ANTIVIRAL AGENT

Abstract

The present invention relates to the use of hydroxymethyl group donors, in particular of hyaluronic acid which contains hydroxymethyl groups, for treating and preventing an infection by enveloped viruses such as coronaviruses, paramyxoviruses, e.g. RS viruses, or orthomyxoviruses, such as influenza viruses, and/or for treating or preventing an inflammatory disease of the respiratory tract, for example COPD, ARDS or cystic fibrosis, in particular an inflammatory disease of the respiratory tract associated with a viral infection.

Claims

1. Hydroxymethyl group donor for use in the treatment or prevention of an infection with coronaviruses, paramyxoviruses or orthomyxoviruses.

2. Hydroxymethyl group donor according to claim 1, characterised in that it is selected from hydroxymethyl group-containing glycosaminoglycans, wherein one or more amino groups and/or hydroxyl groups are substituted with hydroxymethyl, or is selected from taurolidine.

3. Hydroxymethyl group donor according to claim 2, characterised in that the glycosaminoglycan is selected from hyaluronic acid, heparin, chondroitin sulfate, chitosamine and poly-N-acetyl glucosamine, preferably hyaluronic acid, wherein in each case one or more amino groups are substituted with hydroxymethyl.

4. Hydroxymethyl group donor according to claim 2 or 3, characterised in that the glycosaminoglycan is selected from hyaluronic acid.

5. Hydroxymethyl group donor according to any of the claims from 2 to 4, characterised in that the degree of hydroxymethylation is in the range of 200:1 (0.5%) to 1:1 (100%), preferably 100:1 (1%) to 10:1 (10%).

6. Hydroxymethyl group donor according to any of the claims from 2 to 5, characterised in that the hydroxymethyl group-containing glycosaminoglycan is present in non-crosslinked form, the glycosaminoglycan in particular being selected from (i) long-chain glycosaminoglycans with an average molecular weight (weight average) of at least 200 kD and (ii) short-chain glycosaminoglycans with an average molecular weight (weight average) of up to 50 kD or mixtures thereof.

7. Hydroxymethyl group donor according to any of the claims from 2 to 5, characterised in that the hydroxymethyl group-containing glycosaminoglycan is present in crosslinked form, the cross-linking level in particular being in the range of 0.1% to 10%.

8. Hydroxymethyl group donor according to any of the claims from 2 to 7, characterised in that the hydroxymethyl group-containing glycosaminoglycan is present as a mixture of non-crosslinked and crosslinked glycosaminoglycans.

9. Hydroxymethyl group donor according to claim 1 or 2, characterised in that it is taurolidine.

10. Hydroxymethyl group donor according to any of the preceding claims, characterised in that it is present in combination with at least one inhibitor of glycosaminoglycan degradation, the inhibitor of glycosaminoglycan degradation being selected in particular from heparin, indomethacin, salicylates, radical quenchers, such as vitamin A, C or E, and mixtures thereof.

11. Hydroxymethyl group donor according to any of the preceding claims for use in human medicine or veterinary medicine.

12. Hydroxymethyl group donor according to any of the preceding claims for local administration.

13. Hydroxymethyl group donor according to any of the preceding claims for administration on surfaces of the upper respiratory tract.

14. Hydroxymethyl group donor according to any of the preceding claims, characterised in that it is present as an inhalable preparation, in particular as an aerosol, or as a nasal spray.

15. Hydroxymethyl group donor according to any of the preceding claims for administration to patients with an infection of the upper and/or lower respiratory tract.

16. Hydroxymethyl group donor according to any of the preceding claims for treating an infection by coronaviruses, in particular for treating patients with an infection by SARS-CoV-2.

17. Method for treating or preventing an infection with coronaviruses, paramyxoviruses or influenza viruses, characterised in that a subject to be treated, in particular a human subject, is administered a preparation which contains a hydroxymethyl group donor as defined in any of claims 1 to 10, in an amount sufficient for treating the disease.

18. Hydroxymethyl group donor for use as an active agent for treating and preventing an inflammatory disease of the respiratory tract, for example COPD, ARDS or cystic fibrosis, in particular an inflammatory disease of the respiratory tract associated with a viral infection.

19. Method for treating or preventing an inflammatory disease of the respiratory tract, for example COPD, ARDS or cystic fibrosis, in particular an inflammatory disease of the respiratory tract associated with a viral infection, characterised in that a subject to be treated, in particular a human subject, is administered a preparation which contains a hydroxymethyl group donor as defined in any of claims 1 to 10, in an amount sufficient for treating the disease.

20. Pharmaceutical preparation for oral or nasal administration, in particular for administration as an aerosol or nasal spray, characterised in that it contains a hydroxymethyl group donor as an active agent in a pharmaceutically acceptable carrier.

21. Pharmaceutical preparation according to claim 20, characterised in that it contains taurolidine, in particular in a concentration of 0.01 to 1.0% (w/v), in particular 0.01 to 0.5% (w/v), or 0.1 to 0.2% (w/v), in an aqueous carrier.

22. Pharmaceutical preparation according to claim 20, characterised in that it contains hydroxymethyl-modified hyaluronic acid, in particular in a concentration of 0.01 to 1.0% (w/v), in particular 0.01 to 0.5% (w/v), or 0.1 to 0.2% (w/v), in an aqueous carrier.

23. Pharmaceutical preparation according to any of the claims from 20 to 22 for application in the respiratory tract.

24. Pharmaceutical preparation for peroral administration, in particular for administration as a gel, tablet or capsule, characterised in that it contains a hydroxymethyl group donor as an active agent in a pharmaceutically acceptable carrier.

25. Pharmaceutical preparation according to claim 24, characterised in that it is provided with a coating, e.g. a gastric acid-resistant coating.

26. Pharmaceutical preparation according to claim 24 or 25, characterised in that it contains a hydroxymethyl-modified hyaluronic acid, e.g. a hydroxymethyl-modified crosslinked hyaluronic acid gel or a modified polysaccharide such as starch and cellulose in a solid or a liquid carrier.

27. Pharmaceutical preparation according to any of the claims from 24 to 26 for application in the digestive tract.

28. Hydroxymethyl group donor or pharmaceutical preparation, which contains a hydroxymethyl group donor as the active agent, in a method for reducing and/or preventing side-effects of a vaccination against a viral infection.

29. Hydroxymethyl group donor or pharmaceutical preparation, which contains a hydroxymethyl group donor as the active agent, for use according to claim 28, in case of a vaccination against coronaviruses, in particular with SARS-CoV-2.

30. Hydroxymethyl group donor or pharmaceutical preparation, which contains a hydroxymethyl group donor as the active agent, for use according to claim 28 or 29, in case of a vaccination with a genetic vaccine, in particular with a genetic vaccine against a coronavirus such as SARS-CoV-2.

31. Hydroxymethyl group donor or pharmaceutical preparation, which contains a hydroxymethyl group donor as the active agent, for use according to any of the claims from 28-30, in the case of a vaccination with an mRNA or a vector active agent.

32. Hydroxymethyl group donor or pharmaceutical preparation, which contains a hydroxymethyl group donor as the active agent, for use according to any of the claims from 28-31, in the case of a vaccination with a vaccine that contains the genetic information for a coronavirus spike protein.

33. Hydroxymethyl group donor or pharmaceutical preparation, which contains a hydroxymethyl group donor as the active agent, for use according to any of the claims from 28-32 for intraperitoneal, e.g. intravenous, or inhalative administration.

34. In vitro method for inactivating viruses, in particular enveloped viruses such as coronaviruses, e.g. SARS-CoV-2 viruses, paramyxoviruses, e.g. RS viruses, or orthomyxoviruses, e.g. influenza viruses, comprising the treatment of a preparation of viruses, in particular enveloped viruses, with a hydroxymethyl group donor under conditions leading to the killing and/or attenuation of the viruses in the treated preparation.

35. Virus preparation, in particular of enveloped viruses such as coronaviruses, e.g. SARS-CoV-2 viruses, paramyxoviruses, e.g. RS viruses, or orthomyxoviruses, e.g. influenza viruses, characterised in that it contains viruses killed and/or attenuated by a hydroxymethyl group donor.

36. Use of a virus preparation, prepared according to claim 34, or a virus preparation according to claim 35, as a vaccine.

Description

PILOT STUDY

[0091] The clinical effectiveness and/or the antiviral effect of taurolidine and hydroxymethyl-modified hyaluronic acid were checked on the basis of a pilot study with voluntary participants, in the sense of an individual curative treatment.

[0092] Overall, the study was carried out on 19 patients with symptoms of a respiratory tract disease or colds and flu.

[0093] Of these, 6 tested positive and 4 negative for SARS-CoV-2 (point of care test, POCT). In the case of the remaining participants, the clinical symptoms were the indication for the start of treatment.

[0094] The taurolidine treatment was carried out by inhaling 1-2 ml aerosol comprising 0.5% taurolidine, by means of an ultrasonic nebuliser or a compressed air nebuliser. (According to the manufacturer's specifications, these devices generate aerosols having a predominant particle size of 5 micrometres). Depending on the symptoms, the application took place between twice and 4 times a day. Taurolidine was extracted from a commercial 2% stock solution (TauroNova by Tauropharm), and diluted with physiological saline solution or with a buffered saline infusion solution (pH 7.2).

[0095] Alternatively, a 0.5% solution with hydroxymethyl-modified hyaluronic acid was used as an aerosol for inhalation or as a nasal spray. The approved commercial product Lubravisc, having a hyaluronic acid content of 2%, was diluted with physiological saline solution to 0.5%. The hyaluronic acid modification was achieved by isolation from cockscomb, using formaldehyde. In this case, a hydroxymethyl group transfer to the hyaluronic acid takes place.

[0096] In each case the time interval from the start of treatment to the easing of the symptoms was measured. None of the participants were hospitalised.

EXAMPLE 1

[0097] A 64-year-old male participant had a positive SARS-CoV-2 antigen test. 10 days later, he became unwell with a fever of over 38° C., muscle pain, and weakness. He then inhaled 0.5% taurolidine twice a day. 4 days later, the body temperature and wellbeing became normal.

EXAMPLE 2

[0098] A 32-year-old participant had close domestic contact with a person verifiably suffering from Covid-19. When, shortly after, disease symptoms such as increasing body temperature, weakness and back muscle pain appeared, the POCT was positive. Accordingly, he began to inhale taurolidine 0.5% three times a day. The symptoms reduced within 48 hours, until restoration to health was achieved.

EXAMPLE 3

[0099] A 52-year-old participant became unwell with a cough, stinging eyes, fever and lung pain. She had a positive POCT test for Covid-19. Thereupon, she inhaled taurolidine 0.5% 3 times a day. On day 4, following the start of treatment, she was symptom-free.

EXAMPLE 4

[0100] Two participants, a couple, male and female, aged 72 and 69, respectively, became infected from a 96-year-old close relative who had tested positive for SARS-CoV-2, and were quarantined after also having had a positive test result. Over this time, they both developed dry coughs and began to inhale taurolidine 0.5% three times a day. The coughing stopped, in both participants, after 3 days. No further disease symptoms appeared.

EXAMPLE 5

[0101] A 13-year-old participant was living in close domestic contact with his mother, who was unwell and tested positive for SARS-Cov-2. He developed a sore throat, and subsequently also tested positive by POCT. Thereafter, he inhaled taurolidine 0.5% twice a day. On the 4th day he was symptom-free.

EXAMPLE 6

[0102] 2 female and 2 male participants, aged from 27 to 64, members of one family, who had had close contact with two relatives who had tested positive for Covid-19 and had become unwell, prophylactically inhaled taurolidine 0.5%, 3 times a day or twice a day, for 7 days, once they knew of the illness of their relatives, simultaneously with the infected relatives. The 4 participants remained symptom-free, and the POCT for SARS-CoV-2 remained negative in all cases.

EXAMPLE 7

[0103] A 29-year old participant developed a sore throat with unspecific malaise. He inhaled modified hyaluronic acid twice a day. From the 3rd day he was symptom-free. A test for SARS-CoV-2 was not performed.

EXAMPLE 8

[0104] A participant developed a runny nose and a sore throat. She used hyaluronic acid, as a nasal spray, twice a day. The symptoms eased on the 3rd day following the start of treatment.

EXAMPLE 9

[0105] 2 participants with cold symptoms, such as a runny nose, a cough, a sore throat inhaled taurolidine 0.5% three times a day, immediately following the appearance of the symptoms. They were symptom-free after 3 to 5 days following the start of treatment. A SARS-CoV-2 test was not carried out.

EXAMPLE 10

[0106] A 28-year-old participant suffered from cold symptoms, such as a cough, a sore throat, and subfebrile body temperatures for 4 days. She inhaled taurolidine 0.5% once, in the evening of the 4th day, and was symptom-free the following day. A test for SARS-CoV-2 was not carried out.