KR101538385B1 - Composition for preventing and treating Toxoplasma gondii infection comprising crizotinib - Google Patents

Abstract

The present invention relates to pharmaceutical compositions, veterinary compositions, and antigen supplementation adjuvants for the prevention or treatment of toxoplasmosis infectious diseases comprising crizotinib or a pharmaceutically acceptable salt thereof.

Description

TECHNICAL FIELD The present invention relates to a composition for preventing and treating toxoplasmosis infectious diseases,

The present invention relates to pharmaceutical compositions, veterinary compositions, and antigen supplementation adjuvants for the prevention or treatment of toxoplasmosis infectious diseases comprising crizotinib or a pharmaceutically acceptable salt thereof.

Toxoplasma gondii is an opportunistic protozoal parasite that infects macrophages and infects the central nervous system. Toxoplasma gondii are infected by ingesting water directly contaminated with oocyst from the feces of a domesticated cat or ingested in vegetables, or by cysts in meat, such as pigs, sheep and cows, It is infected by feeding on existing toxoplasmosis, and can be infected with various warm-blooded animals including humans. About one-third of the world's population is infected with Toxoplasma gondii and has been reported to have an infection rate of 2 to 25% depending on the group in Korea.

When the mother is infected with toxoplasmosis, her trophozoite is transmitted through the placenta to the fetus. Thus, similar fetal acidity occurs in the fetus, and in the postpartum fetus, symptoms such as visual impairment, hydrocephalus, and mental retardation appear even after normal delivery. Even healthy people eat less livestock or wild meat to infect and infect immune cells, reticuloendothelial cells, etc., and proliferate while destroying cells, resulting in lymphadenitis, retinal choroiditis, encephalomyelitis, etc. In particular, During immunosuppression, cerebral meningitis or retinitis choritis occurs due to the reactivation of cysts present in the brain.

To date, as a treatment for toxoplasmosis infection, either spiramycin or pyrimethamine has been administered alone or pyrimethamine and sulfa, which have been developed as preventive drugs against malaria, have been administered in combination 2-3 weeks of treatment is used, especially in combination with good results are shown. However, there is a problem that Stevens-Johnson syndrome, which is a major symptom of peeling of the epidermis and mucosa at the time of coadministration, may appear as a side effect, and development of safer therapeutic agent is urgent.

Further, as another therapeutic agent against toxoplasmosis infection, a composition comprising an oleuropein compound isolated from an ash tree as an active ingredient (Korean Patent Registration No. 10-0834444), 1- [4- (4-nitro-phenoxy-phenyl -Propane-1-one (Korean Patent No. 10-1148098), 1,5-diphenyl-8-methyl-6,7-dioxa-bicyclo [3.2.2] non- No. 10-0946466), and 7-ethoxycomarin (Korean Patent Registration No. 10-0903287) have been proposed, but the effect has not yet been fully verified.

On the other hand, crizotinib is a lung cancer-targeted anticancer drug used in patients with anaplastic lymphoma kinase (ALK) -based non-small cell lung cancer. It acts as an inhibitor of c-MET / ALK (hepatocyte growth factor receptor) (Epidermal Growth Factor Receptor, EGFR). Crizotinib refers to the compound PF-02341066 developed by Pfizer and is commercially available.

The inventors of the present invention have found that clitorotinib, which is known only as an anticancer agent, is excellent in the effect of inhibiting proliferation of toxoplasmosis, and thus can be used as a therapeutic agent against toxoplasmosis infection.

It is an object of the present invention to provide a pharmaceutical composition for preventing or treating toxoplasmosis infectious disease, which comprises krizotinib or a pharmaceutically acceptable salt thereof.

It is another object of the present invention to provide a method for treating toxoplasmosis infectious disease comprising administering to an individual an effective amount of a composition comprising krizotinib or a pharmaceutically acceptable salt thereof.

It is an object of the present invention to provide a veterinary composition for the prevention or treatment of toxoplasmosis infectious diseases, comprising krizotinib or a pharmaceutically acceptable salt thereof.

It is an object of the present invention to provide an antidiabetic agent for preventing or treating toxoplasmosis infectious diseases, which comprises krizotinib or a pharmaceutically acceptable salt thereof.

In one aspect for achieving the above object, the present invention relates to a pharmaceutical composition for preventing or treating toxoplasmosis infectious disease, which comprises krizotinib or a pharmaceutically acceptable salt thereof.

In a preferred embodiment, the toxoplasmosis infection may be an infection caused by Toxoplama gondii.

In a preferred embodiment, the toxoplasmosis infection may be one or more selected from the group consisting of retinitis, choroiditis, and retinal choroiditis.

In a preferred embodiment, the pharmaceutical composition may comprise 0.1 to 50% by weight of the composition of the present invention, in terms of the total weight of the composition, of clitorotinib or a pharmaceutically acceptable salt thereof.

In a preferred embodiment, the pharmaceutical composition may further comprise a pharmaceutically acceptable carrier, excipient or diluent.

In another aspect, the present invention relates to a method for treating toxoplasmosis infectious disease comprising administering to an individual an effective amount of a composition comprising chrysozyme or a pharmaceutically acceptable salt thereof.

In another aspect, the invention is directed to a veterinary composition for the prevention or treatment of toxoplasmosis infectious disease comprising krytotinib or a pharmaceutically acceptable salt thereof.

In a preferred embodiment, the veterinary composition may be a composition to which the animal to be infected with toxoplasmosis is applied for being a mammal or a poultry.

In another aspect, the present invention relates to an anticarious supplement for the prevention or treatment of toxoplasmosis infectious diseases, comprising clozotinib or a pharmaceutically acceptable salt thereof.

Hereinafter, the present invention will be described in more detail.

The term "toxoplasmosis infection" in the present invention refers to a disease caused by infection of a protozoan protozoa, more preferably toxoplasmosis gondii , including infection with lactic acid and infertility when a woman is infected during pregnancy A type of infectious common infectious disease that can cause abnormalities in the fetus. The toxoplasmosis infection may be expressed as "toxoplasmosis ".

 In the present invention, toxoplasmosis infectious disease includes all diseases and symptoms that can be caused by infection with toxoplasmosis. Toxoplasmosis may be parasitic in various parts of the body such as the lymphatic system, brain, lung, myocardium, spleen, bone marrow, kidney, adrenal gland, nervous system and fast tachyzoite is active in the reticuloendothelial system and circulatory endothelial cells It can divide and proliferate and necrotize the tissue. In addition, depending on the site of infection, various diseases and symptoms can be caused, for example, lymphadenitis, retinitis choritis, meningitis, encephalitis, hepatitis, myositis, myocarditis, pneumonia, tubular disease and the like.

Preferably, the toxoplasmosis infection in the present invention may be an infectious disease that occurs in the retina or choroid, and may be exemplified by retinitis, choroiditis, and retinal choroiditis. Since the retina is in contact with the choroid, inflammation of the retina may cause changes in the choroid, and conversely, inflammation of the choroid may cause changes in the retina. Therefore, retinitis and choroiditis often occur together, and this is called retinal choritis or chorioretinitis.

When toxoplasmosis enters the body, it builds up a pocket in the brain, eyes, and liver. When the immune system weakens, it reactivates. If toxoplasmosis is invaded by eye inflammation, it can cause retinitis, choroiditis and retinal choroiditis have. In the example of the present invention, it was confirmed that the treatment of clitorotinib inhibits proliferation of toxoplasmosis by treating clitorotinib in retinal epithelial cells, thereby confirming that crizotinib has a therapeutic effect comparable to that of pyrimethamine, Respectively.

As used herein, the term "prophylactic " refers to any act that inhibits or delays the onset of toxoplasmosis infectious disease upon administration of the composition of the present invention.

As used herein, the term "treatment" refers to any action that improves or alters the symptoms of toxoplasmosis infectious disease upon administration of the composition of the present invention.

The present invention is characterized by providing clitorotinib or a pharmaceutically or veterinarily acceptable salt thereof as an active ingredient for preventing or treating toxoplasmosis infectious disease.

The term "crizotinib" in the present invention is commercially available, and can be purchased from the market under the chemical name " 3 - [(1R) -1- (2,6-dichloro-3-fluorophenyl) (1-piperidin-4-ylpyrazol-4-yl) pyridin-2-amine, < / RTI >

[Chemical Formula 1]

Also, in the present specification, the term "crizotinib" is used to mean both of crizotinib and its racemates, enantiomers, polymorphs, hydrates and solvates.

The present invention can also include a pharmaceutically acceptable salt of clitorotinib as an active ingredient. The term "pharmaceutically acceptable salt" in the context of the invention includes salts derived from pharmaceutically acceptable inorganic acids, organic acids, or bases. The term "veterinarily acceptable salt" in the context of the invention includes salts derived from veterinarily acceptable inorganic acids, organic acids, or bases.

Suitable acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, , Benzoic acid, malonic acid, naphthalene-2-sulfonic acid, and benzenesulfonic acid. The acid addition salt can be prepared by a conventional method, for example, by dissolving the compound in an excess amount of an acid aqueous solution and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Further, it can be prepared by heating the same molar amount of the compound and the acid or alcohol in water, and then evaporating the mixture and drying, or by suction filtration of the precipitated salt.

Salts derived from suitable bases may include, but are not limited to, alkali metals such as sodium and potassium, alkaline earth metals such as magnesium, and ammonium. The alkali metal or alkaline earth metal salt can be obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the non-soluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable to produce sodium, potassium or calcium salt particularly as a metal salt, and the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).

The combination therapy of pyrimethamine and sulfase, which is currently used as a treatment for toxoplasia spp., Has been increasing in resistance, has little effect on toxoplasmosis of the bradyzoite stage, There is a problem that Stevens-Johnson syndrome can manifest as a side effect.

In the case of chrysotriptyline provided by the present invention, it has already been proved as safe without toxicity or side effects to humans and animals as a result of numerous clinical trials as an anticancer agent. The present inventors have found that the effect of inhibiting proliferation of toxoplasmosis It proved to be excellent.

The content of clitorotinib in the composition of the present invention can be appropriately adjusted depending on the symptom of the disease, the progress of symptoms, the condition of the patient and the like, for example, 0.0001 to 99.9% by weight, preferably 0.001% But it is not limited thereto. The content ratio is a value based on the dried amount from which the solvent is removed.

The composition may further comprise suitable carriers, excipients and diluents conventionally used in the production of pharmaceutical and veterinary compositions and may be formulated into powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols Or the like, an external preparation, a suppository or a sterilized injection solution, and the like.

Examples of carriers, excipients and diluents that can be included in the composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, Cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

When the composition is formulated, it may be prepared by using a diluent such as a filler, an extender, a binder, a wetting agent, a disintegrant, a surfactant, or an excipient. Solid formulations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations may include at least one excipient and / or lubricant. Liquid preparations for oral administration include suspensions, solutions, emulsions, syrups and the like. Various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included in addition to water and liquid paraffin, which are simple diluents commonly used. have. Formulations for parenteral administration may include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, suppositories, and the like.

As used herein, the term "therapeutically effective amount" or "effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to the treatment of toxoplasmosis, and the effective dose level will vary depending on the species, condition and severity, Depending on factors well known in the art and other factors, including the type of infecting bacteria, the activity of the drug, the sensitivity to the drug, the time of administration, the route of administration and rate of release, the duration of the treatment, Can be selected. For a more preferable effect, the dose of the composition of the present invention is preferably 0.1 mg / kg to 100 mg / kg per day based on the active ingredient, but is not limited thereto. The administration may be carried out once a day or divided into several doses. The compositions of the present invention may be administered to a mammal, including a human, in various ways. All modes of administration may be expected, for example, by oral, intravenous, intramuscular, subcutaneous injection, and the like.

The composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents. And can be administered singly or multiply. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without adverse effect, and can be easily determined by those skilled in the art.

Individuals that can be treated with the compositions of the present invention include, but are not limited to, humans, mammals such as pigs, cows and goats, poultry such as pheasants, chickens, ducks and turkeys.

The therapeutic agent for toxoplasmosis infectious disease provided by the present invention is safe without toxicity or side effects to humans and animals, and is excellent in killing effect against toxoplasmosis, so that it can be widely used in the fields of pharmacy and veterinary medicine.

FIG. 1 compares the inhibitory effect of various protein kinase inhibitors (sutinitinib, clitorotinib), the positive control agent pyrimethamine and the untreated control, against toxoplasmosis growth.
Fig. 2 shows the proliferative growth pattern of Toxoplasma gondii in the membrane containing retinas of the retina according to the incubation time.

Hereinafter, the present invention will be described in detail with reference to examples. However, the following examples are illustrative of the present invention, and the present invention is not limited by the following examples.

Example 1. Toxoplasmacicidal effect of chrysotanib

ARPE-19 cells (ATCC, CRL 2302), a human retinal epithelial cell, were maintained in a 1: 1 mixed medium of DMEM and F12 supplemented with 10% fetal bovine serum, (RH) (subcultured and cultivated from the Veterinary Science Quarantine Service) were used. Protein kinase inhibitors include 10 μM of sunitinib (purchased from Sigma Chem Co.), 5.0 μM of pyrimethamine (purchased from Sigma Chem Co.), and crizotinib (purchased from Sigma Chem Co.) 5.0 .mu.M was treated with host cells infected with Toxoplasma gondii, and stained with Giemsa solution every 12 hours for 72 hours to count the number of Toxoplasma pneumoniae per organolepticum.

As a result, as shown in Fig. 1, suinitinib used as a negative control agent showed no effect on the toxoplasmosis which proliferates in the progenitor-containing membrane produced in the retina cells, while the effect of crizotinib was observed above 5.0 μM, The inhibitory effect was similar to that of pyrimethamine (5.0 μM) used as a reference drug. In addition, as shown in Fig. 2, even in the case of the cell staining, the control group treated with the drug did not exhibit the schizophrenia of the toxoplasmosis, whereas the group treated with the clitorotinib maintained the initial penetration because the toxoplasmosis was hardly proliferated.

Claims (8)

A pharmaceutical composition for preventing or treating toxoplasmosis infection, comprising crizotinib or a pharmaceutically acceptable salt thereof.
The pharmaceutical composition according to claim 1, wherein the toxoplasmosis infection is an infection caused by Toxoplama gondii .
The pharmaceutical composition according to claim 1, wherein the toxoplasmosis infection is retinitis, choroiditis, or retinal choroiditis.
2. The pharmaceutical composition according to claim 1, wherein the composition comprises 0.1 to 50% by weight of the composition of claim 1 or a pharmaceutically acceptable salt thereof.
The pharmaceutical composition of claim 1, further comprising a pharmaceutically acceptable carrier, excipient or diluent.
A veterinary composition for the prevention or treatment of toxoplasmosis infectious disease, comprising crytotinib or a veterinarily acceptable salt thereof.
The veterinary composition according to claim 6, which is applied to mammals or poultry as an animal to be toxoplasma-infected.
An anticoagulant for the prevention or treatment of toxoplasmosis infectious diseases, comprising crytotinib or a pharmaceutically acceptable salt thereof.

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