WO2016015691A1

WO2016015691A1 - A pharmaceutical composition having antibacterial and virucidal effects

Info

Publication number: WO2016015691A1
Application number: PCT/CZ2015/050002
Authority: WO
Inventors: Albert SARKESSYAN; Sergey SARKISYAN
Original assignee: Albert SARKESSYAN; Sergey SARKISYAN
Priority date: 2014-07-30
Filing date: 2015-07-30
Publication date: 2016-02-04

Abstract

A pharmaceutical composition having antibacterial and virucidal activity, containing iodine, potassium or sodium iodide, a synthetic polymer soluble in water, carbohydrates and halogenated carbohydrates and water and additionally rutin and ascorbic acid in the following composition: iodine 1-5 25 g/l, potassium or sodium iodide 1.5-25 g/l, synthetic water-soluble polymer 1-10 g/l, carbohydrates 10-200 g/l, halogenated carbohydrates 0.01-100 g/l, rutin 1-10 g/l, ascorbic acid 1-10 g/l, water up to 1 litre. The preferred synthetic water-soluble polymer is polyvinylpyrrolidone.

Description

A PHARMACEUTICAL COMPOSITION HAVING ANTIBACTERIAL AND

VIRUCIDAL EFFECTS

FIELD OF THE INVENTION

The present invention relates to a pharmaceutical composition with virucidal and antibacterial effects, and a use thereof. The composition can be used in pathologies such as bacterial and viral mono- or mixed infections, cancer, systemic connective tissue diseases, certain skin diseases, post radiation conditions, radiation therapy and chemotherapy, after injuries caused by external causes. The composition can be used to treat diseases, against mono- and mixed infections, including HIV-associated, it has an evident antiinflammatory, antioxidative, antiseptic, regenerative, detoxicating, immunomodulatory, cytostatic, antitumor activity, and also exhibits antineoplasma properties without toxic effects on the organism. This pharmaceutical composition may be used alone as a pharmaceutics or in connection with traditional combination therapy.

BACKGROUND

The technical solution relates to a pharmaceutical composition for treating and preventing of infectious diseases including those socially dangerous: brucellosis, hepatitis, anthrax and other viral and bacterial diseases.

These diseases may lead to the reduction of immunoreactive, adaptogenic properties of the human and mammalian body, they increase stress, complicate conventional therapy against viruses and microorganisms, which can be transformed into new strains.

Currently there are numbers of antibacterial agents - antibiotics, both natural, semisynthetic, and synthetic.

Antiviral therapy, unlike antibiotic therapy, has significantly smaller arsenal of drugs. Virucidal efficacy of many chemicals and antivirals has been determined in experimental studies and as a result of numerous clinical trials but only a few of them have been approved for widespread practical use (The International Pharmacopoeia, 4th ed., Vol. 1-2, incl. First Suppl. WHO, Geneva, 2008).

Research of antibacterial and virucidal substances of the carbohydrates and proteins groups has a long history. In this application, only publications that are directly related to the subject invention, are presented, and also links are contained to a number of basic publications (Advances in protein chemistry. V. 1-39. New York, San Francisco, London, Academic Press, 1976; Methods in Carbohydrate Chemistry. V. 1-15 New York: Academic Press, 1980).

Patent US5846951 describes a pharmaceutical composition comprising polysaccharides containing at least five sialic acid residues. As polysaccharides, bacterial ones are designed, e.g. those originating from E. coli K1 , N. meningitidis, Moraxella liquefaciens, or others.

International application WO9722346 describes the use of alkylated and/or acylated mono and/or oligosaccharides, as an antimicrobial, antifungal and/or antiviral active substances.

International application WO97006890 describes antiviral agents which contain as an active ingredient an effective amount of a red microalgae polysaccharide or a mixture of two or more of these polysaccharides.

Antimicrobial antibiotics are known - aminoglycosides (neomycin, monomycin, kanamycin, gentamicin, etc.) (The International Pharmacopoeia. 4th ed., Vol. 1-2, Including First Suppl. WHO, Geneva, 2008) which differ by activity and spectrum and duration of an effect, toxicity. The disadvantage of all the antibiotics containing aminoglycosides is their nephrotoxicity and ototoxicity.

Patent US5646119 A describes the use of peptides based on D- aminogiastatine as antifungal and antibacterial agents. The composition comprises a peptide having an amino acid sequence of at least eight amino acids.

Patent US5869457 discloses modified proteins, and their use in combating viral infections, including influenza and immunodeficiency. The compositions are used in vitro to inhibit merging infected and uninfected cells and viruses, and contain modified proteins or polypeptides as active substance carriers. Patent US5622933 discloses known peptide structures with a branched chain, which are used to treat HIV.

Patent FR2729858 describes a compound based on iodinated polyvinylpyrrolidone and its use for disinfection. The compound may be in the form of powder, granules or tablets.

Patent US6045787 for disinfection of protein contained in the plasma-type solution describes the use of iodinated resin containing 5 to 80 parts of iodine. This resin effectively disinfects solutions, minimally destroys unstable proteins and saves red blood cells and platelets.

Utility model no. 5435, patent PK 6730 discloses a pharmaceutical composition Jodomidol having bactericidal and virucidal effect, containing iodine, potassium iodide or sodium iodide, a synthetic water-soluble polymer acting as a matrix polymer and water. This product is characterized in that it additionally contains a natural polymer, such as polysaccharides, in the following proportions, g/l: iodine - 6-10; potassium or sodium iodide - 9-15; water soluble synthetic polymer - 2; natural polymer (polysaccharides - 80- 20; the rest being water). The pharmaceutical composition may further contain trace elements, such as zinc, manganese, iron, copper, cobalt in an amount of 0.1 g / liter of the total. The disadvantage of this product is its relatively high toxicity.

EP Patent No. 0978289 and Patent of the Republic of Armenia No. 659 describe pharmaceutical compositions with antiviral activity comprising iodine, potassium iodide or sodium iodide, a synthetic water-soluble polymer, a natural mixture of mono-, oligo- and polysaccharides, and lithium chloride in a ratio of ingredients, g/l: iodine - 0,8-25; potassium or sodium iodide - 1 ,2- 38; lithium chloride - 0.1-20; synthetic water-soluble polymer - 0,01-6; a mixture of mono, oligo and polysaccharides - 8-400; water - the rest. This composition may be used in human therapy but also, as the above mentioned preparations, exhibits a high toxicity.

Patent of the Republic of Armenia No. 949 discloses a pharmaceutical product "Armenikum" with virucidal and antibacterial effect, which contains iodine, potassium or sodium iodide or sodium chloride, lithium chloride, a synthetic polymer soluble in water, mono-, oligo-and polysaccharides and water, other halogenated organic compounds in an amount of (g/l): iodine - 8- 25; potassium or sodium iodide - 1 ,2-38; sodium chloride - 9; lithium chloride - 0.1-20; synthetic water-soluble polymer - 0,01-6, mono-, oligo- and polysaccharides, - 8-400, halogenated organic compounds, - 0.001-0.01 , the balance being water. The drawback of the medicament is its low virucidal effect including the effect on HIV infection.

A common disadvantage of those medicines (PK patent no. 6,730, RF Patent no. 2,130,312, Czech Republic utility model no. 5435; European Patent EP0978289, Republic of Armenia patent no. 659, Republic of Armenia patent no. 949) is also a lack of bactericidal effect against mycobacteria and a low bactericidal activity against spores, sporulating bacteria, and fungi ("Armenicum Experimental Studies, Yerevan;" Gitutyun "Publishing House of NAS RA, 2000, p. 176).

Also other biologically active agents containing iodine in certain form are known (RF patent no. 2160090 C2, RF patent application no. 991191 A, RF patent application no. 93005225 A, RF Patent no. 21755 C2), but all of them have also the above mentioned disadvantages.

Comparison of the present product composition and the most similar ones, mentioned in the previous patent applications, is shown in Table 1.

Table no. 1: The composition of products of the documents mentioned hereinbefore and the composition of the product according to the invention (g/l) - comparison.

SUMMARY OF THE INVENTION

The above disadvantages of known solutions are removed by pharmaceutical composition with virucidal and antibacterial effects which contains iodine, potassium or sodium iodide, a water-soluble synthetic polymer, carbohydrates and halogenated carbohydrates, according to the present invention, which is characterized in the addition of rutin and ascorbic acid, whose composition is, as follows:

g/i

iodine 1-25

potassium or sodium iodide 1.5-25 synthetic water-soluble polymer 1-10

carbohydrates 10-200 halogenated carbohydrates 0.01-100 rutin 1-10

ascorbic acid 1-10

water up to 1 liter

Synthetic water-soluble polymer is preferably polyvinylpyrrolidone. Carbohydrates may be monosaccharides, oligosaccharides and/or polysaccharides of natural origin. Water present is supplied in the form of physiological saline solution or a 5% glucose solution.

A pharmaceutical composition according to the invention has virucidal, antibacterial, antioxidant, antiseptic, regenerative, detoxicating, immunomodulatory, cytostatic, antitumor activity, and is used to treat burns, purulent wounds, anal and rectal fissures, acute upper respiratory infections, autoimmune diseases, psoriasis, treatment of viral diseases caused by viruses: influenza, human papilloma virus, polio, herpes simplex, hepatitis B and C, HIV; treatment of cancer, support treatment after irradiation and chemotherapy, the treatment of radiation damage effects.

The concentration ranges of components are not selected randomly. All the properties included in the proposed product are necessary and sufficient to achieve the desired effect. None of them can be excluded or replaced. Otherwise, the technical result will not be achieved. Selection of qualitative and quantitative components contained in the present pharmaceutical compositions was based on numerous research data of the authors (Tables 2-8, figures 1-7) confirming the high therapeutic efficacy of the present formulation, and also the absence of toxicity.

The advantage of the present composition is the minimal toxicity due to the addition of a strong antioxidant rutin and vitamin C - ascorbic acid, which bind free radicals created by virtue of solar radiation to themselves. These substances restrict excessive toxicity, slow down the process of lipid peroxidation and oxidative DNA damage as well as excessive amounts of excluded NaCI, LiCI, heavy metal salts (Zn, Mn, Fe, Cu, Co) that increase toxicity of the compared products. Further reduction of the toxicity of the of the present composition in view of EP 0978289, and also of the Czech utility model No. 5435 was achieved by replacing in the present composition polymethylmethacrylate having chronic toxicity by non-toxic low molecular weight polyvinylpyrrolidone, which is contained in a number of other approved pharmaceutical compositions (e.g. Povidon-iodine).

Iodine is an effective virucidal, antibacterial, antiseptic agent. As it is apparent from experimental studies, at concentrations below 0.8 g/l of iodine, hydrolysis of the same occurs and reduces the shelf-life of the product. If the iodine concentration is above 25 g/l, gelled systems arise. The use of iodine containing products affects metabolism, improves thyroid function. Iodine affects the metabolism of fats and proteins. The use of products containing iodine reduces the level of cholesterol in blood and reduces its clotting. Iodine compositions are used as disinfectants in the treatment of inflammatory and other diseases. High doses of iodine are used in the treatment of polio, viral diseases and certain diseases of the central nervous system. Reflexive increasing of the secretion of mucous glands of the respiratory tract and proteolytic effect explains the use of iodine preparations as expectorants and mucolytics. Iodine is approved for medical use in different dosage forms (including oral, in the form of injectable solutions, etc.), and it is also a component of many approved pharmaceutical compositions (e.g. lodinol, Joks, Betadine etc.).

Potassium or sodium iodide - provides ionized potassium or sodium cations and iodine anions to the composition. In an aqueous solution of drug interactions, just ionized substances have higher bioavailability. In the present product, molecular iodine stabilizes and prevents (together with the polymer matrix - polyvinylpyrrolidone) undesirable processes, such as peroxidation of iodine and formation of toxic iodine radicals.

Upon entering the body at physiological levels, iodides normalize ratio of T3/T4 thyroid hormones triiodothyronine (T3) and thyroxine (T4) which is damaged due to deficiency of iodine. In epithelial cells, thyroid follicular iodide, under the influence thyreoperoxidase, is oxidized to elemental iodine, which provides iodination of tyrosine residues in the side chains of the molecule of thyroglobulin to form precursors of thyroid hormone - monoiodotyrosine (MIT) and diiodotyrosine (DIT).

On the basis of oxidising enzymes activity, MIT and DIT are condensed creating thyronines, of which the major are triiodothyronine (T3) and thyroxine (T4). The complex of thyroglobulin with thyronine in a form of colloid passes by virtue of endocytosis into follicular cell, where it is stored.

Iodides of various metals (potassium, sodium, calcium, etc.) are components of many pharmaceutical agents (e.g. Iodine Vitrum, Jodantin, Jodbalans™, Iodine 100, Iodine 200, Jodomarin 100 Jodomarin 200 Jodostin, Potassium iodide 200 Berlin-Chemie, Potassium iodide tablets, etc.).

Water-soluble polymer (low molecular weight polyvinylpyrrolidone) serves as iodofor, immobilization matrix which provides the body the processes of sorption/desorption of active iodine, when added to blood, it enables the gelling function, plasma substitute function and also prolongs the action of active iodine. It stabilizes molecular iodine and prevents (together with potassium iodide and sodium) unwanted peroxidation processes of molecular iodine and the formation of iodine toxic radicals. Polyvinylpyrrolidone also contributes to the increase of the composition's solubility in liquid and semisolid forms, and also inhibits the iodine crystallisation.

Natural sugars act as immunomodulators determining the energy potential of the body. Carbohydrates may be present in the form of mono-, oligo and/or polysaccharides. It is known that carbohydrates together with proteins and lipids components of biological membranes divide the space between the cell contents and the external environment. Mono-, oligo- and polysaccharides in the product play an important role in the intracellular cognition. Polysaccharides contained in the product have a positive effect on inflammation, on exposure to ionizing radiation, enhance the regeneration of nerve and muscle tissues, inhibit the growth of connective tissue, they also have some antitumor activity. Specific anti-tumor effects of polysaccharides are associated with macrophage and T-lymphocyte activation, interferon stimulation and immunomodulating effects at cellular level.

By using natural sugars with low toxicity (containing no toxic synthetic impurities) it was possible to remove the excessive amount (higher than the maximum allowable concentration) of sodium chloride and lithium chloride, and also heavy metal salts, without loss of qualitative properties of the composition. Natural sugars belong among the approved auxiliary medicine components.

Halogenated carbohydrates - increase the solubility of iodine, perform iodide ion supply, adjust pH and also have an effect on increasing the shelf-life of the composition.

Rutin is an antioxidant, adaptogen, blood vessel protecting substance, which increases the solubility and bioavailability of the formulation components; reinforces blood vessel walls (vitamin P). It strengthens capillary walls, regulates their permeability; enhances the effects of ascorbic acid. It is recommended in cases accompanied by an increase of capillary permeability, capillary toxicoses, radiation sickness, viral and bacterial endocarditis, rheumatism, glomerulonephrosis, hypertension, allergic diseases, for blood function normalizing, and acts as an anti-inflammatory agent.

Ascorbic acid - C-vitamine, is a pH regulator. Ascorbic acid is involved in the conversion of cholesterol to bile acids. Vitamin C is also necessary for detoxification in hepatocytes in the presence of cytochrome P450. It restores ubiquinone and E-vitamine. It participates in immunomodulation by stimulating the interferon synthesis. An important function of the ascorbic acid in the present product is also slowing down the process of haemoglobin glycosylation, inhibits the conversion of glucose (of carbohydrates in their natural form, after hydrolysis in the organism) to sorbitol and thus allows the use of the composition also for the treatment of children and diabetics. It promotes the production of collagen, serotonin from tryptophan, catecholamine synthesis as well as corticosteroid synthesis. Ascorbic acid is involved in conversion of cholesterol to bile acids.

Rutin reacts with enzymes and proteins, increases their biological functions, and thanks to this property, it exhibits antimicrobial, antimutagenic, antineoplastic and antirachitic effects.

Rutin and ascorbic acid as a part of the proposed compound, act as potent antioxidants in order to ensure destruction of toxic free radicals formed during prolonged exposure to direct sunlight, prevents lipid peroxidation processes leading to excessive toxicity compared determining means, and oxidative DNA damage. Rutin also controls the environment pH and removes waste products from the organism due to reaction of the C=C bond and alcoholic OH groups.

Physiological saline or 5% glucose solution dissolve all the components of the pharmaceutical composition according to the invention, provide water solubility and softness of its use. The normal saline solution is used to clean the blood and the body in general, reduces toxicity, it is used in medicine for diluting and dissolving active substances as well as at a loss or lack of extracellular fluid or insufficient influx thereof, hyponatremia and hypochloremia in connection with dehydration, intoxication, etc. A pharmaceutical composition according to the invention having a broad spectrum of activity is an dark blue aqueous solution of molecular iodine and ion complexes with the associates of water-soluble gelling synthetic polymers and natural mono-, oligo- and polysaccharides. pH of the pharmaceutical composition is 6 -7. All the components are dissolved in isotonic saline or 5% glucose solution.

The pharmaceutical composition has low toxicity and weak cumulative properties. All studies were performed three times at 10-day chick embryos. The product has been injected into the allantoic cavity of the embryos beginning the starting dilution up to 1 : 256 in a volume of 0.2 mL. The control group was injected a phosphate buffer composition without adding the product. Embryotoxicity was calculated using the number of dead embryos. During the embryotoxicity examination, it was found that the death rate in the control group was 10%. It was shown that the value of embryotoxicity depends on product dilution. It was found that embryotoxicity of the composition is 0% at a dilution 1 : 4 through 1: 256. When the concentration of the formulation being increased to 1 : 2, toxicity increases up to 50%, using the starting solution - up to 70%. In such a way, it was found that the product has toxic properties as the starting solution and at a dilution of 1 : 2; it exhibits no toxic effects in chicken embryos at a dilution of 1 : 4 and more, see table 2.

Table no. 2: Product embryotoxicity assessment

Starting

Product solution

1 :2 1 :4 1 :8 1 :16 1 :32 1 :64 1:128 1 :256 dilution (51 ,7

mg/kg)

The

proportion

70% 50% 0% 0% 0% 0% 0% 0% 0% of dead

embryos

The effec tive

therapeutical

concentration of

the product

(Examples A, B, L,

R, S, T, U) Note:

1. The starting solution was prepared in accordance with standard methods of the embryotoxicity assessment.

2. Concentration of the starting solution was higher than minimal concentrations of the product (Example A) - 33,3 times; at therapeutical dose

0,2 ml/kg (Examples A, B, L, R, S) - 16, 7 times; at therapeutical dose 0,3 ml/kg (Examples I, R, S, T, U) - 11, 1 times.

No changes in the condition of the animals, overall appearance and behavior have been observed. It was not possible to achieve the upper toxicity limit or an absolute lethal effect by administering gradually increasing doses of the substance (including the maximum possible dose) due to the low toxicity of the composition and its maximum volume for administration. That means that the composition under examination, with respect to the parameters of acute toxicity (LD50 > 5000 mg/kg), is a safe substance.

The pharmaceutical composition has antibacterial and virucidal activity against mono- and mixed infections including those associated with HIV, with a strong anti-inflammatory, antioxidant, antiseptic, regenerating, detoxifying, immunomodulatory, cytostatic, antineoplastic effect and antineoplastic properties shows without any toxic effects on the body.

The pharmaceutical composition having a wide spectrum of pharmacological activity is used in mammals including humans, orally, topically, subcutaneously, intramuscularly, intravenously and intraperitoneally.

BRIEF DESCRIPTION OF DRAWINGS

The solution is further illustrated in the drawings, wherein:

Fig. 1 shows the inhibitory activity of the composition against A/H1 N1 influenza virus.

Fig. 2 shows the inhibitory activity of the composition against A/H3N2 influenza virus

Fig. 3 shows the inhibitory activity of the agent against type B influenza virus Fig. 4 shows the inhibitory activity of the product against A/H5N3 and A/H7N1 influenza viruses.

Fig. 5 shows the fluoroscopic study of the antiviral effectiveness against HPV16 virus.

Fig. 6 shows Western blot method for determining the ability of the composiion in the form of an injection to inhibit HPV16 virus in cells.

Fig. 7 shows Western blot method for determining the ability of the composition in oral form to inhibit HPV16 virus in cells.

Fig. 8 shows Table 7

EXAMPLES

Examples of the formulation (g/l) of the inventive compositions:

Example 1 (minimum concentrations)

1. iodine 1

2. potassium or sodium iodide 1 ,5

3. synthetic water-soluble polymer 1

4. carbohydrates 10

5. halogenated carbohydrates 0,01

6. rutin 1

7. ascorbic acid 1

8. physiological saline solution or 5% glucose solution up to 1 I

Example 2 (maximum concentration)

1. iodine 25

2. potassium or sodium iodide 25

3. synthetic water-soluble polymer 10

4. carbohydrates 200 5. halogenated carbohydrates 100

6. rutin 10

7. ascorbic acid 10

8. physiological saline solution or 5% glucose solution up to 1 I

Note: examples of therapeutic use of the present product in the minimum and maximum concentration, and also as compared with known preparations, are shown in Tables 4, 5.

Use of the product in veterinary medicine

Example A

The product was used in animals (pigs) with Aujeszky's disease at a dose of 0.1-0.2 ml of composition according to Example 1 per 1 kg of body weight. Following a single injection of this dose, clinical manifestations and deaths of animals have ceased.

Example B

The product was used in animals (cattle and sheep), infected by FMD parenterally using the double dose of 0.1 ml of the composition according to Example 1 per 1 kg body weight at intervals of 24 hours. After the treatment, a positive clinical effect was observed in 100% of cases of FMD in animals.

The study of antibacterial properties of the product

Example C

Laboratory tests were performed to scope the bactericidal activity of the product in relation to the strains of microorganisms of anthrax (Bacillus anthracis) in guinea pigs and strains of brucellosis microorganisms (Brucella melitensis, Brucella abortus, Brucella suis) in white mice. Research of the bactericidal activity of the product has shown positive results of in vitro dilution of 1 :64 (anthrax) and 1 :16 (brucellosis). The therapeutic effect of the composition was observed in 60% of animals infected with brucellosis and 75% of animals infected with anthrax.

Example D:

In laboratory studies performed in vitro the composition of Example 1 at a dilution of 1 :10 to 1: 100 showed strong bactericidal activity against gram- positive and gram-negative bacteria, which disappeared within 5-10 minutes after the onset of product activity. The bactericidal effect of the drug was comparable with the one of broad-spectrum antibiotics in the control sample.

Use of the composition in burns, festering wounds, anal and rectal fissures

Pharmaceutical composition according to the invention was used in the treatment of burns, wounds, leg ulcers, in the form of a hydrophilic gel composition as in Example 1. After loading on the wound surface a protective film created, which shortened the period of treatment due to faster healing and burn treatment, lack of irritating and side effects of the drug. Gel did not spread over the surface but topped the injury like the film, which prevented from further wound infection and also, at the same time, did not slow down the regeneration of damaged tissue. Using the gel did not require additional aseptic dressing, i.e. the treatment was carried out in an open manner. Gel was particularly effective on fresh wounds incurred in the treatment of thermal, solar and chemical burns.

A pharmaceutical composition according to the invention as a gel acts on burns as potent anti-inflammatory, antioxidant, apparent sorption and regeneration agent. At the same time, the gel forms a surface film which enables the mechanical protection from the external infecting the wound. Gel softens the scab which reduces its and new epithelium tension stress. Thanks to the effect of the composition in the form of a gel, burns healing takes place without complications and scars forming. Example F The patient, male, age 37, II. degree of burns of hands, arms, 5% of the body surface. Treatment was initiated in the first days after trauma. Every day, 3 times daily, a hydrophilic gel composition according to Example 1 was applied onto the affected area of skin. The wound healing process ran without complications, by day 10 after the accident the complete epithelialization of the skin occurred.

Example G

The patient, female, 29 years old, l-ll. degree of flame burns of feet, 4%, of them 2% of the body surface 11 LA level. The treatment by the gel composition according to the Example I has been started since the first day of the accident. During treatment mechanical removing of scabs was performed. On day 11 superficial burns were completely epithelised. The remaining granulating wounds continued the gel treatment. Complete recovery occurred 32 days after injury. Immediately after the treatment and 3 months after injury gross scarring is found.

Example H

The patient, female, 25 years old, thermal burns of forearm l-ll deg., 2% of the body surface. Treatment was initiated on the first day after the trauma, hydrophilic gel according to Example 1 was applied 2 times a day. The course of wound healing was without complications, by the 8^th day after the injury the complete epithelialization of the skin occurred.

During the treatment a good tolerability for patients without allergic reactions and local irritating effect was proved.

The use of the product in patients with inflammatory diseases of rectum

Example I

The female patient, 44 years, anal fissure. The composition was administered in oral dosage form at a dose of 0.3 ml of the formulation according to Example 1 per 1 kg body weight, and in a form for external administration 2 times daily. After 10 days of starting therapy, a complete healing and epithelization of the wound surface was proved. Recurrences were not identified.

Example J

The patient, female, 39 years old, hemorrhoids. Prescribed treatment: liquid form of the product according to Example 1 was administered as a microclysma of 7 ml of the agent according to Example 1 , 12 times a day; at the same time the hydrophilic gel was applied to the anal area 2 times a day. During the treatment, three days later improvement of the health of patient was proved, the pain and bleeding during defecation completely disappeared. There was a complete recovery after 7 days of treatment.

Effect of the composition on influenza virus and acute upper

respiratory tract infection

Virucidal effect of the composition according to the technical solution of the composition according to Example 1 was studied in chick embryos infected with these viruses and viral antigens: A/New Jersey/8/76 (H1N1), A/Solomon !slands/03/06 (H1N1 ), A/Swine/lowa/15/30 (Hsw1N1), A/Wisconsin/67/05 (H3N2), A/Brisbane/10/06 (H3N2), B/Shandong/07/07 (Victorian line), B/Florida/09/06 (Jamagata line), A/tern/South Africa/1/61 (H5N3), and A/FPV/Rostock/67/05 (H7N1).

To study the effect of virucidal composition according to the technical solution of the composition of Example 1 against influenza virus type A and B was determined by the infectious activity (Table 3).

Table 3: infectious activity of viruses

No. Strain Antigen pattern Value of IgEIDso/t mi

1 A/New Jersey/8/76 H1 N1 6,78

2 A/Solomon Islands/03/06 H1N1 5,63

3 A/Wisconsin/67/05 H3N2 6,75 4 A/Brisbane/10/06 H3N2 5,25

5 B/Shandong/07/07 Victorian line 7,5

6 B/Florida/09/06 Jamagata line 4,33

7 A/Swine/lowa/15/30 Hsw1N1 8,78

8 A/tern/South Africa /1/61 H5N3 8,0

9 A/FPV/Rostock 67/05 H7N1 8,75

The results of the study of virucidal efficacy of the composition according to the invention against influenza A/New Jersey/8/76 (H1N1), A/Solomon Islands/03/06 (H1N1 ) and A/Swine/lowa/15/30 (Hsw1N1 ) are listed on the Figure 1. Showing that the composition according to the invention is able to inhibit completely the reproduction of 100 infectious doses of influenza virus A H1 at dilutions beginning the initial one up to 1 : 8, the inhibitory activity retained to dilutions up to 1 :64.

Effect of composition on serovar H3 influenza virus (A/Winconsin/67/05 and A/Brisbane/10/06) is shown in Figure 2. Maximal inhibitory activity (100%) of the technical solution of the composition according to Example 1 , was demonstrated beginning the initial dilution up to 1: 4, the effect is reduced to 0% at a dilution of 1:64.

The suppression of influenza B (B/ShALSEdng/07/07 and B/Florida/09/06) by the product of the composition according to Example 1 is shown in Figure 3. Composition was demonstrating the inhibitory activity up to dilutions of 1 :16, completely inhibited virus from the initial dilution to a dilution of 1: 4.

Figure 4 shows the effect of the composition according to the technical solution of the composition of Example 1 according to the influenza virus A/H5N3 and A/H7N1. It was found that this composition is effective against these viruses in the dilution up to 1 :16, and approaching 100% inhibition of the maximum dilution of 1 :2.

Studies of antiviral activity have shown that the composition according to Example 1 has significant inhibitory properties against influenza viruses A and B. The best results are against influenza A/H1N1 at dilutions from the beginning up to 1:64. These figures have decreased from the initial to 1 :32 in the activity against influenza virus A/H3N2. As for influenza B viruses, A/H5N3 and A H7N1, effect of the product was observed in a dilution up to 1 :16.

Effect of the composition on hepatitis B virus

Example K

Laboratory tests were carried out on samples of blood serum of patients containing hepatitis antigen (HBsAg). A decrease of serological activity of blood serum was recorded as well as an inhibitory effect against HBsAg of the product according to the technical solution of the composition according to Example 1 at a 1 :20 dilution with incubation time of 2 hours.

Effect of the composition on hepatitis C virus

Exclusion tests of antiviral activity against hepatitis C virus were performed. It was found in laboratory conditions that the composition according to the technical solution of the composition according to Example 1 for oral and injectable administration suppressed the hepatitis C virus in cells. This product effectively protects cells in vitro from the cytopathic effect of hepatitis C.

Example L

Patients with chronic hepatitis C have been administered the product according to the technical solution of the composition according to the Example 1 as follows: one course of treatment included a daily oral dose of 0.2 ml of the composition of the composition according to Example 1 on 1 kg of body weight, which was divided into two doses, morning and evening, for 45 days. The interval between treatments was 15 days. One can say that the entire treatment period consisted of three to five treatments depending on the severity of the disease, the fundamental transaminase levels, viral load and levels of antibodies. The pharmaceutical composition shortened the treatment thanks to the improvement of antiviral efficacy without increasing of toxic effect on the patient^'s body. Treatment reduced blood infection caused by hepatitis C. Significant number of treated patients showed significantly improved health status, work ability, asthenic vegetative syndrome disappearance, alleviation of the pain in the right upper quadrant (table 4) as early as 4-6 weeks after the start of therapy. The method of treatment according to the technical solution ensured clinical and laboratory remission as well as the elimination of hepatitis C virus and normalization of biochemical parameters following the treatment. The dynamics of liver function tests (transaminases and bilirubin) decrease in patients treated by the drug was fast. SVR was observed in 86% of patients (tables 5 and 6). During antiviral therapy, in no patient symptoms were noted that could be considered for side effects.

Table 4: The assessment of clinical symptoms before and after the therapy by the product according to the invention of Example 1.

Note: hereafter the significance of differences between groups * - p<0,05, ** - p<0,01 Table 5: The comparison of effectiveness of theproduct according to Examples 1 and 2 with interferon product in hepatitis C treatment: clinical and laboratory parameters in patients with chronic hepatitis C, mild course of disease

Hb RBC ALT AST Bili HCV RNA

(g/i) x10¹²/l (U/l) (U/l) (μπιοΙ/Ι) (U/ml)

During the therapy by the product according to the technical solution

(Examples 1 and 2)

Before 118,1 ± 4.2 ± 173,0 ± 172,0 ± 37, 1 ± 1610000 ± therapy 7,0 0,15 14,1 0,62 2,28 2700

Example 1 122,9 ± 4,3 ± 24,7 ± 22,8 ± 18,5 ± 0**

(minimum 10,0 0,28 0,7** 1 ,4** 2.52*

concentration)

after 6

months of

therapy

Example 2 125,4 ± 4,4 ± 22,3 ± 19,2 + 17,6 ± 0**

(maximum 1 1 ,0 0,32 0,7** 1 ,6** 2.65*

concentration)

after 6

months of

therapy

During the interferon treatment

Before 123,8 ± 4,6 ± 195,3 ± 144.4 ± 7.1 36,3 ± 164000 ± therapy 9,30 0,42 6,7 2,31 2900

After 6 117,4 ± 4,1 ± 55,3 ± 29,2 ± 21 ,5 + 10 ± 0,8** months of 1 1 ,0 0,78 9,2** 13,5** 2,84*

therapy

Table 6: The comparison of product effectiveness according to the Examples 1 and 2 with interferon product in hepatitis C treatment: clinical and laboratory parameters in patients with chronic hepatitis C, mild course of disease

The effect of the composition on poliomyelitis virus

Example M

Laboratory tests of antiviral activity of the composition according to the technical solution of the composition of Example 1 against polio virus have performed in vitro. Studies have shown that the product according to Example 1 at a dilution of 1 :10 to 1 :40, is able to inhibit viral reproduction (10 ¹ through 10^"5). It was found that the dilutions 1 :10 - 1:40 have strong inhibitory properties against the poliomyelitis virus.

Effect of the composition on human papillomavirus

Example N

Following elimination tests of antiviral activity against human papillomavirus were carried out. Cell suspension containing HPV16 was diluted with culture medium to a concentration 2x10³. Solutions of the composition according to Example 1 at different dilutions were mixed with equal volumes of culture medium with HPV16. Also control (culture medium + viral suspension) and imaginary (culture medium + culture media) samples have been created. Figure 5 shows a fluoroscopic study of antiviral efficacy of the composition according to the invention against the virus HPV16 (A - injectable product B - oral form of the composition according to the invention, C - control). Injection and oral form of the composition at the highest non-toxic concentration (1/24) inhibit the HPV virus ability to penetrate into the cells, while other concentrations have not lead to such an effect.

As shown in fig. 6 and 7, dilution of the composition according to Example 1 in a ratio of 1/24 in injectable and oral forms in the HPV16 cells did not lead to the detectable virus structural protein L1, i.e. the given concentration of composition lead to the inhibition of the ability of the HPV16 to penetrate into cells while other concentrations did not enable such an effect. The results are consistent with the results of fluoroscopic study.

Results of fluoroscopy and Western blot studies showed that the product according to Example 1 of oral and parenteral forms has a good inhibitory effect on the human papillomavirus.

Effect of the composition on type II herpes simplex virus.

Example O

Virucidal effect of the drug was studied in the treatment of vaginitis in mice caused by herpes simplex virus type II. The composition of Example 1 was administered as an ointment three times a day. As a result it was proved that the initial concentration and dilution at 1 : 2 and 1 : 4 has an inhibitory effect on HSV-2.

Virucidal effect of the composition on the composition of Example 1 versus HSV-2 was evaluated in healthy mice by introducing into the vagina of the test substance and the mixture of virus suspension. High therapeutic efficacy appeared which shows its ability to prevent entry of herpes simplex virus type II into cells.

Effect of the composition on HIV

Example P

The product according to Example 1 was administered by intravenous infusion to healthy volunteers - patients with HIV infection. Venous blood was collected 6 and 20 hours after administration of the product. Biological titrations of test samples (serum) were performed on the composition of Hep- 2 cells (a cell line derived from a human laryngeal carcinoma). According to the results of the study, administering to study volunteers induces a weak induction of interferon in serum and mononuclear cells interferon synthesis stimulation with in vitro. High initial level of interferon in a significant number of patients before the product administration steeply decreased following the first treatment and remained at a low level until the end of the study.

Use of a composition according to the invention in patients with malignancy and in patients after radiation and chemotherapy

Experimental study of the product was carried out according to the technical solution of the composition according to Example 1 in various human tumor cell lines: cancer cells of the pancreas, stomach, colon, lungs, malignant melanoma, colorectal cancer or cancer of the colon and rectum, cancer of liver or hepatoma cells, group of blood cells cancers or chronic leukaemia, ovarian cancer, breast cancer, human leukaemia cell line, resistant strains of micro-organisms associated with resistance of lung tumor cells to cisplatina. The results of experimental investigations have shown that the efficacy of maximal inhibition of IC50 in four cell lines (chronic leukaemia, leukaemia cells, malignant breast cancer, hepatoma) was IC50<1.000 pg/ml. Indicator of IC50 maximal inhibition efficiency in tumor cell lines of pancreas, stomach, colon and rectum, lung, malignant melanoma and ovarian cancer, including cells with drug resistance was greater than 1.000 pg /ml. Dose administered to patients with cancer was adjusted individually - 0.2 ml of the composition of Example 1 per 1 kg body weight per day for parenteral administration and 0.3 ml of the composition of Example 1 per 1 kg body of weight per day by oral administration - depending on the severity and stage of the cancer. This mode can be recommended to patients after radiation and chemotherapy as rehabilitative therapy.

Example R

Female patient, 50 years of age, cervical cancer 350 cm³. The composition according to Example 1 diluted with normal saline was administered intravenously, via the subcutaneous venous port for 6 months. During this period, the tumor was reduced up to 0.5 cm. Reduction of tumor was monitored by ultrasound and MRI. Additionally, vaginal swabs soaked by the product according to the composition. The result is that 10 days later the putrid odor from the patient^'s vagina disappeared completely.

Example S

Female patient 49 years old, grade 3 rectal cancer, abdominal metastases. Weight 47 kg before treatment. After the surgery a colostomy was performed, the patient discharged home. The patient in an outpatient care was administered the intravenous agent in a dose of 0.2 ml of the composition acc. to Example 1 per 1 kg body weight daily, alternatively with the administration of the same composition in oral dosage form at a dose of 0.3 ml per 1 kg body weight daily. The duration of treatment was 3.5 years. Colostomy closure surgery has been performed then. The current patient^'s weight is 72 kg. Quality of life was significantly improved, there are no complaints.

According to our observations, all the patients with cancer who were receiving the product with the composition according to Example 1 prior chemotherapy showed good treatment tolerability. Furthermore, patients suffering from cancer and undergoing cancer chemotherapy agent are administered the product with the composition 1 for 10 days after the third day of chemotherapy to reduce toxicity. It was also observed a high rate of excretion of toxin, which resulted in normalization of hematological and biochemical parameters of blood and a significant reduction or absence of complaints of patients. Use of the composition before and after chemotherapy allowed to perform this treatment in patients more frequently. While taking the product, the duration and frequency of adverse effects, such as vomiting, nausea, diarrhea, dizziness, headache were reduced, sleep and appetite were restored and a general weakness disappeared, so adverse effects associated with chemotherapy were partially or completely compensated. The product was well tolerated and did not lead to side effects. Using the product made possible to reduce toxicity, better tolerate radiation therapy and chemotherapy, improve the patients^' quality of life. The composition can be used successfully in patients with cancer to reduce symptoms of intoxication after radiation and chemotherapy. Effective adsorption and detoxifying properties were clearly observed in the product. Due to the adsorption properties, the product is effective against disintegrating products that are formed during irradiation and chemotherapy. Detoxification and adsorption effects of the composition are presented in a direct removal of biologically active substances, xenobiotics, toxins, and other pathological substances from the circulation. Another important component of detoxification is an active dehydrating effect on the intercellular space. The product according to the technical solution allows to minimize the depletion of the antioxidant system and helps to restore the ability of antioxidant protection, remove oxidative stress, tend to normalize cell immunity. Polysaccharides which are included in the composition, activate macrophages, improve the function of cellular and humoral immunity, which reduces the immune reaction caused by cytotoxic drugs, radiotherapy and chemotherapy. The composition, according to the invention, suppresses acute course of cancer, bears the cytostatic effect, reduces the number of mitoses in the cells.

The pharmaceutical composition according to the invention can therefore be used in groups of individuals with oncologic pathology, persons at increased risk for cancer and individuals exposed to carcinogens, radiation and chemical nature.

Use of the composition according to the invention for radiation damage

The pharmaceutical composition according to the invention solves the problem of effective protection of humans and animals against the harmful effects of radioactive isotopes of iodine. Thanks to its composition and biochemical processes in the cell under the action, the product forms biologically active complexes in the body. The substance has an effect on the induction of humoral immunity, the ability to simulate the antibodies production, enhancement of the phagocytic activity of macrophages and neutrophils. Components of a medicament improve the conductivity of the cell membranes and inhibit lipid peroxidation processes. Product enables to reduce efficiently the level of endogenous intoxication during radiation damage.

Example T

The effectiveness of the substance according to Example 1 has been evaluated in oral form in individuals suffering from pathological condition of thyroid gland associated with hypertension that were exposed to irradiation. The composition was used in a 0.3 ml dose according to Example 1 per 1 kg of body weight, in three divided doses for 10 days in patients receiving conventional therapy. Following the treatment by the product the normalization of thyroid function was observed, as evidenced by lowering of the hormone levels that were increased before. The product also affected the drop of initially high levels of blood biochemical parameters (cholesterol, glucose). In patients being administered this medicament, also high blood pressure was reduced.

Use of the composition in autoimmune disease

The use of the present composition in the treatment of said disease enables decreasing circulating immune complex level, normalization of haematological and immunological parameters, recovery of energy metabolism of lymphocytes impaired by autoimmune process. In autoimmune disease the product acts as an antioxidant, which is involved in the inhibition of DNA oxidative damage and improving reparative ability of DNA.

Example U

Female patient 30 years old, Crohn disease lasts for 7 years. She has undergone the conventional treatment without substantial effect. During the last 2 years, the patient lost appetite, there was a sharp decrease in body weight to 42 kg, height 170 cm. A partial bowel obstruction appeared, pain occurred in connection with the development of anal fissures. During the last three months everyday temperature elevation occurred - up to 39 °C. Then the patient started to use the drug in oral form at a dose of 0.3 ml according to the Example 1 per 1 kg body weight per day, and also in the form of rectal application. During treatment, temperature was normalized within 2 months, appetite re-appeared. Currently, the patient continues receiving the product.

Use of the composition for treating psoriasis A study of the effectiveness of the composition according to Example 1 was performed in exclusion tests on formation of a granular epidermis layer in the mice tail, and also on mitosis of basal cells of the vaginal epithelium of mice. It became evident during the tests that oral administration of the composition for 14 days supports enlarging of epidermis granular cell layer on the tail of the mice compared to the control group (p< 0.01), which was administered clobetasol propionate cream (Table 7). See fig. 8 Also during the administration of the composition of Example 1 orally and vaginally for eight days, the number of cells of the vaginal epithelium in the stage of mitosis was decreased, which shows the inhibitory effect on mitosis of vaginal epithelial cells of the basal mice (Table. 8).

Table 8: The effect of the composition according to Example 1 on mice vaginal epithelium mitosis (x ± SD)

The composition according to the present invention also reduces the number of occurrence and duration of the itching. (Table 9)

Table 9: The effect of the composition according to Example itching of mouse vaginal epithelium cells (x ± SD)

The composition according to the invention formulated according to Example 1 acts on pathologically keratinized epidermis cells, on immune system, has antineoplastic properties, has cytostatic effect, which leads to decreasing of the activity of glycolytic and oxidative processes in epidermal cells. The result is a reduction of the number of mitoses in the epidermis, as well as hyperkeratosis and parakeratosis. Example V

In patients with psoriasis, the composition was administered in oral form according to Example 1. Duration of the treatment was dependent on the duration of disease and degree of skin disease severity (PASI score). Thus, when skin lesions were smaller than 3 % of body surface area, duration of therapy was 3-4 months, 3-10% - 6-9 months, more than 10% - 12 to 24 months. When administered intravenously, the length of treatment was reduced substantially. During the treatment, in case of itching and skin dryness, moisturizing creams and baths were used by patients as a symptomatic agent. The use of the product has proved that the treatment of dermatosis is of high clinical efficacy. The sustained clinical remission in 100 % of patients with mild psoriasis has been achieved after 6 months of treatment and in 86% of patients with the moderate course of disease. This product increases functional capacity and quality of life. The results of practical use of the proposed wide spectrum of action composition proved its strong virucidal, antibacterial, anti-inflammatory, apparently antioxidant, regenerating, detoxifying effect, and also immunomodulatory, cytostatic, anticancer and antitumor activity as a result of a complex interaction of the components of the pharmaceutical composition.

INDUSTRIAL APPLICABILITY

The technical solution is applicable as a pharmaceutical composition having virucidal and broad antibacterial effects including the effect against cancer, systemic connective tissue diseases, skin diseases, post-radiation damage.

Claims

1. Pharmaceutical composition having antibacterial and virucidal activity containing iodine, potassium or sodium iodide, a water-soluble synthetic polymer, carbohydrates and halogenated carbohydrates and water; characterized in that said composition additionally contains rutin and ascorbic acid, having the following composition: g/l

iodine 1-25

potassium or sodium iodide 1.5-25

synthetic water-soluble polymer 1-10

carbohydrates 10-200

halogenated carbohydrates 0.01-100

rutin 1-10

ascorbic acid 1-10

water up to 1 liter.

2. Pharmaceutical composition according to claim 1, wherein the synthetic water-soluble polymer is polyvinylpyrrolidone.

3. Pharmaceutical composition according to claim 1, wherein saccharides are selected from the group consisting of monosaccharides, oligosaccharides and polysaccharides.

4. Pharmaceutical composition according to claim 1, wherein water is contained in the form of physiological saline.

5. Pharmaceutical composition according to claim 1 , wherein water is contained in the form of a 5% glucose solution. Pharmaceutical composition according to any preceding claim having the virucidal, antibacterial, antioxidant, antiseptic, regenerative, detoxicating, immunomodulatory, cytostatic, antitumor activity.

Pharmaceutical composition according to any preceding claims for use in the treatment of burns, purulent wounds, anal and rectal fissures, acute upper respiratory infections, autoimmune diseases, psoriasis, treatment of viral diseases caused by viruses: influenza, human papillomavirus, poliomyelitis, herpes simplex, hepatitis B and C, HIV; the treatment of cancer, supportive treatment after irradiation and chemotherapy, the treatment of radiation damage effects.