WO2023021329A1 - Compositions et procédés pour désinfecter, traiter et prévenir des infections microbiennes - Google Patents
Compositions et procédés pour désinfecter, traiter et prévenir des infections microbiennes Download PDFInfo
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- WO2023021329A1 WO2023021329A1 PCT/IB2022/000461 IB2022000461W WO2023021329A1 WO 2023021329 A1 WO2023021329 A1 WO 2023021329A1 IB 2022000461 W IB2022000461 W IB 2022000461W WO 2023021329 A1 WO2023021329 A1 WO 2023021329A1
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Classifications
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N59/00—Biocides, pest repellants or attractants, or plant growth regulators containing elements or inorganic compounds
- A01N59/06—Aluminium; Calcium; Magnesium; Compounds thereof
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
- A01N25/02—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing liquids as carriers, diluents or solvents
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
- A01N37/02—Saturated carboxylic acids or thio analogues thereof; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N59/00—Biocides, pest repellants or attractants, or plant growth regulators containing elements or inorganic compounds
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
- A01P1/00—Disinfectants; Antimicrobial compounds or mixtures thereof
-
- 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
- A61K33/20—Elemental chlorine; Inorganic compounds releasing chlorine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
Definitions
- the present invention relates generally to new compositions comprising combinations of a solid or liquid precursor of an oxidized state of chlorine and acetic acid or its salts, wherein such compositions are useful disinfectants for treating a broad spectrum of bacterial and/or viral, fungal and parasitic pathogens, and collectively denoted microorganisms herein.
- Background Infectious diseases are a leading cause of death worldwide and account for more than 13 million deaths annually including nearly two-thirds of all childhood mortality.
- antibiotic resistance is increasing and is contributing to morbidity in a broad range of human diseases, including pneumonia, tuberculosis and cholera. Of particular concern is that a number of human pathogen have developed resistance to conventional antibiotics.
- the SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome) outbreaks in the early-to-mid 2000s, the H1N1 pandemic in 2009, and the subsequent SARS CoV-2 pandemic in 2020 have focused attention on both treatment and prevention of the spread of these viral pathogens.
- Many viruses that infect the respiratory tract are communicated via droplet infection.
- respiratory droplets containing virus are expelled by an infected person and picked up by others on direct contact or by contact with surfaces on which the droplets land.
- infection proceeds via the binding of the virus to receptors on mucosal or epithelial cells, as a result of entry into the nose, eyes, ears, or mouth.
- Chlorine oxides may also exist as neutral compounds or ions, so-called oxyanions.
- oxyanions There are several oxyanions of chlorine, in which an oxyanion can assume oxidation states of +1, +3, +5, or +7 with the corresponding anions hypochlorite (ClO ⁇ ), chlorite (ClO 2 ⁇ ), chlorate (ClO 3 ⁇ ), or perchlorate (ClO 4 ⁇ ).
- the standard reduction potentials at a low pH of hypochlorous acid (HOCl) is + 1.63
- chlorous acid (HClO 2 ) the standard reduction potential is 1.64, while at basic pH, it is + 0.89 and + 0.78 respectively.
- reduction potentials are higher than + 1.
- hypochlorite and chlorite are generally the most useful oxidation states with a potential to kill microbes and parasites.
- the chloride ion Cl – is in the most stable oxidation state and is not reactive, nor is it effective as a disinfectant.
- Chlorate and perchlorate in oxidation states +5, and +7 are more reactive than the lower oxidation states, and may be more difficult to handle.
- the hypochlorite ion has the chemical formula ClO ⁇ , where chlorine (Cl) is in oxidation state +1, which is a potentially unstable oxidation state since the low-energetic oxidation state of Cl is -1.
- hypochlorite ion and the chlorite ion combine with a number of cations to form hypochlorites and chlorites, as the salts of these oxidized chlorines.
- Common examples include sodium hypochlorite (household bleach) and calcium hypochlorite, the main active ingredient of commercial products including bleaching powder, chlorine powder, or chlorinated lime, generally used for water treatment (e.g., swimming pools and the like).
- the chlorite and hypochlorite ions also referred to herein as the "main chlorine oxides", are useful in various contexts.
- Sodium chlorite and hypochlorite are strong oxidizing agents, and have been used in water purification, disinfection, as well as bleaching and deodorizing animal products.
- hypochlorite produces a highly toxic chlorine gas under acidic conditions
- commercially available aqueous solutions for household purposes are strongly basic solutions, with the pH adjusted using sodium hydroxide.
- Hypochlorous acid is a weak acid that is known to rapidly inactivate bacteria, algae, fungus, and other organics, making it an effective agent across a broad range of microorganisms.
- hypochlorous acid is generally non-toxic to humans because it is a weak acid and people naturally produce certain compounds that allow them to tolerate hypochlorous acid. Due to the combination of its biocidal properties and its safety profile, hypochlorous acid has been found to have many beneficial uses across many different industries, such as the medical, food service, food retail, agricultural, wound care, laboratory, hospitality, dental, or floral industries.
- hypochlorous acid is formed when chlorine dissolves in water.
- hypochlorite generates hypochlorous acid, where the chlorine atom is in oxidation state +1.
- Hypochlorous acid exists in equilibrium with chlorine gas, which can escape from solution.
- Equation 1 The equilibrium is pH-dependent, as illustrated in the following equation (Equation 1): Cl 2 + H 2 O ⁇ HOCl + Cl ⁇ + H + ⁇ ClO ⁇ + Cl ⁇ + 2 H + (1) Increasing pH ⁇
- a high pH drives the reaction to the right, promoting the disproportionation of chlorine into chloride and hypochlorite, whereas a low pH drives the reaction to the left, promoting the release of chlorine gas (Cl 2 ), which can be toxic.
- compositions of the invention comprise an acetic acid activator in combination with a form of hypochlorite.
- formulations of the invention may be combined with a viscosity enhancer, and/or a dye.
- the viscosity of formulations of the invention can be adjusted to form a gel using viscosity enhancers.
- Formulations of the invention are preferably mixed in a container comprising separate chambers as part of a multi-compartment device prior to use.
- Compositions of the invention may be formulated for oral, intravenous, dermal, or inhalation-based administration.
- formulations of the invention can be prepared for inhalation via a nebulizer or similar device for rapid introduction to a patient’s respiratory system.
- compositions of the invention are useful disinfectants for treating a broad spectrum of bacterial and/or viral pathogens, both in vivo and on surfaces.
- the present invention is directed to antimicrobial formulations that provide a safe and effective means of treating and preventing respiratory infections, including both viral and bacterial infections.
- a preferred composition comprises a hypochlorous acid-based broad-spectrum antiviral and/or antibacterial inhalation solution. Solutions of the invention are preferably nebulized for inhalation delivery.
- a preferred formulation comprises hypochlorous acid (HOCl) (from about 25 ppm to about 200 ppm) that is stabilized with acetic acid (approximately 0.25%), resulting in sustainable concentrations of HOCl with significant antimicrobial effects.
- HOCl hypochlorous acid
- acetic acid approximately 0.25%
- the composition preferably is formulated at pH 5.5 and is physiologically isotonic thereby to increase tolerability within airways.
- Compositions of the present invention have unique anti-pathogenic properties.
- compositions of the invention act on enveloped viruses, and provides superior antiviral effects against Corona-type viruses.
- compositions are particularly useful for the treatment, and preventing the spread, of SARS infections (e.g., COVID-19). More specifically, SARS-CoV-2 and many other viruses have surface proteins (i.e., spike proteins), which are entry points into cells of the respiratory system. These spike proteins comprise –SH groups vulnerable to oxidation by HOCl. Even relatively low concentrations of HOCl oxidizes extracellular –SH groups (e.g., on viral spike proteins), while being harmless to normal tissue and intracellular enzymes. As such, the antiviral effect of compositions of the present invention destroy viral particles in the respiratory tract upon first exposure, during infection, and when virions are intracellular and subsequently released by cells in the respiratory tract.
- SARS-CoV-2 and many other viruses have surface proteins (i.e., spike proteins), which are entry points into cells of the respiratory system. These spike proteins comprise –SH groups vulnerable to oxidation by HOCl. Even relatively low concentrations of HOCl oxidizes extracellular –SH groups (e.g., on viral
- compositions of the present invention especially on enveloped viruses, makes such compositions a powerful tool in ongoing efforts to prevent the spread of coronaviruses.
- Such compositions reduce the duration of disease and severity of symptoms amongst a broad population of patients.
- the present invention provides a disinfectant composition which includes a solid oxidized chlorine species salt, an activator, such as acetic acid, and a pharmaceutically-acceptable diluent, adjuvant, or carrier.
- the solid oxidized chlorine species salt is based on the formula M n+ [Cl (O) x ]n n- , where M is an alkali metal, alkaline earth metal, or transition metal ion, n is 1 or 2, and x is an integer between 1 and 4, inclusive.
- the activator is based on the formula R 1 XO n (R 2 ,) m , where the R 1 group comprises between 1 and 10 hydrogenated carbon atoms, optionally substituted with amino, amido, carboxylic, sulfonic or hydroxy groups, wherein group X is selected from carbon, phosphorous and sulfur; n and m are each independently 2 or 3, and R 2 is selected from H, an alkali metal, an alkaline earth metal, a transition metal ion salt, and an ammonium salt.
- the oxidized chlorine salt comprises an alkali metal or alkaline earth metal salt of hypochlorous acid HOCl.
- the activator is acetic acid.
- the oxidized chlorine salt comprises an alkali metal or alkaline earth metal salt of chlorous acid HOClO.
- the activator is acetic acid.
- the composition comprises an osmolality in the range of about 0.1 mOsm to about 500 mOsm.
- an amount of oxidized chlorine species salt, acetic acid or its metal or ammonium salt produces a pH between 4 and 8.
- the composition further includes a viscosity-enhancing agent.
- the viscosity-enhancing agent cannot be oxidized by the oxidized chlorine species.
- the viscosity-enhancing agent comprises a water-soluble gelling agent.
- the water-soluble gelling agent may include, but is not limited to, poly acrylic acid, polyethylene glycol, poly(acrylic acid)-acrylamidoalkylpropane sulfonic acid co-polymer, phosphino polycarboxylic acid, and poly(acrylic acid)-acrylamidoalkylpropane, and sulfonic acid-sulfonated styrene terpolymers.
- the composition comprises a dye.
- the dye preferably produces a colorimetric indicator of the presence an oxidized chlorine compound in the formulation.
- the dye may be a reduction-oxidation dye.
- the color and intensity of the dye is dependent on the oxidation state of the oxidized chlorine compound.
- Formulations of the invention may be composed as an aqueous solution, gel, cream, ointment, or oil. Formulations of the invention may be produced and stored in a multi- compartment container. In some aspects, aqueous and solid components are contained within separate respective compartments prior to combination. Formulations of the invention are useful as antimicrobials on surfaces as well as for application to disease treatments. As such formulations of the invention are useful as inhalation products for use with, for example, a nebulizer, inhaler, vaporizer or other suitable means of delivery. In addition, compositions of the invention can be formulated for application to skin, wounds mastitis or any other infectious diseases in animal or agricultural breeding; as well as antiviral applications.
- FIG.1 is a schematic illustration showing an exemplary multi-compartment or multi- chambered container for producing, storing, and dispensing a disinfectant composition according to embodiments of the present invention.
- FIG.2 shows the results obtained using sample solutions according to the present invention.
- FIG.3 shows the results obtained using sample solutions according to the present invention.
- the present invention relates generally to compositions comprising a combination of a solid and liquid precursor of an oxidized state of chlorine and an activator, e.g. acetic acid or its salts, as well as one or more additional components.
- an activator e.g. acetic acid or its salts
- the use of such compositions acts as disinfectants for treatment of a broad spectrum of bacterial and/or viral pathogens on a variety of biotic and abiotic surfaces and environments.
- Some preferred formulations of the invention are in a solid form, multi-component (i.e., two-component, three-component, four-component, etc.) formulation that instantaneously generates compositions with long-term stability. This reduces limitations related to shelf life typically observed with conventional solutions of hypochlorous acid or chlorine dioxide described in the prior art. More specifically, the immediate generation of ready to use formulations of the oxidized chlorine species from solid precursors (API-P) may be performed in a multi-compartment device or container at the site of use. The multi-compartment device or container is used for the preparation, dispensing, and long term, stable storage of prepared compositions consistent with the present invention.
- API-P oxidized chlorine species from solid precursors
- such multi-compartment containers described herein may have a number of compartments or chambers separately containing the components required to produce compositions of the present invention.
- the formulation comprises a solid precursor of an oxidized state of chlorine and acetic acid or its salts, a viscosity enhancer, and a dye) and is subsequently combined to prepare the antimicrobial composition at the desired time of use and on site.
- Another chlorine oxide useful as an API in antimicrobial formulations is chlorine dioxide, wherein the chlorine atom is in oxidation state +3.
- HOR is usually a mineral acid, such as HCl or citric acid, since a source of protons is needed to convert sodium chlorite, first to chlorous acid, and then to chlorine dioxide, which is a highly water-soluble gas at room temperature.
- An advantage of chlorine dioxide is that it cannot generate chlorine gas, Cl 2 which is known to react to chlorinated hydrocarbons, e.g. trihalo-methanes, which are toxic environmental pollutants.
- compositions comprising a combination of solid precursors of oxidized states of chlorine (OC) and activators providing a source of protons.
- OC oxidized states of chlorine
- a preferred example of an activator is acetic acid or its salts, wherein the disinfectant compositions of the invention are instantly formed in a controlled and immediate process at the site of use with a stability that permits the intended short-term use.
- Such compositions are useful disinfectants for treatment of a broad spectrum of microorganisms.
- the active pharmaceutical ingredient is generated from stable, solid precursors, referred to hereinafter as "API-P" of chlorine oxides at the site of use
- API-P solid precursors
- the inclusion of e.g. acetic acid as an activator that simultaneously is buffering the solution or gel to a biocompatible pH value the stability issue in prior art is no longer present.
- the technical solutions in the prior art fail to address how to secure an ionic strength or osmolality of the final antimicrobial solution biocompatible with biological fluids.
- the prior art fails to show how to regulate and increase contact time and persistence of the API in a region of therapeutic interest, e.g. by regulating rheology and fluidity.
- compositions of the present invention may further include the use of a viscosity enhancer (also referred to herein as "VE") and/or include a combination of a solid precursor of an oxidized state of chlorine and the activator, e.g. acetic acid or its salts.
- VE viscosity enhancer
- Another embodiment of the invention is the inclusion of a dye in the formulation, preferably e.g., a redox sensitive dye, with a color that varies with the oxidation state of the chlorine atom.
- compositions of the invention are in a solid form, multi-- component (i.e., two-component, three-component, four-component, etc.) formulation, separated by breakable walls or barriers that instantly generates the composition with long-term stability.
- multi-- component i.e., two-component, three-component, four-component, etc.
- This eliminates any issues related to shelf life seen with solutions of hypochlorous acid or chlorine dioxide described in the prior art.
- the immediate generation of ready-to-use formulations of the oxidized chlorine species from solid precursors API-P may be performed in a multi-compartment device or container at the site of use.
- the multi-compartment device or container may be used for the preparation, dispensing, and long term, stable storage of prepared compositions consistent with the present invention.
- such multi-compartment containers described herein may have a number of compartments or chambers separately containing the components required to produce the compositions of the present invention.
- the solid precursor of an oxidized state of chlorine and the activator e.g. acetic acid or its salts, a viscosity enhancer, and a dye is mixed, and subsequently the composition generates at the desired formulation of the disinfectant at the desired time and site of use.
- Acetic acid is an abundant natural compound found various mammalian tissues. It is also a by-product of bacterial fermentation of carbohydrates. Sodium acetate is non-toxic and is allowed in drug formulations for oral and parental use. The bactericidal effect of acetic acid is well known.
- acetic acid and its metal salt are very attractive compounds to use in antimicrobial formulations because of its ability to act as a buffer together with its metal salt for stabilization of pH. Further, in addition to its antimicrobial properties, acetic acid is attractive because it cannot be oxidized further by oxidizing agents, such as an OC, and because of its endogenous nature in high concentrations in living tissue.
- the multi-compartment container enables practical use in mixing the components necessary to generate the active solution of the API instantly and at the site of use. It should be noted that, to secure an ionic strength or osmolality of the final antimicrobial solution to adapt to the osmolality on the region of use in the case of medical applications, a pre- calculated amount of NaCl can be included in the multi-compartment device, dependent on the planned use.
- a preferred embodiment of the invention is an inhalation formulation for respiratory administration.
- nebulizers or inhalators generally used for the treatment of cystic fibrosis, asthma, COPD and other respiratory diseases or disorders, that convert liquids into aerosols are useful in the present invention.
- a device for inhalation administration may use compressed air or ultrasonic energy to generate atomization of the formulations of the invention.
- pressurized metered dose inhalers pMDIs
- dry powder inhalers DPIs
- slow mist inhalers SIs
- Any electrostatic or non-electrostatic inhalators e.g. the VORTEX or Pari or Sympotec are also useful to practice the invention.
- the pre-loaded multi-compartment container described herein produces a stable, broad- spectrum antimicrobial solution upon mixing of the components, and leaves only biocompatible inactive chemical species in nature.
- the activation of the API of the invention is produced using an activator, e.g.
- acetic acid which acts synergistically with oxidized chlorine against microbes, and further maintains acidity in pH range between 4 and 8.
- the inventive method and the formulations thereof avoids the inherent lack of long-term stability of oxidized chlorine OC in solution, since there is no need to store the disinfectant composition as a water solution.
- Another advantage of the present invention is the option to add other compounds that will aid in application. For example, in wound healing applications, there is a need to increase the viscosity ( ⁇ ) of the product on the skin to prolong contact time.
- the invention solves for this poblem by the use of a water-soluble or dissolvable viscosity enhancer (VE) that chemically cannot be oxidized by the API, thereby providing improved regulation of contact time and persistence of the API in a region of therapeutic interest.
- VE water-soluble or dissolvable viscosity enhancer
- the VE ensures that the rheology and fluidity is adapted to the respective method and region of disinfection, to generate a solution with full fluidity or a gel.
- the VE may include, for example, a water-soluble gelling agent such as polyacrylic acid, polyethylene glycol or any other oligomer or polymer that cannot be oxidized by the API.
- compositions of the invention may include a one or more dyes, preferably selected from a group of reduction-oxidation dyes (also referred to herein as "ROD” or “RODs”), wherein the color and intensity is dependent on the oxidation state of oxidized chlorine.
- ROD reduction-oxidation dyes
- the RODs further provide an antimicrobial effect of their own. This enhances the synergistic action between the components in the formulation in a novel way.
- One non-limiting example is instant generation of hypochlorous acid from sodium-, or calcium-hypochlorite in the cap 2 according to FIG.1, with a solution of sodium acetate buffer in compartment 4 providing a ready-to-use solution of the API hypochlorous acid with a pH between 5 and 6 in compartment 9, optionally with a color and a viscosity enhancer.
- Another non-limiting example is calcium di-hypochlorite Ca(OCl) 2 , which is a stable and water-soluble API-P for HOCl. It is instantly soluble in water, and only leaves calcium hydroxide, which is present in nature, and which generates HOCl, one of the two the active ingredient in the present invention, which degrades to Cl- and biocompatible species containing hydrogen and oxygen.
- Another preferred embodiment of the present invention is a solid precursor of oxidized chlorine is tetrachloro-decaoxide (TCDO), CAS no.92047-76-2, known as WF10 or stabilized solutions of OXO-K993, prepared as described by Meuer et al in CA2616008, incorporated by reference herein. It can be prepared by combining alkaline or alkaline earth salts of the chlorite ion ClO 2 - with excess oxygen in water.
- TCDO tetrachloro-decaoxide
- WF10 stabilized solutions of OXO-K993
- An aspect of the invention is the combination of the API-P with a molecule comprising a carboxylic acid functionality –COOH, a sulfonic acid functionality –SO 3 H, a phosphoric acid functionality -PO 3 H or a boric acid functionality –B(OH) 2 , each of which serves as the activator of the API-P in the formulation.
- the activator has the general formula R 1 XO n (R 2 ,) m wherein the group R 1 may be a group comprising from about 1 to about 10 hydrogenated carbon atoms, optionally substituted with amino, amido, carboxylic or hydroxy groups.
- the group X may be a carbon, phosphorous or sulfur atom, n and m is 2 or 3 and R 2 is a proton (H), or any alkali metal, alkaline earth metal or transition metal ion.
- R 2 is a proton (H), or any alkali metal, alkaline earth metal or transition metal ion.
- the nature of the substituents in the formula varies according to use and chlorine species, and may be any compound comprising an amino group, e.g. ammonia, an amino acid, e.g. taurine or a therapeutic drug increasing the synergistic potential of the formulation.
- the activator may be any combination or mixture of two or more compounds as defined by the general formula R 1 XO n R 2 .
- Preferred non-limiting examples are carboxylic acids R 3 COOH, wherein R 3 is H, or a linear or branched saturated or unsaturated hydrocarbon chain with from about 1 to about 24 carbon atoms, optionally substituted with hydroxyl groups.
- activator may be acetic acid, citric acid, tartaric acid, lactic acid, hippuric acid, maleic acid, boric acid, sulfuric acid, phosphoric acid, boric acid, 3-(N-morpholino)propanesulfonic acid (MOPS), 2- (carbamoylmethylamino)ethanesulfonic acid (ACES), 2-(carbamoylmethylamino)ethanesulfonic acid (ADA), 2-(carbamoylmethylamino)ethanesulfonic acid (bicine), piperazine-N,N′-bis(2- ethanesulfonic acid, PIPES), or any amino acid.
- MOPS 2- (carbamoylmethylamino)ethan
- Taurine is especially preferred, since it is the endogenous amino acid normally moderating the effect of OC in the body, and may be combined with OC to form endogenous N- chloro-amino acids like ClNH-CH 2 CH 2 -SO 3 H, which in itself has antibacterial properties.
- Acetic acid is preferred because it is endogenous in humans, has antibacterial properties, has very low toxicity and forms buffers in admixture with is metal salts, and is used as a non- limiting example in the further description of the invention.
- An advantage of the invention is that the solid multi-component products according to the invention is not hampered by stability issues in a pharmaceutical or medical device setting, regardless of temperature, air, humidity, light, oxygen or other ambient conditions, since the API-Ps are solid and commercially available in large scale.
- the API-Ps disclosed herein can be soluble in water, and nearly instantly reach physiological pH and ionic strength in the final solution in combination with acetic acid and/or its salts.
- the ability to instantaneously generate the antimicrobial API in situ increases the ease of use and versatility of the product.
- the packaging of the components can be separate and combined on demand, further impacting storage stability and use in the field.
- Viscosity enhancers for preparations of viscous solutions and gels
- components other than the API can be included.
- a viscosity enhancer is preferred for wound healing or skin disinfection.
- Preferred viscosity enhancers are water-soluble gelling agents that do not oxidize the API.
- the gelling agents provide prolonged persistence of the API at the area of interest, e.g., skin.
- examples of gelling agents according to the invention include, but are not limited to, poly acrylic acid (CARBOMER), polyethylene glycol or any other oligomer, polymer or block- copolymer thereof.
- the viscosity enhancer may be selected from, poly(acrylic acid)- acrylamidoalkylpropane sulfonic acid co-polymers, phosphino polycarboxylic acids and poly(acrylic acid)-acrylamidoalkylpropane and sulfonic acid-sulfonated styrene terpolymers.
- Polymers such an acrylate copolymer, function well in formulations of the invention in concentration ranges from about 0.01 to about 5 %.
- Acrylate copolymers are homo- and co- polymers of acrylic acid cross-linked with a polyalkenyl polyether.
- Acrylate copolymers exist in a variety of graft densities.
- One exemplary cross-linker is pentaerytritol, which is very stable.
- Polyacrylic acid (PAA) polymers which are known to stabilize formulations of H 2 O 2 , can be used with the present invention.
- the polymer-stabilized solutions of OC according to the invention have applications in many contexts, e.g. in wound treatment, aseptic packaging, electronics manufacture, and pulp and paper bleaching.
- the API can be formulated as a gel or viscous fluid, which may be applied to target surfaces, either inanimate or representative of the infected epithelial mucosal or skin surfaces so as to ensure prolonged and intimate contact with the necessary levels of API.
- Non- viscous formulations of the API may also be dispersed into the air in confined spaces as a mist in order to achieve environmental disinfection, or for inhalation purposes for treatment of respiratory diseases.
- a concentration of the poly acrylic acid CARBOMER has increasing viscosity in the concentration 0.01 – 0.1 %. If desired, it forms regular gels in the concentration range 0.1 - 1 %.
- Antibacterial redox-sensitive antibacterial dyes as indicators A further additive to formulations of the invention is reduction-oxidation dyes (hereinafter ROD), wherein the color and intensity of the dye is dependent on the oxidation state of the OC.
- RODs themselves have antimicrobial effects, increasing the antimicrobial synergy between constituents of the formulations presented herein. If the standard half-cell potential of the ROD has a lower positive value than OC, the color of the formulation will be maintained as long as the OC is active. Thereby, the color provides a visual clue in the region wherein the formulation has been applied and where there is active OC.
- a formulation according to the invention is used in treatment of mastitis, where large packs of cattle needs to be treated for mastitis; the colored formulation according to the invention visualized which animals have been treated.
- the opposite type of indicator where the color appears when the oxidizing power of the OC is vanishing, is also useful.
- suitable dyes useful in the invention are pH-independent dyes, visible in the presence of an OC.
- N-phenylanthranilic acid (violet-red), N-ethoxychrysoidine (cyan), o-dianisidine (red), sodium diphenylamine sulfonate (red-violet), diphenylbenzidine (violet), diphenylamine (violet) and viologen, which is colorless in the presence of an OC, but deep blue in the absence of an OC.
- pH-dependent dyes that are deep blue in the presence of an active OC, but colorless in the absence of the OD are sodium 2,6-Dibromophenol-indophenol or Sodium 2,6- Dichlorophenol-indophenol, sodium o-cresol indophenol, thionine (syn. Lauth's violet), methylene blue, Gentian Violet, indigotetrasulfonic acid, indigo carmine (syn. Indigo-disulfonic acid), indigomono sulfonic acid.
- dyes that are red or red-violet in the presence of an OC are phenosafranine, Safranin T, neutral red and dialkyl-p-phenylenediamine (SPD, red violet).
- SPD dialkyl-p-phenylenediamine
- Many of these dyes have antibacterial effects in their selves, i.e. methylene blue (MB) and Gentian Violet (GV), and combinations of them have been used as antibacterial dyes in foams in wound dressings in combination with polymers like polyvinyl alcohol or polyurethane, e.g. as described by Edwards in Advances in Wound Care (2016), 5, pp 11-19.
- a particularly useful class of dyes useful in the present invention is microbial phenazines, which are pigmented, redox-active, nitrogenous aromatic compounds with metabolic, ecological and evolutionary significance.
- An additional class of phenazines include the bis-N-oxide phenazines, with even stronger antimicrobial properties than their parent phenazines. Most of these compounds are natural compounds produced by bacteria, and are hetero-aromatic N-oxidized compounds, hereinafter denoted HANOX.
- the HANOX compounds are useful in the present invention because their color is dependent on the oxidation state of the OC. Further, certain phenazine derivatives.
- the phenazine derivatives are particularly useful in the treatment of animal diseases of microbial origin in agriculture.
- a surprising finding with these derivatives is their lack of injurious effects to tissue under the conditions of use, making them particularly suitable for topical application, preferably employed in amount ranging from 0.05 per cent to 1.0 per cent by weight of the composition.
- FIG.1 is a schematic illustration showing an exemplary multi-compartment device for instant generation of a formulation according to the invention.
- the design of the device, including the number of compartments, can be adapted to the specifications of use.
- the device 8 consists of a screw cap 1 associated with the primary compartment, containing the solid precursor of the API, denoted API-P in a dry form (2).
- the screw cap 1 has the ability to open the seal or port 3 by turning it in one direction, letting the API-P into the second compartment 4, comprising a water solution of the activator also comprising a pre-calculated amount of sodium chloride to render the final osmolality of the solution to be iso-osmolal with body fluids.
- the activator and optionally a pre-calculated amount of its metal or amino acid salt in water may optionally be pre- loaded into compartment 4, 5 or 9.
- the smaller grains in 4 illustrate that the API-P is rapidly dissolving in the activator solution to generate the API.
- the third compartment 5 is optional and may contain a solution of a redox dye (ROD), depending on the technical use of the respective device.
- Compartments 4 and 5 are separated by a wall 6. Compartments 4 and 5 are also separated from compartment 9 by a breakable septum or wall 7.
- a fourth compartment at the same level as 4 and 5 can contain an amino acid, e.g. an essential or non- essential amino acid or taurine for stabilization of the API.
- the fourth compartment 9 may optionally be pure water, the activator solution.
- An aspect of the invention is the solid precursor API-P in the screw cap 1, which is the oxidized chlorine species.
- the resulting solution from the multi-compartment device may eventually be used to produce a solution of the viscosity enhancer (VE), in a water solution.
- VE viscosity enhancer
- Any multi-chamber device that functions to permit mixing of the precursor components and additives is useful in the context of the invention, including bottles, bags, syringes, inhalators, hand disinfection devices, spay bottles, flasks, or tanks. As noted above, devices that can be easily activated bedside or in the field without complicated mixing procedures and can be stored at ambient temperatures are preferred.
- the multi-compartment device according to the invention is a closed system and may be designed to eliminate mixing errors, to avoid undesired exposure to patients and personnel, and meets the Joint Commission and USO 797 guidelines.
- Non-limiting examples of design useful in the invention are the Duplex Container from B Braun, the Credence Companion Safety Syringe System, the Dual-Mix multi-chamber bags or the Easyrec kit comprising a screw cap releasing a solid or mixture of solids for mixing into one or more fluid phases to generate the ready to use formulation of the API.
- Use of the invention for antimicrobial purposes with photodynamic therapy Bacterial elimination using antimicrobial photodynamic therapy (aPDT) has been shown using the alternative therapeutic modality in peri-implantitis treatment.
- another preferred embodiment of the present formulation comprising an OC, acetic acid or its salt, optionally a viscosity enhancer, is the inclusion of a ROD exemplified by methylene blue for the use of photodynamic therapy, e.g. to improve wound healing or bacterial infections in mammals.
- the site of administration of the product according to the present invention can be irradiated with light with a wavelength adapted to generation of the photodynamic effect of the dye.
- Stepwise method for API Production provides compositions and methods of the use of solid precursors API-P of chlorinated species, combined with the activator, e.g. acetic acid or its salt, and methods of its use.
- An exemplary method comprises the following 6 steps: 1.
- API-P having the general formula denoted below M n+ [Cl (O) x ] n n- , wherein M can be any alkali metal, alkaline earth metal or transition metal ion, wherein n is an integer 1-5, x is an integer 1-4, y is an integer 1-2,.
- the solid state (API-P) generates a concentration of the API in the final solution in the form of an OC in the interval 0.01 - 1000 ppm, preferably in the range 0.1 - 100 ppm, is loaded into compartment 1 of a multi- compartment device.
- the API-P is mixed with a precalculated amount of NaCl to generate a final osmolality in the interval 0.1 - 500 mOsm, and optionally any other stabilizing solid.
- the activator is dissolved in a pharmaceutically acceptable diluent, adjuvant, or carrier to generate a concentration of the activator in the interval 0.05 - 10 %, preferably in the range 0.08 to 0.5 %, even more preferably in the range 0,10 – 0,2 %.
- the solution in step 2 may comprise an amount of NaCl from step, either way generating a final osmolality in the interval 0.1 - 500 mOsm, preferably around 300 mOsm, corresponding to 150 mM NaCl.
- An aliquot of the solution is loaded into a second compartment of a multi- compartment device. 3.
- compartment 1 and 2 are mixed by opening a port or breaking a seal, membrane barrier or between the first and second compartments to mix the contents in the compartments, followed by ambient squeezing or shaking to generate the disinfectant solution.
- the resulting solutions can be taken out through a cap on the multi-compartment device prior to use.
- the solution is isotonic, has a pH in the interval 4 to 9, preferably between 5 and 6, and is generally used for antimicrobial purposes, e.g. for inhalation therapy using e.g. an asthma inhaler or nebulizer to fight viral infections in the upper airways in mammals.
- a color indicator in step 4 can add information in the therapeutic procedure, e.g. in treatment of mastitis, or for indication of the oxidative activity of the API, a dye with a color that varies with the oxidation state of the API (ROD), in a precalculated amount to generate a concentration of the dye in the concentration range 0.01 - 1000 ppm, is optionally loaded into an optional compartment of a multi-compartment device. 5.
- ROD oxidation state of the API
- a precalculated amount an amino acid as a stabilizer of the API is optionally is optionally loaded into an optional compartment of a multi-compartment device.
- Step 4 is performed to reduce oxidative stress to biological surfaces.
- an amount of a water-soluble viscosity enhancer (VE) that cannot be oxidized by the API in the concentration range 0.01 - 25%, preferably in the range 0.1 - 10 %, even more preferably in the range 0.2 - 1%, is mixed with the solution resulting from a selected sequence of steps 1-3, optionally combined with any of the steps step 4-5.
- VE water-soluble viscosity enhancer
- a VE concentration of 0.01 - 0.1 % generates a viscous but fluid solution, while 0.3 - 1% produce a gel.
- the third compartment in step 3. comprising the VE can be included in the mixing procedure to produce a viscous or gel-formed product.
- a preferred aspect of the present invention is treatment of mastitis using a gel or viscous solution comprising an OC, acetic acid or its salt, the viscosity enhancer VE and a ROD exemplified by methylene blue.
- steps 1-4 and step 6 is performed to yield the instant formulation of use.
- Use of the invention in aquaculture Water quality is a prerequisite for a successful culture of aquatic animals, exemplified by fish, oysters, prawns and shrimps. Open water systems often bring organisms like virus, bacteria, lice, protozoa, fungal pathogens, algae and parasites.
- oxidized chlorine species OC is effective treatment of all these infections and harmful organisms and cells.
- the instant formulations of the OC are highly effective in controlling these waterborne pathogens.
- chlorine dioxide is a broad-spectrum biocide effective to solve the defined problems in the prior art.
- the formulations in the present invention is even employed in special tanks to repeatedly treat e.g. bred salmon without harming the fish gills or any other parts of the bred species, while having a destructive effect on the microorganisms causing the disease.
- the preparations sequence wherein the API-P is NaOClO 2 or Ca(OClO 2 ) 2 is loaded into compartment 1 and mixed with a precalculated amount of acetic acid in step 1-3 is used.
- Antiviral use of the invention Methods disclosed herein for treatment of contaminated surfaces, equipment, e.g. medical equipment, furniture surfaces, doorknobs, devices, clothing or personnel.
- Formulations of the invention can be applied as a gel, aqueous solution, or by misting or vaporization of the API into a surface or confined space.
- the fact that the formulation is prepared on demand makes it possible to treat areas with high-potency antimicrobial without concern for storage degradation.
- Methods of the invention contemplate dispersion of the active agents into crevices and microenvironments, even onto personnel who are suspected of having been contaminated by infectious tissues or bodily fluids. Vaporization of these formulations may enable beneficial therapeutic or prophylactic impacts on resistant viral, bacterial or fungal infections.
- Formulations of the invention can be applied without substantial toxicity risk.
- a preferred embodiment is the treatment of a viral infection in the upper airways.
- compositions of the invention are useful for treating SARS, MERS and other infections, including but not limited to, SARS CoV-2 infections.
- SARS SARS
- MERS MERS
- other infections including but not limited to, SARS CoV-2 infections.
- inhalable hypochlorous acid formulations of OC an activator, e.g. acetic acid, an excipient regulating the rheology of the final solution, an osmolality-regulating agent, e.g. sodium chloride.
- compositions of the invention for delivery via inhalation.
- Formulations for aerosolization may be provided in dry powder form, solution, or suspension form. Fine droplets, sprays, and aerosols can be delivered by an intranasal or intrapulmonary pump dispenser or squeeze bottle. Compositions can also be inhaled via an inhaler, such as a metered dose inhaler or a dry powder inhaler.
- compositions can also be inhaled via a nebulizer, such an ultrasonic wave nebulizer, providing compositions of OC and acetic acid directly to respiratory tracts via inhalable formulations. This prevents and treats infections of the respiratory system caused by viruses as well as other microbes.
- formulations as described herein are safe and effective for the prevention and treatment of viral infections.
- Compositions of the invention may also include a pharmaceutically acceptable carrier, such as a diluent, to facilitate delivery to the respiratory mucosa.
- the carrier might be an aqueous carrier such as saline.
- the composition may be isotonic, having the same osmotic pressure as blood and lacrimal fluid.
- Suitable non-toxic pharmaceutically acceptable carriers are known to those skilled in the art. Various carriers may be particularly suited to different formulations of the composition, for example whether it is to be used as drops or as a spray, a suspension, or another form for pulmonary delivery. Formulations for inhalation may be provided in dry powder form, solution, or suspension form.
- the composition can be delivered by various devices known in the art for administering drops, droplets, and sprays.
- the composition can be delivered by a dropper, pipet, or dispenser. Fine droplets, sprays, and aerosols can be delivered by an intranasal or intrapulmonary pump dispenser or squeeze bottle. Intranasal delivery may be provided via a nasal spray device. Accordingly, the formulations according to the invention may be designed as a nasal spray.
- the nasal spray is insufflated into the nose and is delivered to the respiratory tract.
- Soft mist inhalers use mechanical energy stored in a spring by user-actuation to pressurize a liquid container, causing the contained-liquid to spray out of a nozzle for inhalation in the form of a soft mist.
- Soft mist inhalers do not rely on gas propellant or electrical power for operation.
- the average droplet size in soft mist inhalers is about 5.8 micrometers.
- Jet nebulizers are the most commonly used and may be referred to as atomizers. Jet nebulizers use a compressed gas (e.g., air or oxygen) to aerosolize a liquid medicine when released there through at high velocity.
- a compressed gas e.g., air or oxygen
- the resulting aerosolized droplets of therapeutic solution or suspension are then inhaled by a user for treatment.
- the compressed gas may be pre- compressed in a storage container or may be compressed on-demand by a compressor in the nebulizer.
- Ultrasonic wave nebulizers rely on an electronic oscillator to generate a high frequency ultrasonic wave that, when directed through a reservoir of a therapeutic suspension of solution, aerosolized the medicine for inhalation. Vibrating mesh nebulizers use the vibration of a membrane having thousands of holes at the top of the liquid reservoir to aerosolize a fine-droplet mist for inhalation.
- Vibrating mesh nebulizers avoid some of the drawbacks of ultrasonic wave nebulizers, offering more efficient aerosolization with reduced treatment times and less heating of the liquid being nebulized.
- Treatment of a viral infection is achieved using a synergistic composition of acetic acid and hypochlorous acid.
- the acetic acid component is particularly effective for penetrating into tissues, while the hypochlorous acid is particularly effective for treating infection on the outer surface of tissue.
- these compositions are effective for treating the respiratory tract and for preventing respiratory infection.
- the disclosed compositions are particularly effective because balancing the concentrations of hypochlorous acid and acetic acid with NaCl allows safe treatment of viruses.
- the precise balance depends on the formulation, the treatment site, and even the desired amount of surface penetration.
- the hypochlorous acid can be present in about 5 ppm up to about 1000 ppm or more. Different uses, different delivery methods, and types of tissue may require higher or lower concentrations.
- the acetic acid may be present at about 0.1% up to about 5.0% or more, and preferably about 1.0%. By balancing the two components, the composition can have the dual effect of treating at the surface and beneath the surface of the tissue to which it is applied.
- the OC is hypochlorous acid HOCl
- an instant composition having a concentration of about 15-60 ppm of the OC is normally sufficient for treatment of infected lungs.
- the composition should be in contact with it for a prolonged period, ranging from a few seconds, to several minutes, to an hour or more. Accordingly, in certain embodiments, the composition is in the form of a gel, which allows longer contact times with the infection site.
- the use of the composition in combination with a known antiviral treatment may increase the efficacy of the compositions.
- methods of the invention further comprise administration (simultaneously or sequentially with compositions of the invention) of one or more doses of an antiviral substance.
- acyclovir adefovir, adamantine, boceprevir, brivudin, cidofovir, emtricitabine, entecavir, famciclovir, fomivirsen, foscarnet, ganciclovir, lamivudine, penciclovir, telaprevir, telbivudine, tenofovir, valacyclovir, valganciclovir, vidarabine, m 2 inhibitors, neuraminidase inhibitors, interferons, ribavirin, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, non-structural protein 5a (ns5a) inhibitors, chemokine receptor antagonist, integrase strand transfer inhibitors, protease inhibitors, and purine nucleosides.
- compositions of the invention are also useful in combination with a known antimicrobial treatment.
- methods of the invention further comprise administration (simultaneously or sequentially with compositions of the invention) of one or more doses of an antibiotic substance, including, but not limited to, ciprofloxacin, beta-lactam antibiotics like ampicillin or carbapenems, azithromycin, cephalosporin, doxycycline, fusidic acid, gentamycin, linezolid, levofloxacin, norfloxacin, ofloxacin, rifampin, tetracycline, tobramycin, vancomycin, amikacin, deftazidime, cefepime, trimethoprim/sulfamethoxazole, piperacillin/tazobactam, aztreanam, meropenem, colistin, or chloramphenicol.
- an antibiotic substance including, but not limited to, ciprofloxacin, beta-l
- methods of the invention further comprise administration of one or more doses of an antibiotic substance from an antibiotic class including, but not limited to, aminoglycosides, carbacephem, carbapenems, first generation cephalosporins, second generatin cephalosporins, third generation cephalosporins, fourth generation cephalosporins, glycopeptides, macrolides, monobactam, penicillins, polypeptides, quinolones, sulfonamides, tetracyclines, lincosamides, and oxazolidinones.
- an antibiotic substance from an antibiotic class including, but not limited to, aminoglycosides, carbacephem, carbapenems, first generation cephalosporins, second generatin cephalosporins, third generation cephalosporins, fourth generation cephalosporins, glycopeptides, macrolides, monobactam, penicillins, polypeptides, quinolones, sulfonamides
- methods of the invention comprise administration of a nonantibiotic antimicrobial substance, including but not limited to sertraline, racemic and stereoisomeric forms of thioridazine, benzoyl peroxide, taurolidine, and hexitidine.
- the dosing regimen of the composition may include the amount, frequency, and duration of exposure to the composition. The dosing regimen may depend on the severity of the infection, or on a regimen prescribed for treatment or for prevention of the viral infection.
- the composition may be administered in a single daily dose or in multiple doses, e.g., 2, 3, 4, or more doses, per day.
- the subject receiving the composition may be exposed to the composition for periods of hours or of minutes.
- the duration of exposure may depend on the frequency, amount, or even of the severity of the infection.
- the total daily amount of API formed in the instant solution from the solid precursors may be in the range 0.01 - 1000 mg, depending of the nature of the OC.
- the actual dosage may vary depending upon the specific composition administered, the mode of administration, and other factors known in the art.
- the composition may be administered to any member of the respiratory tract, such as the respiratory epithelium, nasal cavity, nasal epithelium, pharynx, esophagus, larynx, epiglottis, trachea, carina, bronchi, bronchioles, or the lungs.
- Administering the composition to the respiratory tract treats prevents any disease or disorder that is transmitted by a virus.
- compositions of the invention can be used to disinfect whole rooms, facilities medical devices and surgical instruments, for example. Supplies of medical devices are often initially sterile, but may require additional or subsequent cleaning and disinfection or sterilization. In particular, sterilization or disinfection of reusable medical devices prior to reuse employing any known technique is especially important.
- Compositions can be applied to the medical device using. For example, the composition can be applied by wiping or spreading it onto the surface of the device, by spraying an aerosol or mist form of the composition onto the device, by dipping the device into a vessel containing a volume of the composition, or by placing the device into a flow of the composition such as from a faucet.
- compositions may also be stored submerged in the composition and removed at the time of use.
- Some of the disclosed compositions contain acetic acid at 2% or greater, and when in combination with the OC have proven to be safe and effective for treating skin and other tissues.
- the OC in these compositions has been found to have a modulating effect of the acetic acid. This allows the compositions to take advantage of the disinfecting properties of acetic acid without causing harm to the tissue.
- the present invention is directed to a disinfectant composition developed to provide a safe and effective means of treating and preventing the spread of respiratory infections, including SARS-CoV-2.
- compositions for use in treating SARS infections comprise a hypochlorous acid-based, nebulized broad-spectrum antiviral and antibacterial inhalation solution. More specifically, the formulation includes hypochlorous acid (HOCl) (25 ppm to 200 ppm) that has been stabilized with acetic acid (approximately 0.25%), resulting in sustainable concentrations of HOCl with positive antimicrobial effects. The addition of acetic acid increases HOCl stability, thus making it possible to develop a treatment with extended shelf-life. Furthermore, the composition is formulated with increased pH of 5.5 and isotonicity to thereby increase tolerability within airways.
- hypochlorous acid HOCl
- acetic acid approximately 0.25%
- compositions of the present invention have unique virucidal properties, especially on enveloped viruses, and provides superior antiviral activity. Accordingly, such a composition may be particularly useful for the treatment, and prevention of, for example, COVID-19. More specifically, SARS-CoV-2 and many other viruses have surface proteins (i.e., spike proteins), which are referred to as “door openers” into human cells in the respiratory system. These spike proteins comprise –SH groups vulnerable to oxidation by HOCl. Low concentrations of HOCl likely oxidizes extracellular –SH groups (e.g., viral spike proteins), while being harmless to normal tissue and intracellular enzymes.
- the antiviral effect of the composition of the present invention can destroy viral particles in the respiratory tract upon first exposure, during infection, and when virions are intracellular and subsequently released by the human airway cells. Therefore, the unique virucidal properties of the composition of the present invention, especially on enveloped viruses, makes it a powerful potential tool in the ongoing efforts to prevent the spread of the coronavirus.
- Such a composition can reduce duration of the disease and severity of symptoms amongst a broad population of COVID-19 patients, particularly at a time of unprecedented need, given the virulence of coronavirus throughout the world.
- Table 1 (below) provides a listing of the components of the composition of the present invention, which consists of 25 ppm – 200 ppm HOCl + 0.25% acetic acid.
- the active ingredient in preferred compositions of the invention is hypochlorous acid (HOCl).
- This active ingredient is derived from sodium hypochlorite, which is produced as an aqueous solution from the reaction of gaseous Cl2 with water at alkaline pH. A 3% NaOCl is produced and added to the final IS to reach a maximum of 200 ppm (0.01% w/w) HOCl.
- the other ingredients of the composition include the following: Sodium Hydroxide, Ph.Eur./USP-NF grade, 0.1M solution added to required pH (5.5); pH stabilizer Acetic Acid, Ph.Eur./USP-NF grade glacier, 0.25%; Osmolarity adjuster Sodium Chloride, Ph.
- Eur./USP-NF grade added to reach isotonic formulation (303mOsm); and Purified Water, water purified through Reverse Osmosis and deionized by Ion Exchange process or according to Ph.Eur./USP-NF monograph.
- a preferred clinical dosage for the composition is 5 mL of 25 - 100 ppm hypochlorous acid.
- the final product also contains 0.25% acetic acid buffer.
- the solution contains more than 99.1% HOCl and less than 0.9% OCl-.
- HOCl is the active substance in IS and has been found to be 80 times more effective as a sanitizing agent compared to an equivalent concentration of OCl-.
- HOCl serves the dual effect in IS of being the API and acting as an antimicrobial agent to inhibit the growth of microorganisms in the final product.
- the composition may be presented in plastic PET vials/bottles. Before administration to the patient, the composition is transferred to a nebulizer/inhalation device reservoir. This transfer is done in the clinic. After transfer to the nebulizer, the solution is administered immediately (within 1-2 h) to the patient through liquid aerosol delivery. The patient should receive 5 mL of nebulized composition.
- Compositions for viral administration are typically single-dose administration and are delivered to the respiratory tract by nebulization, using, for example, PARI BOY.
- the nebulizer PARI BOY Classic Inhalation System containing PARI BOY Classic Compressor, PARI LC SPRINT nebulizer.
- the nebulizer will be equipped with a PARI SMARTMASK. It should be noted that other nebulizers and inhalers may be used.
- HOCl is produced by the body’s own immune cells, i.e., neutrophils and monocytes/macrophages.
- HOCl is considered by the FDA to be “the form of free available chlorine that has the highest bactericidal activity against a broad range of microorganisms.” HOCl is a strong oxidizing agent, however, in low concentrations ( ⁇ 0.1%), it is very well tolerated and safe in wound care applications.
- Acetic acid activator stock solution (0.125 %, pH 2.95) In 998.75 mL of sterile water, 1.25 mL of acetic acid (mw: 60.05 g/mol) was dissolved.
- Acetic acid activator stock solution (0.125 %, pH 4.3) In 998.75 mL of sterile water, 1.25 mL of acetic acid (mw: 60.05 g/mol) was dissolved. The pH was adjusted to 4.3 using 10 N NaOH.
- Acetic acid activator stock solution (0.25 %, pH 4.3) In 998.75 mL of sterile water, 2.5 mL of acetic acid (mw: 60.05 g/mol) was dissolved.
- Acetic acid activator stock solution (0.25 %, pH 5.0) In 998.75 mL of sterile water, 2.5 mL of acetic acid (mw: 60.05 g/mol) was dissolved.
- Acetic acid activator stock solution (1 %, pH 4.3) In 998.75 mL of sterile water, 10 mL of acetic acid (mw: 60.05 g/mol) was dissolved.
- Acetic acid activator stock solution (2 %, pH 4.3) In 998.75 mL of sterile water, 20 mL of acetic acid (mw: 60.05 g/mol) was dissolved. The pH was adjusted to 4.3 using 10 N NaOH. 2g.
- Acetic acid/sodium acetate activator stock solution (0.1 M, pH 5.0) In 800 mL of distilled water, 5.772 g of sodium acetate (mW: 82 g/mol), 1.778 g of acetic acid (mw: 60.05 g/mol) was added to the solution. The pH was adjusted to 5.0 using 10N HCl or 10 N NaOH, and distilled water was added until the volume was 1 L. 2h.
- Isotonic acetic acid activator stock solution (0.125 %, pH 2.95) In 998.75 mL of sterile water, 1.25 mL of acetic acid (mw: 60.05 g/mol) and 8.4 g NaCl (mw: 58.44 g/mol) was added. 2i. Isotonic acetic acid activator stock solution (0.125 %, pH 4.3) In 998.75 mL of sterile water, 1.25 mL of acetic acid (mw: 60.05 g/mol) and 8.4 g NaCl (mw: 58.44 g/mol) was added. The pH was adjusted to 4.3 using 10 N NaOH. 2j.
- Isotonic acetic acid activator stock solution (0.25 %, pH 4.3) In 998.75 mL of sterile water, 2.5 mL of acetic acid (mw: 60.05 g/mol) and 8.4 g NaCl (mw: 58.44 g/mol) was added. The pH was adjusted to 4.3 using 10 N NaOH. 2k. Isotonic acetic acid activator stock solution (0.125 %, pH 5.0) In 998.75 mL of sterile water, 1.25 mL of acetic acid (mw: 60.05 g/mol) and 8.4 g NaCl (mw: 58.44 g/mol) was added. The pH was adjusted to 5.0 using 10 N NaOH.
- Isotonic acetic acid activator stock solution (0.25 %, pH 5.0) In 998.75 mL of sterile water, 2.5 mL of acetic acid (mw: 60.05 g/mol) and 8.4 g NaCl (mw: 58.44 g/mol) was added. The pH was adjusted to 5.0 using 10 N NaOH 2m.
- Isotonic acetic acid/sodium acetate activator stock solution (0.1 M, pH 5.0) In 800 mL of distilled water, 5.772 g of sodium acetate (mW: 82 g/mol), 1.778 g of acetic acid (mw: 60.05 g/mol) and 8.4 g NaCl (mw: 58.44 g/mol) was added to the solution. The pH was adjusted to 5.0 using 10N HCl or 10 N NaOH, and distilled water was added until the volume was 1 L. 2n.
- Acetate buffer (0.1 M, pH 5.0) In 800 mL of sterile water, 5.772 g of sodium acetate (mW: 82 g/mol) and 1.778 g of acetic acid (mw: 60.05 g/mol) was added to the solution. The pH was adjusted to 5.0 using 10N HCl, and distilled water was added until the volume was 1 L. 2o.
- ACES buffer (0.1 M, pH 6.7) In 800 mL of sterile water, 18.22 g of N-(2-acetamido)-2-aminoethanesulfonic acid (mW: 182.2 g/mol) was added to the solution.
- Citric acid solution (0.1 M, pH 2.2) An amount of 19.2 g of citric acid (mw: 192.1 g/mol) was dissolved in 1L of sterile water. 2q.
- Citrate buffer (0.1 M, pH 6.0) In 800 mL of sterile water, 12.044 g of sodium citrate (mW: 294.1 g/mol) and 11.341 g of citric acid (mw: 192.1 g/mol) was added to the solution. The pH was adjusted to 6.0 using 0.1 N NaOH, and distilled water was added until the volume was 1 L. 2r.
- ADA buffer (0.1 M, pH 6.6)
- ADA 2-[(2-amino-2-oxoethyl)-(carboxymethyl)amino]acetic acid
- ADA mW: 190.22 g/mol
- ADA dissolved when the pH was adjusted to 6.6 using pH using 10N NaOH, and distilled water was added until the volume was 1 L. 2s.
- EBBS buffer including the dye Phenol Red (pH 7.0)
- Phenol Red (pH 7.0)
- 800 mL of sterile water 200 mg of CaCl2 (mW: 110.98 g/mol), 200 mg of MgSO4-7H2O (mW: 246.47g/mol), 400 mg of KCl (mW: 75 g/mol), 2.2 g of NaHCO 3 (mW: 84.01 g/mol), 6.8 g of NaCl (mw: 58.44 g/mol), 140 mg NaH 2 PO 4 H 2 O (mw: 138 g/mol), 1 g D-Glucose (Dextrose) (mw: 180.16 g/mol) and 10 mg phenol red Phenol Red (mw: 354.38 g/mol) was added to the solution.
- CaCl2 mW: 110.98 g/mol
- MgSO4-7H2O mW: 246.47g/
- Example 3 Instant preparation of ready to use disinfectant formulations from solid salts of oxidized chlorine combined with solutions from Example 1.
- Example 3.1 Non-limiting steps of a general procedure 1. An aliquot of 90 mg of any of the powders from example 1 is loaded into compartment 4 of the multi-compartment device. 2. An aliquot of 10 mL of any of the activator solutions from Example 2 is loaded into compartment 4 of the multi-compartment device. 3.
- the seal, barrier or port 3 according to FIG.1 between the screw cap and compartment 4 is broken or opened to mix the contents in compartment 1 with the solution in compartment 4, followed by gently squeezing or shaking to generate the disinfectant solution.
- the resulting solution can be taken out through the opening after removing the screw cap on the multi-compartment device, and are now ready to use.
- the isotonic solutions have a pH in the interval 4 to 9, preferably between 5 and 6, is generally used for antimicrobial purposes. 4.
- a water-soluble dye in solid form with a color that varies with the oxidation state of the API (ROD), in a precalculated amount to generate a concentration of the dye in the concentration range 0.01 - 1000 ppm, is optionally loaded into compartment 9 of the multi-compartment device, and the procedure in 3 is repeated including mixture of compartments 1, 4 and 9. 5.
- a precalculated amount an amino acid as a stabilizer of the API, preferably taurine in the same concentration as the API is optionally loaded into compartment 5 of the multi-compartment device. and the procedure in 3. is repeated including mixture of compartments 1, 4 and 5. 6.
- the intended use e.g.
- an amount of a water-soluble viscosity enhancer (VE) that cannot be oxidized by the API, precalculated to gain a concentration of VE in the final solution in the concentration range 0.01 - 25%, is loaded into compartment 5 of the multi-compartment device.
- a VE concentration of 0.01 - 0.1 % generates a viscous but fluid solution, while 0.3 - 1% produce a gel.
- the dispersion of the VE in the solution from step 3, 4 and/or 5 is converted to a viscous solution or a gel using a Silverson Mixer or an Ystral Mixer, and used on site for skin or wound applications.
- Example 3.2 General procedure for preparation of reconstitutable hypochlorous acid- based composition 1. An aliquot of reconstitutable agent(s) is mixed with a diluent to thereby form a ready to use disinfectant formulation in accordance with the present invention, including, but not limited to, the hypochlorous acid-based broad-spectrum antimicrobial solution described herein. The reconstitutable agent(s) and diluent are mixed in a multi-compartment device, similar to the device illustrated in FIG.1 and described herein. 2.
- the reconstitutable agents may include, but are not limited to, dry powdered agents, including any of the powders from Example 1, as well as any of the activator solutions from Example 2 that have been prepared into dry powder form.
- one of the reconstitutable agents may include calcium hypochlorite in dry powder form (provided in a first compartment of a multi-compartment device) and a second reconstitutable agent may include sodium acetate in dry powder form (provided in a second compartment of the multi-compartment device).
- a diluent, such as water (or other aqueous medium) is provided in a third compartment. 3.
- each of the reconstitutable agents (the powdered calcium hypochlorite and powdered sodium acetate) and the diluent are maintained in separate respective compartments of the mixing device until a user is ready to combine and mix the agents and diluent to form an antimicrobial solution as described herein.
- the device may include one or more breakable seals separating one or more of the compartments from one another, such that a user need only break the seal to thereby initiate mixing of the reconstitutable agents and diluent together. Once the agents and diluent are mixed, a user need only shake the device to agitate and adequately combine the agents and diluent.
- the device may include one or more filters for filtering the diluent prior to mixing with the reconstitutable agents and/or filtering the resulting antimicrobial solution prior to use.
- the device may come preloaded with the reconstitutable agents but without the diluent (i.e., water). Accordingly, in the field and at the site of use, a user need only provide water (i.e., from a water source) to the device, at which point a filter may filter out any impurities in the water to provide an adequate diluent.
- the solution may pass through a one way filter when a user applies the solution to the site of intended use (i.e., wound irrigation, hand disinfectant, inhalation solution, countermeasures towards biological and chemical weapons, and the like. Accordingly, the filter prevents contaminated solution from reentering the device during use. 4.
- a colorimetric indicator may be added to the composition to provide a visual indication of the level of antimicrobial effects in the solution.
- the colorimetric indicator may include a dye, for example, such as a reduction-oxidation dye (ROD), such that the color and intensity of color of the dye is dependent on an oxidation state of the oxidized chlorine compound.
- ROD reduction-oxidation dye
- the color of the formulation will be maintained as long as the OC is active. Thereby, the color provides a visual clue in the region wherein the formulation has been applied and where there is active OC. Further, employment of the opposite type of indicator, where the color appears when the oxidizing power of the OC is vanishing, is also useful.
- the mixing device itself may also include a color scale of sorts that provides various shades of color indicating levels of concentration and appropriate uses/applications for such levels of concentration. 5.
- Various techniques to prepare dry powders are known and practiced. Such techniques include lyophilization, spray-drying, spray-freeze drying, bulk crystallization, vacuum drying, and foam drying.
- Lyophilization is often a preferred method used to prepare dry powders (lyophilizates) containing proteins.
- Various methods of lyophilization are well known to those skilled in the art.
- the lyophilization apparatus and process applies a vacuum that converts liquid portions of a composition into a solid which is subject to a sub-atmospheric pressure to create a vapor.
- the vapor is drawn from the lyophilization chamber through vapor passages and exhausted to regions external of the lyophilizing apparatus.
- the lyophilizing process reduces the liquid composition to a dried powdery or granular form.
- freeze drying, or lyophilization is a dehydration technique.
- Steps in freeze drying include pretreatment, freezing, primary drying and secondary drying. Pretreatment includes any method of treating the product prior to freezing. This may include concentrating the product, formulation revision (i.e., addition of components to increase stability and/or improve processing), decreasing a high vapor pressure solvent or increasing the surface area.
- Methods of pretreatment include: freeze concentration, solution phase concentration, and formulating specifically to preserve product appearance or to provide lyoprotection for reactive products. 7. Accordingly, by providing the reconstitutable agents and diluent(s) within a mixing device, as described herein, the resulting antimicrobial solution can be produced at the desired time and at the desired site of use without facing storage degradation. As previously described herein, certain antimicrobial solutions may typically have a relatively short shelf-life, as they may contain compounds that degrade rapidly and lose their effectiveness. As such, some formulations may require refrigeration and special packaging, or require immediate use upon being produced. Such special treatment, however, adds to operating costs and complicates storage, particularly in areas where such storage is not available.
- Example 4 In vitro anti-biofilm effect of example 3 test solutions of HOCl and acetic acid. Three different test solutions were generated form the multi-compartment device. All three test solutions are generated as described in example 3.1 from the multicompartment device, loaded with 90 mg of dry powder comprising 200 ppm sodium hypochlorite in sodium chloride (example 1c) in compartment 1. Three aliquots of 10 mL of acetic acid solutions from (0.125 %, pH 4,3, example 2b) in compartment 4 in three different multicompartment-devices.
- Solution 1 (0,25 %, pH 4,3, example 2c)
- Solution 2 (1 %, pH 4,3, example 2e)
- Solution 3 (2 %, pH 4,3, example 2f).
- Experimental setup Test organisms Pseudomonas aeruginosa or Staphylococcus aureus wild-type strains
- Biofilm type 48 hours- or 24 hours-old biofilms grown on semipermeable membranes placed on solidified medium supplemented with 0.5% glucose. In the case of 48h-old biofilms, the membranes with biofilms were transferred onto fresh plates after 24h.
- Initial viable cell amount 5 x 10 9 colony forming units (CFUs)
- Treatment method Membranes with biofilms were transferred to new plates.
- FIG. 2 shows the results obtained using the sample solutions. Increasing the HAc concentrations from 0.25% to 1% and 2% in a 200ppm HOCl solution gradually increased the killing of S. aureus biofilms. The effect of 1 % acetic acid alone had only minor effect on the biofilm. The three test solutions were compared to 4 different competing wound healing products on the market which all showed only minor effects on the S. aureus biofilms. An even stronger effect was shown for biofilms from P.
- Example 5 In vivo toxicity studies
- the rat inhalation study is performed according to the Organization for Economic Cooperation and Development (OECD).
- test solution is generated as described in example 3.1 from the multicompartment device, loaded with 90 mg of dry powder comprising 100 ppm sodium hypochlorite in sodium chloride (example 1 b) in compartment 1 and an aliquot of 10 mL of acetic acid solution (0.125 %, pH 4.3, example 2b) in compartment 4.
- Test Guideline 412 Sprague-Dawley rats is exposed to filtered fresh air (sham) as a reference, or the test solution. Care and use of the animals is in accordance with the American Association for Laboratory Animal Science Policy (1996). All animal experiments are approved by the Institutional Animal Care and Use Committee (IACUC).
- the histopathological evaluation is performed at defined anatomical sites of the nose and of the left lung according to a defined grading system.
- Free lung cells are determined in bronchoalveolar lavage fluid by flow cytometry, and inflammatory mediators are measured by multi-analytes profiling (MAP).
- MAP multi-analytes profiling
- RNA samples from specific sites in the respiratory tract are obtained, i.e., respiratory nasal epithelium (RNE) and lung.
- RNA isolation respiratory epithelium of main bronchus and lung parenchyma is separated by Laser Capture Microdissection (LCM) and further processed, and analyzed on whole genome Affymetrix microarrays (GeneChip® Rat Genome 2302.0 Array).No major perturbations are found related to inflammation, cell stress, cell proliferation in bronchi or lung parenchyma.
- Example 6 Treatment of mastitis
- a color indicator in step 4 can add information in the therapeutic procedure, e.g. in or for indication of the oxidative activity of the API, the compartment comprising the ROD is included in the procedure.
- Example 7 Clinical antiviral therapy
- the medicine cup of Gima Aerosol Corsia Nebulizer is loaded with 5 mL of the test solution generated as described in example 3.1 from the multicompartment device, loaded with 90 mg of dry powder comprising 1 ppm sodium chlorite in sodium chloride (example 1j) in compartment 1 and an aliquot of 10 mL of citric acid solution (0.1 M, pH 2,2, example 2p) in compartment 4.
- the mouth of a patient with a coronavirus lung infection is attached to the hose and the face mask attached to the nebulizer, which is started. After 10-15 minutes of breathing, the fluid is used up, and the nebulizer is turned off. The patient is monitored for several hours to secure that no side effects of the treatment is taking place.
- Example 8 Pharmacology of inhalation solution (IS) The virus-inactivating properties of the inhalation solution (IS) of the composition against modified vaccinia virus Ankara (MVA) have been investigated.
- the IS products at 50, 100, and 200 ppm HOCl (pH 5.5) (and diluted 50% solutions) showed virus inactivation properties suggesting that the lowest concentration of the IS product showing virus inactivation was at 25 ppm HOCl. Further dilutions were tested and diluted solutions with concentrations of 5, 10 and 20 ppm did not show any virus inactivation and effect suggesting that the non-active lower range was demonstrated.
- HOCl demonstrated antiviral activity against the enveloped DNA vaccinia virus for all tested HOCl concentrations. Products that have antiviral activity against the vaccinia virus are considered active against all enveloped viruses, including SARS-CoV-2.
- IS has been shown to inactivate SARS- CoV-2 between 10 and 200 ppm HOCl.
- antibacterial activity overnight cultures of S. aureus and P. aeruginosa were grown for 2 and 24 hours, respectively, to test IS against both planktonic and biofilm growing bacteria. Full effect was seen for 50 ppm HOCl IS for P. aeruginosa and S.
- Example 8.1 Antiviral efficacy Antiviral effectiveness of HOCl against vaccinia virus Antiviral assays were performed to evaluate the virucidal activity of HOCl against modified vaccinia virus Ankara (MVA).
- the product used was IS containing 50, 100, and 200 ppm HOCl at the following concentrations: ⁇ Undiluted (80.0%) ⁇ Diluted with aqua bidest. (50.0%) ⁇ Diluted with aqua bidest. (10.0%) ⁇ Diluted with aqua bidest.
- test methods involved exposing the test products (50, 100, & 200 ppm HOCl) at dilutions between 1-80% to BHK21-cells infected with MVA, as confirmed via infectivity assay.
- the product was in contact with MVA infected cells for either 1 or 2 minutes then an inactivation assay was performed to determine virucidal activity. Determination of cytotoxicity was also performed following product contact.
- Method To prepare the test virus suspension BHK 21-cells were cultivated with MEM and 10% or 2% fetal calf serum. Cells were infected with a multiplicity of infection of 0.1. The test product was tested undiluted.
- Infectivity was determined as endpoint titration according to EN 5.5 transferring 0.1 mL of each dilution into eight wells of a microtiter plate to 0.1 mL of freshly splitted cells (10-15 x 103 cells per well), beginning with the highest dilution. Microtiter plates were incubated at 37 °C in a 5% CO2-atmosphere. The cytopathic effect was read by using an inverted microscope. Calculation of the infective dose TCID50/mL was calculated with the method of Spearman and Kärber.
- the virucidal activity of the test disinfectant was evaluated by calculating the decrease in titer in comparison to the control titration without disinfectant. The difference is given as reduction factor (RF).
- RF reduction factor
- a disinfectant or a disinfectant solution at a particular ⁇ oncentration has virus-inactivating efficacy if the titer is reduced at least by 4 log10 steps within the recommended exposure period. This corresponds to an inactivation of ⁇ 99.99%.
- Determination of virucidal activity has been carried out according to EN 5.5. Inactivation tests were carried out in sealed test tubes in a water bath at 20 °C ⁇ 1.0 °C. Aliquots were retained after appropriate exposure times and residual infectivity was determined.
- cytotoxicity was performed according to EN 5.5.4.1. As reference for test validation a 0.7% formaldehyde solution according to EN 5.5.6 was included. Contact times were 5, 15, 30 and 60 minutes. In addition, cytotoxicity of formaldehyde test solution was determined according to EN 5.5.6.2 with dilutions up to 10 -5 . Results All undiluted test products (i.e., 50, 100, 200 ppm HOCl) in an 80.0% assay were able to inactivate MVA after 1 minute of exposure time.
- the reduction factors were the following: ⁇ 50 ppm HOCl: ⁇ 5.25 ⁇ 0.33 ⁇ 100 ppm HOCl: ⁇ 5.13 ⁇ 0.25 ⁇ 200 ppm HOCl: ⁇ 5.25 ⁇ 0.33 These corresponded to an inactivation of ⁇ 99.999%.
- the 50.0% solutions were also able to inactivate MVA after 1 minute of exposure time.
- the reduction factors were the following: ⁇ 50 ppm HOCl: ⁇ 4.25 ⁇ 0.33 ⁇ 100 ppm HOCl: ⁇ 4.13 ⁇ 0.25 ⁇ 200 ppm HOCl: ⁇ 4.25 ⁇ 0.33 These corresponded to an inactivation of ⁇ 99.99%.
- the 10.0% solutions were not able to inactivate MVA within 1 minute of exposure time.
- Example 8.2 Antibacterial and anti-biofilm efficacy
- An antibacterial assay was performed to evaluate the bactericidal activity of IS against P. aeruginosa and S. aureus grown for either 2 or 24 hours to represent planktonic and biofilm bacteria, respectively.
- the product used was the IS (i.e., with 0.25% acetic acid, pH 5.5, isotonic) at the following concentrations: ⁇ 10 ppm HOCl ⁇ 50 ppm HOCl ⁇ 100 ppm HOCl ⁇ 200 ppm HOCl ⁇ 500 ppm HOCl
- the product was in contact with either P. aeruginosa or S. aureus for 1 hour then an aliquot was plated and left to incubate overnight. The next day the plates were evaluated for growth and log reductions were quantified in the case of partial growth.
- Method MH340 P. Aeruginosa PAO1
- NCTC-8325-4 S.
- bacteria were treated with 0.9% NaCl (control), 10 ppm HOCl, 50 ppm HOCl, 100 ppm HOCl, 200 ppm HOCl, and 500 ppm HOCl IS at 37°C for 1 hour. After the treatment period (one hour) 20 ⁇ L per well was spotted on LB plates and cultured at 37°C overnight. The day after the plates were checked for growth (saline is control) or no growth. Results As seen in Table 2 below, P. aeruginosa planktonic bacteria and biofilms were eradicated at lower product concentrations than S. aureus. There is full antibacterial effect of the final IS product (100 ppm HOCl) across the board in representative planktonic and biofilm S.
- the product used was the IS (i.e., with 0.25% acetic acid, pH 5.5, isotonic) or acetic acid alone at the following concentrations: ⁇ 25 ppm HOCl ⁇ 50 ppm HOCl ⁇ 100 ppm HOCl ⁇ 0.25% acetic acid, pH 5.5, isotonic
- the product was in contact with either P. aeruginosa or S. aureus for 1 hour then an aliquot was plated and left to incubate overnight. The next day the plates were evaluated for growth and log reductions were quantified in the case of partial growth. Method Diluted overnight cultures (OD of 0.5, ⁇ 10 7 for S. aureus and ⁇ 10 8 for P. aeruginosa) of S.
- the product used was IS at the following concentrations: ⁇ 10 ppm HOCl ⁇ 50 ppm HOCl ⁇ 100 ppm HOCl ⁇ 200 ppm HOCl
- the test method involved exposing the test product at concentrations between 10-200 ppm HOCl to Vero E6 cells infected with SARS-Cov-2 for 48 hours. The cells were then stained, and the number of virus antigen positive cells were enumerated. A cell proliferation assay was performed to evaluate cytotoxicity. Method Vero E6 cells/well were seeded in 96-well plates, the virus (multiplicity of infection 0.002) was added and incubated for 1 h at 37°C or media only for non-treated controls and for cytotoxicity assays.
- the virus was removed and IS 10 ppm HOCl, 50, 100, or 200 ppm HOCl, either undiluted or diluted by half was added for 15 min, thereafter the assay was incubated for 48 h.
- the incubated cells were fixed and stained with primary antibody SARS-CoV-2 spike chimeric monoclonal antibody and with secondary antibody F(ab')2-Goat anti-Human IgG Fc Cross- Adsorbed Secondary Antibody, HRP. Single infected cells were visualized with DAB substrate and counted automatically by an ImmunoSpot series 5 UV analyzer. Cytotoxicity assays were performed using the Cell Titer AQueous One Solution Cell Proliferation Assay.
- results in this study the antiviral effect of the test compound was evaluated by amount of VERO cells free of virus compared to the control. Based on the results IS lowered the amount of virus positive VERO cells, thus IS inactivated SARS-CoV-2 in concentration from 10 ppm to 100 ppm HOCl without killing the VERO cells. VERO cells have been reported to be extremely fragile and not well suited to study IS thus even better antiviral activity might have been obtained with more robust cells. However, it has not been possible to run these experiments in other cell types due to the classification of SARS-CoV-2 as a Class 3 microorganism. The viral inactivation and cytotoxicity results are presented in FIG.3. Referring to FIG.3, each bar represents the mean with standard error of the mean (error bars).
- Example 9 Toxicology of inhalation solution (IS)
- IPF inhalation solution
- Non-GLP in vivo inhalation toxicity studies in Göttingen minipigs have been performed at Ellegaard Göttingen Minipigs in Denmark. These studies include a 5-day repeated dosing study in minipigs by intubation with nebulized IS, including a recovery period of 2 or 4 weeks for selected animals.
- a small pilot study by intubation was performed to aid selection of dose levels for the subsequent studies. Intubation was selected as the dose route in these studies to maximize the amount of the IS that reached the lungs.
- Example 9.1 Repeat-dose toxicity
- the initial toxicity studies were conducted at Ellegaard Göttingen Minipigs in Denmark.
- An additional preliminary non-GLP study was performed at Covance in England and a GLP study is on-going at Covance in England. All completed and planned repeat-dose toxicity studies are summarized in the following subsections.
- Example 9.1.1 In vivo inhalation study - intubated Forty-two healthy young-adult Göttingen minipigs, 21 males and 21 females, 6-8 months of age, were used in this experiment. The minipigs weighed approximately 12 kg. The minipigs were bred and housed at Ellegaard Göttingen Minipigs in AAALAC International approved barrier facility housing and according to the facilities’ standard for local environment, feeding, and care. The experimental protocol was approved by the Danish Animal Experiments Inspectorate (license no.2020-15-0201-00530), and all procedures were carried out according to the Danish Animal Testing Act. The study was not performed according to GLP, however data were recorded and reported according to the documented Study Plan and to local Standard Operating Procedures. The study was performed in two separate phases.
- the animals were allocated to the dosing groups as follows: Main phase ⁇ 0.9% NaCl as control (4 males and 4 females) ⁇ 50 ppm HOCl + 0.25% HAc, pH 5.5, isotonic (4 males and 4 females) ⁇ 100 ppm HOCl + 0.25% HAc, pH 5.5, isotonic (4 males and 4 females) ⁇ 200 ppm HOCl + 0.25% HAc, pH 5.5, isotonic (4 males and 4 females)
- Recovery phase ⁇ 200 ppm HOCl + 0.25% HAc, pH 5.5, isotonic (1 male and 1 female killed following the final dose) ⁇ 200 ppm HOCl + 0.25% HAc, pH 5.5, isotonic (2 males and 2 females killed after 2 weeks recovery) ⁇ 200 ppm HOCl + 0.25% HAc, pH 5.5, isotonic (2 males and 2 females killed after 4 weeks recovery)
- four minipigs were
- All minipigs were anaesthetized (with propofol potentiated by butorphanol by intravenous catheter) daily for five days to receive 5 mL nebulized product (saline for the control group) through an endotracheal tube.
- the minipigs were ventilated using a GE anesthesia machine at volume-controlled ventilation with a total flow of 2 L/min (50% oxygen) and a tidal volume of 10 mL/kg.
- Spirometry including P peak (our major outcome parameter, to assess potential bronchoconstriction), was recorded every two minutes as well as capnometry, non-invasive blood pressure, heart rate (ECG), and temperature.
- the animals were allowed at least 10 min of stabilization at the ventilator system before observations, including P peak , were recorded.
- the animals were monitored for 10 min as baseline measurements; thereafter the nebulization of 5 mL product was started (Aerogen Solo nebulizer, Timik Aps, Kolding, Denmark). Nebulization lasted 11-20 min (as according to manufacturer, 2- 5 min/mL). After all product was nebulized, the animals were monitored for another 15 min (post-inhalation) before they could regain consciousness. Every morning before and every afternoon after the anesthesia/inhalation, all animals were scored to assess general condition, appetite, behavior, coughing, lung function, and mobility. Blood samples were taken before the first dose and again after the last dose and evaluated for clinical pathology parameters.
- Example 9.1.2 In vivo inhalation study - masked
- healthy minipigs were treated daily for five days with 10 mL (10 mL is added to the nebulizer, but the expected delivery was 8.8 mL, as residual volume is 1.2 mL) of the nebulized IS or nebulized saline solution (0.9% w/v NaCl, as a control) by mask covering the snout.
- NOAEL 100 ppm was tested as well as 50 ppm and compared to saline control.
- Twelve healthy young-adult Göttingen minipigs (6-8 months of age) were used in this experiment (31355).
- the minipigs (6 males and 6 females) weighed approximately 12 kg.
- the minipigs were bred and housed at Ellegaard Göttingen Minipigs in AAALAC International approved barrier facility housing and according to the facilities’ standard for local environment, feeding, and care.
- the experimental protocol was approved by the Danish Animal Experiments Inspectorate (license no.2020-15-0201-00530), and all procedures were carried out according to the Danish Animal Testing Act.
- the minipigs were trained to accept the sling confinement on two occasions during the week before the study. During the study, two minipigs at a time were placed in slings in a calm and light-dimmed procedure room.
- the animals were lightly sedated with low-dose midazolam (0.3- 0.7 mg/kg – increased during the five days as necessary to keep each animal calm) and their eyes were covered to keep them calm. Thereafter a mask was placed over the snout and the mask was connected to a Pari Boy® classic nebulizer.
- the nebulizer chamber was initially filled with 4 mL IS or saline, and was continuously refilled (three times @ 2 mL) until 10 mL was administered after approximately 30 min. According to the manufacturer, the residual volume is approximately 1.2 mL, therefore the administered dose was ⁇ 8.8 mL.
- a pulse oximeter was connected to the tail of each animal to measure pulse and oxygen saturation; measurements, including counting of respiratory frequency, were noted after 5, 10, 15, and 20 minutes of inhalation.
- the animals were placed in a recovery box and observed until full recovery and thereafter guided back to their stall. The procedure was repeated daily for five days. On day five, the animals were euthanized after the last inhalation. Every morning before and afternoon after the procedure, all animals were scored to assess general condition, appetite, behavior, coughing, lung function, and mobility. Blood samples were drawn the first day before inhalation (baseline) and on the last day of inhalation after the inhalation. Standard biochemistry and hematology, including differential count, were performed.
- Routine necropsy with special attention to the respiratory system was performed following euthanasia by an experienced veterinary pathologist to observe potential macroscopic signs of toxicity in situ.
- Lungs and mediastinal lymph nodes were weighed.
- Samples for histopathology were collected proximally (including the main bronchus) and distally from the right cranial and the left caudal lung lobes, from the trachea, carina, mediastinal lymph nodes, heart (right and left ventricular muscles), kidney, and liver.
- the nasal passages were collected for histopathology by using a standardized approach to investigate three nasal levels.
- Lungs including trachea, carina, bronchi, and bronchioles), lymph nodes (sub carinal), nasal passages (the squamous, transitional, respiratory, and olfactory epithelium covering the nasal opening, nasoturbinate, maxiloturbinate, vomernasal organ, ethmoturbinates and nasopharynx), liver, kidney, and heart were examined histologically. On a few occasions, a few coughs or a sneeze were heard in relation to inhalation or after removal of the mask from the snout; this was noted for one animal in the control group, two animals in the 50ppm group, and one animal in the 100ppm group.
- Example 10 Cytotoxicity of wound irrigation solution (WIS) In vitro cytotoxicity of a Wound Irrigation Solution (WIS) at 200 ppm HOCl has been evaluated in two cytotoxicity studies. The objective of the studies was to determine whether WIS is toxic to cultured mammalian L929 cells in vitro. The tests comply with the methods described in ISO 10993-5 and the formulation of the test items were prepared in compliance with ISO 10993-12.
- Example 10.1 In vitro cytotoxicity of WIS (200 ppm HOCl)
- WIS (SOF 0001/05-01), containing 0.25% acetic acid and 200 ppm HOCl, pH: 4.3, was examined to determine the potential cytotoxic activity on cultured mammalian cells (mouse fibroblasts). The test was performed in accordance with the US Pharmacopeia, Method ⁇ 87> and the ISO 10993-5 guidelines.
- a formulation of WIS (SOF 0001/05-01) was prepared with complete cell culture medium (Ham’s F12 medium supplemented with 10% fetal bovine serum and 50 ⁇ g/mL gentamycin).
- a diluent ratio of 0.2 g test item/mL diluent medium was used. This formulation was tested undiluted as well as diluted 1 part formulation + 3 parts fresh cell culture medium. Positive control (sodium lauryl sulphate (SLS), 0.2 mg/mL) and untreated control cultures (served also as negative control, treated with complete cell culture medium) were included in the study. Triplicate cell cultures were treated at each test point for 48 hours. The control treatments produced appropriate responses, demonstrating the correct functioning and sensitivity of the test system. The diluted formulation showed no toxicity (cytotoxicity grade 0 in all cases), while the undiluted formulation showed cytotoxicity (cytotoxicity grade 4 in all cases).
- SLS sodium lauryl sulphate
- Example 10.2 In vitro cytotoxicity of WIS (200 & 448 ppm HOCl)
- the in vitro cytotoxicity of the WIS (200 ppm HOC1, 0.25% acetic acid), SOF 003/53 (448 ppm HOC1, 1% acetic acid) and SOF 003/51 (200 ppm HOC1, 1% acetic acid) formulations were evaluated.
- the applied in vitro assays measure the release of lactate dehydrogenase (LDH) from ruptured cell membranes and the metabolic activity (MTT) in the cell line NCTC clone 929 (L-929) after exposure towards the formulations for 1, 4, 24, and 48 hours.
- LDH lactate dehydrogenase
- MTT metabolic activity
- the assays were performed according to the EUNCL SOP (EUNCL-GTA-03). For all the tested formulations, no significant membrane rupture was measured at the tested concentrations (10-0.005%) and exposure periods (1, 4, 24, and 48 hours). According to the guidelines in the ISO-10993-5 international standard, none of the WIS formulations caused a cytotoxic effect (i.e., more than 30% reduction in cell viability) in the NCTC clone 929 (L-929) cells at the two shortest exposure periods (1 and 4 hours).
- Example 11 Genotoxicity of inhalation solution (IS) GLP in vitro studies with IS have been performed at Charles River Laboratories, Hungary.
- Example 11.1 In vitro bacterial reverse mutation assay An inhalation solution of the invention was tested for potential mutagenic activity using the Bacterial Reverse Mutation Assay. The study was performed according to GLP.
- the experiment was carried out using histidine-requiring auxotroph strains of Salmonella typhimurium (Salmonella typhimurium TA98, TA100, TA1535, and TA1537) and the tryptophan- requiring auxotroph strain of Escherichia coli (Escherichia coli WP2 uvrA) in the presence and absence of a post-mitochondrial supernatant (S9 fraction) prepared from the livers of phenobarbital/ ⁇ -naphthoflavone-induced rats.
- the study included a Preliminary Compatibility Test and an Assay 1 (Plate Incorporation Method).
- concentrations were selected and provided by the Sponsor with appropriate documentation as follows: 50 ppm, 100 ppm, 200 ppm and 500 ppm, these are equivalent to 0.05, 0.1, 0.2 and 0.5 mg/mL. At the highest treatment volume (500 ⁇ L) these were equivalent to 25, 50, 100 and 250 ⁇ g/plate; these concentrations were used in Assay 1. Due to cytotoxicity, additional treatment plate concentrations were also used with lower treatment volumes per plate of the 50ppm test item concentration: 0.3162, 1.0, 3.162 and 10 ⁇ g/plate using treatment volumes of the supplied material at 6.3 ⁇ L, 20 ⁇ L, 63.2 ⁇ L and 200 ⁇ L, respectively.
- test concentration was 250 ⁇ g and the minimum was 0.3162 ⁇ g test item/plate (a total of eight concentrations). Inhibitory, cytotoxic effect of the test item (absent / slight reduced background lawn development) was observed in all examined bacterial strains without metabolic activation at 250, 100 and 50 ⁇ g/plate concentrations, and with metabolic activation at 250 ⁇ g/plate concentration. In the assay the number of revertant colonies did not show any biologically relevant increase compared to the solvent controls. There were no reproducible dose-related trends and there was no indication of any treatment-related effect.
- Example 11.2 In vitro mammalian cell micronucleus assay An inhalation solution of the invention was tested in an in vitro micronucleus test using mouse lymphoma L5178Y TK+/- 3.7.2 C cells. The study was performed according to GLP. Two assays were performed (Assay 1 and Assay 2).
- the selected concentration intervals were not sufficiently refined to evaluate at least three test concentrations to meet the acceptability criteria (within the appropriate cytotoxicity range). Any result with a Relative Increase in Cell Count (RICC) of ⁇ 40% was not acceptable for the assay, the aim should be to have a cytotoxicity of approximately 40%-50% achieved in the assay to demonstrate the concentrations used were sufficient to meet the guideline criteria. Therefore, an additional experiment (Assay 2) was performed with modified and more closely spaced concentrations to give further information about the cytotoxic effects and to meet the regulatory acceptability criteria. The examined concentrations of the test item in Assay 2 (with and without metabolic activation) were the same as in Assay 1, however, additional lower treatment concentrations were applied.
- RRC Relative Increase in Cell Count
- concentrations of 10, 5 and 2 ⁇ g/mL were chosen for evaluation in case of the short treatment with metabolic activation, and concentrations of 6, 2 and 1 ⁇ g/mL (a total of three) were chosen for evaluation in case of the short treatment without metabolic activation, and concentrations of 7, 6, 2 and 1 ppm (a total of four) were chosen for evaluation in case of the long treatment without metabolic activation. None of the treatment concentrations caused a biologically or statistically significant increase in the number of micronucleated cells when compared to the appropriate negative (vehicle) control value in the experiments with and without metabolic activation.
- IS did not cause statistically or biologically significant reproducible increases in the frequency of micronucleated mouse lymphoma L5178Y TK+/- 3.7.2 C cells in the performed experiments with and without metabolic activation. Therefore, IS was considered as not being genotoxic in this test system under the conditions of the study.
- Example 12 Other toxicity studies
- Example 12.1 In vitro lung surfactant functionality An Inhalation Solution of the invention was tested in a simulated alveoli model to evaluate its’ effect on lung surfactant function. Lung surfactant reduces lung surface tension, allowing normal expansion and contraction during respiration. Inhalation of aerosols that interfere with the lung surfactant may induce a toxic response.
- the test method involved exposing a small volume of lung surfactant to nebulized IS during simulated breathing cycles while quantifying lung surfactant surface tension. Change in surface tension was evaluated.
- Method A previously well-described constant flow through set-up of a constrained drop surfactometer was used to test the product’s effect on lung surfactant function. This method has shown 100% sensitivity in detecting harmful substances when compared to in vivo studies.
- a drop of lung surfactant (10 ⁇ g) was exposed to nebulized 500 ppm HOCl IS (5 mL over five minutes) during simulated breathing cycles of the lung surfactant (to mimic an alveoli).
- the surface tension was evaluated continuously by axisymmetric drop shake analysis to detect potential critically low surface tension (below 10 mN/m) as would induce atelectasis in vivo.
- Results No inhibition of the lung surfactant function was measured when lung surfactant was exposed to nebulized inhalation product in the highest concentration (500 ppm HOCl + 0.25 % acetic acid, pH 5.5, isotonic). Similar results were obtained for 0.9% NaCl (control).
- Example 12.2 Ocular irritation test using the isolated chicken eye method Since the solution will be delivered to the mouth and nose, a study to investigate possible irritant properties to the eye was performed.
- a GLP study, Test for Ocular Irritation Isolated Chicken Eye Method with Inhalation Solution (SIS) was performed according to the method described in guideline OECD 438.
- Four concentrations of IS were provided by the Sponsor with respectively 500, 200, 100 or 50 ppm hypochlorous acid (HOCl).
- the study was performed over 2 days and each day was referred to as an Experiment (i.e., Experiment 1 and Experiment 2).
- three eyes were treated with 30 ⁇ L of test item (500 ppm or 200 ppm in Experiment 1 and 100 ppm or 50 ppm in Experiment 2).
- the outcome of this study is that the test substance is allocated to one of three categories; either non-irritant or severe irritant or that there is a requirement for further information.
- the 500 ppm, 200 ppm and 100 ppm test item concentrations were classified as needing further information.
- An in vivo study is indicated at these concentrations.
- the 50ppm test item concentration was classified as non-irritant.
- Example 13 Antibacterial tests with inhalation solution (IS) An inhalation solution of the invention was tested in an antibacterial assay against planktonically-grown gram-positive (Staphylococcus aureus) and gram-negative (Pseudomonas aeruginosa) bacteria, and it showed efficient killing of both bacteria at concentrations of 10-25 ppm HOCl. The tests were performed at Costerton Biofilm Center, University of Copenhagen. The results of such tests are provided in Table 4 below.
- Example 14 Antiviral activity according to the standard EN 14476 of IS (starting with 25 ppm HOCl), against vaccinia virus EN 14476 for general virucidal activity is conducted on chemical disinfectants and antiseptics. This is a quantitative suspension test for the evaluation of virucidal activity in the medical area and is performed by an accredited laboratory. Results for IS: The test product of IS, 50 ppm as 50% dilution, 25 ppm HOCl, was able to inactivate the vaccina virus after 1 minute of exposure time under clean conditions (see Table 5).. Therefore, the activity was not measured after 30 or 60 minutes. The reduction factor was ⁇ 4.25 ⁇ 0.33 (1 minute).
- Example 15 Antimicrobial effectiveness testing Challenge testing may be performed according to USP42-NF372S chapter ⁇ 51> efficacy or Ph. Eur.5.1.3 antimicrobial preservation. solution batches (pH 4.3, representative HOCl batches to IS were challenged with various microorganisms and below, testing according to USP42-NF37 2S chapter ⁇ 51> is presented in Table 6 below: Results and Summary: The acceptance criteria for antimicrobial efficacy test as described in USP 42-NF372S chapter ⁇ 51> were met for all test microorganisms both at day 14 and day 28. In addition, the lowest concentration of IS may be tested according to USP42-NF372S chapter ⁇ 51> for antimicrobial effectiveness.
- Example 16 Minimum inhibitory concentration (MIC) tests Determination of minimal inhibitory concentration (MIC) against five pathogenic bacterial strains was carried out by broth microdilution (dilutions of the highest concentration of the test substance, HOCl solution, pH 4.3, 100 ppm HOCl + 1% acetic acid and dilutions), representative to IS. Following incubation for 24 hours after the treatment in the microtiter tray, the optical density was measured to evaluate growth. Furthermore, the suspensions were plated on agar and controlled for growth the following day. All tests were performed at Biofilm Test Facility, University of Copenhagen, Faculty of Health and Medical Sciences, Department of Immunology and Microbiology.
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Abstract
La présente invention concerne des compositions antimicrobiennes et désinfectantes stables faisant intervenir un précurseur solide d'un état oxydé de chlore. L'invention concerne également des récipients de stockage et de mélange à la demande et des procédés de préparation et d'administration de formulations à la demande. De plus, l'invention concerne des utilisations antimicrobiennes, antibiotiques et antimicrobiennes générales, in vivo, sur des surfaces et par l'intermédiaire d'applications de pulvérisation.<i />
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