaceutical composition for administration through nasal route.
  • the present invention provides a pharmaceutical composition for administration through nasal route intended for the treatment of infectious respiratory diseases.
  • the present invention provides a pharmaceutical composition in the form of suspension, emulsion, solution, spray colloids and the like. More specifically, the present invention provides the pharmaceutical composition in the form of suspension.
  • the present invention provides the pharmaceutical composition in the form of nanosuspension for administration through nasal route.
  • the present invention relates to the pharmaceutical composition in the form of nanosuspension for administration through nasal route wherein the said nanosuspension is administered with the help of nebulizer.
  • the present invention provides a synergistic aqueous nebulization suspension comprising active ingredients that synergistically show activity against infectious respiratory diseases.
  • the present disclosure provides a synergistic aqueous nebulization suspension comprising active ingredients that synergistically show activity against infectious diseases, such as bacterial infections, viral infections, fungal infections, protozoan infections that affect the respiratory system.
  • infectious diseases such as bacterial infections, viral infections, fungal infections, protozoan infections that affect the respiratory system.
  • the present disclosure also provides a process for the preparation of such composition and its use.
  • the present invention provides the synergistic aqueous nebulization suspension comprising at least one metal cation, metal anion, at least one organic acid and at least one metal nanoparticle, and one or more pharmaceutically acceptable excipients.
  • the present invention provides a synergistic aqueous nebulization suspension comprising natural cation, anion, organic acids and metal nanoparticle with specific pH and ionic strength may act as potent antimicrobial and antiviral therapy.
  • the synergistic aqueous nebulization suspension as described above comprising combination of Sodium Chloride (NaCl), Magnesium Sulphate (MgSo4), Calcium bicarbonate [Ca(HCO3)2], Potassium Chloride (KC1), Iodine (12) / Hypoiodous acid, Aluminium Nanoparticle (Gamma A12O3) having Particle size 5-50 nm, Glyoxylic acid, Malonic acid, Succinic acid in a therapeutically effective amount.
  • the synergistic aqueous nebulization suspension disclosed herein further includes one or more pharmaceutically acceptable excipients.
  • exemplary pharmaceutically acceptable excipients include, but not limited to, preservative(s), chelating agent(s), pH modifying agent(s), antioxidant(s), buffer(s), stabilizing agent(s), and other parenterally acceptable excipients, including any mixtures thereof.
  • Magnesium the second most plentiful cation in intracellular fluid acts as a natural calcium channel blocker. Magnesium competes with sodium for binding sites on vascular smooth muscle cells, increases prostaglandin E, binds to potassium in a cooperative manner, induces endothelial- dependent vasodilation, improves endothelial dysfunction in hypertensive and diabetic patients, decreases intracellular calcium and sodium, and reduces blood pressure.
  • the calcium channel blocker mimetic effect of magnesium may result in production of nitric oxide. In high enough concentrations, such as produced by inducible nitric oxide synthase, reactive nitrogen species can kill M. tuberculosis.
  • K+ is an essential ion for the function of the Na+ and K+ transporting ATPase.
  • the inhibition of active transport of K+ into the cell is hypothesized to lead to membrane hyperpolarization which in turn disrupts ion transport activity.
  • mycobacterial phagosomes require K+ efflux from the bacterium for the successful generation of reactive oxygen species, and potassium deficiency results in increased survival of intracellular bacteria. Changes in K+ concentration may induce bacterial responses leading to dormancy that enables bacilli to survive long-term in-vivo.
  • Calcium and sodium salts appear to have antimicrobial properties as well. High concentrations of extracellular calcium, as can be achieved by the aerosol delivery of calcium salts that may promote expression of antiviral and immune-inducing molecules as well as chemokine recruiters of leukocytes.
  • the aerosol nebulization composition of the present invention may further comprise sodium channel blockers not limited to, choline chloride, choline iodide, lithium chloride, meglumine chloride, L-lysine chloride, D-lysine chloride, ammonium chloride, potassium sulfate, potassium nitrate, potassium gluconate, potassium iodide, ferric chloride, ferrous chloride, potassium bromide, and the like.
  • sodium channel blockers not limited to, choline chloride, choline iodide, lithium chloride, meglumine chloride, L-lysine chloride, D-lysine chloride, ammonium chloride, potassium sulfate, potassium nitrate, potassium gluconate, potassium iodide, ferric chloride, ferrous chloride, potassium bromide, and the like.
  • Iodine due to its high penetrating and oxidizing property, acts rapidly on vital pathogen structures such as amino acids, nucleic acids and membrane components. Electron microscopy and biochemical observations support the hypothesis that iodine may disrupt microbial cell walls by inducing pore formation, leading to cytosol leakage. The lack of reported resistance to iodine and its derivatives is thought to be due to the sheer diversity of susceptible targets within each pathogen, an important aspect to be considered in the face of rising concerns for antibiotic resistance.
  • Gamma- A12O3 nanoparticles may show positive zeta potential with minimum aggregates and optimum colloidal stability at acidic pH and low ionic strength electrolyte suspension.
  • Gamma-A12O3 nanoparticles may selectively and effectively bind negatively charged M. tuberculosis capsule located in acidic pH in-vivo.
  • gamma-A12O3 nanoparticles may show negative zeta potential with minimum aggregates and optimum colloidal stability at weakly alkaline pH and medium ionic strength electrolyte suspension. With this ideal negatively charged surface and particle size, gamma- A12O3 nanoparticles may be able to selectively and effectively bind positively charged spike protein of SARS-CoV-2.
  • aluminium salts are the oldest and the most well-established. Surprisingly, some outcomes of human clinical trials revealed that alum alone could induce potent inflammatory responses and a sustained increase in cell-mediated immune responses even in the absence of overt antigens to modulate responses to persistent infections.
  • the synergistic aqueous nebulization suspension can include one or more chelating agents.
  • the chelating agent is preferably the disodium salt of ethylenediaminetetraacetic acid (EDTA), or other pharmaceutically acceptable salt of EDTA, although other pharmaceutically acceptable sequestering or chelating agents can also be employed, such as diethanolamine, triethanolamine, diethylene triamine penta acetic acid and pharmaceutically acceptable alkali metal salts thereof, 1 ,2-diaminocyclohexane-N,N' -tetraacetic acid and pharmaceutically acceptable alkali metal salts thereof, and the like.
  • Chelating agent may be present at concentrations of from about 0.001 to about 1% w/v.
  • the synergistic aqueous nebulization suspension of this disclosure can include one or more preservatives. Suitable preservatives include but not limited to benzyl alcohol, methylparaben, propylparaben, phenol, cresol and a combination thereof. Preservative(s) may be present at concentrations of from 0.1 to 5% w/v.
  • the synergistic aqueous nebulization suspension can include one or more antioxidants.
  • Suitable antioxidants include but not limited to lipoic acid, thioglycerol (also known as monothioglycerol) and analogs thereof, propyl gallate, methionine, cysteine, metabisulfites, sodium formaldehyde sulfoxylate, phenol-containing aromatic and aliphatic compounds, dihydrolipoic acid and mixtures thereof.
  • Antioxidant(s) may be present at concentrations of from 20 0.05 to 3% w/v.
  • the synergistic aqueous nebulization suspension can include one or more buffers.
  • Suitable buffers include but not limited to sodium and potassium phosphates, sodium and potassium citrates, mono-, di- and triethanolamines, bicarbonate buffer, carbonate buffer, histidine buffer, tartrate buffer, and mixtures thereof.
  • Buffer(s) may be present at concentrations of from 0.05 to 2% w/v.
  • the pH value of the synergistic aqueous nebulization suspension may be adjusted if necessary to pH 8 to 9.
  • the pH can be adjusted by adding a pH modifying agent.
  • pH modifying agents include sodium hydroxide, potassium hydroxide, sodium bicarbonate, hydrochloric acid and a combination thereof.
  • the pH value of the synergistic aqueous nebulization suspension may be adjusted if necessary to pH 3 to 9.
  • the pH of the synergistic aqueous nebulization suspension is between 4.5 and 6.5 for use against bacterial infections; and between 8 and 9 for use against viral infections.
  • the pH of M. tuberculosis containing phagosomes was in the range of 4.7 to 5.5 and that of lysosomes of macrophages ranged in pH from 4.5 to 4.8.
  • the phagolysosomal pH falls to 4.5 to 5.0.
  • Phagosomal acidity may provide a critical cue for adaptation of M. tuberculosis to the host niche. To ensure survival, the bacterium prevent excessive entry of protons into its cytosol and expel them to maintain pH homeostasis.
  • phagosomal acid believed to be bactericidal, its acidification gives positive signal for phagosome maturation. Interference with acidification of the phagosomal compartment may favour the survival of mycobacteria.
  • M. tuberculosis adopts “Glyoxylate Shunt Pathway” for metabolism of host associated fatty acids and to meet its carbon diet. This metabolic mechanism is required for persistence of M. tuberculosis within macrophages during chronic phase of infection.
  • Glyoxylate cycle is an alternative pathway to generate energy when tricarboxylic acid cycle is downregulated. By utilizing glyoxylate cycle, some beta oxidation steps in TCA cycle are bypassed. The point of differentiation for these two cycles begins when acetyl-CoA is converted to isocitrate. In glyoxylate cycle, two important enzymes required are isocitrate lyase (ICL) and malate synthase (MS).
  • ICL isocitrate lyase
  • MS malate synthase
  • ICL carries the function to reversibly cleave the isocitrate to glyoxylate and succinate while MS will convert glyoxylate into malate by adding an acetyl group.
  • MS Malate synthase
  • Glyoxylate detoxification is an essential physiologic function of M. tuberculosis malate synthase.
  • Glyoxylate was recently reported to activate isocitrate dehydrogenase in mycobacteria, driving flux through the TCA cycle. It can be assumed that providing exogenous glyoxylic acid may forcefully switch dormant M. tuberculosis infection to acute stage. Thus, this mechanism “wakes up” dormant drug resistant M. tuberculosis pathogens and enables to bring them at “starting point” where the other synergistic bactericidal channels are optimized for further complete elimination. [0065] The exogenous supply of glyoxylic acid may switch M.
  • SARS-CoV-2 the spike protein plays a crucial role in binding to human ACE2.
  • Human ACE2 has a negatively charged binding surface while S protein receptor binding domain are overall positively charged, which provides dominantly attractive forces between ACE2 and S proteins (Xie et al., 2020).
  • S protein receptor binding domain are overall positively charged, which provides dominantly attractive forces between ACE2 and S proteins (Xie et al., 2020).
  • At mild alkaline pH (8-9) negatively charged gamma- A12O3 nanoparticles may selectively and effectively bind positively charged spike protein of SARS-CoV- 2. and may disrupt cell integrity and damage viral nucleoprotein.
  • High concentrations of chloride, delivered via hypertonic saline to nasal epithelial tissues believed to depolarize
  • Succinic acid, glyoxylic acid and malonic acid individually or synergistically may act as a potent antiviral agent by modification of the viral nucleoprotein and thus disrupting viral replication cycle.
  • the synergistic aqueous nebulization suspension of this disclosure may be presented in unit-dose or multi-dose forms.
  • the synergistic aqueous nebulization suspension of this disclosure comprises, based on the total volume of the composition.
  • the effective therapeutic range of synergistic aqueous nebulization suspension for management of respiratory disorders including but not limited to tuberculosis and SARS-CoV-2 is exhibited in Table 1. The units for values are depicted in millimoles as well as percent weight by volume.
  • Table 1 Composition of synergistic aqueous nebulization suspension for Tuberculosis and SARS-Cov-2
  • unit dose forms contain the synergistic aqueous nebulization suspension as described above, comprising combination of Sodium Chloride (NaCl), Magnesium Sulphate (MgSo4), Calcium bicarbonate [Ca(HCO3)2], Potassium Chloride (KC1), Iodine (12) / Hypoiodous acid, Aluminium Nanoparticle (Gamma A12O3) having Particle size 5- 50 nm, Glyoxylic acid, Malonic acid Succinic acid.
  • the unit dose contains from about 1 ml to about 5 ml of the aqueous injectable composition formulated as a sterile solution suitable for administration via a nebulizer.
  • the unit dose contains about 1 ml, 2 ml, 3 ml, 4 ml or 5 ml. In a particularly preferred embodiment, the unit dose contains about 3 ml - 5 ml.
  • Each unit dose can contain 100-250mM of Sodium Chloride (NaCl), 75-125mM of Magnesium Sulphate (MgSo4), 8-12mM of Calcium bicarbonate [Ca(HCO3)2], 20-30mM of Potassium Chloride (KC1), 15-25mM of Iodine (12) / Hypoiodous acid, l-10pg / L of Aluminium Nanoparticle (Gamma A12O3) having Particle size 5-50nm, 50-125mM of Glyoxylic acid, 5- 25mM of Malonic acid, and 5-20mM of succinic acid.
  • the unit dose can be administered to a human subject 3-6 times daily for 1-9 weeks.
  • One of skill in that art will realize that the particular administration schedule will depend on the human subject and the dosage being used.
  • the administration schedule can also be different for individual subjects or change during the course of the therapy depending on the subject's reaction.
  • the synergistic aqueous nebulization suspension of this disclosure is presented in unit dose form in ampoules, vials or pre-filled containers of 1 ml - 5 ml capacity.
  • the present disclosure is directed to a process for preparing a synergistic aqueous nebulization suspension for use in the treatment of microbial infections, which comprises the steps of: a) dissolving Sodium Chloride (NaCl), Magnesium Sulphate (MgSo4), Calcium bicarbonate [Ca(HCO3)2], Potassium Chloride (KC1), Iodine (12) / Hypoiodous acid, Aluminium Nanoparticle (Gamma A12O3) having Particle size 5-50 nm, Glyoxylic acid, Malonic acid Succinic acid in the aqueous solvent to form a suspension; b) adding a pH modifying agent to the solution of step a) to adjust pH 3 to 9; and c) adding water to the solution of step b) to reach a predetermined total volume and homogenizing the resulting suspension to obtain the synergistic aqueous nebulization suspension.
  • NaCl sodium Chloride
  • MgSo4 Magnesium
  • the process can include the steps of: a) dissolving, based on the total volume of the composition, 100-250mM of Sodium Chloride (NaCl), 75-125mM of Magnesium Sulphate (MgSo4), 8-12mM of Calcium bicarbonate [Ca(HCO3)2], 20-30mM of Potassium Chloride (KC1), 15-25mM of Iodine (12) / Hypoiodous acid, l-10pg / L of Aluminium Nanoparticle (Gamma A12O3) having Particle size 5-50nm, 50- 125mM of Glyoxylic acid, 5-25mM of Malonic acid, and 5-20mM of succinic acid in the aqueous solvent to form a solution; b) adding a pH modifying agent to the solution of step a) to adjust pH 3 to 9; and c) adding water to the solution of step b) to reach a predetermined total volume and homogenizing the resulting suspension to
  • aluminium nanoparticles which are insoluble in pure water.
  • aluminium nanoparticles may form stable suspension in solution containing Sodium Chloride (NaCl), Magnesium Sulphate (MgSo4), Calcium bicarbonate [Ca(HCO3)2], Potassium Chloride (KC1), Iodine (12) / Hypoiodous acid, Glyoxylic acid, Malonic acid and Succinic acid at pH 4.5-6.2 and pH 8-9.
  • Ultrasonication can be applied to get homogenous distribution of nanoparticle in the suspension.
  • Another method to form stable, uniform, homogenous colloidal suspension is to use suitable stabilizer / dispersant / surfactant with concentration range of 0.0000001 to 1% w/v depending on concentration of aluminium nanoparticle used.
  • the active ingredients can be mixed with a preservative selected from the group consisting of benzyl alcohol, methylparaben, propylparaben, phenol, cresol, Benzalkonium chloride, EDTA, or a combination thereof.
  • Nebulization suspension may be preservative free or with preservatives as stated above.
  • the active ingredients are admixed in the aqueous solvent having a temperature between 20°C and 70° C.
  • the pH modifying agent can be used in an amount sufficient to adjust the pH of the solution of step b) to the range set forth above, i.e., 3 to 9.
  • Non-limiting examples of pH modifying agents include sodium hydroxide, sodium bicarbonate, hydrochloric acid and a combination thereof.
  • the synergistic aqueous nebulization suspension obtained in step c) may be subsequently filtered prior to packaging, e.g., in ampoules or vials.
  • the filtration may be performed in a sterilized filtration unit under an inert gas atmosphere such as nitrogen or argon.
  • filtration may be performed at a pressure in the range of 1.0 kg/cm2 to 2.0kg/cm2.
  • the filtered solution may be divided into unit doses, each containing above- mentioned quantities of active ingredients.
  • the unit dose form can be a packaged preparation where the packaging contains discrete quantities of the filtered solution in ampoules or vials.
  • the filling and packaging of ampoules or vials may also be performed in an inert gas atmosphere such as nitrogen or argon.
  • the filtered synergistic aqueous nebulization suspension is divided into unit doses.
  • Each 3 mL or 4 mL or 5 mL unit-dose contains 100-250mM of Sodium Chloride (NaCl), 75-125mM of Magnesium Sulphate (MgSo4), 8-12mM of Calcium bicarbonate [Ca(HCO3)2], 20-30mM of Potassium Chloride (KC1), 15-25mM of Iodine (12) / Hypoiodous acid, l-10pg / L of Aluminium Nanoparticle (Gamma A12O3) having Particle size 5-50nm, 50- 125mM of Glyoxylic acid, 5-25mM of Malonic acid, and 5-20mM of succinic acid.
  • the filtered synergistic aqueous nebulization suspension may be aseptically filled and stored in ampoules or vials for further usage.
  • the prepared formulation may be stored in a cool and dark place protected from light under room temperature (15 - 30 deg C).
  • the synergistic aqueous nebulization suspension of the present disclosure provides the active ingredients in calculated amounts to avoid side-effects, toxicity or overdosing.
  • the synergistic aqueous nebulization suspension of the present disclosure has components that have synergistic activity/functional reciprocity.
  • the synergistic aqueous nebulization suspension has a long shelf-life.
  • the shelf-life may be about 12 to about 36 months.
  • the aqueous injectable composition has a shelf-life of 18 months.
  • the present disclosure provides a method for treating bacterial or viral infection in a human subject, comprising administering the synergistic aqueous nebulization suspension by nebulizer to the human subject a unit dose of the synergistic aqueous nebulization suspension of this disclosure.
  • the unit dose comprises 1 ml to 5 ml of the aqueous composition containing 100-250mM of Sodium Chloride (NaCl), 75-125mM of Magnesium Sulphate (MgSo4), 8-12mM of Calcium bicarbonate [Ca(HCO3)2], 20-30mM of Potassium Chloride (KC1), 15- 25mM of Iodine (12) / Hypoiodous acid, l-10pg / L of Aluminium Nanoparticle (Gamma A12O3) having Particle size 5-50nm, 50-125mM of Glyoxylic acid, 5-25mM of Malonic acid, and 5-20mM of succinic acid.
  • the present disclosure provides a method for treating bacterial or viral infection in a human subject, comprising administering the synergistic aqueous nebulization suspension by nebulizer to the human subject a 3ml dose of the synergistic aqueous nebulization suspension of this disclosure which contains in solution 100-250mM of Sodium Chloride (NaCl), 75-125mM of Magnesium Sulphate (MgSo4), 8-12mM of Calcium bicarbonate [Ca(HCO3)2], 20-30mM of Potassium Chloride (KC1), 15-25mM of Iodine (12) / Hypoiodous acid, l-10pg / L of Aluminium Nanoparticle (Gamma A12O3) having Particle size 5-50nm, 50- 125mM of Glyoxylic acid, 5-25mM of Malonic acid, and 5-20mM of succinic acid..
  • NaCl Sodium Chloride
  • MgSo4 Magnesium Sulph
  • the nebulizers transform the synergistic aqueous nebulization suspension in a carrier into a therapeutic aerosol mist either by means of acceleration of compressed gas, through a narrow venturi orifice, by means of ultrasonic agitation or by means of a vibrating porous plate.
  • the carrier may be water (and most preferably sterile, pyrogen-free water), a dilute aqueous alcoholic solution or propylene glycol. Perfluorocarbon carriers may also be preferred.
  • the nebulizer is a pressure-driven aerosol nebulizer or an ultrasonic nebulizer.
  • the aerosol is nano sized that have average sizes ranging in the nanometer scale. However, many aerosol particles have wider ranges of sizes.
  • the aerosols may have a diameter 25 of at least about 1 nm, 10 nm, 50 nm, 100 nm, 200 nm, 300 nm, 400 nm, 500 nm, 600 nm, 700 nm, 800 nm, 900 nm, 1000 nm, 1100 nm, 1200 nm, 1300 nm, 1400 nm, 1500 nm, 1600 nm, 1700 nm, 1800 nm, 1900 nm, 2000 nm, 2500 nm, 3000 nm, 4000 nm, 5000 nm, 6000 nm, 7000 nm, 8000 nm, or at least 9000 nm.
  • the nanoparticles may have a diameter of less than 10,000 nm, 9000 nm, 8000 nm, 7000 nm, 6000 nm, 5000 nm, 4500 nm, 4000 nm, 3500 nm, 3000 nm, 2500 nm, 2000 nm, 1900 nm, 1800 nm, 1700 nm, 1600 nm, 1500 nm, 1400 nm, 1300 nm, 1200 nm, HOO nm, 1000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 250 nm, or less than 100 nm.
  • the diameter of nanoparticles can range from any of the minimum values described above to any of the maximum values described above, for example from 1 nm to 10,000 nm, 50 nm to 5,000 nm, 100 nm to 2500 nm, 200 nm to 2000 nm, or 500 nm to 1000 nm.
  • the size of the nano sized antidepressant ranges from about 1 nm to about 500 nm.
  • the conditions treatable by the methods of the present disclosure include, but not limited to, bacterial infections, viral infections, fungal infections not limiting to M. tuberculosis infection, SARS-CoV-2 infections, and the like.
  • the exogenous supply of suspension, through nebulization may act synergistically adopting mechanism including disruption of pathogen membrane potential and integrity, triggering of the host immune responses, altering pathogen cellular environment with ion-channel blockers / efflux pump alteration and excessive accumulation of toxic organic metabolites in pathogens affecting energy flux may help complete elimination of persistent drug resistant tuberculosis.
  • the exogenous supply of suspension, through nebulization may act synergistically adopting mechanism including disruption of pathogen membrane potential and integrity, triggering of the host immune responses, altering pathogen cellular environment with excessive accumulation of toxic organic metabolites in pathogens affecting viral nucleoprotein leading to disruption of replication cycle and complete elimination of SARS-CoV-2.
  • the suspension inspired by environmental cue also recommends a complimentary approach towards managing various respiratory disorders by establishing future healthcare centers or rehabilitation centers at coastal regions free from anthropogenic emissions (exhibited in Figure- 1).
  • the synergistic aqueous nebulization composition has the antimycobacterial activity which evaluated using the in-vitro anti-mycobacterial study adopting MGIT (Mycobacteria Growth Indicator Tube) method.
  • the MGIT 960 method is a widely accepted, FDA approved, effective, accurate and reliable method for rapid diagnosis of multi-drug resistant tuberculosis sample.
  • the MGIT culture tube consists of liquid broth medium that is known to yield better recovery and faster growth of mycobacteria.
  • the MGIT tube contains 7.0 ml of Middlebrook 7H9 broth base along with an oxygen-quenched fluorochrome, tris 4, 7- diphenyl-1, 10-phenonthroline ruthenium chloride pentahydrate, embedded in silicone at the bottom of the tube.
  • an oxygen-quenched fluorochrome tris 4, 7- diphenyl-1, 10-phenonthroline ruthenium chloride pentahydrate, embedded in silicone at the bottom of the tube.
  • the free oxygen is utilized and is replaced with carbon dioxide. With depletion of free oxygen, the fluorochrome is no longer inhibited, resulting in fluorescence within the MGIT tube.
  • the BACTEC MGIT 960 instrument continuously monitors tubes for increased fluorescence. The intensity of fluorescence is directly proportional to the extent of oxygen depletion.
  • the BACTEC MGIT 960 instrument is a fully automated system that exploits the fluorescence of an oxygen sensor to detect growth of mycobacteria in culture. Its performance was compared to those of the radiometric BACTEC 460 instrument and egg-based Lowenstein-Jensen medium.
  • MGIT tubes were provided with the test samples and observed for Mycobacterium tuberculosis growth inhibition against control.
  • the method is based on the fluorescence produced from reduced oxygen in the MGIT medium due to microbial growth. Growth was monitored by the BACTEC 960 instrument which interprets results as susceptible or resistant. The fluorescence generated is then converted to “Growth Units” (GU). In general, higher GU indicates more growth. When the GU of the growth control reaches 400 within 4-14 days, the DST (Drug Sensitivity Test) is valid for the system to interpret.
  • DST Drug Sensitivity Test
  • a synergistic aqueous nebulization suspension was prepared using the ingredients and quantities thereof listed in the below Table 2.
  • Table 2 Composition of synergistic aqueous nebulization suspension for Tuberculosis and SARS-Cov-2.
  • Table 3 Physicochemical properties of synergistic aqueous nebulization suspension for Tuberculosis and SARS-Cov-2.
  • Table 4 Dose, delivery, recovery period and storage related aspects of formulation for Tuberculosis and SARS-CoV-2. In-vitro anti-mycobacterial study:
  • MGIT tubes were provided with the test samples and observed for Mycobacterium tuberculosis growth inhibition against control. The method is based on the fluorescence produced from reduced oxygen in the MGIT medium due to microbial growth. Growth was monitored by the BACTEC 960 instrument which interprets results as susceptible or resistant. The fluorescence generated is then converted to “Growth Units” (GU). In general, higher GU indicates more growth. When the GU of the growth control reaches 400 within 4-14 days, the DST (Drug Sensitivity Test) is valid for the system to interpret. If a drug-containing MGIT tube yields GUM 00, the organism is interpreted as susceptible to the drug or test sample and if GU is > 100, the organism is resistant. [0099] Two in-vitro trials were conducted of which first trial was performed to assess sensitivity as well as identifying optimum dose concentration of the formulations. The treatment groups along with their composition is exhibited in Table-5.
  • Table-5 Treatment groups with their composition: Table-6: pH of individual treatment groups (adjusted)
  • In-vitro study-I was consisting of six treatment groups. Control group was kept as blank and no treatment was given in MGIT tube so as to observe growth of M. tuberculosis after adding sputum sample. Treatment groups T12 and T13 were without y-A12O3 and treatment groups T21, T22 and T23 were with y-A12O3. The pH of all groups was adjusted between 4.6 to 5 with 20% KOH. The pH values of individual treatment groups are depicted in Table-6.
  • Treatment groups were selected for further In-vitro Study-II.
  • the selected treatment groups were T12 and T22.
  • Treatment group T12 was without y-A12O3 and T22 was with y-A12O3.
  • one more fresh treatment group T33 was added which was without y-A12O3 and with increased adjusted pH (9.0).
  • TBS TB susceptible
  • MDR multi-drug resistant
  • XDR extremely drug resistant
  • the sputum samples are routinely delivered at “Infectious Disease Division (Focus TB) Laboratory, Thyrocare Diagnostic Technologies Ltd., Turbhe, Navi Mumbai (INDIA) for drug sensitivity testing (DST). Permission to use sputum samples was procured from Joint Director of Health Services (Leprosy & TB), Government of Maharashtra State, Pune. The treatment wise alignment of sputum samples during In-vitro Study-I is depicted in Table-9.
  • TBS, MDR and XDR 1ml of treatment solutions
  • T12, T13, T21, T22 and T23 in In-vitro Study-I and T12, T22 and T33 in In-vitro Study-II Growth control MGIT tubes were inoculated with 1: 100 diluted cultures and were without any treatment solutions. Each MGIT tube was then sealed with cap and mixed well by inverting 5-6 times. The MGIT tubes were further loaded for incubation in BACTEC 960 instrument at 37°C for 12 days with growth control tube at first position for growth monitoring. On 12 th day, each MGIT tube was observed for fluorescence development and results were recorded. Results of the in-vitro anti-mycobacterium study:
  • the BACTEC MGIT 960 method of assessing drug sensitivity is based on the fluorescence produced from reduced oxygen in the MGIT medium due to microbial growth. Growth is monitored by the BACTEC 960 instrument which interprets results as susceptible or resistant. The fluorescence generated is then converted to “Growth Units” (GU). In general, higher
  • GU indicates more growth.
  • the DST Drug Sensitivity Test
  • the organism is interpreted as susceptible to the drug or test sample and if GU is > 100, the organism is resistant.
  • the growth units (GU) observed and recorded during In-vitro Study-I is exhibited in
  • TBS TB susceptible
  • MDR Muli-drug resistant
  • XDR Extremely drug resistant
  • Treatment wise assessment revealed that treatment group T12 successfully inhibited the growth of 4 samples out of 6, that includes TBS-2, MDR-1, MDR-2 and XDR-2 indicating that T12 can be a potential formulation that can inhibit susceptible, multi-drug resistant and extremely drug resistant isolates.
  • Treatment group T13 inhibited the growth of 3 samples out of 6, that includes TBS-2, MDR-1 and MDR-2. However, T13 was unable to inhibit any of XDR sample.
  • Treatment group T21 showed error to MDR-2 sample. While, out of remaining 5 samples it has shown susceptibility to 3 samples including TBS-2, XDR-1 and XDR-2.
  • Treatment group T22 successfully inhibited 3 samples out of 6, that includes TBS-2, MDR-1 and MDR-2.
  • sample XDR-2 was very close to susceptibility to T22 with GU value 108.
  • Treatment group T23 successfully inhibited growth of 4 samples out of 6, that includes TBS-2, MDR-1, MDR-2 and XDR-2.
  • TBS TB susceptible
  • MDR Muli-drug resistant
  • XDR Extremely drug resistant
  • MDR-4 exhibited clear susceptibility to almost all groups and MDR- 5 for T33. Out of 5 subjects, 2 subjects were found susceptible to either T12 (near susceptibility), T22 or T33 with 40% success rate. [00115] Among XDR, it was very surprising to interpret that out of 15 samples from 5 subjects,
  • the formulation containing Glyoxylic acid, Succinic acid and Malonic acid individually or synergistically may act as a potent anti-mycobacterial agent.
  • M. tuberculosis adopts “Glyoxylate Shunt Pathway” for metabolism of host associated fatty acids and to meet its carbon diet. This metabolic mechanism is required for persistence of M. tuberculosis within macrophages during chronic phase of infection.
  • Glyoxylate cycle is an alternative pathway to generate energy when tricarboxylic acid cycle is downregulated. By utilizing glyoxylate cycle, some beta oxidation steps in TCA cycle are bypassed. The point of differentiation for these two cycles begins when acetyl-CoA is converted to isocitrate.
  • ICL isocitrate lyase
  • MS malate synthase
  • MS Malate synthase
  • the second enzyme of the glyoxylate shunt essential to mitigate the toxicity of glyoxylate excess arising from metabolism of even-chain fatty acids in M. tuberculosis.
  • Glyoxylate detoxification is an essential physiologic function of M. tuberculosis malate synthase (Puckett et al., 2017). Glyoxylate was recently reported to activate isocitrate dehydrogenase in mycobacteria, driving flux through the TCA cycle (Murima et al., 2016). It can be assumed that providing exogenous glyoxylic acid may forcefully switch dormant M. tuberculosis infection to acute stage.
  • this mechanism “wakes up” dormant drug resistant M. tuberculosis pathogens and enables to bring them at “starting point” where the other synergistic bactericidal channels are optimized for further complete elimination.
  • the exogenous supply of glyoxylic acid may switch M. tuberculosis glyoxylate cycle to TCA cycle where the elevated succinic acid or malonic acid with elevated endogenous itaconic acid may participate in abolishing energy flux leading to complete elimination of M. tuberculosis.
  • Gamma- A12O3 nanoparticles may show positive zeta potential with minimum aggregates and optimum colloidal stability at acidic pH and low ionic strength electrolyte suspension.
  • Gamma-A12O3 nanoparticles may selectively and effectively bind negatively charged M. tuberculosis capsule located in acidic pH in-vivo.
  • gamma-A12O3 nanoparticles may show negative zeta potential with minimum aggregates and optimum colloidal stability at weakly alkaline pH and medium ionic strength electrolyte suspension. With this ideal negatively charged surface and particle size, gamma- A12O3 nanoparticles may be able to selectively and effectively bind positively charged surface molecule.
  • Iodine due to its high penetrating and oxidizing property, acts rapidly on vital pathogen structures such as amino acids, nucleic acids and membrane components. Electron microscopy and biochemical observations support the hypothesis that iodine may disrupt microbial cell walls by inducing pore formation, leading to cytosol leakage. The lack of reported resistance to iodine and its derivatives is thought to be due to the sheer diversity of susceptible targets within each pathogen, an important aspect to be considered in the face of rising concerns for antibiotic resistance.
  • Sodium chloride Magnesium sulphate, Calcium bicarbonate and Potassium chloride may effectively exhibit the kill efficacy by ion channel blocking in-vivo.
  • Magnesium the second most plentiful cation in intracellular fluid acts as a natural calcium channel blocker.
  • Magnesium competes with sodium for binding sites on vascular smooth muscle cells, increases prostaglandin E, binds to potassium in a cooperative manner, induces endothelial-dependent vasodilation, improves endothelial dysfunction in hypertensive and diabetic patients, decreases intracellular calcium and sodium, and reduces blood pressure.
  • the calcium channel blocker mimetic effect of magnesium may result in production of nitric oxide. In high enough concentrations, such as produced by inducible nitric oxide synthase, reactive nitrogen species can kill M. tuberculosis.
  • K+ is an essential ion for the function of the Na+ and K+ transporting ATPase.
  • the inhibition of active transport of K+ into the cell is hypothesized to lead to membrane hyperpolarization which in turn disrupts ion transport activity.
  • mycobacterial phagosomes require K+ efflux from the bacterium for the successful generation of reactive oxygen species, and potassium deficiency results in increased survival of intracellular bacteria. Changes in K+ concentration may induce bacterial responses leading to dormancy that enables bacilli to survive long-term in-vivo.
  • Calcium and sodium salts appear to have antimicrobial properties as well. High concentrations of extracellular calcium, as can be achieved by the aerosol delivery of calcium salts that may promote expression of anti-mycobacterial and immune inducing molecules as well as chemokine recruiters of leukocytes.
  • the pH of M. tuberculosis containing phagosomes range between 4.7 to 5.5 and that of lysosomes of macrophages ranged in pH from 4.5 to 4.8.
  • the phagolysosomal pH falls to 4.5 to 5.0 (MacMicking et al., 2003).
  • Phagosomal acidity may provide a critical cue for adaptation of M. tuberculosis to the host niche.
  • the bacterium prevent excessive entry of protons into its cytosol and expel them to maintain pH homeostasis.

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Abstract

La présente divulgation concerne une formulation non antibiotique visant l'élimination de troubles respiratoires infectieux. Plus spécifiquement, la présente divulgation concerne : une suspension de nébulisation aqueuse synergique comprenant une combinaison de chlorure de sodium (NaCl), de sulfate de magnésium (MgSo4), de bicarbonate de calcium [Ca(HCO3)2], de chlorure de potassium (KCl), d'iode (I2)/acide hypoiodeux, de nanoparticules d'aluminium (Gamma Al2O3) ayant une taille de particule de 5 à 50 nm, d'acide glyoxylique, d'acide malonique, d'acide succinique en une quantité thérapeutiquement efficace qui présentent de manière synergique une activité contre des maladies infectieuses qui affectent le système respiratoire comme la tuberculose et le SARS-CoV-2 ; et un processus de préparation de celle-ci.
PCT/IN2024/050213 2023-03-01 2024-02-29 Suspension de nébulisation aqueuse synergique pour la gestion de troubles respiratoires infectieux et processus de préparation Pending WO2024180569A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003086347A1 (fr) * 2002-04-17 2003-10-23 Chiesi Farmaceutici S.P.A. Procede de preparation d'une suspension sterile de particules de corticosteroides, destinee a etre administree par inhalation
WO2004054545A1 (fr) * 2002-12-18 2004-07-01 Chiesi Farmaceutici S.P.A. Preparation de suspensions aqueuses steriles comprenant des ingredients actifs cristallins micronises, destinees a l'inhalation
US20220323489A1 (en) * 2019-03-05 2022-10-13 Wonder Spray, LLC Hypochlorous acid solutions for the treatment of drug resistant pneumonia and tuberculosis

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003086347A1 (fr) * 2002-04-17 2003-10-23 Chiesi Farmaceutici S.P.A. Procede de preparation d'une suspension sterile de particules de corticosteroides, destinee a etre administree par inhalation
WO2004054545A1 (fr) * 2002-12-18 2004-07-01 Chiesi Farmaceutici S.P.A. Preparation de suspensions aqueuses steriles comprenant des ingredients actifs cristallins micronises, destinees a l'inhalation
US20220323489A1 (en) * 2019-03-05 2022-10-13 Wonder Spray, LLC Hypochlorous acid solutions for the treatment of drug resistant pneumonia and tuberculosis

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Title
MARTIN ANDREW R, FINLAY WARREN H: "Nebulizers for drug delivery to the lungs", EXPERT OPINION ON DRUG DELIVERY, INFORMA HEALTHCARE, GB, vol. 12, no. 6, 3 June 2015 (2015-06-03), GB , pages 889 - 900, XP093208745, ISSN: 1742-5247, DOI: 10.1517/17425247.2015.995087 *
THIAGO C. CARVALHO, MCCONVILLE JASON T.: "The function and performance of aqueous aerosol devices for inhalation therapy", JOURNAL OF PHARMACY AND PHARMACOLOGY : JPP, JOHN WILEY & SONS LTD, LONDON, GB, vol. 68, no. 5, 1 May 2016 (2016-05-01), GB , pages 556 - 578, XP055730729, ISSN: 0022-3573, DOI: 10.1111/jphp.12541 *

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