阅读说明：本技术 电化学活化的盐溶液 (Electrochemically activated salt solutions ) 是由 M·巴罗尼安 F·卡利 E·基耶利尼 E·巴尔勒 于 2019-07-10 设计创作，主要内容包括：本申请涉及一种电化学活化的盐溶液(ECAS),其生产以及其用于治疗感染的用途。(The present application relates to an electrochemically activated salt solution (ECAS), its production and its use for the treatment of infections.)

1. An electrochemically activated salt solution (ECAS) comprising:

the total chlorine content is between 1mg/l and 500mg/l, preferably between 100mg/l and 450 mg/l;

the chloride content is between 2g/l and 8g/l, preferably between 3g/l and 7 g/l;

an oxidation-reduction potential of from +150mV to +1350mV, preferably from +600mV to +1100mV, more preferably from +700mV to +1050mV, more preferably from +700mV to +1000 mV;

osmolality of 20-800 mOsm/kg, preferably 200-400 mOsm/kg, more preferably 250-350 mOsm/kg;

the pH value is 6.0-7.8, preferably 7.1-7.4; and

optionally at least one boric acid (salt) and/or at least one phosphoric acid (salt).

2. Electrochemically activated salt solution (ECAS) according to claim 1, comprising at least one phosphoric acid (salt), preferably in an amount of 0.01-1000 g/l, more preferably 0.1-100 g/l.

3. Electrochemically activated salt solution (ECAS) according to any one of the preceding claims, comprising at least one boric acid (salt), preferably in an amount of 0.01 to 1000g/l, more preferably 0.1 to 500 g/l.

4. Electrochemically activated salt solution (ECAS) according to any one of the preceding claims, comprising hypochlorite ions and/or hypochlorous acid, in particular in a total concentration of from 1mg/l to 10000mg/l, more preferably in a total concentration of from 10mg/l to 1000 mg/l.

5. Electrochemically activated salt solution (ECAS) according to any one of the preceding claims, further comprising at least one organic or inorganic adhesion promoter, such as a polymer.

6. Electrochemically activated salt solution (ECAS) according to any of the preceding claims, which is free of additional therapeutically active agents, such as drugs.

7. Electrochemically activated salt solution (ECAS) according to any one of the preceding claims, which is free of additional preservative.

8. Pharmaceutical formulation comprising an electrochemically activated salt solution (ECAS) according to any one of claims 1-7, preferably further comprising at least one pharmaceutically acceptable excipient.

9. Electrochemically activated salt solution (ECAS) according to any one of claims 1-7 for use in the treatment of infections, preferably eye infections, such as infections caused by bacteria, fungi and/or viruses.

10. Electrochemically activated salt solution (ECAS) for use according to claim 9, wherein the bacteria and/or fungi are selected from the group of: staphylococcus aureus, methicillin-resistant Staphylococcus aureus, Escherichia coli, Staphylococcus epidermidis, Pseudomonas aeruginosa, Acinetobacter calcoaceticus, Enterobacter aerogenes, Streptococcus gordonii, Streptococcus pyogenes, Candida albicans, Aspergillus brasiliensis, Serratia marcescens, and Acinetobacter petrii.

11. Electrochemically activated salt solution (ECAS) for use according to claim 9, wherein the virus is selected from the group of: adenoviruses, enteroviruses and herpes viruses, such as herpes simplex virus 1 and 2.

12. Electrochemically activated salt solution (ECAS) for use according to any one of claims 9 to 11 for the treatment of conjunctivitis, in particular bacterial conjunctivitis, keratitis, blepharitis and/or endophthalmitis.

13. Electrochemically activated salt solution (ECAS) for use according to any one of claims 9-12, which is to be administered onto the eye, preferably directly after infection.

14. Method for producing an electrochemically activated salt solution (ECAS) according to any one of claims 1 to 7, comprising the following steps:

(i) electrolyzing an aqueous chloride solution in an electrolysis reactor, preferably comprising a cylindrical cathode coaxially mounted within a cylindrical anode;

(ii) optionally adding at least one boric acid (salt) and/or at least one phosphoric acid (salt); and

(iii) optionally diluting the ECAS by adding water for injection.

15. The method of claim 14, wherein the electrolysis is performed at a current of 10.0A-30.0A, preferably 15.0A-20.0A.

Technical Field

The present application relates to an electrochemically activated salt solution (ECAS), its production and its use for the treatment of infections.

Background

The electrochemically activated salt solution is usually obtained by electrolysis of a sodium chloride solution. Electrochemically activated salt solutions are known as cleaning or disinfecting agents in, for example, the agricultural, dental, medical and food industries. It can be used for surface disinfection of work boards, tables, floors etc., for cold disinfection procedures in agriculture, for elimination of microorganisms, for cleaning and laundry, for swimming pools, and even as a preventive measure against athlete's foot.

WO2004/031077 discloses an apparatus for producing a biocide solution by subjecting an aqueous salt solution to an electrolytic process. WO2005/065388 discloses an oxidative reductive potential water solution and its use as a wound treatment disinfectant.

JP1997/0040444 discloses an acidic ECAS as an ophthalmic formulation having a pH of 2.0-6.0.

US2010/0330204 discloses an acidic ECAS having a pH of 1.0-4.0 for the treatment of an external ocular disorder selected from cataract, ocular keratitis, corneal neovascularization, epithelial cell deficiency (epithelial deficiency) and chronic opacity (chronic opacity).

WO2009/013019 discloses a biphasic pharmaceutical formulation comprising an active ingredient and ECAS for medical application. ECAS has also been suggested as a vehicle for the manufacture of pharmaceutical formulations.

If timely treatment is not taken (mostly active treatment), eye infections can cause serious eye disease and severely threaten vision. In the past few years, cephalosporins and aminoglycosides have been used as the first treatment of infectious ocular diseases. However, the problems associated with topical antibiotics and the emergence of antibiotic-resistant bacteria have led to interest in finding therapeutic alternatives (Romanowski et al, 2005, Willcox, 2011).

Recently, the use of preservatives such as benzalkonium chloride (BAK) in ophthalmology has also been controversial due to allergic reactions. On the other hand, preservative-free medicaments are usually provided in a single-use form only. In addition, preservative-free formulations typically have an acidic pH of less than 5, while ophthalmically recommended pH values are neutral to slightly alkaline to avoid eye irritation and enable higher patient compliance.

In view of the above, there is an urgent need for new formulations for treating ocular infections that overcome the disadvantages of known drugs.

It is therefore an object of the present application to provide an effective medicament which is stable over a long period of time and which improves patient compliance by minimizing any harmful side effects upon application.

In a first aspect, the present application relates to an electrochemically activated salt solution (ECAS) comprising:

-a total chlorine content comprised between 1mg/l and 500mg/l, preferably between 100mg/l and 450 mg/l;

-a chloride content of between 2 and 8g/l, preferably between 3 and 7 g/l;

-an oxidation-reduction potential of from +150mV to +1350mV, preferably from +600mV to +1100mV, more preferably from +700mV to +1050mV, more preferably from +700mV to +1000 mV;

an osmolality of 20-800 mOsm/kg, preferably 200-400 mOsm/kg, more preferably 250-350 mOsm/kg; and

the pH value is 6.0-7.8, preferably 6.2-7.6, more preferably 7.1-7.4.

The ECAS of the present application may also comprise at least one boric acid (salt) and/or at least one phosphoric acid (salt). The ECAS of the present application preferably further comprises at least one salt of boric acid and/or at least one salt of phosphoric acid, more preferably at least one salt of phosphoric acid. In another embodiment, the ECAS of the present application further comprises at least one salt of boric acid. In another embodiment, the ECAS of the present application further comprises at least one salt of boric acid and at least one salt of phosphoric acid.

The salt of boric acid is typically a borate salt (BO)₃ ^3-). The salt of phosphoric acid may comprise a phosphate salt (PO)₄ ^3-) Hydrogen Phosphate (HPO)₄ ^2-) And/or dihydrogen phosphate (H)₂PO₄ ^-). Suitable counter ions (counter ions) for the above salts are alkali ions, such as sodium (Na)⁺) And potassium (K)⁺) Ammonium (NH)₄ ^*) Or Ca²⁺. In a preferred embodiment of the process according to the invention,the ECAS of the present application further comprises monobasic and dibasic sodium phosphate.

(salts of) phosphoric acid-if present-are preferably present in a total amount of 0.01g/l to 1000g/l, more preferably 0.1g/l to 100g/l. Boric acid (salts), if present, are preferably present in a total amount of 0.01g/l to 1000g/l, more preferably 0.1g/l to 500 g/l.

The electrochemically activated salt solution is preferably stable for more than one year, more preferably more than two years, when stored in a closed High Density Polyethylene (HDPE) container at 20 ℃. It has surprisingly been found that an ECAS comprising at least one borate and/or at least one phosphate may even improve the stability of the ECAS of the present application compared to an ECAS of the present application lacking at least one borate and/or at least one phosphate. Furthermore, it has been found that storage in high density polyethylene material (HDPE) provides good stability compared to other materials such as Low Density Polyethylene (LDPE) or polypropylene (PP).

In one embodiment "stable" or "stability" in the sense of the present application means that the redox potential of the ECAS of the present application decreases by up to 20%, preferably by 1% to 10%, after 6 months of storage under the respective storage conditions. Alternatively, the ECAS of the present application has a reduction in redox potential of up to 25%, preferably 1% to 10%, after 12 months of storage under the respective storage conditions. Alternatively, the ECAS of the present application has a reduction in redox potential of up to 30%, preferably 2% to 15%, after 24 months of storage under various storage conditions.

The redox potential can be determined by established methods known to those skilled in the art.

On the other hand, the ECAS according to the present application may contain hypochlorite ions and/or hypochlorous acid, in particular in a total concentration of 1mg/l to 10000mg/l, more preferably in a total concentration of 10mg/l to 1000 mg/l.

The total content of chlorite and/or chlorate ions is preferably below toxic levels, e.g. less than 10mg/l, more preferably 0.001mg/l to 10mg/l, even more preferably 0.001mg/l to 4 mg/l.

Further, the total content of heavy metals and heavy metal ions in the ECAS according to the present application is preferably below the toxicity level, e.g. less than 10 μ g/g, preferably less than 6 μ g/g, more preferably between 0.001 μ g/g and 6 μ g/g, and the content of each heavy metal and heavy metal ion individually is preferably less than 0.5 μ g/g. The heavy metals and heavy metal ions may be or be derived from silver, arsenic, gold, iridium, palladium, platinum, rhodium, thallium, cadmium, cobalt, mercury, lead, ruthenium, chromium, molybdenum, antimony, tin-copper, nickel, osmium or vanadium. Heavy metals (ions) can be detected by ICP-MS analysis according to ISO 17025.

In another aspect, the ECAS of the present application may contain at least one tackifier, such as a polymer. Any polymer used may be an organic polymer or an inorganic polymer. Suitable polymers may be cellulose, cellulose derivatives such as carboxymethyl cellulose (CMC) or hydroxypropylmethyl cellulose (HPMC), polysaccharides such as glycosaminoglycans, e.g. Hyaluronic Acid (HA), polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), silica gel, magnesium and/or aluminium metasilicate.

The ECAS of the present application preferably does not comprise, i.e. is free of, additional therapeutically active agents, such as drugs. It has surprisingly been found that the ECAS of the present application is effective in treating ocular infections without the need for additional therapeutically active agents.

The ECAS of the present application does not comprise, i.e. is free of, additional preservatives, such as BAK, sodium perborate, oxychloro complexes, zinc borate complexes, etc. It has surprisingly been found that the ECAS of the present application has sufficient disinfecting power per se to prevent microbial growth.

In another aspect, the present application relates to a process for producing the electrochemically activated salt solution (ECAS) described above, comprising the steps of:

(i) electrolyzing the aqueous chloride solution in an electrolysis reactor;

(ii) optionally adding at least one boric acid (salt) and/or at least one phosphoric acid (salt); and

(iii) optionally diluting the ECAS by adding water for injection.

The electrolytic reactor preferably comprises a cylindrical cathode coaxially mounted within a cylindrical anode. The cathode and anode may be separated by a microporous membrane, wherein an electric current is applied to the electrodes. The electrolysis is carried out at a current of 10.0A to 30.0A, preferably 15.0A to 20.0A. The electrolysis reactor is preferably configured for continuous electrolysis. One or more of the reactors may be combined in parallel or in series.

The concentration of the aqueous chloride solution used in step (i) in the water for injection (sterile water) is preferably at most 10g/l, preferably from 2g/l to 9 g/l.

The ECAS obtained in step (i) or (ii) may be diluted with an aqueous medium, preferably sterile water. The ECAS obtained in step (i) or (ii) may be obtained, for example, by contacting the ECAS with an aqueous medium: the aqueous medium is diluted in a ratio of between 1:6 and 6:1, preferably in a ratio of between 1:0.5 and 1: 3.

In another aspect, the present application relates to a pharmaceutical formulation comprising an electrochemically activated salt solution (ECAS) of the present application and optionally at least one therapeutically effective agent. A pharmaceutical formulation according to the present application may comprise at least one pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient may be selected from, for example, buffers, adjuvants, fillers, diluents and the like.

In another aspect, the electrochemically activated salt solutions (ECAS) of the present application are used for the treatment of infections, in particular eye infections, caused by microorganisms, such as bacteria, fungi and/or viruses. Bacterial and fungal infections may be caused by one or more species selected from the group consisting of: staphylococcus aureus (Staphylococcus aureus), methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli (Escherichia coli), Staphylococcus epidermidis (Staphylococcus epidermidis), Pseudomonas aeruginosa (Pseudomonas aeruginosa), Acinetobacter calcoaceticus (Acinetobacter calcoaceticus), Enterobacter aerogenes (Enterobacter aeogens), Streptococcus angina (Streptococcus anginosus), Streptococcus pyogenes (Streptococcus pyogenes), Candida albicans (Candida albicans), Aspergillus bracteatum (Aspergillus brasiliensis), Serratia marcescens (Aeromonas marcescens), and Acinetobacter cutaneus (Acinetobacter pitestis). The viral infection may be caused by a virus selected from the group consisting of: adenoviruses such as human adenovirus B and human adenovirus C, enteroviruses such as enterovirus 70 or coxsackie viruses (coxsackie viruses), and herpes viruses such as herpes simplex virus 1 and herpes simplex virus 2.

In another aspect, the electrochemically activated salt solution (ECAS) of the present application may in particular be used for the treatment of ophthalmic infections, preferably for the treatment of conjunctivitis, blepharitis, endophthalmitis, more preferably for the treatment of keratitis and/or conjunctivitis, even more preferably for the treatment of conjunctivitis. It has surprisingly been found that the ECAS of the present application shows the best efficacy in the treatment of bacterial conjunctivitis and bacterial keratitis, without causing harmful side effects, by both in vitro and in vitro studies.

Thus, in a highly preferred embodiment, the electrochemically activated salt solution (ECAS) of the present application may be used for the treatment of conjunctivitis, such as conjunctivitis caused by a microorganism, such as a bacterium, fungus or virus, more preferably for the treatment of bacterial conjunctivitis.

Thus, in another preferred embodiment, the electrochemically activated salt solution (ECAS) of the present application may be used to treat keratitis, such as bacterial keratitis.

For treatment of ocular infections, the electrochemically activated salt solutions (ECAS) of the present application may be topically applied to the eye, lacrimal sac, and/or eyelid. In a preferred embodiment, the electrochemically activated salt solution (ECAS) of the present application may be applied directly to the eye after infection.