LU101842B1 - Pharmaceutical Composition for treating or preventing lesions and infections in a mammal - Google Patents
Pharmaceutical Composition for treating or preventing lesions and infections in a mammal Download PDFInfo
- Publication number
- LU101842B1 LU101842B1 LU101842A LU101842A LU101842B1 LU 101842 B1 LU101842 B1 LU 101842B1 LU 101842 A LU101842 A LU 101842A LU 101842 A LU101842 A LU 101842A LU 101842 B1 LU101842 B1 LU 101842B1
- Authority
- LU
- Luxembourg
- Prior art keywords
- pharmaceutical composition
- aqueous solution
- hypochlorous acid
- concentration
- taurine
- Prior art date
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- 239000002904 solvent Substances 0.000 description 1
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- 231100000057 systemic toxicity Toxicity 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000003568 thioethers Chemical group 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
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- 238000004448 titration Methods 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
-
- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- 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
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
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Abstract
The present invention relates to a pharmaceutical composition comprising: (i) an hypochlorous acid (HOCl) aqueous solution stabilized at a pH from 3,5 to 5, (ii) a taurine haloamine aqueous solution, and (iii) a concentration of an sodium salt inferior to or equal to 125 mM. The present invention also relates to the first medical use and the second medical use of this pharmaceutical composition.
Description
Title: Pharmaceutical composition for treating or preventing lesions and infections in a mammal.
The present invention concerns a new composition based on chlorinated or brominated compounds for the treatment of mucous immune dysregulation, which promotes not only the development of viral infections (i.e., COVID-19, etc.), bacterial infections (i.e., periodontitis, etc.) or fungal infections, but also mucosal inflammation.
The invention composition is especially useful (a) as topical immuno-regulatory and/or (b) on the activation of tissue healing.
Through its positive action on immune system and the restoration of defense homeostasis, his locally immuno-regulatory treatment constitutes an effective indirect therapy on (i) viral, bacterial and/or fungal infections, and/or (ii) chronic, progressive or acute inflammatory processes, and/or (iii) on the activation of the inflammation turn-over (arrest of the inflammatory phase and activation of tissue repair). Prior art: FR 0100862 relates to a halogen composition (at pH 10 to 10,5), its manufacture process and its uses.
FR 1301868 relates to a pharmaceutical composition for treating an inflammation (periodontal disease). EP 2999341 relates to a stabilized hypochlorous acid antimicrobial solution and use thereof (at pH 3,5 to 5,5). Problem solution approach: -The closest prior art is FR 1301868 because it concerns a pharmaceutical composition for treating an inflammation (periodontal disease) and has the most technical features in common with the present invention. -The technical difference between the present invention and FR 1301868 is that a pH of 3,5 to 5 is used in the present invention.
-The technical effect of the above mentioned difference is in that it results from the composition of hypochlorite aqueous solution which is dependent of its pH:
1. When the pH increases from 9.5, the concentration of the solution reaches its maximum level, becoming 100% sodium hypochlorite (EP 0471129 A1 specifies the pH of stabilized NaOCI which must be between 10 and 10.5) and which corresponds to the composition claimed in FR 0100862 and FR
1301868.
2. At pH values above 5.5, the hypochlorite ion (OCI7) forms, and around pH
7.5 (the pKa of HOCI of chlorine species in solution is 50/50% of the mixture).
3. With a pH range from 5 to 6, the predominant species is HOCI.
4. When the pH value is between 3,5 to 5, the solution becomes 100% hypochlorous acid and it is stabilized and which corresponds to the composition claimed in the present invention.
5. At a pH below 3.5, the solution exists in the form of a mixture of chlorine (Clz) in the aqueous phase, chlorine gas in the headspace, trichloride (Cls-)
6. At pH below 3, a significant amount of Cl gas is formed, which can lead to the rapid loss of all active chlorine in an open container.
-The objective technical problem to be solved by the difference is to use a stabilized hypochlorous acid solution and in order to maintain its desired stable activity, the pH of the hypochlorous acid solution must remain between 3.5 and 5 and the solution must be stored in an airtight container and protected from light (Wang et al., 2007).
-A man skilled in the art would not be led to use a pH of 3,5 to 5 in the teaching of FR 1301868 because a man skilled in the art would only work with a pH of 10 to 10,5 as it isteached in FR 0100862 at page 6 lines 4 to 7 (both prior art documents being publications of the same applicant).
A man skilled in the art would not be led to combine FR 1301868 with EP 2999341 because EP 2999341 teaches in its claim 1 to work with an acidic pH of 3,5 to 5,5 and its paragraph 19 taught that a low pH antimicrobial solution (pH of 3,5 to 5,5) is useful as both a low-level disinfectant capable of a four log (104) reduction in the concentration of live microorganisms and a high-level disinfectant capable of a six log (108) reduction in concentration of live microorganisms. The pharmaceutical composition of the present invention is not a disinfectant but aims (a) to treat immune dysregulation and/or (b) to activate tissue healing in mammals (e.g. human beings). Summary of the invention: The present invention relates to a pharmaceutical composition comprising: (i) an hypochlorous acid (HOCI) aqueous solution stabilized at a pH from 3,5 to 5, (ii) a taurine haloamine aqueous solution, and (iii) a concentration of a sodium salt inferior to or equal to 125 mM. The present invention relates also to a pharmaceutical composition comprising: (i) an hypochlorous acid (HOCI) aqueous solution stabilized at a pH from 3,5 to 5, (ii) a taurine haloamine aqueous solution, and (iii) a concentration of an sodium salt inferior to or equal to 125 mM wherein low concentration of hypochlorous acid is used in order to generate a regulation of immune system, and wherein the antiseptic and anti-inflammatory properties are conserved through the restoration of the immune system and/or the tissue healing homeostasis.
The present invention relates also to a pharmaceutical composition comprising: (i) an hypochlorous acid (HOCI) aqueous solution stabilized at a pH from 3,5 to 5, (ii) a taurine haloamine aqueous solution, and (iii) a concentration of an alkaline metal salt inferior to or equal to 125 mM wherein the concentration of hypochlorous acid has an advantage to be further decreased in order to promote the activation of tissue healing and without generating any impact on its immune-regulatory properties, and wherein the antiseptic and anti-inflammatory properties are conserved through the restoration of the immune system and/or the tissue healing homeostasis.
The present invention relates also to a pharmaceutical composition comprising: (i) an hypochlorous acid (HOCI) aqueous solution stabilized at a pH from 3,5 to 5, (ii) a taurine haloamine aqueous solution, and
(iii) a concentration of a sodium salt inferior to or equal to 125 mM for use as a medicament. The present invention relates also to a pharmaceutical composition comprising: (i) an hypochlorous acid (HOCI) aqueous solution stabilized at a pH from 3,5 to 5, (ii) a taurine haloamine aqueous solution, and (iii) a concentration of an sodium salt inferior to or equal to 125 mM for use in the prevention and/or the treatment of immune dysregulation. The present invention relates also to a pharmaceutical composition comprising: (i) an hypochlorous acid (HOCI) aqueous solution stabilized at a pH from 3,5 to 5, (ii) a taurine haloamine aqueous solution, and (iii) a concentration of sodium salt inferior to or equal to 125 mM for use in the stimulation/activation of tissue healing.
The present invention relates also to a pharmaceutical composition comprising: (i) an hypochlorous acid (HOCI) aqueous solution stabilized at a pH from 3,5 to 5, (ii) a taurine haloamine aqueous solution, and (iii) a concentration of sodium salt inferior to or equal to 125 mM for use in the treatment of viral, bacterial and/or fungal infections. The present invention relates also to a pharmaceutical composition comprising: (i) an hypochlorous acid (HOCI) aqueous solution stabilized at a pH from 3,5 to 5, (ii) a taurine haloamine aqueous solution, and (iii) a concentration of an alkaline metal salt inferior to or equal to 125 mM for use in the local treatment of inflammations. The present invention relates also to a pharmaceutical composition comprising: (i) an hypochlorous acid (HOCI) aqueous solution stabilized at a pH from 3,5 to 5, (ii) a taurine haloamine aqueous solution, and (iii) a concentration of sodium salt inferior to or equal to 125 mM, for use in locally treating or preventing lesions and infections in a mammal linked to COVID-19 via a local administration.
The present invention relates also to a pharmaceutical composition comprising: (i) an hypochlorous acid (HOCI) aqueous solution stabilized at a pH from 3,5 to 5, (ii) a taurine haloamine aqueous solution, and (iii) a concentration of a sodium salt inferior to or equal to 125 mM, 5 for use in locally treating or preventing lesions and infections in a mammal linked to periodontal diseases.
The present invention relates also to a pharmaceutical composition comprising: (i) an hypochlorous acid (HOCI) aqueous solution stabilized at a pH from 3,5 to 5, (ii) a taurine haloamine aqueous solution, and (iii) a concentration of an alkaline metal salt inferior to or equal to 125 mM for use in locally treating of burn lesions.
Preferably, the halogen of the haloamine is a bromine or a chlorine.
Preferably, the hypochlorous acid aqueous solution has a concentration of 0,1 to 15 mM.
Preferably, the taurine-haloamine is a taurine N-chloramine (N-TauCl) having a concentration of 10 to 55 mM.
Preferably, the local administration for the COVID-19 treatment is achieved via a nebulizer.
Preferably, the pharmaceutical composition contains a pharmaceutically acceptable carrier.
The pharmaceutical composition of the present invention presents immuno-regulatory properties.
The pharmaceutical composition of the present invention presents bio-modulatory properties (induction of inflammation turn-over and stimulation/activation of tissue healing).
The pharmaceutical composition of the present invention presents immune regulation and/or the bio-modulation generating anti-septic properties with large spectrum and with unknown resistance and an anti-inflammatory action.
The pharmaceutical composition of the present invention comprises (i) at least an aqueous solution of stabilized hypochlorous acid and (ii) at least an aqueous solution of taurine N-haloamine for the preparation of a drug intended for the prevention and/or the treatment of dysregulation of innate immunity.
The pharmaceutical composition of the present invention comprises (i) at least an aqueous solution of stabilized hypochlorous acid and (ii) at least an aqueous solution of taurine N-haloamine for the preparation of a drug intended for the activation of tissue healing.
The pharmaceutical composition of the present invention is a drug useful to the local treatment of viral, bacterial or fungal infections.
The pharmaceutical composition of the present invention is a drug useful to the local treatment mucous membrane inflammation, whether chronic, progressive or acute inflammations.
The pharmaceutical composition of the present invention is a drug useful to the local treatment lesions and infections linked to COVID-19 disease.
The pharmaceutical composition of the present invention is a drug useful to the local treatment lesions and infections linked to periodontal diseases.
The pharmaceutical composition of the present invention is a drug useful to the local treatment of first and/or second degree burns called “sunburns”. The pharmaceutical composition of the present invention can be prepared by a process comprising mixing together on the pathologic site in an extemporaneous manner, an aqueous solution of stabilized hypochlorous acid with an aqueous solution of taurine N- chloramine.
The present invention can contain more than one independent claim in the same category (product) because the invention relates to different uses of a product and because it also relates to alternative solutions to a particular problem.
Detailed description of the invention: The pharmaceutical composition of the present invention is based on the combination of three active substances: 1) A hypochlorous acid (Active agent n°1), which is stabilized at a pH between 3.5 and 5 in aqueous solution (in opposition to sodium hypochlorite which is stabilized at a pH of 10-10.5). 2) A N-chloramine and/or a N-bromamine (Active agent n°2) of an amino acid from the taurine family. 3) Purified water. As previously described in FR 1301868, the purified water may be qualified as active agent as it allows the reduction of the molar concentrations of sodium salt in the aqueous solutions (1) and (2) at rates significantly lesser than the isotonic concentration (i.e., 0.9% NaCl, or 154 mM). It results in the induction of an osmotic suction pump effect from the external mucosa medium to the internal tissue medium. We called it ‘osmotic suction”. This suction generates a liquid flux in direction of the Extracellular Matrix (ECM) of the treated tissues which carry with it the active agents. Therefore, there is an active assimilation of the two other active agents within the ECM. In order to achieve this process, the molar concentration of sodium salt (Na*) of the final extemporaneous mixture solution may be lower or equal to 125 mM-(Na®).
The inventor paid particular attention to the characteristics of stabilized hypochlorous acid (i.e., with a 3,5-5 pH). Effectively, the use of stabilized hypochlorous acid (HOCI) in place of sodium hypochlorite (NaOCI) constitutes a significant innovative advance in the technology previously described in FR 0100862.
As previously described in FR 0100862, the hypochlorous acid is extremely reactive, especially with thiols and thioethers groups of peptides, proteins (including protein part(s) of glyco-proteins and fatty acids). It also reacts quickly with primary and secondary amines, the amides, the nucleic acids, the fatty acids, etc, hence its legendary toxicity.
In the case of sodium hypochlorite (NaOCI), NaOCl need a pH superior to 5,5 to be present within the aqueous solution, and NaOCI is stabilized with a pH between 10 and 10,5. This basic pH induces a strong association of the sodium salt to the hypochlorous acid component of sodium hypochlorite resulting in the neutralization of the hypochlorous acid molecule. The above-said sodium—mediated neutralization of hypochlorous acid results in a high reduction of sodium hypochlorite reactivity and, therefore, its toxicity. This better safety of sodium hypochlorite with an assumed similar efficiency promotes the development of sodium hypochlorite solution, which took place at the expense of hypochlorous acid. This also allowed the development of a more concentrated drug by Dakin during the First World War (i.e., 0,5% or 70 mM), at a time when controlling very low rates was particularly complicated, and this without significant side effect. Despite its lower toxicity, sodium hypochlorite is known to induce mild chemical burns in case of repeated uses (je, more than twice a day local applications), and especially on cleaned wounds (Vidal dictionary).
The man skilled in the art is currently confronted with the continuing development of bacterial resistance to antibiotics, and while controversy regarding the use of topical antiseptics persists, the need for research and development of new classes of antimicrobial agents, which are safe and widely effective and have low toxicity and a low propensity to induce antimicrobial resistance, inevitably becomes critical. Currently, the use of broad spectrum topical antibiotics to treat non-healing wounds or those at risk of infection is not recommended by the United States Department of Health and Human Services. These recommendations are based on the following reasons: antibiotics can cause allergic reactions; especially when applied topically may have lower tissue distribution; greater effect on endogenous microflora (disruption of normal commensal microflora); induce resistance; and ultimately reduced therapeutic effectiveness.
The effectiveness of topical antimicrobial agents in the management of serious infections, such as biofilm and catheter-related wounds, especially when they are chronic and not healing, is inconclusive. These observations vary considerably due to (a) inconsistent in vitro test specifications, (b) the use of different models of animal species, (c) the use of different organisms to determine the efficacy results. Therefore, the overall results make direct comparisons less than ideal. Although in vitro tests are necessary to select potential agents for clinical trials, these models will never fully mimic the conditions in vivo (Wang et al, 2007).
Likewise, the use of antiseptics is not encouraged due to their higher toxicity, the potential development of resistance (like antibiotics) and, more importantly, a direct impact on the healing process of wounds.
Thus, the objective of the man skilled in the art is to use an antiseptic drug with a good safety, without known induction of resistance, and above all without impact on the healing process of wounds. The ideal drug shall promote tissue healing.
The man skilled in the art thought he had found the dream product in the sodium hypochlorite. It is a well-known drug with acceptable side-effects, which is used for about a century. It has no known resistance and has high clinical antimicrobial efficacy with slight and acceptable harming tissue repair.
For its part, hypochlorous acid is known to be cytotoxic above 10 mM (Wang et al., 2007), to be instable and to have a negative impact on wound healing above 1 mM in vitro (Sakarya ef al., 2014), or above about 5 mM if we take into consideration the organic matter present in vivo (Haws et al., 2018).
In addition, the hypochlorous acid reputation is so bad in Europe that the “Neutrophase” (solution of 0,03% stabilized HOCI) has not been marketed there by Novabay Pharmaceutical, although it is marketed in USA for several years.
The choice of the man skilled in the art is obvious: he will not take any risks (even if two or three publications prove the opposite) and will choose sodium hypochlorite with a 0.5% rate (Dakin COOPER stabilized) or with 0.06 % (Amukine).
The man skilled in the art remains a human with his faults. The major fault of humans is to have believes himself superior to nature.
It is to forget that the natural selection, which was carried out over some millennia, did not remain sodium hypochlorite, but low concentrated hypochlorous acid.
Here are the reasons.
Indeed, in the closest prior art is FR 1301868, the lowest claimed concentration of sodium hypochlorite is 7 mM. This rate is higher than the threshold concentration of active chlorine described by Sakarya (i.e., 1 mM) above in which the hypochlorite solution has a negative impact on tissue wound healing.
Thus, a slight harmful effect on tissue repair can be expected from sodium hypochlorite solutions.
On the other hand, stabilized hypochlorous acid (with a 3,5 — 5 pH) showed the following properties with low concentrations, i.e., 0,01% (1,93 mM), 0,03% (5,77 mM) et 0,1% (19,3 mM) (Wang et al., 2007 ; Robson et al., 2007 ; Sakarya et al., 2014): + Excellent antimicrobial activity. * No known resistance + No toxicity and excellent safety at all concentrations studied on the eyes of “New Zealand white rabbits” and on the skin of "Guinea pigs". Absorption and systemic toxicity are insignificant in rats and "mini-pigs" after daily applications for 28 days. * The lower the molar concentration goes on, the more the activation of tissue repair increases.
Fig.1 shows the effect of stabilized hypochlorous acid (HOCI) solution treatment on skin fibroblast cell migration in a wounding healing assay.
Skin fibroblast cells were cultures to confluence, and a single wound was made across each monolayer.
At 0, 4, 8 and 24 hours, images of each monolayer were captured and cell migration into the wound after 4, 8 and 24 hours was compared to the monolayer at 0 hour. * significantly decreased in stabilized HOCI solution treated skin fibroblast cells migration compared to the media control at P< 0.05. Fig.2 shows images of wounded skin fibroblast cell monolayer with 1/32 dilution of povidone iodine and hypochlorous acid solution at 24 hours.
Dotted lines indicate wound boundaries at 0 hour.
H: hours.
According to Sakarya ef al. 2014 : 1/16 Dilution = 0,00136% (0,25 mM) 1/32 Dilution = 0,000681% (0,125 mM) e Important immune-regulatory activities: neutralization of certain mediators in the extracellular matrix (ECM) 1) Direct oxidation: HOCI neutralizes IL-6 and the leukotrienes B4 & C4, 2) Mechanism of indirect oxidation (oxidation of a2-macroglobulins), by this mechanism, HOCI has the following properties (Mainnemare et al., 2004): a) Neutralization of TNF-a, IL-1B, IL-2, IL-6 (Wu et al., 1998), b) To be involved in the inflammation turn-over. c) Stimulation of tissue repair by release of growth factors B-NGF, PDGF- BB, TGF-B1 and TGF-B2.
3) Detoxification of the inflammatory site by chlorination of the antigens and an irreversible aggregation of the proteins, which leads to a strong reduction in the quantity of antigens presented (Chapman ef al., 2003; Fu ef al., 2002; Pullar et al., 2001; Raftery et al., 2001; Ogino et al., 1997). In addition, the presentation of the above-mentioned aggregates by B-cells is recognized by a tolerance mechanism (Davidson & Diamond, 2001). 4) Neutralization by oxidation of a cysteine residue in their active site of bacterial endo- and exotoxins, as well as other enzymes that degrade the extracellular matrix, antigens and/or viral agents (Mainnemare ef al., 2004; Curtis ef al., 2001). In order to conclude on stabilized hypochlorous acid, the Robson MC team compared stabilized hypochlorous acid and sodium hypochlorite effects (Wang ef al, 2007 & Robson et al., 2007). e Time necessary to kill bacteria: NaOCI is lesser efficient than stabilized HOCI on Gram positive bacteria and requires a rate 5 times higher to obtain a similarly effectiveness.
Table 3. Comparative time kill studies of HOCH NaOCT, and Ha (dy against 3 test organisms af room femperaiure Foro total of SO min Time kill (min) Pathogen ATCC HOCI OCT Hy, Escherichia coli 23922 {1 <5 22 DE Psciatomentss aeruginess 27355 «1 «20 «13 Staphviorocous aureus 235213 {1 <1 >88 ATUS indicates American Type Culture Collection.
WANG FT AL Table 4 Comparative MBC {pu AD af HOCL Nat and Ha Oy tested CEZEHRSE 3 CRESS FF Fn temperature for FH meine MRC (AT Pathogen ATC Hew Oct Hoty, ExcherioRis ond 25922 5.6 U T 500 Prewsdomaonar ETUI 27853 6.2 tH} 228,000 Staphylocncous wrens 25243 125 58 > 24,000 ATCC india ts American Type Culture Doffection: MBI, mands Hescbermeichert doncestontion, e Cell toxicity: The cellular toxicity of stabilized HOCI is approximately half that of NaOCl. Fig.3 shows relative cell toxicity of hypochlorous acid (HOCI; pH 4.0), hypochlorite (OCI; pH 10.5) and hydrogen peroxide (H:Oz; pH7.0) on L929 cells. Cytotoxicity measured in a cell proliferation assay is expressed as the concentration (microgram/mL) that reduces the cell number by 50% of vehicle-treated control. CTs is shown as the average of 7, 3 and 5 independent experiments (consisting of 10 different concentrations of each test article plus/minus the standard deviation), respectively.
e The relative therapeutic index: Although their therapeutic index is close, that of stabilized HOCI is generally better than that of NaOCI. Fig. 4 shows relative therapeutic index of hypochlorous acid (HOCI; pH 4.0), hypochlorite (OCI; pH 10.5) and hydrogen peroxide (HO; pH 7.0). Therapeutic index is expressed as a ratio of the CTsy concentration (microgram/mL) on L929 cells divided by the minimum bactericidal concentration (microgram/mL) for Staphylococcus aureus 29213, Pseudomonas aeruginosa 27853 and Escherichia coli 2592. The higher the therapeutic index, the safer the test article will be. e Their toxicity and safety on the animal. There was no comparative study. Dakin COOPER (NaOCl at 0.5%) and Amukine (NaOCl at 0.06%) have a Marketing Authorization and they can be cytotoxic (induction of slight chemical burns) with repetitive uses (several times a day) (VIDAL pharmaceutical dictionary). At the effective doses, Stabilized HOCI showed no cytotoxicity and perfect safety.
WANG ET AL Table 3. Saferr studies with control vs véabiiired HOC in 4 different animal species Spudties Species Site applied NYO. PT SV Results BEN Rabbit Bye OR for 72H Sabine No irritation Bs CHEN Betadine Progressive irmiation Eveiraitetion Pastas Evang Saline No irritation Satara SEO ET NEHER Oar a dose SESE Haptiee-derivet SE Saline No sensitization ASC EIRE qe MOT EI esl Nuria hon ARRET dese 2$-Duy toxicology Bat Fulldfiekgess Saline Nan TOR RAC A day wand DOE G03, snd BY SE
AST AN hextine 2e Day ioxfobiy Munem Fau-Bnchness Seline KO SYNC RERO sien Sous or a amd us dose and Ristopatholngs SS FE own Bestine e The effect on tissue repair. Robson et al. showed in 2007 that in contrast to the other antiseptics tested, the in vivo application (i.e., dermal wounds on the rat) of Stabilized HOCI (called NVC-101 by the authors) is an effective antiseptic without inhibiting the tissue repair process. Fig.5 shows wound healing trajectories from experiment 2, demonstrating the superiority of groups Il and Ill, which consisted of a brief application of NVC-101, followed by gentle wiping, and a second application of NVC-101 (HOCI) over other regimens. The two groups with the fastest healing were also the most effective at controlling the tissue bacterial bioburden. Sakarya ef al., demonstrated in 2014 that the beneficial effect of stabilized HOCI on wound healing takes place at very low concentration and in part by an increase in the migration of fibroblasts and human cutaneous keratinocytes. e Effect on biofilm: The antiseptic activity of stabilized HOCI is effective and very fast at very low doses (Sakarya ef al., 2014):
EC Sa Saenz ven | Swestieen à lap BaeginosalCill yes Can we) © albicans (CL 11) je 9 Ts
AR SIUC: Anal Tyne Ce OK ak ae NBR minimum bettondldal sonesitratin. Fig.6 shows a screen capture of a video microscopic image of the time kill of green fluorescent protein-transfected P. aeruginosa with 1/32 dilution of stabilized HOCI solution at 1, 6 and 12 seconds.
It is incredible to see that the publications went unnoticed and that they had no influence on the therapeutic behavior of the men skilled in the art. In fact, at least three factors are necessary for such a great discovery to have an influence on the therapeutic behavior of man skilled in the art:
1. To be published in a medical journal with a very high impact factor (greater than 20, such as Science, Nature, The Lancet, New England Journal of Medicine, Cell, etc.).
2. To be confirmed by dozens of other independent studies.
3. To benefit from great media publicity.
This is unfortunately not the case for the stabilized HOCI, especially since NaOCl is an aqueous solution that is partly composed of HOCI, which is very well known to men skilled in the art and explains their disinterest, and therefore the ignorance they have for stabilized HOCI.
The inventor hereby assumes that the immune system is capable of eliminating all pathogens, but that infectious diseases of the mucous membranes develop mainly because they benefit from a weakened immune system.
It is remarkable and very innovating in that this innovation targets more the restoration of the immune homeostasis and the activation of the tissue repair to induce secondarily and indirectly (by a regulated and rebalanced immune system) a destruction of the pathogenic agent and these harmful effects.
To obtain this result, the author proposes to reduce the dosages of active agents to non-toxic but very effective low concentrations, in order to generate both an innate immune regulation and the inflammation turn-over, and at the end a tissue repair activation. The inventor specifies that it must be taken into account of the high reactivity of the active agents selected with the organic matter and the virulent agents present within all inflammatory sites so that there remains sufficient active agents to obtain the desired effects (Haws et al., 2018).
The present innovation relates more particularly to degenerative diseases having an auto-inflammatory pathogenesis, which is characterized by a destruction of the affected tissues induced by a more or less significant, violent and rapid dysregulation of the innate immunity. The initiator of this immune dysregulation may be very varied. For non-exhaustive examples, it can be cited:
1. COVID-19: SARS-CoV-2 coronaviruses bind to the ACE2 receptors of epithelial and endothelial cells, which induce in response a massive, altered and uncontrolled activation of cell production of cytokines (i.e., IL-1B, IL-2, IL -7, IL-6, IL-17, IFN-y, G- CSF, IL-10, MCP-1, MIP-1a, TNF-a), named the “cytokine storm”. It is this hurricane of cytokines which is responsible for the tissue destruction/alterations affecting the respiratory organs, the cardiovascular system, the hepatic system, the kidneys, the small intestine etc. The consequences can be dramatic, with hospitalization in an intensive care unit for 2% of affected patients and by death for
0.5% of them. On February 11, 2020 the World Health Organization stated the meaning of COVID 19 as being (CO= Corona; VI= Virus; D=Disease; 19= year of appearance of the virus) and replaced the previously used denomination of SARS- CoV-2 by COVID 19.
2. Periodontitis: the attacking agents are anaerobic bacteria and the virulence factors that they release. An altered and excessive immune response is involved not only in the irreversible destruction of periodontal tissue (tissue supporting the teeth), but also in a greatly increasing of the patient's risk to develop systemic inflammation. The latter is a powerful risk factor in the development of systemic diseases linked to immunity alteration, such as cardiovascular diseases, diabetes, autoimmune diseases, obesity, complications of pregnancy, etc.
3. Some first and second degree burns, better known as "sunburn." The inducing agents are UV radiations, which induce an innate immune disorder responsible of skin alterations.
The common feature of these diseases is the dominant of an auto-inflammatory process. It is a set of reaction phenomena triggered, in a living organism, by an aggression and which implement altered immunological defense processes on genetically predisposed organ to immune dysregulation.
The "normal" process includes local phenomena (which the study of a tissue fragment accounts for) and general phenomena (expressed clinically by fever and possibly deterioration in general condition and biologically by inflammatory syndrome). Now, this process is an omni-tissue phenomenon which normally tends to limit, eliminate and repair the effects of aggression. It ends with the repair of the lesion and can only take place in vascular tissue.
At the origin of this process, we find the cell production and release of a massive and altered immune mediators which can be pro- or anti-inflammatory, leading to auto- inflammation. These mediators can modify or maintain the inflammatory response.
There are exogenous and endogenous pathogens whose mode of action is not unequivocal. However, infectious causes are only a small part of the causes of inflammation. Among the exogenous elements responsible for inflammation, we can list the physical causes (trauma, heat, cold, ionizing radiation, etc.), chemical causes (foreign bodies, caustics, toxic, etc.), biochemical causes (allergens or all antigenic substances, especially food) or infectious agents, which can act locally or remotely via the release of toxins (microbes, viruses, parasites, fungi, etc.). Now, we can add to these also endogenous elements with trophic causes (vascularization or innervation disorders), degenerative lesions, metabolic disturbances (urea, ...), immune causes (auto-immunity, immune deficiency, or dysimmunity), or any lesions that do not have inflammation as a base such as tumors or atheroma This inflammatory process can be defined as a sequence of events, the main stages of which are as follows:
1. Stage of destruction and elimination of the aggression causing inflammation.
2. The turn-over of the process with the restoration of tissue homeostasis, the cessation of the elimination phase and the initiation of the healing/repair phase.
3. Tissue healing/repair phase.
The initial events are very difficult to capture. Schematically, the contact between the pathogen and the organism receptor(s) can trigger the following phenomena, which are not mutually exclusive: (i) process of complete or non-elimination of the pathogen by non-specific defense cells, NK cells, macrophages, mast cells, Paneth cells, etc., which produce proteins that are directly toxic for the pathogen (e.g., defensing in Paneth cells, toxic granular proteins in mast cells and NK, vasoactive substances (histamine, serotonin),...); (ii) capture of the pathogen and presentation of its antigens by a cell located on the border between the exterior and the organism. This border is located at the level of the epithelia (digestive, bronchial). The cells involved can be epithelial cells, Langerhans cells, intra-epithelial lymphocytes. During this interaction mediators (pro- inflammatory cytokines, inducible chemokines) are produced which will on the one hand activate endothelial and mononuclear cells, on the other hand attract inflammatory cells to the conflict site.
Cell lesions are generated. They can be reversible, linked to metabolic disturbances, or irreversible with nuclear and/or cytoplasmic alterations.
Now, and for an efficient treatment, it is also necessary, and depending on the active agent(s), that the concentrations of said active agents are as follows: * For stabilized HOCI, the concentration must be greater than or equal to 0,1 mM, preferably greater than or equal to 1 mM, and particularly preferably between 1 mM and 10 mM, 2 and 9 mM, 3 and 8 mM, 4 and 7 mM, 5 and 6 mM. » For Taurine N-chloramine, the concentration must be greater than or equal to 5 mM, preferably greater than 10 mM and preferably between 25 mM and 55 mM, 30 mM and 50 mM, 35 mM and 45 mM, 30 mM and 40 mM, 35 mM and 40 mM. + “Salt” means a calcium or sodium salt, preferably sodium.
The composition according to the invention will have a sodium composition lesser than or equal to 125 mM, preferably lesser than or equal to 100 mM, and particularly preferably lesser than or equal to 75 mM, lesser than or equal to 65 mM, lesser than or equal to 60 mM, lesser than or equal to 55 mM, lesser than or equal to 50 mM, lesser than or equal to 45 mM, lesser than or equal to 40 mM, lesser than or equal to 35 mM, lesser than or equal to 30 mM, lesser than or equal to 25 mM, lesser than or equal to 20 mM, lesser than or equal to 15 mM, lesser than or equal to 10 mM.
Simultaneously, this composition will comprise a sodium composition greater than or equal to 1 mM, preferably greater than or equal to 5 mM, and in a particularly preferred manner greater than or equal to 10 mM.
Now, said one or more salts come from the active agents: a stabilized aqueous solution of (i) stabilized hypochlorous acid and (ii) sodium salt of taurine N-chloramine (NCT). The composition according to the invention may also comprise a pharmaceutically acceptable carrier.
The term "pharmaceutically acceptable" refers to molecular entities or compositions that are physiologically tolerable and do not typically produce an allergic reaction or similar non-tolerable reaction, such as intestinal disturbance or dizziness, when administered to the subject.
Preferably, the term "pharmaceutically acceptable" used herein means approved by a regulatory agency of a federal or state government or listed in the American pharmacopoeia or any other pharmacopoeia generally recognized for use in animals, and more especially in humans.
The term "support" refers to a diluent, adjuvant, excipient or vehicle with which the compound according to the invention is administered.
Such pharmaceutical carriers can be sterile liquids, such as water or oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut, soy, mineral or sesame oils or olive oils.
Water or any aqueous solution, saline solution or even aqueous dextrose or glycerol solution are preferably used as carriers, and more particularly for injectable solutions.
For example, the composition may include emulsions, micro emulsions, oil-in-water emulsions, anhydrous lipids and water-in-oil emulsions, or other types of emulsions.
Pharmaceutically acceptable carriers are described in the book "REMINGTON's Pharmaceutical Sciences" by E.W.
Martin.
The composition according to the present invention may also comprise one or more additives such as diluents, excipients, stabilizers and preservatives.
Such additives are well known to those skilled in the art and are described in particular in "Ullmann's Encyclopedia of Industrial Chemistry, 6th Ed." (Various publishers, 1989-1998, Marcel Dekker); and in “Pharmaceutical Dosage Forms and Drug Delivery System” s (ANSEL et al., 1994, WILLIAMS & WILKINS). Finally, the composition according to can be administered in one or more times.
Process of manufacture: The process of manufacture of the pharmaceutical composition of the present invention is as follows: Hypochlorous acid solutions can be developed by acidifying NaOCI with HCI or electrolyzing NaOCI solutions 1) Hypochlorous acid was prepared in 154 mM NaCl by acidifying reagent-grade NaOCl to the pH range of 3.5 to 4.0 with dilute HCI.
A Beckman pH meter was used to accurately measure the final pH values.
The concentration of active total chlorine species in solution expressed as [HOCI]T (where [HOCI]T = [HOCI] + [Cla] + [Cls-] + [OCI-]) in 0.9% saline was determined by converting all the active chlorine species to OCI- with 0.1 M NaOH and measuring the concentration of OCI-. The concentration of OCI- was determined spectrophotometrically at 292 nm (€ = 362 M- 1 cm- 1)15 with an Agilent 8453 UV-visible spectrophotometer (Wang et al., 2007).
2) Electrolysis of sodium chloride solution. Electrolysis yields super-oxidized water with pH of 5.0 - 6.5 and an oxidation-reduction potential of > 950 mV and containing about 30 - 50 ppm of HOCI (Eryilmaz et al., 2013). Taurine N-chloramine sodium salt is prepared GMP conditions by a stoichiometric reaction of taurine amino acid with chloramine T in presence of ethanol, which is used as solvent. The purity is achieved through the use of capillary electrophoresis or UPLC, and the titration through a capillary electrophoresis use. The reaction from 1 equivalent-taurine result in the production of 1,5 equivalent taurine N-chloramine.
TESTS RESULTS: Several in vitro tests are currently undertaken but the results are not yet available. Our major concern was to first file a patent application for protecting the present invention. Of course, we will provide the results of such tests in the future to prove the credibility of the present invention.
1. Mainnemare A (2001). Composition halogénée, son procédé de préparation et ses utilisation - Brevet FR 0100862, N° de publication FR 2 819 723 B1 ; 23.01.2001.
2. Mainnemare A (2013). Nouvelle composition pour le traitement de l’inflammation - Brevet FR 1301868, N° de publication FR 3 009 196 A1 ; 02.08.2013.
3. Northey R (2014). Stabilized hypochlorous acid solution and use thereof - Brevet EP 2 999 341 B1; 22.05.2014. 4, Deroux J, Le Rat M, Compagnon JP (1990). Solution d'hypochlorite de sodium stable - Brevet EP 0471129 B1 ; 09.08.1990.
5. Wang L, Bassiri M, Najafi R, Najafi K, Yang J, Khosrovi B, Hwong W, Barati E, Belisle B, Celeri C, Robson MC (2007). Hypochlorous acid as a potential wound care agent: part |. Stabilized hypochlorous acid: a component of the inorganic armamentarium of innate immunity. J Burns Wounds. 2007 Apr 11;6:e5
6. Sakarya S, Gunay N, Karakulak M, Ozturk B, Ertugrul B. (2014). Hypochlorous Acid: an ideal wound care agent with powerful microbicidal, antibiofilm, and wound healing potency. Wounds. 2014 Dec;26(12):342-50.
7. Haws MJ, Gingrass MK, Porter RS, Brindle CT. (2018) Surgical Breast Pocket Irrigation With Hypochlorous Acid (HOCI): An In Vivo Evaluation of Pocket Protein Content and Potential HOCI Antimicrobial Capacity. Aesthet Surg J. 2018 Oct 15;38(11):1178-1184
8. Robson MC, Payne WG, Ko F, Mentis M, Donati G, Shafii SM, Culverhouse S, Wang L, Khosrovi B, Najafi R, Cooper DM, Bassiri M. (2007). Hypochlorous Acid as a Potential Wound Care Agent: Part Il. Stabilized Hypochlorous Acid: Its Role in Decreasing Tissue Bacterial Bioburden and Overcoming the Inhibition of Infection on Wound Healing. J Burns Wounds. 2007 Apr 11,6:e6
9. Mainnemare, A., Mégarbane, B., Soueidan, A., Daniel, A., & Chapple, |. L. C. (2004). Hypochlorous Acid and Taurine-N-Monochloramine in Periodontal Diseases. Journal of Dental Research, 83(11), 823-831. Wu et al., 1998
10. CHAPMAN, A. L. P., WINTERBOURN, C. C., BRENNAN, S. O., JORDAN, T.
W., &KETTLE, A. J. (2003). Characterization of non-covalent oligomers of proteins treated with hypochlorous acid. Biochemical Journal, 375(1), 33-40. doi:10.1042/bj20030685 Fu et al., 2002;
11. Pullar JM, Visser MCM, Winterbourn CC (2001). Glutathioneoxidation by hypochlorous acid in endothelial cells producesglutathione sulfonamide as a major product but not glutathionedisulfide. J Biol Chem 276:22120-22125.
12. Raftery, M. J., Yang, Z., Valenzuela, S. M., & Geczy, C. L. (2001). Novel Intra- and Inter-molecular Sulfinamide Bonds in S100A8 Produced by Hypochlorite Oxidation. Journal of Biological Chemistry, 276(36), 33393-33401. doi:10.1074/jbc.m101566200
13. Ogino T, Packer L, Maguire JJ. (1997). Neutrophil Antioxidant Capacity During the Respiratory Burst: Loss of Glutathione Induced by Chloramines. Free Radic Biol Med, 1997;23(3):445-52. doi: 10.1016/s0891-5849(97)00115-9.
14. Davidson, A., & Diamond, B. (2001). Autoimmune Diseases. New England Journal of Medicine, 345(5), 340-350. doi:10.1056/nejm200108023450506
15. Curtis MA, Aduse-Opoku J, Rangarajan M (2001). Cysteine proteases of Porphyromonas gingivalis. Crit Rev Oral Biol Med 12:192-216.
16. Eryilmaz, M., & Palabiyik, |. (2013). Hypochlorous Acid - Analytical Methods and Antimicrobial Activity. Tropical Journal of Pharmaceutical Research, 12(1).
doi:10.4314/tjpr.v12i1.20
Claims (15)
1. A pharmaceutical composition comprising : (i) an hypochlorous acid (HOCI) aqueous solution stabilized at a pH from 3,5 to 5, (ii) a taurine haloamine aqueous solution, and (iii) a concentration of a sodium salt inferior to or equal to 125 mM.
2. A pharmaceutical composition comprising : (i) an hypochlorous acid (HOCI) aqueous solution stabilized at a pH from 3,5 to 5, (ii) a taurine haloamine aqueous solution, and (iii) a concentration of an sodium salt inferior to or equal to 125 mM, wherein low concentration of hypochlorous acid is used in order to generate an optimal regulation of immune system, and wherein the antiseptic and anti- inflammatory properties are conserved through the restoration of the immune system and/or the tissue healing homeostasis.
3. A pharmaceutical composition comprising : (i) an hypochlorous acid (HOCI) aqueous solution stabilized at a pH from 3,5 to 5, (ii) a taurine haloamine aqueous solution, and (iii) a concentration of a sodium salt inferior to or equal to 125 mM, wherein the concentration of hypochlorous acid is decreased in order to promote the activation of tissue and without generating any impact on its immune- regulatory properties, and wherein the antiseptic and anti-inflammatory properties are conserved through the restoration of the immune system and/or the tissue healing homeostasis.
4. A pharmaceutical composition comprising : (i) an hypochlorous acid (HOCI) aqueous solution stabilized at a pH from 3,5 to 5, (ii) a taurine haloamine aqueous solution, and (iii) a concentration of a sodium salt inferior to or equal to 125 mM for use as a medicament.
5. A pharmaceutical composition comprising : (i) an hypochlorous acid (HOCI) aqueous solution stabilized at a pH from 3,5 to 5, (ii) a taurine haloamine aqueous solution, and (iii) a concentration of an sodium salt inferior to or equal to 125 mM for use in the prevention and/or the treatment of immune dysregulation.
6. A pharmaceutical composition comprising : (i) an hypochlorous acid (HOCI) aqueous solution stabilized at a pH from 3,5 to 5, (ii) a taurine haloamine aqueous solution, and (iii) a concentration of sodium salt inferior to or equal to 125 mM for use in the stimulation/activation of tissue healing.
7. A pharmaceutical composition comprising : (i) an hypochlorous acid (HOCI) aqueous solution stabilized at a pH from 3,5 to 5, (ii) a taurine haloamine aqueous solution, and (iii) a concentration of sodium salt inferior to or equal to 125 mM for use in the treatment of viral, bacterial and/or fungal infections.
8. A pharmaceutical composition comprising : (i) an hypochlorous acid (HOCI) aqueous solution stabilized at a pH from 3,5 to 5, (ii) a taurine haloamine aqueous solution, and (iii) a concentration of an sodium salt inferior to or equal to 125 mM for use in the local treatment of inflammations.
9. A pharmaceutical composition comprising : (i) an hypochlorous acid (HOCI) aqueous solution stabilized at a pH from 3,5 to 5, (ii) a taurine haloamine aqueous solution, and (iii) a concentration of sodium salt inferior to or equal to 125 mM, for use in locally treating or preventing lesions and infections in a mammal linked to COVID-19 via a local administration.
10. A pharmaceutical composition comprising : (i) an hypochlorous acid (HOCI) aqueous solution stabilized at a pH from 3,5 to 5, (ii) a taurine haloamine aqueous solution, and (iii) a concentration of a sodium salt inferior to or equal to 125 mM,
for use in locally treating or preventing lesions and infections in a mammal linked to periodontal diseases.
11. A pharmaceutical composition comprising : (i) an hypochlorous acid (HOCI) aqueous solution stabilized at a pH from 3,5 to 5, (ii) a taurine haloamine aqueous solution, and (iii) a concentration of an sodium salt inferior to or equal to 125 mM for use in locally treating of burn lesions.
12. The pharmaceutical composition of claim 1 or claim 2 or claim 3, the pharmaceutical composition for use as a medicament according to claim 4, the pharmaceutical composition for use according to claim 5 to claim 11, wherein the halogen of the haloamine is a bromine or a chlorine.
13. The pharmaceutical composition of claim 1 or claim 2 or claim 3, the pharmaceutical composition for use as a medicament according to claim 4, the pharmaceutical composition for use according to claim 5 to claim 11, wherein the hypochlorous acid aqueous solution has a concentration of 0,1 to 15 mM.
14. The pharmaceutical composition of claim 1 or claim 2 or claim 3, the pharmaceutical composition for use as a medicament according to claim 4, the pharmaceutical composition for use according to claim 5 to claim 11, wherein the taurine-haloamine is a taurine N-chloramine (N-TauCl) having a concentration of 10 to 55 mM.
15. The pharmaceutical composition of claim 1 or claim 2 or claim 3, the pharmaceutical composition for use as a medicament according to claim 4, the pharmaceutical composition for use according to claim 5 to claim 11, wherein it contains a pharmaceutically acceptable carrier.
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