WO2015160195A1 - Agent for treating hepatitis c - Google Patents

Abstract

The present invention relates to an iodine containing pharmaceutical composition containing iodine, potassium iodide, sucrose, glucose, starch, polyvinyl alcohol, sodium chloride and sodium carbonate. The composition of the present invention is safe and effectively exhibits antiviral activities, and thus can be useful for treatment of hepatitis C, in particular.

Description

Hepatitis C Virus Treatment

The present invention relates to a hepatitis C virus therapeutic agent.

Hepatitis C virus (HCV) is the leading cause of chronic liver disease worldwide. Hepatitis C virus belongs to Flaviridae and is a single stranded RNA virus with a genome of about 9600 bases. HCV develops chronic hepatitis in most infected patients after the first acute infection. In particular, it is chronicized at a high rate due to the lack of T-lymphocyte response and a high propensity for mutation of HCV.

Currently the main treatment of HCV is based on the combination therapy of nucleoside analogue ribavirin with interferon-α. Such combination therapy may have significant side effects such as influenza-like symptoms, blood disorders and neuropsychiatric syndromes. There is a need for the development of more effective, simple and safe treatments.

To date, iodine-containing drugs have been used primarily as disinfectants. Many infectious agents are susceptible to iodine-containing drugs that exhibit antifungal activity, cystocidal activity, and antiprotozoal activity, and exhibit activity against spores and do not form acquisition resistance to these drugs. Problems with iodine use are toxic at high concentrations and are irritating to the skin and mucous membranes. However, iodine is mainly complexed with polysaccharides and polymers to reduce toxicity while maintaining antimicrobial activity, and act more slowly and continuously (within 6 hours).

The present inventors have completed the present invention by identifying an iodine-containing composition that unexpectedly shows a high therapeutic effect on hepatitis C virus while studying an iodine-containing drug.

It is an object of the present invention to provide an iodine-containing pharmaceutical composition having high safety and excellent activity against antiviral, in particular hepatitis C virus, and a method for producing the same.

In order to achieve the above object, the present invention provides a pharmaceutical composition having an antiviral effect, comprising iodine, potassium iodine, sucrose, glucose, starch, polyvinyl alcohol, sodium chloride and sodium carbonate.

Preferably 0.8 to 1.2 parts by weight of iodine, 1.0 to 2.0 parts by weight of potassium iodine, 0.6 to 1.0 parts by weight of sucrose, 1.2 to 1.6 parts by weight of glucose, 5.0 to 7.0 parts by weight of starch, 0.2 to 0.4 parts by weight of polyvinyl alcohol, sodium chloride 0.8 to 1.0 parts by weight, sodium carbonate 0.3 to 0.5 parts by weight.

The pharmaceutical compositions of the present invention can be used for injection, in particular intravenous, in the form of suspensions obtained by suspension in aqueous media such as distilled water for injection. The pharmaceutical composition of the present invention has excellent antiviral activity and may be particularly useful for treating hepatitis C virus.

The composition of the present invention exhibits safe and effective antiviral activity, and can be used particularly effectively in the treatment of hepatitis C viral infection. In particular, the composition of the present invention is free of expensive components, easy to manufacture and use, can reduce the cost of treatment of viral hepatitis C, and can shorten the treatment period.

Figure 1 shows the changes in blood cells and hemoglobin such as platelets, leukocytes, erythrocytes of the experimental group to which the composition of the present invention was administered compared with the control rats.

2 is a micrograph of the lung, liver, kidney and heart of control animals.

3 to 5 are micrographs of lungs, liver, kidneys, and hearts of experimental animals on Days 5, 10, and 15 of the first experimental group, respectively.

Figure 6 is a micrograph of the lung, liver, kidney and heart of the experimental animals on day 5 of the second experimental group.

Figure 7 is a micrograph of the lung, liver, kidney and heart of experimental animals on day 10 of the third experimental group.

Figure 8 is a micrograph of the lung, liver, kidney and heart of experimental animals on day 15 of the fourth experimental group.

The present invention provides a pharmaceutical composition having an antiviral effect, comprising iodine, potassium iodine, sucrose, glucose, starch, polyvinyl alcohol, sodium chloride and sodium carbonate.

Preferably 0.8 to 1.2 parts by weight of iodine, 1.0 to 2.0 parts by weight of potassium iodine, 0.6 to 1.0 parts by weight of sucrose, 1.2 to 1.6 parts by weight of glucose, 5.0 to 7.0 parts by weight of starch, 0.2 to 0.4 parts by weight of polyvinyl alcohol, sodium chloride 0.8 to 1.0 parts by weight, sodium carbonate 0.3 to 0.5 parts by weight.

The compositions of the present invention may be administered by oral or parenteral route, and may be formulated and administered for injection, especially intravenous, intramuscular, subcutaneous injections and the like.

When formulated for injection, each of the components is present in an aqueous medium such as water (distilled water, water for injection or sterile purified water, etc.) at the following compositional ratios: 0.8-1.2% iodine, 1.0-2.0% potassium iodine, shoe 0.6-1.0 wt% cross, 1.2-1.6 wt% glucose, 5.0-7.0 wt% starch, 0.2-0.4 wt% polyvinyl alcohol, 0.8-1.0 wt% sodium chloride, 0.3-0.5 wt% sodium carbonate and residual aqueous medium.

The present inventors have found that the compositions of the present invention having the above components and composition ratios exhibit particularly excellent antiviral activity and are suitable for use in injectable forms.

The principles of modern binding chemistry have been applied to form the pharmaceutical product of the present invention as an integral substance. One of the main functions of the components used in the composition is to create a special structure that allows transport and distribution throughout the body with the oxidative power of iodine maintained.

The composition of the present invention, having the above components and composition ratios, forms an iodine-polymer complex that functions as a matrix in an aqueous solution, from which an active ingredient, ie, an iodine in active form, is assigned. Starch, sucrose and glucose combinations participate in matrix and union formation.

By introducing potassium iodine it is possible to achieve the formation of a physicochemical system which prevents long term inactivation of the main active ingredient (iodine). It is well known that carbohydrates are an essential component of the bacterial cell wall and are the first to come into contact with the host's immune system. Due to this fact, the mechanisms of the innate immune system include the recognition of glycoconjugates related to the function of many cellular receptors of lectin type recently discovered on the surface of bacterial carbohydrates and phagocytic cells. In the presently accepted view, amylose-iodine complex formation is linked to the helix amylose chain and forms a channel-like hole in the center of the spiral that is large enough to receive iodine molecules. This iodine complex formation does not change the viscosity of the amylose solution.

The starch-iodine complex forms hexagonal crystals. As a result of studying the structure of the starch-iodine complex, it acts as an inclusion compound with donor-recipient binding, the valence of which is measured as the ratio of eight monomer units of polymer per atom of iodine, The charge of the iodine component was found to be zero. In the presence of starch, the I ₂ molecules dissociate to form complex ions I ₃ and IO, and only complex I ₃ anions that disappear from the solution participate in starch-iodine complex formation. Complex anion IO, on the other hand, remains in solution without forming a complex. The concentration sharply increases due to the decomposition of I ₂ . The biologically active forms of iodine are believed to be part of the polarized molecule I ₂ and oxyanion I (O ⁻ ), ie the monovalent cation form of the oxidized state. The composition of the present invention is particularly believed to allow iodine to be distributed in vivo in an active state to exhibit viral activity. Iodine and its complexes halogenate (iodize) DNA and RNA containing viruses both inside and outside cells due to recognition mechanisms and specific chemical interactions. This results from the substitution of hydrogen atoms in the purine and pyrimidine base groups contained within the molecular components of DNA and RNA containing viruses. Halogenation results in the formation of new substances that no longer have viral properties. Polyvinyl alcohol slows the absorption of iodine and reduces tissue irritation. In addition, binding to molecular iodine causes accumulation of the active form of molecular iodine, thereby reducing the release of iodine and prolonging the interaction between tissues in the body, thereby increasing the pharmacological activity of the present formulation. Sodium carbonate neutralizes the acidic medium, thereby eliminating unwanted complications.

The antiviral activity of the compositions of the present invention is believed to be due to the interaction mechanism between these components and iodine. The components of the present invention provide for selective oxidation of essential molecular components of viruses and bacteria by the main active ingredient (iodine).

The components of the composition thus maintain their stability and structure on the one hand and, on the other hand, exhibit direct expression of two main functions: antiviral activity and immunomodulatory activity. In addition, due to the combination of the components unique to the present invention, the iodine polymer composite of the present invention exhibits 2-8 times higher activity than potassium iodine and molecular iodine solutions.

Over the decade we have conducted studies of various high concentrations of iodine-polymer drugs and conducted clinical trials on these drugs. Research has continued to determine the compositions of the most effective ingredients and their preparation techniques, with the findings of which are compositions of the present invention.

The present invention also provides a method of preparing the composition of the present invention.

Crystalline iodine and potassium iodine solutions in distilled water are prepared. Preferably, crystalline iodine is added to a saturated solution of potassium iodine and mixed thoroughly. Sucrose, glucose, polyvinyl alcohol, sodium carbonate and starch viscosity are added to distilled water with constant stirring and mixed. At this time, distilled water is preferably used hot water of 90 to 95 degrees. Sodium chloride is added for stabilization to prepare the composition of the present invention.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, these examples are for illustrating the present invention, and the scope of the present invention is not limited to these examples.

Example 1 Preparation of Pharmaceuticals of the Invention

15 g of potassium iodine was added to distilled water for injection to make a saturated solution, and 10 g of crystalline iodine was added thereto, followed by complete mixing to prepare an iodine-containing solution. 8 g of sucrose, 14 g of glucose, 3 g of polyvinyl alcohol, 4 g of sodium carbonate, and 60.0 g of starch slurry were added to the distilled water for injection heated to 90-95 ° C. and mixed. After cooling, these two solutions were mixed, 9 g of sodium chloride was added and the total solution was 1 L, the iodine-containing agent of the present invention in the form of iodine-specific flavor and black to dark blue liquid syrup (hereinafter referred to as "IAMA"). ) Was prepared.

Experimental Example 1: Confirmation of Toxicity of the Agent of the Present Invention

In order to investigate the toxicity of the drug "IAMA" of the present invention prepared in Example 1, an animal test was performed. The medicament of the present invention was intraperitoneally injected into experimental animals (rats, average body weight 180.0-210.0 g) once daily at various doses by dilution or non-dilution in physiological saline solution. The dose volume was chosen to be 5 ml by the maximum recommended allowable amount of the intraperitoneal injection solution and the dose was determined according to the toxicity classification of the compound according to national standard 12.1.007-76. Rats were divided into four groups with different dosages as follows and the control group.

First Experimental Group: 0.06 ml + 3.0 ml of the physiological solution of the formulation of Example 1 was intraperitoneally administered once daily. This dose is in excess of 1.7 times the therapeutic dose. Rats were sacrificed 5, 10 and 15 days after the start of the experiment.

Second experimental group: 0.66 ml + 3.0 ml of the physiological solution of the formulation of Example 1 was intraperitoneally administered once daily. This dose is in excess of 11 times the therapeutic dose. Rats were sacrificed 5 days after the start of the experiment.

Third experimental group: 2 ml + 3.0 ml of the physiological solution of the formulation of Example 1 was intraperitoneally administered once daily. This dose is in excess of 33 times the therapeutic dose. Rats were sacrificed 10 days after the start of the experiment.

Fourth experimental group: 5 ml of the formulation of Example 1 was intraperitoneally administered once daily. This dose is in excess of 83 times the therapeutic dose. Rats were sacrificed 15 days after the start of the experiment.

The experimental schedule is briefly shown in the table below.

TABLE 1

Basic data and morphological composition (total erythrocyte count, hemoglobin content in erythrocytes, total leukocyte count and total platelet count) of blood collected from the sacrificed animals were measured and shown in FIG. 1. Solid lines in Figure 1 represent the control.

As can be seen in Figure 1, the formulation "IAMA" of the present invention did not cause a statistically significant change in blood cells of the experimental animal compared to the control rat. The change in blood composition of rats in the experimental group did not exceed 10% compared to rats of the control group, thus confirming that the drug of the present invention does not show any toxicity to the blood system.

In addition, histological analysis of organs (lung, liver, kidney, heart) of control and experimental animals is shown in FIGS. 2-8.

Histological examination of experimental animals confirmed the following:

There was no significant change in the microstructure of the irradiated organs in the experimental animals on day 5 of the first experimental group.

No disruptive changes in the cytoplasm of the irradiated organ were observed in the experimental animals on day 10 of the first experimental group, but vascular congestion was observed in the lung-bronchi and vascular wall.

In experimental animals on day 15 of the first experimental group, no significant changes were seen in the kidneys. However, epidermal dropout of the alveolar epithelium in the lung, partial vascular congestion of the heart and hepatocellular fear formation in the liver were observed.

Taken together, for the first experimental group greater than 1.7 times the therapeutic dose, no specific pathological changes, physiological abnormalities, or behavioral abnormalities were found, the overall condition was good, no weight loss, Appetite, eye and hair condition were normal.

In the second experimental group, no significant structural changes were observed in the kidneys, heart and lungs, but in the kidneys, symptoms of flattening of the epithelium and symptom of hydronephrosis were observed. The septum between the alveoli was slightly thickened and the formation of small non-nuclear foci in the hepatocytes was observed, but the central part of the trachea remained normal. The overall condition was still good and externally healthy.

In the third experimental group, muscle fibers slightly morphologically in the heart, and some circulatory disorders were observed with vascular congestion in the liver. Epithelial edema was observed in the proximal and distal canals of the kidney. However, despite the 33 times higher dose than the therapeutic dose, all experimental animals survived and no physiological abnormalities were found.

In the fourth experimental group, local necrosis was observed in epithelial cells of liver and kidney. The septum between the alveoli thickened extensively, and flattening of the epithelium and vascular congestion were observed. Parenchymal degeneration was observed in the heart. There was a decrease in exercise, deterioration of hair condition and decreased appetite, but despite the dose being 83 times higher than the therapeutic dose, no mortality was observed in the experimental animals. This also confirms the nontoxicity of the formulations of the invention.

Experimental Example 2 Inhibition of Chronic Hepatitis C Viral Infections of the Inventive Agent

This study was performed on 36 patients with chronic hepatitis C viral virus (HCV) confirmed by IFA diagnosis (positive anti-HCV response, positive PCR for HCV). All patients found antibodies to non-structural proteins (anti-NS) and anti-HCV class Ig M, from which it was confirmed that they are in the chronic phase of disease at the reactivation phase.

Transaminase levels (ALT), bilirubin (beconjugate) on day 6 (after the first course), 15, 30 and 90 days after the course of treatment, before administration of the agents of the present invention to all patients And conjugated) and thymol tests are shown and shown in Table 2 below. In addition, quantitative PCR was performed after the second treatment course was completed, and quantitative PCR was repeated after 10 days, 30 days, 3 months, and 6 months (delayed viral response).

If hepatitis C virus was found again in the blood after one month, these patients performed quantitative PCR on HCV RNA and then repeated the treatment cycle according to the same plan. The viral infection levels before treatment, after the first, second and third treatment cycles are shown in Table 3 below.

The dosing schedule of the medicament of Example 1 of the present invention is shown in Table 4 below.

TABLE 2

TABLE 3

TABLE 4

The criterion of this therapeutic effect is the loss of HCV RNA, normalization of aminotransferase levels, ie complete removal of virus from blood (in hepatocytes and extracellular cells) based on the results of quantitative PCR on HCV RNA. As shown in Tables 2 and 3 above, the agents of the present invention effectively normalized aminotransferase levels and, depending on the viral blood levels before treatment, form C after the first, second or third cycle administration of the agents of the present invention. Complete removal of the virus has been confirmed, from which it can be seen that the agent of the present invention can very effectively treat chronic hepatitis C virus.

On the other hand, no deterioration of the patient's condition, including drug intoxication or phlebitis, was observed during the administration of the drug of the present invention. Upon completion of the treatment cycle, all patients showed improvement in health, ie, increased appetite and achievement efficiency, reduced fatigue or loss.

Experimental Example 3: Monitoring of Side Effects and Formulation Characteristics of Drugs of the Present Invention

Sterility: Example 1 Formulations were prepared by National pharmacopeia RK XI, issue 2, p. The test was carried out by direct inoculation according to the requirements of 187 and found sterile.

Pyrogenicity: Example 1 A test dose of 0.1 mg of the formulation diluted in 1 ml of water for injection per kilogram of body weight in gray rabbits was used as a test dose of National pharmacopeia RK XI, issue 2, p. As a result of intravenous injection according to 183, it was confirmed that the body temperature fluctuation after the injection was less than 1.2 DEG C as follows, which was non-pyrogenic.

TABLE 5

Toxicity Example 1 A test dose of 0.1 mg diluted in 0.5 ml of water for injection per kg of body weight of an animal (white mouse, body weight 19.0-20.8 g) was used as a test dose of National Pharmacopeia RK XI. Intravenous injections according to Issue.2, page 182 were found to be nontoxic.

Stability: Example 1 The formulation was tested for stability according to CPMP / ICH / 2736/99 "Stability Testing of New drugs and Products" and shelf life was determined to be 2 years based on the results of qualitative and quantitative tests. It became.

As discussed above, the formulation of the present invention did not show statistically significant changes in the histological structure of blood or internal organs, and no behavior or fatality was observed during the test period and was nonpyrogenic. This confirmed that the formulation of the present invention is a very safe formulation.

Claims (6)

1. A pharmaceutical composition having an antiviral effect, comprising iodine, potassium iodine, sucrose, glucose, starch, polyvinyl alcohol, sodium chloride and sodium carbonate.
2. According to claim 1, 0.8 to 1.2 parts by weight of iodine, 1.0 to 2.0 parts by weight of potassium iodine, 0.6 to 1.0 parts by weight of sucrose, 1.2 to 1.6 parts by weight of glucose, 5.0 to 7.0 parts by weight of starch, 0.2 to 0.4 weight of polyvinyl alcohol Part, 0.8 to 1.0 parts by weight of sodium chloride, 0.3 to 0.5 parts by weight of sodium carbonate.
3. The pharmaceutical composition of claim 1, formulated for injection.
4. The pharmaceutical composition of claim 3 for intravenous injection.
5. The pharmaceutical composition according to any one of claims 1 to 4, for the treatment of hepatitis C virus.
6. A therapeutic agent for hepatitis C virus, comprising the composition of any one of claims 1 to 4.

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