WO2018185347A1 - Pharmazeutische zusammensetzung zur behandlung von inneren entzündungen - Google Patents

Pharmazeutische zusammensetzung zur behandlung von inneren entzündungen Download PDF

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Publication number
WO2018185347A1
WO2018185347A1 PCT/EP2018/059056 EP2018059056W WO2018185347A1 WO 2018185347 A1 WO2018185347 A1 WO 2018185347A1 EP 2018059056 W EP2018059056 W EP 2018059056W WO 2018185347 A1 WO2018185347 A1 WO 2018185347A1
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treatment
solution
chlorine dioxide
ppm
intestinal
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PCT/EP2018/059056
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German (de)
English (en)
French (fr)
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Andreas Ludwig KALCKER
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Schweizer Zentrum für wissenschaftliche Forschung, Innovation und Entwicklung
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Publication of WO2018185347A1 publication Critical patent/WO2018185347A1/de

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/20—Elemental chlorine; Inorganic compounds releasing chlorine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0031—Rectum, anus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin

Definitions

  • the present invention relates to a pharmaceutical composition based on an aqueous solution of chlorine dioxide, for the therapeutic treatment of internal inflammations, inflammatory conditions and / or related, clinically relevant pathological symptoms or conditions in the human or animal body.
  • chlorine dioxide has been used as an effective antimicrobial agent, with applications that have so far been limited primarily to surface disinfection and water sanitation.
  • medical-therapeutic applications are also known, albeit to a surprisingly small extent, for example for external skin and wound disinfection, root canal treatments in dentistry, bad breath mouth rinses or candidiasis, and similar topical applications to humans and animals.
  • US5252343 describes 1,993 the successful treatment of cattle mastitis with a chlorine dioxide solution (CDL) by rinsing the teats on the udder of the cow, whereas unlike conventional antibiotic therapy the milk of the CDL treated animals did not have to be discarded, but continued to be consumed could be used. This is because the treatment with CDL evidently produced no pollutants of any kind and no potentially harmful decomposition products of CI02 were detectable in relevant concentrations.
  • CDL chlorine dioxide solution
  • ROS reactive oxidative species
  • Oxidative Shielding or Oxidative Stress is a protective mechanism and should not be a target for anti-oxidative therapy.
  • Inflammations are an essential part of the highly complex immune defense of the human and animal organism and serve - very simply said - especially the detection and removal of damaged or infected cells of the human or animal body and the removal of cellular debris of dead cells.
  • mitochondria both as energy suppliers and producers of reactive oxidative species (ROS) and important signal molecules on the one hand, and macrophages as scavenger cells and modulators of the immune defense on the other, are of paramount importance.
  • ROS reactive oxidative species
  • Chlorine dioxide is itself a representative of such ROS, but has a different spectrum of activity than the ROS generated by the mitochondria. How the systemic or topical administration of therapeutic doses of CI02 interferes in detail with the immune defense process is not fully understood at present.
  • chlorodixoid unlike chlorite and chlorate ions, does not indiscriminately attack any organic material, but primarily 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.
  • 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.
  • cysteine methionine and glutathione
  • aromatic amino acids such as tyrosine and tryptophan.
  • Molecules such as e.g. CI02, especially in relation to apoptosis triggering, 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, rapid elimination of individual, damaged, especially infected cells in order to hinder or prevent a rapid multiplication 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., 201 3, PLoS ONE 8 (1 1): e791 57.
  • This object is solved by a composition as described in the independent claim. Further advantageous features of the invention are set forth in the dependent claims.
  • Fig. 1 a and 1 b show treatment progress in the foot in diabetes mellitus
  • Figs. 2a and 2b show treatment progress on the open leg in diabetes
  • Context are understood to be those clinically relevant inflammatory and inflammatory conditions that are not or not exclusively at the external
  • Body surface i. on the skin or in the outer skin layers, but the underlying tissues, internal organs, mucous membranes, joints, body fluids, blood vessels, nerves, bones, etc. are active.
  • those clinically relevant, pathological symptoms or conditions are to be included, which are directly related to inflammatory processes in the human or animal body, either as a cause or as a consequence, as described e.g. autism, fibromyalgia syndrome, Leaky-Gut syndrome, hypoxia, ALS, diabetes mellitus, and venous thrombosis.
  • CI02 is administered concomitantly with DMSO or MSM (dimethylsulfone), this results in a weakened, more controllable oxidative intervention while simultaneously attenuating the oxidative stress present in the diseased organism of a patient and suppressing the formation of superoxides and hydrogen peroxide by the mitochondria .
  • DMSO or MSM dimethylsulfone
  • flushing of the intestinal tract or urethra and urinary bladder may at the same time also affect the antiviral and anti-microbial effects of CI02 and may, if appropriate, significantly support the curative effect of this treatment method. It is also possible to specifically influence the microbiome of the intestinal tract with a colonic irrigation according to the invention and to prepare it in a favorable manner for the regeneration of a healthy intestinal flora.
  • reaction products on the side of CI02 are ultimately NaCl and water in physiological fluids.
  • the invention therefore relates to a pharmaceutical composition which preferably contains high purity chlorine dioxide (CIO 2) in an aqueous medium and is suitable for therapeutic use in the form of solutions for single or multiple irrigation of the intestine, ureter and / or urinary bladder and can be used.
  • CIO 2 high purity chlorine dioxide
  • 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 most suitable.
  • "High purity" in this context means that the composition is substantially free of chlorine gas, hydrochloric acid, chlorite and chlorate ions, ie typically containing these components only in concentrations of less than 1% of the CIO 2 concentration. This is achieved by a manufacturing process, which does not follow the usual scheme of producing a chlorine dioxide solution (CDL) by acidification of a sodium chlorate solution, but CI02 by electrolysis of a pH-neutral NaCl solution, followed by gas scrubbing generated.
  • CDL chlorine dioxide solution
  • the concentrations of Na-chlorite, Na-chlorate, chlorine gas and hydrochloric acid are typically in the freshly prepared, concentrated CDL, which contains mostly 1000-2000 ppm (mg / L) CIO 2, but if necessary also up to 3000 ppm CIO 2 and more within a maximum range of 10-20 ppm and in the ready-to-use, diluted CDL at a maximum of 1 -2 ppm (mg / L) or below.
  • a comparable high purity chlorine dioxide solution prepared by another method would also be usable provided it meets the criteria for a high purity solution set forth herein.
  • CDL high-purity CDL
  • a composition according to the invention which, in addition to external, topical application, should be suitable above all for systemic, internal applications in the form of intestinal or bladder irrigation, may contain a tonicity regulator which allows the solution to be rendered isotonic.
  • a tonicity regulator which allows the solution to be rendered isotonic.
  • Tonizticiansregulatoren ionic substances such as NaCl or KCl come into question, but also non-ionic substances and in particular representatives of 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 low molecular weight polyols are preferably selected from the group: glycerol, erythritol, lactitol, mannitol, sorbitol, inositol, xylitol, threitol and maltitol.
  • An isotonic saline solution contains 9g NaCl per liter of water (0.9%), the resulting osmolarity of 290-300 mosmol / l corresponds essentially to the osmolarity of the blood, which can also be determined by means of KCl or a mixture of two or more several of the mentioned ionic and nonionic Tonizticiansregulatoren can be adjusted.
  • a pH regulator in particular a buffer system
  • Suitable is a bicarbonate buffer or a phosphate buffer, e.g. PBS, viewed.
  • compositions according to the invention in particular those intended for prolonged, repeated use, the addition of further components, for example from the group of preservatives, vitamins, mineral salts and trace elements, may be advantageous.
  • the CDL according to the invention can be produced as a concentrate with a CIO 2 content of typically 1000-2000 ppm, if necessary but also with higher contents of 3000 ppm and more of CIO 2, which is filled under aseptic conditions into 25 ml glass ampoules made of brown standard ampoule glass and stored at about 8 ° C until use.
  • the concentrate may further contain 1 - 5 wt.% (10 - 50 g / L) of DMSO or MSM (methylsulfonylmethane, dimethylsulfone), or a mixture of both components.
  • DMSO or MSM methylsulfonylmethane, dimethylsulfone
  • the storage stability of a concentrated CI02 solution with 1% DMSO addition is at least 1 2 months with a loss of activity of available CI02 of max. 10%.
  • the concentrate is mixed immediately before use with e.g. isotonic, pH neutral or optionally bicarbonate buffered, NaCl solution by a factor of 2 - 500 diluted to adjust the mentioned CI02 contents of typically 5 - 1000 ppm of a ready to use solution.
  • a 25 ml glass ampoule (CI02 concentration 1000 ppm) is diluted with pH neutral or preferably slightly alkaline saline (pH 7.3-7.5, with bicarbonate buffer) and diluted to 500 ml resulting in a CI02 Concentration of about 50 ppm results.
  • a 25 ml vial 1000 ppm can be diluted to one liter.
  • inflammations themselves can be treated but also often associated side effects or symptoms such as increased local body temperature, fever, small tissue lesions, pain, redness, swelling, growths, thickening, hardening, nodules, tumors and ulcers
  • inflammatory associated symptoms and symptoms include anal and genital warts, anal cancer, anal fissures, anorectal abscesses, appendicitis, autism, celiac disease, colon cancer, constipation, Crohn's disease, diarrhea, diverticulitis, fecal incontinence, anal fistulas, flatulence, hemorrhoids, Hirschsprung's disease, inflammatory Inflammatory bowel disease, intestinal adhesions, intestinal pseudo-obstruction, irritable bowel, lactose intolerance, leaky gut syndrome, lupus erythematosus, intestinal polyps, proctitis, rectal cancer, short bowel syndrome, ulcerative co
  • the CDL according to the invention it is possible to reduce damage to the intestinal mucosa, for example caused by chemotherapy or radiation therapy, and also to reduce damage caused by e.g. Antibiotics or other medicines positively affect and regenerate pathologically impaired intestinal flora.
  • a 48-year-old woman has been treated for hypertension since May 201 3. She takes a Micardis plus ® tablet every morning. It was operated on the thyroid gland 20 years ago and its leukocyte counts are consistently high, but in the opinion of the treating physician they are tolerable.
  • Thymanax ® as an antidepressant.
  • Table 1 shows some blood levels before starting treatment with CDL in May 201 3:
  • 1% by weight of dimethylsulfoxide was added to a concentrate of the aqueous, highly pure and pH-neutral chlorine dioxide solution (concentration 1000 ppm) as slightly retarding, oxidation-retarding agent.
  • concentration 1000 ppm concentration 1000 ppm
  • the DMSO-containing chlorine dioxide solution was filled under aseptic conditions in 25 ml glass ampoules made of brown standard ampoule glass and stored at about 8 ° C until use.
  • a total of 8 times 250 ml of CDL with a concentration of 50 ppm CI02 were intravenously administered in a 3-day cycle within 20 days.
  • an infusion rate of 2 to 3 drops per second was set, which was increased to 5 drops per second after the consumption of approximately half of the liquid volume.
  • the ATEC Score severe rating of autism
  • the second child was always prone to self-harm and had to be treated several times in the emergency room.
  • the concentration of the solutions was about 25ppm.
  • both children were given a special diet without gluten, without dairy products and without sugar.
  • the ATEC Score fell to 5 for the first child and 7 for the second child. Both started talking again. Up to an ATEC score of 10, a child is still considered normal.
  • Diagnosis severe fibromyalgia syndrome since 5 years, patient is mostly bedridden and incapacitated, has severe pain and depression; In addition, she suffers from hypertension, osteoarthritis and insulin resistance.
  • PSA value is 1 5.5 ng / ml. The patient could not hold water and was depressed because of this fact. A catheter was placed.
  • a pH-neutral, 200ppm CI02 solution is sprayed 2 to 4 times a day on the face.
  • the acne has decreased by about 80% after treatment.
  • the patient has more energy and concentration and is very happy with the result.
  • the bowel movement has normalized.
  • the diet continues to be used. No adverse effects were observed.
  • Oxygen saturation increased from 31 .9% to 55.2% and C02 partial blood pressure dropped from 65.3 to 46.0 mmHg.
  • ALS amyotrophic lateral sclerosis
  • the subject an ALS suffering surgeon, was already at an advanced stage with nocturnal artificial respiration, artificial nutrition,
  • One dose of 2L water containing 200 ppm chlorine dioxide was orally administered daily for one month daily. Thereafter, the first intravenous administration was carried out with 5 ml of 0.3% chlorine dioxide solution in 250 ml of isotonic saline, in three rows daily, over a period of 7 days.
  • the dose was gradually increased up to 25 ml of 0.3% chlorine dioxide solution in 500 ml of isotonic saline, about pH 3.5, and administered for another 7 days. Care was taken to extend the duration of infusion as long as possible in order to maintain a constant oxygen supply.
  • the subject was a 57 year old male who was diagnosed with type 2 diabetes mellitus.
  • Chlorine dioxide solution treated directly.
  • the amputation could be successfully averted and the open wounds could heal, which was previously not possible for years. It could Surprisingly enough, even necrosis receded and new healthy tissue developed in previously dead areas.
  • Figures 1 a and 1 b show the progress of treatment on the foot, the figures 2a and 2b those on the open leg.
  • EXAMPLE 1 1 Venous thrombosis
  • Venous thrombosis is a vascular disease in which a blood clot (thrombus) forms in a blood vessel. This has the consequence that the blood circulation within the blood vessel stops due to the blood clot.
  • a blood clot thrombus
  • the subject took 2L of a chlorine dioxide solution of this invention at 400 ppm per day, over the period of one month, throughout the day.

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Inorganic Chemistry (AREA)
  • Dermatology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Reproductive Health (AREA)
  • Urology & Nephrology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/EP2018/059056 2017-04-07 2018-04-09 Pharmazeutische zusammensetzung zur behandlung von inneren entzündungen WO2018185347A1 (de)

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CH00474/17A CH713095B1 (de) 2017-04-07 2017-04-07 Pharmazeutische Zusammensetzung zur Behandlung von Entzündungen.

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5252343A (en) 1992-03-20 1993-10-12 Alcide Corporation Method and composition for prevention and treatment of bacterial infections
US20040104127A1 (en) * 2002-12-02 2004-06-03 Rojas Juan Luis Araya Process and composition for obtaining an aqueous chlorine dioxide ready for its use, stabilized in a carbonate buffer, being a powerful disinfecting agent with ecological, non residual non toxic and non phytotoxic cataloging in the concentrations of usage
WO2011086579A1 (en) * 2010-01-18 2011-07-21 Prophylaxis Process for producing stable and pure liquid form of chlorine dioxide
EP2926819A1 (en) * 2012-11-29 2015-10-07 Xuewu Liu Method for initiating stem cells of mammals and use of chlorine dioxide in preparation of drug for initiating stem cells of mammals

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5252343A (en) 1992-03-20 1993-10-12 Alcide Corporation Method and composition for prevention and treatment of bacterial infections
US20040104127A1 (en) * 2002-12-02 2004-06-03 Rojas Juan Luis Araya Process and composition for obtaining an aqueous chlorine dioxide ready for its use, stabilized in a carbonate buffer, being a powerful disinfecting agent with ecological, non residual non toxic and non phytotoxic cataloging in the concentrations of usage
WO2011086579A1 (en) * 2010-01-18 2011-07-21 Prophylaxis Process for producing stable and pure liquid form of chlorine dioxide
EP2926819A1 (en) * 2012-11-29 2015-10-07 Xuewu Liu Method for initiating stem cells of mammals and use of chlorine dioxide in preparation of drug for initiating stem cells of mammals

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
"Oxidative Shielding or Oxidative Stress?", THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, vol. 342, no. 3, 2012, pages 608 - 618
ANDREAS LUDWIG KALCKER: "GESUNDHEIT VERBOTEN", March 2017, NEUE LICHT / JIM HUMBLE VERLAG, Roermond, ISBN: 978-90-8879-156-7, pages: 43-66,139-387,419,441 - 444, XP002782877 *
ANONYMOUS: "BfR rät von der Einnahme des Produkts "Miracle Mineral Supplement" ("MMS") ab", 2 July 2012 (2012-07-02), XP055486271, Retrieved from the Internet <URL:http://www.bfr.bund.de/cm/343/bfr-raet-von-der-einnahme-des-produkts-miracle-mineral-supplement-mms-ab.pdf> [retrieved on 20180620] *
ANONYMOUS: "Bundesinstitut für Arzneimittel und Medizinprodukte stuft zwei "Miracle Mineral Supplement"-Produkte als zulassungspflichtig und bedenklich ein", BFARM PRESSE, 26 February 2015 (2015-02-26), XP055489398, Retrieved from the Internet <URL:https://www.bfarm.de/SharedDocs/Pressemitteilungen/DE/2015/pm3-2015.html> [retrieved on 20180702] *
ANONYMOUS: "FDA Warns Consumers of Serious Harm from Drinking Miracle Mineral Solution (MMS)", 30 July 2010 (2010-07-30), XP055486143, Retrieved from the Internet <URL:https://www.pharmpro.com/news/2010/07/fda-warns-consumers-serious-harm-drinking-miracle-mineral-solution-mms> [retrieved on 20180620] *
ANONYMOUS: "Verordnung über Trinkwasser und über Wasser für Lebensmittelbetriebe (Trinkwasserverordnung - TrinkwV)", BGBL, 5 December 1990 (1990-12-05), XP055489433, Retrieved from the Internet <URL:https://www.ihph.de/publikationen/trinkwvero/Sonstige%20Dokumente/Alte%20TVO.pdf> [retrieved on 20180702] *
LEE ET AL., WATER RESEARCH, vol. 44, 2010, pages 555 - 566
NOSZTICZIUS Z; WITTMANN M; KÄLY-KULLAI K; BEREGVÄRI Z; KISS I ET AL.: "Chlorine Dioxide Is a Size-Selective Antimicrobial Agent", PLOS ONE, vol. 8, no. 11, 2013, pages e79157

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