EP4213862A1 - Préparation pharmaceutique améliorée - Google Patents

Préparation pharmaceutique améliorée

Info

Publication number
EP4213862A1
EP4213862A1 EP21777210.2A EP21777210A EP4213862A1 EP 4213862 A1 EP4213862 A1 EP 4213862A1 EP 21777210 A EP21777210 A EP 21777210A EP 4213862 A1 EP4213862 A1 EP 4213862A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical preparation
reactive chlorine
compound
acid
acids
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP21777210.2A
Other languages
German (de)
English (en)
Inventor
Mark Andre Freyberg
Dirk Kaiser
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cytogenesis Ltd
Original Assignee
Cytopharma Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cytopharma Ltd filed Critical Cytopharma Ltd
Publication of EP4213862A1 publication Critical patent/EP4213862A1/fr
Pending legal-status Critical Current

Links

Classifications

    • 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
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00—Inhalators
    • A61M15/0001—Details of inhalators; Constructional features thereof
    • A61M15/0003—Details of inhalators; Constructional features thereof with means for dispensing more than one drug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00—Special media to be introduced, removed or treated
    • A61M2202/04—Liquids
    • A61M2202/0468—Liquids non-physiological

Definitions

  • the present invention relates to an improved pharmaceutical preparation.
  • compositions which contain a reactive chlorine-oxygen compound as the active ingredient are known from the prior art and already show good properties as pharmaceuticals. However, there is a constant need to improve these properties. These include, inter alia, the effectiveness, the tolerability, the manageability, the dosage and the dosability of these pharmaceutical preparations.
  • the object of the present invention to provide an improved pharmaceutical preparation.
  • the pharmaceutical preparation should be as simple and inexpensive to produce.
  • the pharmaceutical preparation should be able to be produced in a large amount.
  • the pharmaceutical preparation should be very well tolerated and have as few side effects as possible.
  • the pharmaceutical preparation should have a high level of effectiveness.
  • it should be possible to administer the pharmaceutical preparation at the first sign of a condition that makes drug treatment appear expedient, without unacceptable harm to the patient being associated with this.
  • the pharmaceutical preparation should have such a high level of effectiveness that even patients with a severe form of a disease experience a significant increase in the probability of survival after administration of the medicament.
  • the pharmaceutical preparation should be able to be easily adapted to specifications in relation to the dosage, so that, for example, a relatively high dosage can be administered.
  • the pharmaceutical preparation should contribute to an improvement in the quality of life and not additionally impair it.
  • the pharmaceutical preparation to be provided should lead to a great improvement in the survival rate in patients with a serious illness, in particular in the case of a serious lung disease or a more serious infectious disease, in particular a bacterial or viral infectious disease.
  • the subject matter of the present invention is a pharmaceutical preparation containing a reactive chlorine-oxygen compound as an active ingredient, which is characterized in that the reactive chlorine-oxygen compound is provided in the form of a medicament that can be inhaled into the lungs.
  • the present invention has the effect that the efficacy, tolerability, manageability, dosage and dosability of a pharmaceutical preparation containing a reactive chlorine-oxygen compound as an active ingredient can be unexpectedly improved.
  • a pharmaceutical preparation according to the present invention enables a surprisingly effective treatment of a lung disease.
  • a reliable treatment with few side effects can be achieved for patients with a lung disease, which, among other things, improves the course of the disease and reduces the severity of the disease.
  • the survival rate in the case of severe lung diseases, some of which are associated with a high mortality rate can surprisingly be greatly increased.
  • a pharmaceutical preparation according to the invention shows excellent tolerability, in particular few side effects. Farther a pharmaceutical preparation according to the present invention leads to an improvement in the quality of life and does not additionally impair it.
  • a pharmaceutical preparation according to the invention is very well tolerated and has relatively few side effects.
  • a pharmaceutical preparation according to the invention shows a high level of effectiveness, with the pharmaceutical preparation being able to be administered at the first sign of a disease, preferably an infectious disease and/or a lung disease, particularly preferably a lung infectious disease, without causing unreasonable harm to the patient.
  • a pharmaceutical preparation according to the present invention is so effective that even patients with a severe form of an infectious disease and/or a lung disease, particularly preferably an infectious lung disease, experience a significant increase in the probability of survival after administration of the drug.
  • the pharmaceutical preparation can preferably be produced relatively easily and inexpensively. Furthermore, a pharmaceutical preparation can be produced in a large amount.
  • the pharmaceutical preparation can be handled safely and easily.
  • the medicament can be applied not only by professional nursing staff but also directly by untrained people, for example patients, so that, for example, self-care of an infectious disease and/or a lung disease, particularly preferably an infectious lung disease, is made possible.
  • the pharmaceutical preparation can easily be adapted to specifications in relation to the dosage, so that, for example, relatively high or low dosages can be administered, so that it can be adapted to the respective needs of the patient.
  • Chloro-oxygen compound is provided in the form of a medicament that can be inhaled into the lungs.
  • lung inhalable means that Drug can penetrate into the lungs.
  • the reactive chlorinated oxygen compound is provided as an aerosol.
  • the reactive chlorine-oxygen compound is provided as an aerosol with an average particle size of at most 10 pm, preferably at most 5 pm, particularly preferably at most 3.5 pm, measured as Mass Median Aerodynamic Diameter (MMAD) with a 7-stage cascade impactor (Next Generation Impactor (NGl)) (DIN EN 13544-1:2007+A1:2009).
  • MMAD Mass Median Aerodynamic Diameter
  • Nl Next Generation Impactor
  • the reactive chlorine-oxygen compound is provided as an aerosol, the mass fraction of particles with a particle size of less than 5 ⁇ m being at least 50%, preferably at least 60% and particularly preferably at least 70%, measured with a 7-stage cascade impactor (Next Generation Impactor (NGl)).
  • Nl Next Generation Impactor
  • the pharmaceutical preparation of the present invention comprises at least one reactive chlorine-oxygen compound as an active ingredient.
  • the pharmaceutical preparation of the present invention can contain precisely one, two, three, four or more reactive chlorine-oxygen compounds.
  • Reactive chlorine-oxygen compounds are compounds comprising oxygen and chlorine that contribute to amelioration of a disease state, disease, or disease. These include the lung diseases and/or infectious diseases detailed above and below, such as bacterial or viral infectious diseases. These also include chronic lung diseases. It can be assumed here that reactive chlorine-oxygen compounds can chemically or biochemically intervene in the processes described above and below that contribute to a disease, without any limitation being intended as a result.
  • oxyacids of chlorine, their salts or derivatives of these oxyacids can preferably be used as reactive chlorine-oxygen compounds.
  • Derivatives of reactive chlorine-oxygen compounds include carbonic acid adducts of oxygen acids of chlorine or similar compounds.
  • Reactive chlorine-oxygen compounds are already being used or at least proposed for some pharmaceutical applications.
  • hypochlorites in particular sodium hypochlorite, are used in dentistry or for the treatment of patients with atopic eczema.
  • Chlorites, including sodium chlorite are used to treat wounds, with further proposed use in the treatment of amyotrophic lateral sclerosis (ALS).
  • Chlorates, especially sodium chlorate are used to treat wounds and perchlorates, especially potassium perchlorate, to treat thyroid disorders.
  • these compounds have not been provided in the form of a medicament inhalable into the lungs.
  • peroxochlorine compounds from WO 00/48940 A1 and dichlorooxygen compounds from WO 2005/049483 A2 are known, which are particularly suitable as wound treatment agents. Providing these compounds in the form of a medicament that can be inhaled into the lungs has not previously been suggested.
  • dichlorooxy acids set out in WO 2005/049483 A2 are superior here to the peroxochloric acids described in WO 00/48940 A1. This applies in particular with regard to their effectiveness and with regard to their tolerability and their durability. Thus, dichloro oxyacids are particularly preferred. This also applies to the salts, anions and derivatives of these acids.
  • Peroxochloric acids or their salts which are described inter alia in WO 00/48940 A1, and dichlorooxyacids or their salts, which are described inter alia in WO 2005/049483 A2, are superior to hypochlorites, chlorites, chlorates and perchlorates.
  • peroxochloric acids and dichlorooxo acids are preferred, with dichlorooxo acids being particularly preferred. This applies in particular to their effectiveness and tolerability. This also applies to the salts, anions and derivatives of these acids (peroxochloric acids and dichlorooxy acids).
  • the reactive chlorine-oxygen compound to comprise a peroxochloric acid, a peroxochlorous acid and/or a dichlorooxy acid, preferably a dichloroperoxo acid or a pharmaceutically acceptable salt of these acids.
  • the preferred reactive chlorine compounds also include dichlorooxoacids, particularly preferably dichloroperoxoacids, their intermediates, such as peroxochloric acid and peroxochlorous acid, and their respective derivatives, salts and anions.
  • dichlorooxoacids are preferred over other reactive chlorine compounds, with dichloroperoxoacids being particularly preferred.
  • Dichlorox acids are oxygen acids of chlorine that have two chlorine atoms.
  • Dichloroperoxoacids are oxyacids of chlorine which have two chlorine atoms and at least four, preferably six, oxygen atoms.
  • the reactive chlorine-oxygen compound comprises a gross molecular formula selected from HCIO, HCIO2, HCIO3, HCIO4 and/or H2CI2O6 or a pharmaceutically acceptable salt of these acids, preferably a gross molecular formula selected from HCIO3, HCIO4 and/or H2CI2O6 or a pharmaceutically acceptable salt of these acids.
  • [O2CIOOCIO2] 2 ' includes and / or the anion of the reactive chlorine compound Gross molecular formula C ⁇ Oe 2 ' includes.
  • This structure can be present as an acid and/or as a salt, the salt preferably being pharmaceutically acceptable.
  • peroxochloric acids with the general formula HCIO4, the anion preferably having a structure [C ClOO]', which in particular has a peroxo group (O-O).
  • chlorine has the oxidation state +5, and these compounds are described, inter alia, in WO 00/48940 A1.
  • a reactive chlorine-oxygen compound preferably a peroxochloric acid or a salt of this acid, is preferably obtainable by a process in which one
  • dichlorooxoacids with the general formula H2Cl2O6 and their derivatives, anions or salts as the reactive chlorine-oxygen compound. These compounds are also referred to herein as dichloroperoxoacids, regardless of the structure of the anion of that acid.
  • dichlorooxy acids with the general formula H2Cl2O6 and their derivatives, anions, or salts, with the structural formulas of the anions
  • dichloric acids of the anions of structural formulas I - III being particularly preferred.
  • dichlorooxo acids No. 1 to No. 3 are particularly preferred embodiments of the compounds to be used.
  • anions are referred to in this disclosure, the presence of required counterions (especially in solution) is implied. It should with the The term anions is used to express that in solution the dichlorate (C ⁇ Oe 2- ) is the more stable form compared to the profaned acid (H2CI2O6). However, according to the invention, depending on the context, the term “anion” can also represent the acid, the term “acid” can also represent the “anion”.
  • the counterions are preferably pharmaceutically acceptable cations that are generally known.
  • the reactive chlorine-oxygen compounds to be used according to the invention can also be used as a mixture.
  • dichlorooxoacids and peroxochlorous acid and also the anions present at physiological pH values can also be present in solution as a mixture with peroxochlorate and chlorite and can be used as such.
  • Such a solution comprising dichlorooxo acids, peroxochlorous acid, peroxochlorate and chlorite is therefore one of the particularly preferred exemplary embodiments of the present invention.
  • the end product of the solutions according to the invention contains chlorite in no more than 20-fold, preferably no more than 5-fold, and in particular no more than ß-fold excess in Parts by weight compared to other reactive chlorine compounds, in particular dichlorooxoic acids, preferably dichloroperoxoic acids, based on the total weight of the solution.
  • dichlorooxo acids to be used with preference and the peroxochlorous acid are present in this solution in amounts of about 0.1-20% by weight, preferably 3-5% by weight, based on the proportion by weight of CIO2 used.
  • the qualitative detection succeeds via Raman spectroscopy. Performing this type of spectroscopy is obvious to those skilled in the art.
  • the spectrograms obtained from dichlorooxo acids, preferably dichloroperoxo acids differ significantly from the compositions which are obtained using the method of WO 00/48940.
  • the quantitative proportion can be determined via titration.
  • dichloroperoxoacids versus other reactive chlorine compounds, in particular peroxochloric acid are also preferred. Accordingly, it is particularly preferred if in the end product of the solutions according to the invention peroxochlorate (CIC) is not more than 20-fold, preferably not more than 5-fold, and in particular not more than ß-fold excess in parts by weight compared to other reactive chlorine-oxygen compounds, in particular dichlorooxo acids, preferably dichloroperoxo acids, based on the total weight of the solution.
  • the proportion of peroxochlorate (CIO4-) is particularly preferably below 25% by weight, preferably below 15% by weight, particularly preferably below 5% by weight, based on the weight of the dichlorooxoacids present.
  • a reactive chlorine-oxygen compound is particularly preferably obtainable by a method in which one
  • dichlorooxo acids preferably dichloroperoxo acids
  • the reactive chlorine-oxygen compounds to be used with preference can be obtained in particular by a process which preferably consists in Chlorine dioxide with aqueous or hydrous hydrogen peroxide or another peroxide or hydroperoxide known to those skilled in the art, such as
  • Peroxocarbonate or perborate or the urea adduct of hydrogen peroxide at a pH of 6.5 or higher, preferably pH 10-12. It is preferable to keep the pH at a constant value.
  • peroxochloric acid occurring as an intermediate and its anions and derivatives can also be obtained by reacting chlorine dioxide with other oxidizing agents which contain the peroxo group.
  • the reaction can be carried out in an aqueous medium or in a water-containing medium.
  • a water-containing medium for example, in addition to water, there can also be water-miscible solvents, such as alcohols, such as alkanols, such as methanol, ethanol or the like, or mixtures thereof.
  • chlorine oxides can also be used.
  • chlorine monoxide preferably in its dimeric form (Cl2O2)
  • a hydroperoxide preferably hydrogen peroxide
  • the reaction temperature can be increased, for example up to about 50°C; in the case of purely aqueous systems, the lowest temperature is preferably around 0°C. However, you should not work with chlorine dioxide below +10 degrees Celsius, since the chlorine dioxide gas liquefies below this temperature and deflagration can occur. If additional organic solvents and/or high concentrations of the reagents involved are present, lower temperatures, i.e. temperatures below the freezing point of water, can also be used. It is preferred to work at room temperature.
  • the chlorine dioxide required for the reaction is available to the person skilled in the art and can be produced in a customary manner.
  • it can be prepared by reacting a chlorite with an acid (e.g. sodium chlorite with sulfuric acid) or by reducing a chlorate, e.g. with sulphurous acid.
  • the chlorine dioxide obtained in this way can optionally be freed in a manner known per se (Granstrom, Marvin L; and Lee, G. Fred, J. Amer. Water Works Assoc. 50, 1453-1466 (1958)) after removal of any traces of chlorine present .
  • CIO2 is formed which is contaminated with CO2 and/or the carbonic acid adducts described in WO00/48940.
  • the gas stream containing chlorine dioxide and carbon dioxide should be passed through a washing bottle filled with lye. With short contact times, the CO2 is absorbed by the lye, but not the CIO2. However, it is better to remove the carbonate impurities by fractional crystallization of the sodium chlorite used. Carbonate contamination of the peroxochlorate can easily be seen in the Raman spectrum. Instead of the sharp band at 1051 cm'1 , a double band is obtained at 1069 cm'1 (broad) and the band at 1051 cm'1 (sharp).
  • the chlorine dioxide can be conveyed with an inert gas such as nitrogen or an inert gas such as argon, but also with air or oxygen for reaction with the peroxo compound or the hydroperoxide such as hydrogen peroxide or percarbonate or perborate.
  • an inert gas such as nitrogen or an inert gas such as argon
  • air or oxygen for reaction with the peroxo compound or the hydroperoxide such as hydrogen peroxide or percarbonate or perborate.
  • the pH of the reaction mixture is maintained at or above 6.5 by addition of a base. It is preferred to keep the pH constant. This can be done either manually or automatically by a "pH-Stat" device.
  • Customary inorganic or organic bases such as alkali metal hydroxides, for example sodium hydroxide solution or potassium hydroxide solution or alkaline earth metal hydroxides, ammonia or organic bases such as nitrogen bases can be used as bases.
  • the hydroxides of quaternary ammonium salts, in particular alkyl, such as trialkyl or tetraalkyl ammonium hydroxides, or zinc hydroxides can also be used.
  • the content of hydroperoxide in the reaction mixture can be determined, for example, by potentiometric titration with an acid such as hydrochloric acid.
  • solutions obtained by the process described above can be used as such or in a modified form.
  • excess hydrogen peroxide can be removed in a conventional manner, e.g., with a heavy metal compound such as manganese dioxide.
  • Excesses of the other oxidizing agents can be eliminated analogously.
  • chloret-containing product is not preferred over other pharmaceutical preparations, so that generation of chloret should be avoided.
  • the proportion of chloret (CIOs-) is particularly preferably below 25% by weight, preferably below 15% by weight, particularly preferably below 5% by weight, based on the weight of the chlorinated oxyacids present.
  • pH is suitable, for example at pH 10 or more.
  • This pH can be adjusted with a suitable base, as described above for the production process.
  • the mixture resulting from the initiation of stage (a) of the manufacturing process described above initially contains very high concentrations of chlorite ions (CIO2-).
  • CIO2- chlorite ions
  • the chlorite content can be significantly reduced by “transferring” the gas flow to a basic solution.
  • the chlorinated oxyacids of all kinds are expelled as volatile compounds in a profaned (neutral) form, which, however, are very unstable.
  • There is a base in the template whereby the chlorinated acids are deprotonated and the anions are formed.
  • the anions of the dichlorooxo acids which are to be used with particular preference, are then formed.
  • Dichlorooxo acids to be used with preference can be obtained by a process in which the reactive chlorine-oxygen compound obtainable according to steps a) to c) described above is incubated with chlorite at a pH of 6 to 8.
  • the incubation time can be selected relatively arbitrarily, too short incubation times leading to incomplete conversion and too long incubation times to possible decomposition of the dichlorooxoic acids, which are to be used with particular preference.
  • the incubation time can preferably be in the range from 1 second to 1 week, particularly preferably in the range from 1 minute to 24 hours and especially preferably 5 minutes to 1 hour.
  • the incubation time can be regulated by adjusting the pH, the incubation being terminated by increasing the pH to above 8, in particular above 9.
  • the proportion of chlorite can be within a wide range. High amounts of chlorite, based on the reactive chlorine compound obtained according to steps a) to c) described above, lead to very complete conversion to the dichlorooxo acids, which are to be used with particular preference. Small amounts of chlorite in relation to the reactive chlorine-oxygen compound obtained according to steps a) to c) described above lead to residual amounts of the reactive chlorine-oxygen compounds obtained according to steps a) to c) described above.
  • the chlorite can be used with an excess of up to 100 times, preferably up to a fold excess, based on the reactive chlorine-oxygen compound obtained according to steps a) to c) described above.
  • the molar ratio of chlorite to the reactive chlorine-oxygen compound obtained according to steps a) to c) described above is in the range from 10:1 to 1:10, preferably 2:1 to 1:2 and particularly preferably 1:1 to 1:1.2.
  • step c) the gaseous free reactive chlorine compound can be trapped, for example, in a base such as an alkali metal base, alkaline earth metal or zinc base or nitrogen base such as ammonia or an organic amine.
  • a base such as an alkali metal base, alkaline earth metal or zinc base or nitrogen base such as ammonia or an organic amine.
  • All metal cations and organic cations such as those of nitrogen bases, in particular quaternary ammonium salts, are suitable as counterions.
  • Alkaline earth or alkali metals preferably Na + or K + , or Zn 2+ are particularly preferred for pharmaceutical applications.
  • aqueous solutions therefrom with high pH values, eg with pH values of 10, 11 or 12 and above, in particular in the range from pH 10 to pH 13 in order to achieve long storage lives.
  • the free acid can be obtained again from such solutions, as described above, and optionally converted into solutions with the desired pH or into salts.
  • the pharmaceutical preparation preferably shows a signal in a mass spectrum at 189.0 m/z. This signal is preferably based on the reactive chlorine-oxygen compound used. Accordingly, reactive chlorine-oxygen compounds showing a peak at 189.0 m/z in the mass spectrum are preferred.
  • the mass spectrum of the pharmaceutical preparation can have a signal at 99 m/z, the signal preferably being based on the reactive chlorine-oxygen compound used.
  • the signal at 189.0 m/z of the mass spectrum of the pharmaceutical preparation is higher than at 99 m/z.
  • the mass spectrum of the pharmaceutical preparation can have a signal at 83.2 m/z, the signal preferably being based on the reactive chlorine-oxygen compound used.
  • the signal at 83.2 m/z of the mass spectrum of the pharmaceutical preparation is higher than at 99 m/z.
  • the mass spectrum can be obtained using conventional methods, this preferably being carried out according to the method set out in the examples.
  • a preferred pharmaceutical preparation for use according to the present invention may have a reactive chlorine-oxygen compound which shows a peak at a retention time of 15 minutes in an ion chromatogram.
  • the ion chromatography can be carried out using customary methods, this preferably being carried out according to the method set out in the examples.
  • dichlorooxo acids to be used with particular preference preferably exhibit two transitions in a titration curve, as is clearly shown in FIGS.
  • This titration curve shows two transitions which can be assumed to be due to the pKa values of the particular Dichloroxic acids to be used with preference are due.
  • dichlorooxo acids to be used with particular preference preferably have two pKa values, one pKa value being in the range of 8.5 and one pKa value being in the range of 5. These values are determined potentiometrically at 25° C. with a 0.1 M hydrochloric acid.
  • dichlorooxoacids to be used with preference according to the invention or the peroxochlorous acid, their respective derivatives, or anions and salts thereof can be provided as such and in particular in aqueous or water-containing solution as a pharmaceutical preparation in the form of a medicament that can be inhaled into the lungs.
  • unexpected benefits are obtained in the treatment of a wide range of diseases, especially in the treatment of lung diseases.
  • the preparations can contain the active ingredient alone or, preferably, together with one or more pharmaceutically acceptable carriers.
  • the pharmaceutical preparation may preferably include a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier will preferably adapted to the dosage form.
  • the pharmaceutical carrier preferably comprises water, the proportion of water preferably being at least 90% by weight, based on the weight of the pharmaceutical carrier, preferably based on the weight of the pharmaceutical preparation.
  • the pharmaceutical preparation is an aqueous solution.
  • the aqueous solution comprises the reactive chlorine-oxygen compound set out above.
  • the reactive chlorine-oxygen compound in the pharmaceutical preparation is present in a molar concentration of at least 0.01 mmol/l, preferably at least 0.1 mmol/l, particularly preferably at least 0.3 mmol/l and especially preferably at least 0. 5 mmol/l is present, with water preferably being used as the pharmaceutically acceptable carrier and the proportion of reactive chlorine-oxygen compound being determined by titration.
  • the concentration of the reactive chlorine-oxygen compound can be determined by any convenient method, preferably a titration with HCl.
  • the concentration of HCl in the titration solution is preferably in the range from 0.01 to 1 mol/l, particularly preferably about 0.1 mol/l.
  • the concentration of reactive chlorine compound is determined via the pH of the composition. More details on this can be found in the examples.
  • the reactive chlorine-oxygen compound in the pharmaceutical preparation is present in a molar concentration in the range from 0.01 mmol/l to 100 mmol/l, preferably from 0.1 mmol/l to 50 mmol/l, particularly preferably from 0 3 to 20 mmol/l and particularly preferably from 0.5 mmol/l to 10 mmol/l, with water preferably being used as the pharmaceutically acceptable carrier and the proportion of reactive chlorine compound being determined by titration.
  • the molar concentration can preferably be determined via a titration with HCl, as explained in more detail above.
  • concentration by weight of reactive chlorinated oxygen compound can be determined by any convenient method, preferably employing a titration with HCl as set forth above.
  • the molar mass of the reactive chlorine compound is used for the conversion, and in a preferred embodiment, in particular in the case of dichlorooxo acids with a molecular formula CI2O6 2 ', this can be set at about 167 g/mol.
  • the anion can preferably be used as the basis.
  • the reactive chlorine-oxygen compound in the pharmaceutical preparation is in a molar concentration in the range from 2 mg/l to 20,000 mg/l, preferably from 20 mg/l to 10,000 mg/l, particularly preferably from 600 mg/l to 4000 mg/l and particularly preferably from 100 mg/l to 2000 mg/l, water being preferably used as the pharmaceutically acceptable carrier and the proportion of reactive chlorine-oxygen compound being determined by titration.
  • the concentration of reactive chlorine compound based on the weight can preferably be obtained via a titration with HCl and a subsequent conversion taking into account the molar mass, the molar mass of the anion being particularly preferably used.
  • a pharmaceutical preparation can comprise at least one other active ingredient that differs from a reactive chlorine-oxygen compound, as is the subject of the present application.
  • a further object of the present invention is accordingly a pharmaceutical preparation comprising at least one reactive chlorine-oxygen compound as described above and below, and at least one pharmaceutically active substance which differs from the reactive chlorine compound described above and below.
  • the preferred additional active ingredients that differ from a reactive chlorine-oxygen compound include, inter alia, steroids such as cortisone, beta-2 sympathomimetics such as indacaterol, salbutamol, fenoterol, reproterol, salmeterol and formoterol, anticholinergics such as butylscopolamine, ipratropium bromide, and tiotropium bromide.
  • steroids such as cortisone, beta-2 sympathomimetics such as indacaterol, salbutamol, fenoterol, reproterol, salmeterol and formoterol
  • anticholinergics such as butylscopolamine, ipratropium bromide, and tiotropium bromide.
  • the dosage of the reactive chlorine-oxygen compound to be used according to the invention can be selected according to the disease, the clinical picture and the condition of the patient.
  • the pharmaceutical preparation can be provided in a form that is administered in a single dose.
  • the pharmaceutical preparation is preferably provided in the form of a preparation which can be administered several times.
  • the pharmaceutical preparation can be administered at least twice, preferably at least three times, particularly preferably at least four times and especially preferably at least five times.
  • the pharmaceutical preparation is preferably provided in such a way that there is a period of time between administrations of 1 hour to 5 days, preferably 2 hours to 2 days and particularly preferably 3 hours and 1 day.
  • the dosage of the reactive chlorine-oxygen compound to be used according to the invention depends on the disease to be treated, the clinical picture to be treated, and on the species, its age, weight and individual condition, individual pharmacokinetic conditions and the mode of administration.
  • the dosage (preferably in humans) is preferably in the range from 0.01 to 100 pmol/kg, in particular between 0.1 to 100 pmol/kg, i.e. for example in a human with a body weight of 70 kg at 1 mg to 1 g/day, particularly at 8.5 mg to 850 mg/day, in one or divided doses.
  • the reactive chloroxygen compound is provided in the form of a medicament inhalable into the lungs.
  • the pharmaceutical preparation is preferably provided via an inhaler.
  • the inhaler provides the pharmaceutical preparation with a nebulization time of at most 10 minutes for 2.5 ml of pharmaceutical preparation.
  • the inhaler contains the pharmaceutical preparation with a Nebulization output of 0.10 ml/min to 2 ml/min, preferably 0.15 to 1.0 ml/min and particularly preferably 0.20 ml/min to 0.60 ml/min.
  • the pharmaceutical preparation containing as an active ingredient a reactive chlorine-oxygen compound is provided in the form of a pulmonary inhalable medicament. Accordingly, a reactive chlorine-oxygen compound is introduced into the lungs via a gas flow, preferably an air flow.
  • a gas flow preferably an air flow.
  • an amount of 0.5 ml to 15 ml, preferably 1 to 10 ml, particularly preferably 2 to 8 ml of pharmaceutical preparation can be inhaled over a period of 1 second to 2 hours, preferably 1 minute to 60 minutes, particularly preferably 10 minutes to 30 minutes can be provided.
  • the amount of pharmaceutical preparation is calculated on the basis of the liquid to be evaporated or the solid to be aerosolized, which preferably comprises at least one pharmaceutically acceptable carrier, preferably water, in addition to the reactive chlorine-oxygen compound.
  • the pharmaceutical preparation with a concentration in the range of 1*10 -6 to 20% by volume, preferably in the range of 1*10'5 to 5 % by volume, particularly preferably in the range of 0, 0001 to 1% by volume is provided, this specification relating to the ratio of the volume of the pharmaceutical preparation to the nebulizing gas (air).
  • the dosage of the other active ingredients can be selected according to the clinical picture to be treated, as well as species, their age, weight and individual condition, individual pharmacokinetic conditions and the mode of administration of the / the other active ingredient / s, where these can be chosen based on the usual dose(s) for the other active ingredient(s).
  • the invention also relates to a pharmaceutical composition for the prophylactic and in particular therapeutic treatment thereof described disease states, preferably for the prophylactic or therapeutic treatment, preferably of a warm-blooded animal suffering from such a disease, containing one or more reactive chlorine compounds, preferably peroxochloric acid, peroxochlorous acid and / or dichloric acids, particularly preferably dichlorooxo acids and / or peroxochloric acid, very particularly preferably Dichloroperoxoacids, or their respective derivatives or salts, in an amount effective prophylactically or, in particular, therapeutically against said disease, and one or more pharmaceutically acceptable carriers in the form of a medicament that can be inhaled into the lungs.
  • a pharmaceutical composition for the prophylactic and in particular therapeutic treatment thereof described disease states preferably of a warm-blooded animal suffering from such a disease, containing one or more reactive chlorine compounds, preferably peroxochloric acid, peroxochlorous acid and / or dichloric acids, particularly preferably dichloroo
  • the invention also relates to a method for the treatment of disease states, preferably for prophylactic and/or therapeutic treatment - in particular in a warm-blooded animal, in particular a human being - comprising the administration of reactive chlorine compounds, preferably peroxochloric acid, peroxochlorous acid and/or dichloro acids, particularly preferably dichlorooxo acids and/or peroxochlorous acid, very particularly preferably dichloroperoxoacids, or their respective derivatives, anions or salts, in an amount effective against the diseases mentioned, to a warm-blooded animal, eg a human, who requires such treatment in the form of a medicament that can be inhaled into the lungs.
  • reactive chlorine compounds preferably peroxochloric acid, peroxochlorous acid and/or dichloro acids, particularly preferably dichlorooxo acids and/or peroxochlorous acid, very particularly preferably dichloroperoxoacids, or their respective derivatives, anions or salts
  • the invention also relates to the use of the reactive chlorine compounds, preferably peroxochloric acid, peroxochlorous acid and/or dichloroacids, preferably dichlorooxoic acids and/or peroxochlorous acid, particularly preferably dichloroperoxoacids, and their derivatives, anions or salts for use in a method for the treatment of humans or animals body in the form of a drug that can be inhaled into the lungs.
  • the reactive chlorine compounds preferably peroxochloric acid, peroxochlorous acid and/or dichloroacids, preferably dichlorooxoic acids and/or peroxochlorous acid, particularly preferably dichloroperoxoacids, and their derivatives, anions or salts for use in a method for the treatment of humans or animals body in the form of a drug that can be inhaled into the lungs.
  • the invention relates in particular to the use of reactive chlorine compounds, preferably peroxochloric acid, peroxochlorous acid and/or dichloroacids, preferably dichlorooxoic acids and/or peroxochlorous acid, particularly preferably dichloroperoxoacids, their derivatives, anions or salts for the manufacture of a medicament for the treatment of the human or animal body, preferably for prophylactic and / or therapeutic treatment - especially in a warm-blooded animal, especially a human - of the disease states described above or below in the form of a medicament inhalable into the lungs.
  • reactive chlorine compounds preferably peroxochloric acid, peroxochlorous acid and/or dichloroacids, preferably dichlorooxoic acids and/or peroxochlorous acid, particularly preferably dichloroperoxoacids, their derivatives, anions or salts for the manufacture of a medicament for the treatment of the human or animal body, preferably for prophylactic and / or therapeutic treatment
  • the pulmonary inhalable medicament may be provided in appropriate unit dosage forms.
  • the medicament which can be inhaled into the lungs can be administered via an inhaler.
  • the inhalant can be fed into the inhaler using conventional methods, appropriate storage forms being known.
  • the medicament can be stored in the form of, for example, ampoules, vials, syringes or bags and fed to the inhaler accordingly for administration.
  • Other forms of administration especially for solutions of reactive chlorine compounds, preferably dichloroacids, preferably dichlorooxoacids, particularly preferably dichloroperoxoacids or peroxochlorous acid, their anions, derivatives or salts, are, for example, sprays that are provided in a lung-inhalable form and the like.
  • the dosage unit forms eg ampoules, vials, syringes or bags, preferably contain from about 0.005 g to about 10.0 g, in particular from 8.5 mg to 850 mg, of a salt of reactive chlorine compounds, preferably peroxochloric acid, peroxochlorous acid and/or dichloric acids , particularly preferably dichlorooxyacids and/or peroxochlorous acid, very particularly preferably dichloroperoxoacids, their anions, derivatives with customary carriers.
  • a salt of reactive chlorine compounds preferably peroxochloric acid, peroxochlorous acid and/or dichloric acids , particularly preferably dichlorooxyacids and/or peroxochlorous acid, very particularly preferably dichloroperoxoacids, their anions, derivatives with customary carriers.
  • the pharmaceutical preparation is provided in a container, which comprises at least two chambers for storing at least two liquids, which can be opened by mechanical action, so that after opening the chambers, the liquids can be mixed, one of the chambers having a liquid comprises a reactive chlorine-oxygen compound of the present invention and one of the chambers comprises a liquid pH adjusted to a physiological pH.
  • This container is used in particular for storing the pharmaceutical preparation.
  • the container is matched to an inhaler in such a way that the container is placed in the inhaler and the inhaler opens the at least two chambers for storing at least two liquids and mixes the liquids when operated.
  • the inhaler preferably provides the reactive chlorine-oxygen compound in the form of a medicament that can be inhaled into the lungs.
  • This method of preparation is expedient in particular in the case of reactive chlorine-oxygen compounds, the pH of which should be adjusted to a physiologically tolerable value before application.
  • another active substance, which differs from a reactive chlorine compound, is used together with this, it can be stored in one of the two chambers, depending on its stability.
  • this is preferably provided in a third chamber, the container being constructed in such a way that the pH of the reactive chlorine-oxygen compound is first adjusted to a physiologically tolerable value, after which the resulting mixture is mixed with the contents of the third chamber.
  • the pharmaceutical preparations of the present invention are manufactured in a manner known per se, e.g., by means of conventional mixing, dissolving or lyophilization processes.
  • a 0.005 to 1 M solution of one or more reactive chlorine compounds preferably peroxochloric acid, peroxochlorous acid and/or dichloro acids, particularly preferably dichlorooxo acids and/or peroxochlorous acid, very particularly preferably dichloroperoxo acids and/or a salt of these acids or their derivatives dissolved in twice-distilled water at a pH equal to or >10, preferably 10 to 13, in particular 12.5.
  • this solution is diluted with sodium chloride, sodium or potassium bicarbonate and bidistilled water to a concentration of approx. 1 - 10 mM to make it isotonic and the pH is then brought to a physiological level.
  • This solution is suitable for application via the lungs.
  • An inhaler can preferably be used for this purpose.
  • the reactive chlorine compounds preferably peroxochloric acid, peroxochlorous acid and/or dichloroacids, particularly preferably dichlorooxoic acids and/or peroxochlorous acid
  • the reactive chlorine compounds are very particularly preferred
  • a physiological pH is adjusted with a physiologically tolerable acid, preferably HCl.
  • a physiologically tolerable acid preferably HCl.
  • Additives that can neutralize traces of transition metals are particularly suitable when the drug is filled into plastic containers, since transition metals are dissolved in the walls during storage and can catalyze decomposition of the active substance.
  • examples of such additives are oligo- or polyalcohols such as ethylene glycol, desferrioxamine or EDTA (eg as disodium EDTA).
  • the solution obtained in this way can be administered directly by inhalation, preferably via an inhaler, particularly preferably as an aerosol.
  • the anions of the preferred dichloric acids or peroxochloric acid are stable, the acids themselves decompose relatively quickly. Drug stabilization can therefore be achieved via the pH value. To improve tolerability, the active ingredient solution can be reduced to an approximately physiological value by diluting the buffer immediately before use.
  • the pharmaceutical preparation is used in particular for the treatment of infectious diseases or lung diseases, preferably lung diseases.
  • the lung disease can be a fungal, bacterial or viral infection preferably a bacterial or viral infection, particularly preferably a viral infection.
  • the bacterial lung disease represents an infection caused by Streptococcus pneumoniae, in particular pneumococci, Pseudomonas aeruginosa, Burkholderia cepacia complex (BCC), Staphylococcus (S.) aureus, methicillin-resistant Staphylococcus aureus, Pandoraea (related to Burkholderia ), Stenotrophomonas maltophilia, Achromobacter xylosoxidans, Haemophilus influenzae, Nocardia, Ralstonia pickettii, Inquilinus, enterobacteria, and/or mycobacteria, such as Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium africanum, Mycobacterium microti.
  • mycobacteria such as Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium africanum, Mycobacterium microti.
  • the reactive chlorinated oxygen acids administered via the lungs are very effective against bacteria that are particularly critical and difficult to combat.
  • S. pneumoniae are Gram-positive bacteria that can cause a variety of diseases. These diseases can be particularly dangerous for infants, young children, the elderly and people with underlying chronic diseases.
  • Pseudomonas aeruginosa is the most common germ found in the airways of cystic fibrosis. Pseudomonads are mainly found in humid environments, especially in humid biotopes and standing water, but also in the lungs of humans.
  • Pseudomonas aeruginosa has the ability to form a biofilm in which the bacteria congregate and, in a embedded in a gelatinous protective layer that survive attacks from the immune system and antibiotics.
  • BCC Burkholderia cepacia complex
  • BCC Burkholderia cepacia complex
  • B. Burkholderia multivorans
  • B. cenocepacia and B. dolosa are particularly important for cystic fibrosis patients. Under certain circumstances, these bacteria can trigger the so-called Cepacia syndrome, an acute deterioration in lung function with life-threatening complications. After lung transplantation, B. gladioli and B. cenocepacia can lead to serious infections.
  • Staphylococci are spherical bacteria that occur naturally in the environment and also on the skin and mucous membranes of healthy people. Staphylococcus (S.) aureus is a very resilient germ and can survive for months in dry dust or on surfaces.
  • S. aureus is the most common germ in young cystic fibrosis patients and is later usually “replaced” by other germs, especially Pseudomonas aeruginosa. Infection with S. aureus can be asymptomatic, but it can also lead to increased coughing with purulent sputum (sputum) in CF patients and, rarely, cause severe pneumonia.
  • Non-resistant S. aureus are also referred to as so-called methicillin-sensitive S. aureus (MSSA): They can usually be treated well with antibiotics. However, infection with MSSA can also become chronic and impair lung function in the long term.
  • MRSA methicillin-resistant form
  • the mycobacteria in particular Mycobacterium tuberculosis, Mycobacterium bovis, Mycobacterium africanum and/or Mycobacterium microti, often trigger tuberculosis, in particular pulmonary tuberculosis.
  • the viral lung disease represents an infection caused by respiratory syncytial viruses, rhinoviruses, influenza viruses, parainfluenza viruses, human bocaviruses, corona viruses (e.g. the SARS and MERS viruses), adenoviruses and /or human metapneumoviruses.
  • the reactive chlorinated oxygen acids administered via the lungs are very effective against viruses that are particularly critical and difficult to combat.
  • this applies to corona viruses, in particular SARS-associated coronavirus, Middle East respiratory syndrome-related coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), respiratory syncytial viruses, rhinoviruses, influenza viruses.
  • Corona viruses cause very different diseases in humans, ranging from severe acute respiratory syndrome.
  • infections of the lower respiratory tract occur, especially in the case of co-infections with other respiratory pathogens. Severe disease progression is observed above all in pre-existing diseases.
  • Rhinoviruses (“cold” or “cold viruses”) cause symptoms mainly in the upper respiratory tract. In CF patients, however, they can also infect the lower airways. Studies have shown that CF patients with rhinovirus infection have had to take antibiotics for significantly longer periods of time, indicating more severe or prolonged bacterial lung infections following rhinovirus infection. However, long-term damage to the lungs by rhinoviruses has not been observed to date.
  • influenza virus causes the "real" flu, which differs from the flu-like infections caused by other viruses.
  • An influenza virus infection can severely and permanently deteriorate the lung function of cystic fibrosis patients and severe lung damage up to and including lung failure can occur.
  • the infection usually progresses without long-term complications. Cystic fibrosis patients should therefore be vaccinated against influenza annually.
  • the mycotic lung disease represents an infection that is triggered by Aspergillus fumigatus, Scedosporium, Exophiala dermatitidis and/or Candida.
  • Aspergillus fumigatus is a mold. Its spores floating in the air can be inhaled and thus reach the deep human respiratory tract. This can trigger various symptoms, especially in immunocompromised people.
  • airway colonization with Aspergillus can lead to allergic bronchopulmonary aspergillosis (ABPA).
  • ABPA allergic bronchopulmonary aspergillosis
  • the patient's immune system is 'allergic' to Aspergillus, producing substances that cause excessive inflammation in the lungs. This narrows the airways and breathing can be dangerously restricted.
  • the black mold Scedosporium is a rare pathogen of skin and soft tissue infections that can cause serious complications, especially after transplantation, due to immunosuppression.
  • Scedosporium S. aurantiacum, S. prolificans, S. apiospermum
  • Exophiala dermatitidis is also a rare pathogen that can enter the human body and cause skin and soft tissue infections. This fungus has also been found in cystic fibrosis patients and associated with pneumonia. Very rarely, after transplantation, invasive infections with Exophiala can cause serious complications.
  • Candida The yeast fungus Candida (most commonly known as Candida albicans) is found on the mucous membranes of the mouth, throat, genitals and digestive tract in most people without causing any symptoms.
  • the most common clinical picture is thrush, i.e. local infection of the mucous membranes with reddening, whitish coating and itching.
  • thrush i.e. local infection of the mucous membranes with reddening, whitish coating and itching.
  • Candida can also lead to infections in the respiratory tract. Chronic colonization with Candida can worsen lung function in CF patients.
  • the pharmaceutical preparation which is provided in the form of a medicament inhalable into the lungs, can preferably be provided for use in the treatment of a chronic lung disease.
  • the present invention provides in particular a treatment method for chronic lung diseases that are difficult to treat.
  • the chronic lung disease represents bronchial asthma and/or COPD (chronic obstructive pulmonary disease).
  • Bronchial asthma is a chronic, inflammatory disease of the airways.
  • the inflammation can lead to attacks of shortness of breath due to narrowing of the airways (bronchial obstruction). Included increased mucus is formed, the bronchial muscles spasm and edema of the bronchial mucosa develops.
  • asthma attack can last from a few seconds to several hours. In Germany, about ten percent of children and five percent of adults suffer from bronchial asthma. The airways in asthmatics react to certain, otherwise usually harmless stimuli (e.g. psychological stress, overexertion) with increasing sensitivity and constrict spasmodically. Triggers can also be used.
  • Asthma can be diagnosed based on medical history, a physical exam, and using pulmonary function tests and allergy testing. Treatment for allergic asthma is avoidance of the allergen.
  • an asthma spray active ingredients are e.g. beta-2 sympathomimetics, cortisone, antileukotrienes
  • active ingredients are e.g. beta-2 sympathomimetics, cortisone, antileukotrienes
  • the doctor injects the drug directly into the vein.
  • COPD Chronic obstructive pulmonary disease
  • COPD COPD cannot be cured.
  • medication can be used to alleviate the symptoms and reduce the number of coughing fits so that this lung disease does not progress any further.
  • Physical resilience can be improved, relapses and complications prevented, thereby increasing quality of life and life expectancy.
  • the pharmaceutical preparation provided in the form of a medicament inhalable into the lungs, preferably for use in the treatment of cystic fibrosis, SIRS (systemic inflammatory response syndrome), sepsis, pulmonary fibrosis, bronchial carcinoma, lung cancer (lung carcinoma), pulmonary emphysema, pulmonary hypertension (pulmonary hypertension), bronchitis, pneumonia, interstitial lung disease and/or tuberculosis.
  • SIRS systemic inflammatory response syndrome
  • sepsis sepsis
  • pulmonary fibrosis bronchial carcinoma
  • lung cancer lung carcinoma
  • pulmonary emphysema pulmonary hypertension
  • bronchitis pneumonia
  • interstitial lung disease and/or tuberculosis preferably for use in the treatment of cystic fibrosis, SIRS (systemic inflammatory response syndrome), sepsis, pulmonary fibrosis, bronchial carcinoma, lung cancer (lung carcinoma), pulmonary emphysema, pulmonary hypertension
  • SIRS systemic inflammatory response syndrome
  • SIRS is triggered by various triggering events such as B. infections with bacteria, fungi or injuries, but they have in common that a series of reactions of the body occurs that lead to a life-threatening condition with multiple organ failure and shock (blood pressure drop).
  • triggering events such as B. infections with bacteria, fungi or injuries, but they have in common that a series of reactions of the body occurs that lead to a life-threatening condition with multiple organ failure and shock (blood pressure drop).
  • the term sepsis was coined by Schottmüller a few years after Pasteur first detected bacteria in the blood of diseased patients in 1880 (Annane, D., et al (2005) "Septic shock” Lancet 365(9453):63-78).
  • pulmonary fibrosis Over 100 different diseases of the lungs can lead to pulmonary fibrosis.
  • pulmonary fibrosis As a result of an inflammatory reaction, there is increased formation of connective tissue between the alveoli and the blood vessels in the lungs. As a result, less oxygen gets into the blood. The stiffening of the lungs makes it harder to breathe. There is a reduction in physical resilience with shortness of breath. Because not always the causes of this lung disease are known, pulmonary fibrosis is divided into diseases with known and unknown causes (idiopathic pulmonary fibrosis).
  • Known causes include, for example, inhaling asbestos or certain organic substances (e.g. protein components of hay dust or components of pigeon droppings).
  • Diagnosis includes computed tomography (CT), lung function tests, and bronchoscopy. If the cause is known, contact with the triggering substance must first be avoided. The inflammation is treated with anti-inflammatory drugs (e.g. cortisone, azathioprine). Depending on the cause, additional therapies may be required.
  • lung cancer lung carcinoma
  • bronchial cancer Lung carcinoma is the third most common cancer in Germany.
  • Smoking is the main risk factor for the development of lung cancer. Cigarette smoke can be assumed to be the main cause in 80 to 90% of male and 30 to 60% of female lung cancer patients.
  • Other risk factors are inhaled dust and vapors at the workplace (e.g. asbestos, quartz dust, arsenic, chromates, nickel and aromatic hydrocarbons), environmental influences (e.g. the radioactive noble gas radon, high levels of air pollution) and, to a certain extent, hereditary predisposition .
  • Pulmonary emphysema is usually regarded as a form of chronic obstructive pulmonary disease in which the air sacs (alveoli) in the lungs are irreversibly enlarged and destroyed. Since the dividing walls of the alveoli are enzymatically dissolved, large bubbles are formed in which the breath air accumulates. Even though the lungs contain air, there is shortness of breath. As a result, the body is not supplied with sufficient oxygen and it can lead to injuries get to the organs. Smoking is the main cause of pulmonary emphysema. Other risk factors are polluted air indoors, open fireplaces, inhalation of gases and dust at work and possibly genetic predisposition and frequent infections of the respiratory tract.
  • Pulmonary emphysema can include: can be diagnosed via lung function tests (e.g. spirometry), blood gas analysis and imaging tests (e.g. x-ray of the lungs). In addition to stopping smoking immediately or avoiding other triggering stimuli, the lungs can be reduced in size and particularly large bubbles removed by surgery. In extreme cases, a lung or lung transplantation may also be necessary.
  • lung function tests e.g. spirometry
  • blood gas analysis and imaging tests e.g. x-ray of the lungs.
  • the lungs can be reduced in size and particularly large bubbles removed by surgery. In extreme cases, a lung or lung transplantation may also be necessary.
  • pulmonary hypertension In pulmonary hypertension (pulmonary hypertension), there is increased blood pressure in the pulmonary circulation, which leads to shortness of breath, reduced oxygen supply to the body and reduced physical performance. Chest pain and edema in the legs can also occur. The causes of pulmonary hypertension are not yet fully understood. However, there is evidence that this lung disease occurs more frequently with HIV infection, certain autoimmune diseases and certain drugs (e.g. appetite suppressants, psychogenic stimulants).
  • ECG Cardiac current measurements
  • chest x-rays chest x-rays
  • lung function tests are often done because of the symptoms.
  • transthoracic echocardiography an ultrasound examination from the outside through the chest, gives indications of pulmonary hypertension.
  • the blood pressure in the pulmonary circulation is measured by a specialist using a heart-lung catheter (right heart catheter). Pulmonary hypertension is primarily treated with medication.
  • Bronchitis is the inflammation of the mucous membrane in the bronchi of the lungs. It can be acute or chronic.
  • Chronic bronchitis is the form of bronchitis in which coughing and sputum production occurs most days for at least three months for two consecutive years. Chronic bronchitis is not caused by pathogens, but by cigarette smoke (or its ingredients) or other inhaled irritants.
  • This lung disease is usually triggered by viruses, and in rare cases also by bacteria. Therefore, acute bronchitis usually heals without drug treatment; antibiotics are only effective if the cause is bacterial.
  • Pneumonia or pneumonia is an acute or chronic inflammation of the lung tissue, which is usually caused by an infection with bacteria (mostly Streptococcus pneumoniae), viruses or fungi.
  • bacteria mostly Streptococcus pneumoniae
  • the air sacs in the lungs, the lung tissue between the alveoli or the blood vessels can be affected by the inflammation.
  • Elderly people, infants and small children, as well as immunocompromised people whose immune system is either not fully developed or only partially functional are particularly at risk.
  • the suspected diagnosis can often be made after the physical examination and based on the clinical picture. Usually, an x-ray of the lungs is taken to confirm, or a sample of the sputum is taken to determine the pathogen. Treatment is usually with an antibiotic.
  • Interstitial lung diseases include various diseases of the lungs and are rather rare. They affect the tissue between the lungs (interstitium) or the air sacs (alveoli). Interstitial lung diseases include, for example, pulmonary fibrosis (abnormal proliferation and scarring of the lung tissue) or sarcoidosis (formation of small connective tissue nodes in the lungs).
  • Tuberculosis is an infectious disease caused by bacteria that primarily affects the lungs. In the majority of those infected with tuberculosis, the disease does not manifest itself.
  • the pharmaceutical preparation is characterized by very good tolerability and few side effects.
  • the reactive chlorine compound can be combined with other treatment methods and/or other active ingredients in order to improve the patient's chances of survival.
  • treating a pulmonary disease in a human subject may include the simultaneous or sequential administration of cystic fibrosis therapy, exercise therapy, nutritional therapy, and/or dialysis therapy to the subject.
  • Another object of the present invention is a use of a reactive chlorine-oxygen compound for the production of a medicament for the prophylactic and/or therapeutic treatment of a lung disease.
  • Another object of the present invention is a combination preparation comprising separate packs of at least one pharmaceutical preparation for use in the form of a medicament that can be inhaled into the lungs and/or for the treatment of a lung disease according to the present invention and at least one medicament that differs from the reactive chlorine-oxygen compound described above differs, as this is the subject of the present application.
  • Preferred other drugs other than a reactive chlorine compound include antibiotics, antipyretics, drugs for the treatment of disseminated intravascular coagulation (DIC), antibodies, cytokines, chemokines, antimicrobial peptides, sphingomyelinase inhibitors, statins , alpha-2- macroglobulin, thrombin-derived C-terminal peptide, sphingosine-1-phosphate, curcumin, ascorbic acid, resveratrol, melatonin, glycyrrhizin and erythropoietin, steroids such as cortisone, beta-2 sympathomimetics such as indacaterol , salbutamol, fenoterol, reproterol, salmeterol and formoterol, anticholinergics such as butylscopolamine, ipratropium bromide, and tiotropium bromide.
  • DIC disseminated intravascular coagulation
  • antibodies
  • antibiotics include, inter alia, ⁇ -lactam antibiotics such as penicillins, in particular benzylpenicillin, phenoxymethylpenicillin, propicillin, azidocillin, flucloxacillin, dicloxacillin, cloxacillin, oxacillin, methicillin, aminopenicillins such as amoxicillin, ampicillin and bacampicillin, acylaminopenicillins such as mezlocillin and piperacillin , pivmecillinam; cephalosporins, basic cephalosporins, cefuroxime, cefamandole, cefoxitin, cefotiam, cefotaxime, cefovecin, ceftazidime, cefepime, cefodizime, ceftriaxone; oral cephalosporins, cefaclor, cefadroxil, cefalexin,
  • glycopeptides are among the preferred antibiotics, such as vancomycin, dalbavancin and teicoplanin.
  • the preferred antipyretics include, inter alia, non-steroidal anti-inflammatory drugs such as ibuprofen, naproxen, nimesulide and ketoprofen (arylpropionic acid derivatives), acetylsalicylic acid; paracetamol (aminophenol derivatives); pyrazolone derivatives such as phenazone, propyphenazone, metamizole; nabumetone (arylacetic acid derivatives) and quinine.
  • non-steroidal anti-inflammatory drugs such as ibuprofen, naproxen, nimesulide and ketoprofen (arylpropionic acid derivatives), acetylsalicylic acid; paracetamol (aminophenol derivatives); pyrazolone derivatives such as phenazone, propyphenazone, metamizole; nabumetone (arylacetic acid derivatives) and quinine.
  • Drugs of choice for treating disseminated intravascular coagulation include, but are not limited to, antithrombin, protein C and APC (activated protein C), thrombomodulin(TM), heparin, tissue factor pathway inhibitor (TFPI).
  • the preferred antibodies include, inter alia, immunoglobulins, cytokine inhibitors, in particular antibodies against IL-1, IL-17A or IL-18; antibodies or other molecules that block the binding of PD-L1 to its receptor PD-1 (programmed cell death-1); and antibodies and other blocking molecules directed against surface proteins on platelets (abciximab, tirofiban, and eptifibatide) and immune cells (CD39).
  • the preferred cytokines include interleukin 7 (IL-7), IL-15 and GM-CSF (granulocyte-macrophage colony stimulating factor).
  • Preferred chemokines include CXCL10.
  • the preferred antimicrobial peptides include thymosin alpha 1 .
  • Preferred sphingomyelinase inhibitors include amitriptyline.
  • Preferred statins include atorvastatin and simvastatin, among others.
  • Another object of the present invention is an inhaler with a pharmaceutical preparation to be nebulized, which is characterized in that the pharmaceutical preparation comprises at least one reactive chlorine-oxygen compound.
  • Inhalers are medical devices used to generate aerosols or vapors, which aerosols or vapors generated can be inhaled by patients.
  • Inhalers therefore generally comprise a container containing a pharmaceutical preparation and a means for generating an aerosol or a vapor from the pharmaceutical preparation present in the container and a means for facilitating inhalation of the generated aerosol or vapor by the patient.
  • the means for generating an aerosol or a vapor from the pharmaceutical preparation present in the container can be, for example, a pressure-generating device, in particular a compressor, which provides an air flow which is passed through a nebulizer.
  • an aerosol or vapor is generated from the pharmaceutical preparation contained therein, which directs the aerosol or vapor via a hose into a mouthpiece or breathing mask, which makes it easier for the patient to inhale the aerosol or vapor generated.
  • the inhaler has a volume flow in the range from 0.05 l/s to 10 l/s, preferably from 0.1 l/s to 4 l/s, particularly preferably from 0.2 l/s to 3 l/s (liters per second). Furthermore, it can be provided that the inhaler provides a nebulization time of at most 10 minutes for 2.5 ml of pharmaceutical preparation.
  • the inhaler an aerosol with an average particle size of at most 10 pm, preferably at most 5 pm, especially preferably at most 3.5 pm, measured as Mass Median Aerodynamic Diameter (MMAD) with a 7-stage cascade impactor (Next Generation Impactor (NGl)) (DIN EN 13544-1:2007+ A1:2009).
  • MMAD Mass Median Aerodynamic Diameter
  • Nl Next Generation Impactor
  • Inhalers with these properties are well known and commercially available. These include the "MicroDrop® Pro2” device from MPVMedical, the “Inhalator IH 26” device from Beurer, the “IN 550 Inhalator” device from Medisana, the “InnoSpire Elegance” device from Philips, the “ CompAir NE-C28P” from Omron Healthcare and the device “BR-CN 116" from Omnibus. Devices of this type are also described, inter alia, in the publications DE 20 2009 004147 U1 and DE 10 2004 049338 A1.
  • reactive chlorine compounds preferably peroxochloric acids and dichlorooxo acids, particularly preferably dichlorooxo acids, can be tested in animal models, for example with regard to the antiviral properties.
  • the nebulization of 5 mM DPOCL solution compared to conventional inhalable solutions such as e.g. B. 0.9% NaCl solution (B. Braun, Melsungen) and ISOMAR, sea salt solution 3% (MPV Medical, Putzbrunn) by nebulization with an inhaler, such as a MicroDrop Prop2 inhalation device.
  • the measured nebulization times of all 3 substances under different conditions and with different volumes can all be set within a comparable range with a variance of the nebulization speeds of +/- 5%, with particularly preferred reactive chlorine compounds, which have a high water content as a carrier, essentially the have the same nebulizing properties as the salt solutions mentioned above.
  • Figure 1 shows the titration of the anions of the peroxo acids (dichloric acid, peroxochlorous acid) present in the solution to determine the concentration of the acid anions.
  • Figure 2 shows the derivation of the titration curve from Figure 1, which is used to determine the concentration precisely.
  • Figures 3 and 4 show examples of UV spectra.
  • the UV absorption measurements allow the concentration of chlorite present to be determined and indicate any dissolved free chlorine dioxide present.
  • Figure 5 shows a mass spectrum of the product solution where the peroxochlorite (mass 83.2) and the anion of dichloro acid (mass 189) were detected.
  • FIG 6 shows the result of an ion chromatography.
  • the retention times of comparative substances are given in Example 4 - Part 5.
  • the dichloric acid is detected at 19.77 min, but no chlorate (CIOs’) is detectable, ruling out chloret as the cause of the peak in the mass spectrum at 82.3 in Figure 5.
  • a solution of sodium perborate or sodium percarbonate or another peroxo compound such as the H2O2 adduct of urea can also be used.
  • the pH value is controlled with a glass electrode.
  • the pH is kept at 12 during the course of the reaction by adding 4M NaOH.
  • the hydroperoxide or the peroxo compound provided is used up when the introduction of gas leads to a permanent yellow coloration.
  • the yellow solution is then decolorized again with a drop of the solution of the oxidizing agent (e.g. H2O2).
  • the solution containing reactive chlorine is added dropwise, with stirring, to a solution of 500 g of citric acid in 3 liters of water which has previously been adjusted to pH 4.5 with 2 M sodium hydroxide solution.
  • the reactive chlorine compound formed is expelled with a strong stream of gas (N2 or O2).
  • the gas stream should preferably be cooled.
  • the hose connections should be as short as possible.
  • the gas is collected, for example, in three wash bottles connected in series, each of which is charged with 50 mL of 0.1 M NaOH.
  • the contents of the wash bottles are pooled and maintained at pH>10.
  • the pH is adjusted to 7 with, for example, hydrochloric acid, and a 2-fold molar excess of sodium chlorite is added.
  • the pH is adjusted to 7 with, for example, hydrochloric acid, and an equimolar amount of sodium chlorite is added.
  • a pH value of approximately greater than or equal to 10 to approximately 13 is set.
  • the total content of reactive chlorine anions is determined by potentiometric titration with 0.1M HCl in a manner well known to those skilled in the art.
  • different compounds can be determined using the pKa values of the various anions that can be obtained via the titration curve.
  • the dichloric acids formed are in solution in a mixture with a defined amount of chlorite and other reactive chlorine compounds.
  • the presence of the dichloric acids is detected using Raman spectroscopy.
  • Example 2 Analytical determinations of the solution obtained from Example 1:
  • the pH value is determined with the single-rod glass electrode.
  • the product content and the position of the equilibrium depend on the pH value.
  • the titration is used, for example, for the quantitative determination of the dichloric acid content or the content of peroxochloric acid or peroxochlorate.
  • Each 1 mL of the product solution is titrated potentiometrically with 0.1 M hydrochloric acid. Titration curves (pH vs. mL 0.1 M HCl) are recorded. From the acid consumption between pH 8.5 and 4.5 determined in the derivation of the titration curve, the content of anions of the corresponding acids is determined in total.
  • FIG. 1 A recorded titration curve is shown in Figure 1: Figure 2 shows the derivation of the titration curve and determination of the concentration.
  • FIGS. 3 and 4 show the spectra of a chlorite-containing and a chlorite-free product solution.
  • the chlorite signal is at 260 nm; Chlorine dioxide originating from the process shows a signal at 360 nm.
  • the absorbance values are determined at 260 nm and 500 nm in 1 cm quartz cuvettes.
  • ESI mass spectrometry was performed using a Bruker Esquire-LC spectrometer in standard MS mode.
  • the sample was an aqueous product solution that was diluted with methanol prior to measurement.
  • the scan range used was between 30 m/z and 400 m/z, with capillary exit -65 volts and skim -15 volts; the spectrum represents an average value of 50 measurements.
  • MVA Virus Modified Vaccinia Virus
  • Strain Ankara Strain Ankara
  • Passage 4 ZK-1608
  • 1 ml of the challenge substance is pipetted into a container whose volume is suitable for sufficient mixing. 1 ml of virus test suspension is added to the container; care must be taken not to touch the upper part of the inside. It is mixed well.
  • test substance 8 ml product test solution (test substance) is added to the container. It is mixed, the stopwatch is started immediately and the container is placed in a water bath for 30 or 90 minutes, which is set to the selected test temperature (20 +/- 1 °C) in a controlled manner. The effect of the product is determined for the selected exposure times. Immediately after the selected exposure time has elapsed, the mixture is mixed and 0.5 ml of the test mixture is pipetted into 4.5 ml of ice-cold MEM and placed in an ice bath. Within 30 minutes a Dilution series made by a factor of ten from this mixture (test mixture + MEM). The pipette tips should be changed after each dilution to prevent virus spread. After incubation, the virus titer is to be calculated, the reduction in virus infectivity is calculated from the difference in Ig virus titers before and after treatment with the product.
  • the stress substance 3.0 g/l % BSA shows an average reduction in the virus titer of over 90%.
  • the tests with the stress substance 3.0 g/l BSA + 3.0 ml/l Erys lead to comparable results.
  • Human CaCo-2 cells from colon carcinoma obtained from the German Collection of Microorganisms and Cell Cultures (DSMZ; Braunschweig, Germany) are used for the test.
  • the cells are cultivated at 37° C. in MEM (minimal essential medium) with 10% FCS (fetal calf serum) with 100 IU/ml penicillin and 100 pg/ml streptomycin. All chemicals are sourced from standard suppliers such as Sigma.
  • SARS-CoV-2 viruses are prepared from samples taken from travelers who have returned to Frankfurt am Main (Germany) from Wuhan (China). The Viruses are propagated in the human CaCo-2 cell line from colon carcinoma. SARS-CoV-2 viruses used for the test are cultivated for one passage in the CaCo-2 cells and frozen at -80°C for storage. The virus titer was determined as TCID50/ml in confluent cells in 96-well microtiter plates. (The TCID50 - Median Tissue Culture Infectious Dose) is a method for checking the virus titer. TCID50 denotes the concentration at which 50% of the cells are infected.
  • confluent cell lawns of CaCo-2 cells in 96-well microtiter plates are mixed with a suspension of SARS-CoV-2 viruses at an MOI (multiplicity of infection; ratio of virus particles to cells) of 0.01.
  • MOI multipleplicity of infection; ratio of virus particles to cells
  • the virus suspension is added at the same time as different concentrations of DPOCI in MEM culture medium with 2% FCS.
  • CPE cytopathogenic effect
  • confluent cell lawns are exposed to different test conditions and concentrations.
  • the vitality of the cells is determined using a typical vitality test, e.g. B.: determined with Rotitest Vital (Roth) or the MTT test. At least one determination is carried out in triplicate and the results are presented in the form of dose-response curves.

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Abstract

La présente invention concerne une préparation pharmaceutique dans laquelle un composé chlore-oxygène réactif se présente sous la forme d'un médicament qui peut être inhalé par les poumons.
EP21777210.2A 2020-09-15 2021-09-07 Préparation pharmaceutique améliorée Pending EP4213862A1 (fr)

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DE102020123989.0A DE102020123989A1 (de) 2020-09-15 2020-09-15 Verbesserte Pharmazeutische Zubereitung
PCT/EP2021/074603 WO2022058203A1 (fr) 2020-09-15 2021-09-07 Préparation pharmaceutique améliorée

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AU2912300A (en) 1999-02-19 2000-09-04 Kurt-Wilhelm Prof. Dr. Dr. Stahl Peroxochloric acid, derivatives and anions, salts thereof, method for producing them and use of the same
ES2611458T3 (es) 2003-11-21 2017-05-09 Dermatools Biotech Gmbh Soluciones acuosas de compuestos de cloro reactivos
DE102004049338A1 (de) 2004-07-24 2006-02-16 Behrens, Stephan Verwendung eines Inhalators und dem mit einem Inhalator hergestellen salzhaltigen Aerosol
DE202009004147U1 (de) 2009-03-27 2009-06-04 EIFELFANGO Chemisch-Pharmazeutische Werke J. Graf Metternich GmbH & Co. KG Wässrige Salzlösung zu Inhalationszwecken
US20190142864A1 (en) * 2017-10-11 2019-05-16 California Institute Of Technology Methods and systems, for interfering with viability of bacteria and related antimicrobials and compositions
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