CH713711A2 - Pharmaceutical composition for the treatment of infectious diseases. - Google Patents

Abstract

The invention relates to a pharmaceutical composition for the parenteral treatment of infectious diseases, based on an aqueous, sterile and pyrogen-free solution of chlorine dioxide, the 5 to 1000 mg / l (ppm) of dissolved chlorine dioxide (CIO2) and 3 to 10 g / l of a ionic tonicity regulator, optionally in combination with a non-ionic tonicity regulator. The composition preferably also contains a pH regulator, in particular a pH buffer system adjusted to pH 7.3-7.5, and may further contain DMSO or MSM. The composition is free from chlorate ions, hydrochloric acid and gaseous chlorine in the ready-to-use state or contains these components in a maximum concentration of 1 mg / l (1 ppm).

Description

Description TECHNICAL AREA

The present invention relates to a composition, in particular an infusion or injection solution, for the treatment of infectious diseases and inflammation in humans and animals.

STATE OF THE ART

For surface disinfection various chemicals are used, mostly oxidizing substances such as chlorine gas, ozone, hydrogen peroxide, chlorite, chlorate or perchlorate solutions. These chemicals react unspecifically with organic material by oxidation of, in particular, amino groups, sulfhydryl groups, double bonds and aromatic systems. This effect is essentially based on their antibacterial and antiviral activity.

In addition, however, chlorine dioxide has also been used as an effective antimicrobial agent for almost one hundred years, with the applications hitherto being restricted, above all, to surface disinfection and water sanitation. However, medical therapeutic applications are also known, albeit to a surprisingly small extent, for example for external skin and wound disinfection, for dental root canals, bad breath mouth rinses or candidiasis, and similar topical applications to humans and animals.

US 5,252,343 describes in 1993 the successful treatment of cattle mastitis with a chlorine dioxide solution (CDL) by rinsing the teats of the cow on the udder, whereas in contrast to conventional antibiotic therapy, the milk of the CDL treated animals did not have to be discarded, but continued to be rejected Consumption could be used. This is because the treatment with CDL apparently did not produce any kind of pollutants and no potentially harmful decomposition products of CI02 were detectable in relevant concentrations.

[0005] There is ample literature on the possible mechanisms of action of CIO2 with respect to proteins, amino acids, nucleic acids, polysaccharides, lipids, lipid membranes, bacteria, spores, viruses, fungi, protozoa, and higher parasites. It is all the more astonishing that this simple oxidant CI02 is still not widely used in the medical and veterinary therapy of inflammation and infectious diseases. This may have to do with an incomplete understanding of the physiology of the human and animal immune system that is widespread in the art, as a result of which many diseases are considered to be caused by free oxygen or nitric oxide radicals, and the therapy therefore aims at elimination of such free radicals - Also referred to in the literature as "reactive oxidative species" (ROS) - by the administration of antioxidants.

In his review "Oxidative Shielding or Oxidative Stress?" From 2012 (The Journal of Pharmacology and Experimental Therapeutics, 2012, Vol. 342, No. 3, pp 608-618), Robert Naviaux tries to investigate this fact and points out that reactive oxidative species such as free oxygen radicals are not the cause but the result of diseases. Oxidative shielding is a protective mechanism and should not therefore be a target for an anti-oxidative therapy.

[0007] The Possible Mechanism of Action of CIO 2: Although the mechanism of action may not always be clarified in detail, the pertinent literature does show that chlorodioxide, unlike chlorite and chlorate ions, does not indiscriminately adsorb any organic material but especially proteins and amino acids with secondary and tertiary amines and / or sulfhydryl groups, especially cysteine, methionine and glutathione, as well as aromatic amino acids such as tyrosine and tryptophan. In general, the literature refers to "electron-rich" organic molecule regions (see, e.g., Lee et al., Water Research 44, (2010), 555-566), which are preferentially oxidized by chlorine dioxide in one or more sequential steps. The reaction products on the side of the CI02 are ultimately chloride ions, in physiological solutions, ie NaCl, and water.

Reservations in parts of the professional world about a therapeutic use of CI02 therefore appear to be based on an inadequate evaluation of the existing expertise, perhaps also on certain prejudices, in the light of the one-tailed literature. For example, recent studies on model organisms in vitro indicate that antiviral effects are likely to result from either changing spikes depending on the type of virus so that attachment to the host cell can no longer occur, or significantly altering the viral capsid, resulting in immunogenicity or that certain steps in protein biosynthesis are adversely affected, so that either the transcription of the viral RNA or DNA fails to function properly or the assembly of the virus particles is disrupted.

In the antibacterial and antifungal activity, the art seems to have recognized that this microbicidal effect is mainly caused by a disturbance of the cell membranes or the lipid membranes of important organelles by CI02-effect, such as by damage of Membrane proteins, eg Tunneling proteins, a non-specific permeability of the membranes is caused for certain ions, whereby the cells, organelles and / or bacterial spores can no longer maintain their membrane potential and perish. There are also some interesting reports on the signal function ("signaling") of small molecules, e.g. CI02, especially with respect to apoptosis

Draw, either directly or indirectly via the modulation of ATP, ADP or GMP concentrations. Apoptosis is by no means considered negative in the context of immune defense, but rather as the limited, targeted elimination of individual, infected cells to impede rapid proliferation and spread of the pathogens, for the benefit of the whole organism.

Noszticzius et al. Describe in their paper "Chlorine Dioxide Is a Size Selective Antimicrobial Agent" (Noszticzius Z, Wittmann M, Kaly-Kullai K, Beregvari Z, Kiss I, et al., 2013, PLoS ONE 8 (11): e79 157. doi: 10.1371 / journal.pone.O 079 157) detail why CDL administration selectively kills small organisms such as bacteria and viruses and leaves cells unencumbered. Among other things, they approach the topic from the reaction kinetic side and very plausibly show that certain proteins and amino acids are primarily attacked (see above) and that, on the other hand, the flooding of small entities such as bacteria with CI02 in a germ-destroying amount is simply faster works as much larger cells as blood cells or somatic cells. In addition, eukaryotic cells have repair mechanisms against oxidative damage, especially those of sulfhydryl groups lacking viruses and bacteria.

Reservations in parts of the professional world about a therapeutic use of CI02 therefore seem to rest on the basis of the relevant specialist literature rather on an inadequate evaluation of existing specialist knowledge, perhaps also on certain prejudices.

It is an object of the present invention, these thoughts of Naviaux on the one hand and Noszticzius et al. on the other hand, to provide a water-based composition containing high purity chlorine dioxide as an oxidative agent and suitable for the parenteral systemic and topical treatment of many pathological conditions and diseases in humans and animals. This object is achieved by a composition as described in the independent claim. Further advantageous features of the invention are set forth in the dependent claims.

DESCRIPTION OF THE INVENTION

In one embodiment, the invention relates to a pharmaceutical composition containing high purity chlorine dioxide (CIO 2) in an aqueous medium and suitable for systemic parenteral application.

The composition contains dissolved CIO 2 in a concentration of typically 5 to 1000 ppm, corresponding to 5 to 1000 mg / l. For most applications, however, a concentration range of 10-500, especially 25-300 ppm is best.

In this context, "high purity" means that the composition is substantially free of chlorine gas, hydrochloric acid and chlorate ions. This is achieved by a manufacturing process that does not follow the usual Schematic of producing a chlorine dioxide solution (CDL) by acidifying a sodium chlorate solution, but instead generates CIO 2 by means of electrolysis of a pH-neutral NaCl solution followed by a gas scrubbing process. The gentle electrolysis carried out at a voltage of 6 V leads directly to the formation of CIO 2, with NaClO 2 and NaClO 3 being formed as by-products only in very small amounts, typically in concentrations of less than 1% based on the concentration of CIO 2. Even free hydrochloric acid and gaseous chlorine are produced - if at all - only in the smallest amounts. The concentrations of Na-chlorate, chlorine gas and hydrochloric acid are in the freshly prepared, concentrated CDL (1000-2000 ppm CI02) typically in a range of not more than 10-20 ppm and in the ready-to-use, diluted CDL at a maximum of 1-2 ppm or underneath.

Above all, the advantage of a high-purity CDL is that the possibility of any undesirable effects, which are described for Na-chlorite and above all for Na-chlorate in the specialist literature, is reduced even further, which is especially true for formulations and compositions is of particular importance, which should be used as infusion solutions or injection solutions.

A composition according to the invention which, in addition to external, topical application, should be suitable above all for systemic, parenteral applications in the form of injection or infusion solutions, may contain at least one tonicity regulator which makes it possible to adjust the solution isotonic. Suitable tonicity regulators are ionic substances such as NaCl or KCl, but also non-ionic substances and, in particular, representatives from the group of monosaccharides, disaccharides, oligosaccharides and low molecular weight polyols.

The mono- and disaccharides are preferably selected from the group: glucose, fructose, sucrose and mannose, and the polyols are preferably selected from the group: glycerol, erythritol, mannitol, sorbitol, inositol, xylitol, threitol and maltitol.

An isotonic saline solution containing 9g NaCl per liter of water (0.9%), the resulting Osmolaritât of 290-300 mosmol / l corresponds to the Osmolaritât of the blood, which also means KCI or a mixture of two or more of the ionic and not mentioned ionic tonicity regulators can be adjusted.

Especially for injection and infusion solutions, it may be of crucial importance to adjust the pH of the CDL to those of the blood in a range of about pH 7.3-7.5 in order to avoid any undesired effects. For this purpose, a pH regulator, in particular a buffer system, can be added to the CDL. As appropriate, a bicarbonate buffer or phosphate buffer (e.g., PBS) is considered. Although studies in vitro have shown that for some applications a higher pH of the CDL would be beneficial, it is important to ensure compatibility with the blood pH in injection solutions. For other applications, for example rectal enemas or intestinal irrigation, higher or possibly lower pH values can also be set.

For the compositions according to the invention, in particular those intended for a longer, recurring use, the addition of further components from the group of preservatives, gums, vitamins, mineral salts and trace elements may be advantageous.

The CDL according to the invention can be prepared as a concentrate having a CIO 2 content of typically 1000-2000 ppm, which is mixed with e.g. Isotonic, pH neutral, or optionally pH buffered, NaCl solution is diluted by a factor of 2-500 to adjust the reported therapeutic CIO 2 content of about 5-1000 ppm of a ready to use solution. The concentrated composition may further contain 1-5 wt.% (10-50 g / L) of DMSO or methylsulfonylmethane (also "dimethylsulfone") MSM, or a mixture of both components. These components attenuate and delay the action of the chlorine dioxide, so that administration by long-term treatments or by the administration of larger amounts does not cause unwanted oxidative stress within a short time. In addition, these sulfur-containing components improve the storage stability of the concentrated CDL.

Although the results of Noszticzius et al. In the context of the present invention, however, these findings were nevertheless taken up and, for the first time, examined and tested for their transferability in the systemic use of intravenous, subcutaneous, intramuscular or other injections and infusions. In accordance with the reaction kinetic findings from the topical application of Noszticzius et al. could be confirmed in the course of development of the present invention that contrary to the concerns of other parts of the art a parenteral therapeutic use, optionally in combination with oral use of reactive oxidative species such as CI02 by no means must be accompanied by undesirable or even damaging effects. In fact, no such reports of severe side effects or even deaths have appeared to date in the literature, and no such effects have been brought about in the course of experimental use in the context of the present invention.

By means of the methods according to the invention for the treatment of viral or mibrobial infections, for example the following bacteria can be combated: Blakeslea trispora, Bordetella bronchiseptica, Brucella, Burkholderia, Campylobacter jejuni, Clostridium botulinum, Corynebacterium bovis, Coxiella burneti, Escherichia coli, Franscicella tularensis , Hélicobacter pylori, Helminthosporium solani, Klebsiella pneumonia, Lactobacillus, Légionella, Leuconostoc citreum, Leuconostoc mesenteroides, Listeria, Me-thicillin-resistant Staphylococcus aureus (MRSA), Multiple Drug Resistant Salmonella Typhimurium (MDRS), Mycobacterium, Mycobacterium tuberculosis, Pediococcus acidilacti, Pseudomonas aeruginosa, Salmonella, Shigella, Staphylococcus aureus, Staphylococcus faecalis, Enterococcus faecalis (VRE), Vibrio spp., Yersinia.

Furthermore, spores of the following bacteria can be killed by CIO 2: Alicyclobacillus acidoterrestris, Bacillus anthracis, Bacillus atrophaeus, Bacillus coagulans, Bacillus megaterium, Bacillus polymyxa, Bacillus pumilus, Bacillus subtilis, Bacillus thuringiensis, Clostridium sporogenes, Geobacillus stearo-thermophilus The following viruses can be killed by the CDL according to the invention: Adenovirus Type 40, Calicivirus, Canine Parvovirus, Coronavirus, Feiine Calicivirus, Foot and Mouth Disease Virus, Hantavirus, Hepatitis A Virus, Hepatitis B Virus, Hepatitis C Virus , Human Coronavirus, Human Immunodeficiency Virus, Human Rotavirus Type 2 (HRV), Influenza A Virus, Newcastle Disease Virus, Norwalk Virus, Parvovirus, Polio Virus, Rotavirus, SARS Virus, Coronavirus, Sendai Virus, Vaccinia Virus.

The following fungi can be killed by the CDL according to the invention: Alternaria alternata, Aspergillus, Botrytis species, Candida, Chaetomium globosum, Cladosporium cladosporo-rioides, Debaromyces etchelisii, Eurotium spp., Fusarium solani, Lodderomyces elongisporus, Mucor, Pénicillium , Phor-midium boneri, Pichia pastoris, Poitrasia circinans, Rhizopus oryzae, Roridin A, Saccharomyces cerevisiae, Stachybotrys chartarum, T-mentag, Verrucarin A.

The following protozoa can be killed by the CDL according to the invention: Amoeba, Chironomid larvae, Cryptosporidium, Cryptosporidium parvum, Oocyst spp., Cyclospora cayetanensis oocysts, Giardia lamblia.

The following examples are intended to further illustrate the invention and to underpin the therapeutic applicability of the oxidative intervention by means of chlorine dioxide solution. It should also be noted that the treatments in the following patient examples were performed either by doctors or under medical supervision. EXAMPLE 1: Lyme Disease Lyme disease is caused by infection with the bacterium Borrelia burgdorferi, typically due to a tick bite. Borrelia belong to a category of spirochaetes. The disease is a multi-system disease affecting the skin, the nervous system, the heart and the joints. In the first stage of the disease, the symptoms are similar to the onset of influenza, including severe headache, fatigue, joint and muscle pain, fever, and possibly swollen lymph glands. In a second stage, several weeks after the tick bite, more severe symptoms occur, including neurological complications such as facial palsy, irritability, and poor motor coordination. Furthermore, heart problems associated with irregular heartbeat and dizziness may occur.

A third stage of the disease may occur months or years after the first infection and may include chronic arthritis or chronic neurological effects. Only immediate treatment with antibiotics in the first two stages of the disease, according to orthodox medicine, allows a - often not completely - recovery.

However, Lyme disease is also present in animals. For example, antibodies to Borrelia burgdorferi have been detected in cattle in Europe, Australia, the United Kingdom and the United States.

In the context of the present invention, a new treatment method has been used. In this case, a high purity Chlordixoidlösung, prepared by electrolysis from a NaCl solution followed by Gaswaschver-drive and without addition of acid, administered as an infusion solution.

In order to avoid oxidative stress to a great extent and to avoid any possible phlebitis at the injection site of the infusion tube, a concentrate of the aqueous, highly pure and pH-neutral chlorine dioxide solution (concentration 1000 ppm) was admixed with 1% by weight of dimethyl sulphoxide as slightly retarding, oxidation-inhibiting Agent added. The DMSO-containing chlorine dioxide solution was filled under aseptic conditions in 25 ml glass ampoules of standard brown ampule glass and stored at about 8 ° C until use. The storage stability of this concentrated solution is at least 12 months with an activity loss of available CI02 of max. 10%.

Immediately prior to treatment, a 25 ml glass ampoule each with pH-neutral or preferably slightly alkaline saline solution (pH 7.3-7.5, adjusted with bicarbonate buffer) is diluted to 500 ml, resulting in a CIO 2 concentration of approx. 50 ppm results. The concentration of 50 ppm is checked photometrically by means of a photometer HI96771C from Hanna Instruments.

Each 500 ml of this solution is administered intravenously at a rate of 3 drops per second for 2 weeks at 4-day intervals:

Infusion 1, day 01: 500 ml;

Infusion 2, day 05: 500 ml;

Infusion 3, day 09: 500 ml;

Infusion 4, day 13: 500 ml.

According to this Schéma, two male and one female patient are treated between the ages of 30 and 50 years. Patients complain of feeling exhausted, headache, joint pain, limb weakness and impaired muscle movement. Blood analyzes carried out in Germany and Spain confirm the presence of Borrelia. It is not known exactly how long the patients are already suffering from these symptoms, according to subjective data for several weeks to several months. In addition, immunohistochemical analyzes in the female patient show a considerable compromise of the immune system as well as IgM antibodies against Epstein-Barr virus and Mycoplasma pneumoniae.

Under the microscope, the erythrocytes are in the typical datura shape.

After the 4 infusions according to the above Schéma, all three patients were symptom free and full of energy. No notable adverse effects were observed. The blood count was back to normal and there was no methaemoglobinemia.

All three patients were discharged as healthy. EXAMPLE 2: Lyme Disease The infusion solution was prepared as in Example 1, but the dilution to the ready-to-use concentration was carried out with pH-neutral, isotonic saline, without pH buffer.

Two patients, female, 30-35 years, with clinically diagnosed Lyme disease for several years, received CI02 infusions administered with 50-70ppm CI02 intravenously, three drops per second, according to the following Schéma:

Day 01: 1 x 100 ml

Day 05 1 x 400 ml

Day 09 1 x 500 ml

Day 13 1 x 500 ml

Day 17 1 x 500ml The result was highly pleasing and positive in both patients and no significant unwanted side effects were observed. While Borrelia was clearly detectable under the microscope before treatment, it was no longer detectable after treatment. EXAMPLE 3 Tetanus Treatment in a Dog A 4-month-old Old English Bulldog weighing 17.5 kg injured a cane in the lumbar region and developed tetanus symptoms within three days, which were declared final and untreatable by the veterinarian. including the jaw clamp, stretching cramps, dizzy spells and the effects of light.

The treatment with chlorine dioxide solution took place over 8 days according to the following scheme: In the first four days, 4 ml of a high-dose, pH-neutral chlorine dioxide solution (CDL) of 500 ppm, 4 times a day, pérorai were administered to the animal. From day 5, 100 ml of a low-dose, bicarbonate-buffered (pH 7.4) CDL of 50 ppm was administered intravenously 4 times per day.

The animal is completely recovered after this treatment. Example 4: Treatment of the foal form of a foal A foal suffering from foal disease (foal septicemia), a serious infectious disease caused by various bacteria (blood poisoning), was already terminally ill and which was unfortunately untreatable by the veterinarians on the spot As a last resort, the following treatment was carried out by means of CDL: For 10 days, 200 ml of CDL at a concentration of 50 ppm pérorai were administered twice a day. Subsequently, 500 ml of 100 ppm CDL were intravenously administered for an additional 4 days.

Result: after 14 days of treatment, the foal was completely healthy and well again.

1. A pharmaceutical composition based on an aqueous solution of chlorine dioxide, characterized in that the solution is sterile and pyrogen-free and contains the following components: a) 5 to 1000 mg / l (ppm) dissolved chlorine dioxide (CIO 2); b) 3 to 10 g / l of a tonicity regulator of ionic or nonionic nature, or a mixture thereof; wherein the composition in the ready-to-use state is substantially free of chlorate ions, hydrochloric acid and gaseous chlorine or contains these components in a concentration of not more than 1% of the chlorine dioxide concentration. 2. Pharmaceutical composition according to claim 1, characterized in that it contains dimethyl sulfoxide (DMSO) or dimethyl sulfone (MSM) in a concentration of 0.1 to 20 g / L. 3. Pharmaceutical composition according to claim 1 or 2, characterized in that it contains a pH buffer system adjusted to pH 7.3-7.5. 4. A pharmaceutical composition according to claim 1, characterized in that the ionic Toxizittsregu-lator is selected from the group NaCl and KCl and the non-ionic Tonizitats regulator from the group of monosaccharides, disaccharides, oligosaccharides, and low molecular weight polyols. 5. Pharmaceutical composition according to claim 4, characterized in that the mono- and disaccharides are selected from the group: glucose, fructose, sucrose and mannose and the polylols from the group: glycerol, erythritol, mannitol, sorbitol, inositol, xylitol, threitol and maltitol. 6. A pharmaceutical composition according to claim 1, adapted as an isotonic injection or infusion solution, for use in the systemic, parenteral treatment of viral, bacterial or fungal, plasmodia or protozoan-induced infectious diseases of the human or animal body. 7. A pharmaceutical composition according to claim 3, adapted as an isotonic injection or infusion solution, for use in the systemic, parenteral treatment of viral, bacterial or fungal, plasmodia or protozoan-induced infectious diseases of the human or animal body.

Claims (10)

Day 01: 1 x 100 ml day 05 1 x 400 ml day 09 1 x 500 ml day 13 1 x 500 ml day 17 1 x 500 ml The result was very pleasing and positive in both patients and no significant, uner -wanted side effects observed. While Borrelia was clearly detectable under the microscope before treatment, it was no longer detectable after treatment. EXAMPLE 3 Tetanus Treatment in a Dog A 4-month-old Old English Bulldog weighing 17.5 kg injured a cane in the lumbar region and developed tetanus symptoms within three days, which were declared final and untreatable by the veterinarian. including the jaw clamp, stretching cramps, dizzy spells and the effects of light. The treatment with chlorine dioxide solution took place over 8 days according to the following scheme: In the first four days, 4 ml of a high-dose, pH-neutral chlorine dioxide solution (CDL) of 500 ppm, 4 times a day, pérorai were administered to the animal. From day 5, 100 ml of a low-dose, bicarbonate-buffered (pH 7.4) CDL of 50 ppm was administered intravenously 4 times per day. The animal is completely recovered after this treatment. Example 4: Treatment of the foal form of a foal A foal suffering from foal disease (foal septicemia), a serious infectious disease caused by various bacteria (blood poisoning), was already terminally ill and which was unfortunately untreatable by the veterinarians on the spot As a last resort, the following treatment was carried out by means of CDL: For 10 days, 200 ml of CDL at a concentration of 50 ppm pérorai were administered twice a day. Subsequently, 500 ml of 100 ppm CDL were intravenously administered for an additional 4 days. Result: after 14 days of treatment, the foal was completely healthy and well again. claims 1. A pharmaceutical composition based on an aqueous solution of chlorine dioxide, characterized in that the solution is sterile and pyrogen-free and contains the following components: a) 5 to 1000 mg / l (ppm) of dissolved chlorine dioxide (CIO 2); b) 3 to 10 g / l of a tonicity regulator of ionic or nonionic nature, or a mixture thereof; wherein the composition in the ready-to-use state is substantially free of chlorate ions, hydrochloric acid and gaseous chlorine or contains these components in a concentration of not more than 1% of the chlorine dioxide concentration. 2. Pharmaceutical composition according to claim 1, characterized in that it contains dimethyl sulfoxide (DMSO) or dimethyl sulfone (MSM) in a concentration of 0.1 to 20 g / L. 3. Pharmaceutical composition according to claim 1 or 2, characterized in that it contains a pH buffer system adjusted to pH 7.3-7.5. 4. A pharmaceutical composition according to claim 1, characterized in that the ionic Toxizittsregu-lator is selected from the group NaCl and KCl and the non-ionic Tonizitats regulator from the group of monosaccharides, disaccharides, oligosaccharides, and low molecular weight polyols. 5. Pharmaceutical composition according to claim 4, characterized in that the mono- and disaccharides are selected from the group: glucose, fructose, sucrose and mannose and the polylols from the group: glycerol, erythritol, mannitol, sorbitol, inositol, xylitol, threitol and maltitol. 6. A pharmaceutical composition according to claim 1, adapted as an isotonic injection or infusion solution, for use in the systemic, parenteral treatment of viral, bacterial or fungal, plasmodia or protozoan-induced infectious diseases of the human or animal body. 7. A pharmaceutical composition according to claim 3, adapted as an isotonic injection or infusion solution, for use in the systemic, parenteral treatment of viral, bacterial or fungal, plasmodia or protozoan-induced infectious diseases of the human or animal body. A pharmaceutical composition according to claim 6 or 7, for use in combination with oral and / or topical application of a chlorine dioxide solution containing 5-1000 ppm CI02. The pharmaceutical composition of claim 6 or 7 for use in the treatment of Lyme disease, tetanus or septicemia. 10. Chlorine dioxide in aqueous solution at a concentration of 5-1000 ppm for use as a therapeutic in the systemic, parenteral treatment of viral or microbial infections of the human or animal body.