KR20140113063A - Use of Alpha Lipoic Acid for Preventing or Treating Radiation Induced Fibrosis - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating radiation-induced fibrosis containing alpha lipoic acid or a pharmaceutically allowable salt thereof as effective components. As alpha lipoic acid of the present invention shows an effect of suppressing and alleviating radiation-induced fibrosis effectively, alpha lipoic acid can be used for the purpose of preventing or treating radiation-induced fibrosis.

Description

Use of Alpha Lipoic Acid for Preventing or Treating Radiation Induced Fibrosis < RTI ID = 0.0 >

The present invention relates to novel uses of alpha-lipoic acid, and more particularly to the use of alpha-lipoic acid for the prevention or treatment of radiation-induced fibrosis.

Fibrosis is a disease in which abnormal formation, accumulation and deposition of extracellular matrix by fibroblasts occurs. It refers to abnormal accumulation of collagen matrix due to injury or inflammation that changes the structure and function of various tissues. Regardless of the location of the onset of fibrosis, most of the etiology of fibrosis involves excessive accumulation of the collagen matrix that replaces normal tissue. Fibrosis, particularly in the kidneys, liver, lungs, heart, bone or bone marrow, and skin, can lead to organ dysfunction and even death in the worst case. The fibroblasts function to form a precursor of extracellular matrix in a normal state to form a fibrous tissue. The extracellular matrix, which is the intercellular material of the connective tissue, is present in the form of proteins such as fibronectin, laminin, chondronectin, and collagen.

Radiation-induced fibrosis refers to a gradual transition to abnormal fibrous tissue over a period of at least 1 month to several years in normal tissues or organs exposed to excessive radiation. Most of the fibrosis occurring in the human body is caused by persistent and chronic inflammation, but radiation fibrosis is characterized by sustained fibrosis after a certain period of time after irradiation, although the radiation causing the radiation has disappeared . It is characterized by the loss of parenchymal cells constituting normal tissue, which leads to the atrophy of the tissue and its replacement with fibrotic tissue. If this process is triggered, loss of organ function due to tissue atrophy may occur, and fibrosis itself may result in organs, tissue hardening, curvature, and pain. Radiation-induced fibrosis can occur in all tissues of the body except for certain organs such as the central nervous system.

The fact that radiation induced fibrosis is differentiated from fibrosis due to other causes is the fact that tissue damage due to radiation occurs at the same time in addition to changes in substrate such as excessive formation of collagen commonly observed in fibrosis. This histologic change by radiation is characterized by a nonspecific overall pathologic change pattern, including vascular tissue, to the extent that radiation is irradiated. Pathologically, radiation damage causes atrophy, dysplasia, and atypia of tissue parenchyma. Recently, it has been shown that the development of molecular biology research has led to the development of a highly dynamic and reversible process in the microenvironment rather than the irreversible stopping of the fibrosis due to this complex process. Improvement by treatment has been reported, and this phenomenon is supported. In conclusion, radiation-induced fibrosis is a highly dynamic and reversible pathologic process in the microenvironment where radiation-induced tissue damage and interactions are combined, unlike fibrosis, which occurs in common causes. And it should be discriminated in the therapeutic approach as well.

Korean Patent Laid-Open No. 10-2009-0028880 discloses a method for treating fibrosis based on the mechanism of fibrosis, but no specific treatment method for radiation-induced fibrosis has been disclosed.

Therefore, the present invention aims to provide a novel use of a compound having the effect of preventing or treating radiation-induced fibrosis.

In order to solve the above problems, the present invention provides a pharmaceutical composition for preventing or treating radiation-induced fibrosis containing alpha lipoic acid or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides a cosmetic composition for preventing or improving radiation-induced fibrosis containing alpha lipoic acid as an active ingredient.

The alpha-lipoic acid of the present invention has an effect of effectively inhibiting and alleviating the fibrosis induced by radiation, and thus can be usefully used for the prevention or treatment of radiation-induced fibrosis.

1 is a photograph of an acrylic fixture for measurement of leg shrinkage used in Example 1. Fig.
FIG. 2 is a graph showing the effect of the present invention's alpha-lipoic acid on the degree of contraction of the legs induced by dermal fibrosis by radiation.
FIGS. 3 and 4 are photographs showing the comparison of the leg lengths of the radiation-induced fibrosis-induced mice. In particular, Fig. 4 shows the degree of inflammation or tissue entrapment of the epidermis.
FIG. 5 is a photograph showing the effect of the present invention's alpha-lipoic acid on the degree of collagen accumulation and inflammatory cell deposition in lung lungs induced by radiation.
FIG. 6 is a graph showing the number of inflammatory cells and collagen accumulation of mouse lung in which pulmonary fibrosis was induced by scoring.

The present invention provides a pharmaceutical composition for preventing or treating radiation-induced fibrosis containing alpha lipoic acid and a pharmaceutically acceptable salt thereof as an active ingredient.

Alpha-lipoic acid is represented by the following formula (1) and is also referred to as 6,8-dithiooctanoic aci or thioctic acid:

[Chemical Formula 1]

Alpha-Lipoic acid is used as a main ingredient of functional cosmetics that prevent and remove wrinkles and anti-aging by its strong antioxidant effect, as a safe nutrient to prevent and treat diabetes patients' blood sugar and to prevent and treat neuropathy of diabetic patients. Recently, And weight loss effects have been proven. α-Lipoic acid is sometimes called 'universal antioxidant' because it is well soluble in both fat and water. It is involved in cell metabolism in the body and contains yeast and liver. In particular, several studies have shown that alpha-lipoic acid is much better at inhibiting protein oxidation than vitamin E, which is known to be associated with aging and heart disease. It also inhibits the oxidation of low density lipoprotein, which is known to increase both the risk of heart disease and oxidative stress in diabetic patients, while enhancing insulin action, thereby improving blood glucose control. As described above,? -Lipoic acid has so far been mainly used as an antioxidant, or as a preventive or therapeutic agent for glycemic control and neuropathy of diabetic patients. However, no application has been disclosed for the prevention or treatment of radiation-induced fibrosis.

The inventors of the present invention have been studying a compound having therapeutic effects of radiation-induced fibrosis, and when the above-mentioned alpha-lipoic acid is orally administered to an animal model of a radiation dermatophyte mouse to the leg, the degree of leg shrinkage of the mouse is alleviated, And tissue organs were suppressed. Thus, it was confirmed that the alpha-lipoic acid of the present invention is effective for radiculopathy. In addition, when the alpha lipoic acid is orally administered to an animal model of a radiation pulmonary fibrosis-induced mouse, collagen accumulation degree and inflammatory cell deposition of lung tissue are inhibited, and the present invention has been completed.

Therefore, as shown in the following examples, the alpha-lipoic acid according to the present invention effectively inhibits radiation-induced dermal fibrosis as well as pulmonary fibrosis and can be used for prevention or treatment of radiation-induced fibrosis. Accordingly, the present invention provides a pharmaceutical composition for preventing or treating radiation-induced fibrosis comprising alpha lipoic acid or a pharmaceutically acceptable salt thereof as an active ingredient, alpha lipoic acid for the preparation of a therapeutic agent for radiation- ) Or a pharmaceutically acceptable salt thereof, and a method for treating radiation-induced fibrosis comprising administering to a subject a therapeutically effective amount of alpha lipoic acid or a pharmaceutically acceptable salt thereof.

The alpha-lipoic acid of the present invention can be used in the form of a pharmaceutically acceptable salt. As the salt, acid addition salt formed by a pharmaceutically acceptable free acid is useful. As the free acid, inorganic acid and organic acid can be used. As the inorganic acid, hydrochloric acid, bromic acid, sulfuric acid, sulfurous acid, phosphoric acid and the like can be used. As the organic acid, citric acid, acetic acid, maleic acid, fumaric acid, , Acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid and arpartic acid. Preferably, hydrochloric acid is used as the inorganic acid, and methanesulfonic acid is used as the organic acid.

In addition, the alpha-lipoic acid of the present invention includes not only pharmaceutically acceptable salts, but also all salts, hydrates and solvates which can be prepared by conventional methods.

The addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving alpha-lipoic acid in a water-miscible organic solvent such as acetone, methanol, ethanol, or acetonitrile, adding an excessive amount of organic acid, Adding an aqueous solution, and precipitating or crystallizing it. Subsequently, in this mixture, a solvent or an excess acid is evaporated and dried to obtain an additional salt, or the precipitated salt may be produced by suction filtration.

In one embodiment of the present invention, radiation-induced fibrosis refers to a gradual transition to abnormal fiber tissue over a period of at least 1 month to several years in normal tissue or organ exposed to excessive radiation.

Fibrosis may be in the location of the kidneys and may be caused by glomerulonephritis (Yoshioka et al., Lab Invest 68: 154-63 (1993)), diabetic nephropathy (Yamamoto et al., Proc Natl Acad Sci USA 90: 1814-8 (1993)), transplant rejection (Shihab et al., J Am Soc Nephrol 4: 671 (1993)), HIV nephropathy (Border et al., J Am Soc Nephrol 4: 675 Fibrosis is observed in Lupus nephropathy; In the case of liver, cirrhosis (Castilla et al., N Engl J Med 324: 933-940 (1991) and Nagy et al., Hepatology 14: 269-73 Engl J Med 328: 1592-8 (1993)), fibrosis is observed in hepatitis C virus infection, alcohol-induced hepatic fibrosis and autoimmune hepatic fibrosis; In the case of lungs, autoimmune fibrosis (Deguchi et al., N Engl J Med 328: 1592-8 (1993) and Brockelmann et al., Proc Natl Acad Sci USA 1991; 88: Ann Rheum Dis 1992; 51: 362-5) and bleomycin-induced fibrosis; In the case of skin, systemic sclerosis (Kulozik et al., J Clin Invest 1990; 86: 917-22), keloid (Peltonen et al., J Invest Dermatol 1991; 97: 240-8), wound (Ghahary et al. J Lab Clin Med 1993; 122: 465-73) and eosinophilia-muscle pain syndrome (Varga et al., Ann Intern Med 1992; 116: 140-7); In the central nervous system, fibrosis is observed in guanine fibrosis (Conner et al., J Clin Invest 1989; 83: 1661-6); In the case of cardiovascular, vascular restenosis (Nikol et al., J Clin Invest 1992; 90: 1582-92); In the case of nose, fibrosis is observed in costemia (Ohno et al., J Clin Invest 1992; 89: 1662-8); Fibrosis is also observed in bone or bone marrow (Reith, J. D. et al., Am J Srg Pathol, 1996 20 (11): 1368-1377); Fibrosis is also observed in endocrine organs (Endocrinology, 3rd Edition, edited by Leslie J. DeGroot, Vol.1, pp. 165-177 and pp. 747-751); And fibrosis is also observed in the gastrointestinal tract (Tahara, E., J. Cancer Res. Clin. Oncol., 1990, 116 (2), 121-131).

Radiation-induced fibrosis, which is prevented or treated by the pharmaceutical compositions of the present invention, includes fibrosis which occurs at various locations as described above by radiation. Preferably, the fibrosis to be prevented or treated by the pharmaceutical composition of the present invention is skin or pulmonary fibrosis.

In one embodiment of the present invention, the pharmaceutical composition for the prevention or treatment of radiation-induced fibrosis containing alpha lipoic acid or a pharmaceutically acceptable salt thereof as an active ingredient can be used in a conventional manner for the preparation of a pharmaceutical composition One or more adjuvants selected from the group consisting of suitable carriers, excipients, disintegrants, sweeteners, coating agents, swelling agents, lubricants, lubricants, flavors, antioxidants, buffers, bacteriostats, diluents, dispersants, surfactants, May be further included.

Specific examples of carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, Cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. Solid formulations for oral administration may be in the form of tablets, pills, powders, granules, capsules These solid preparations can be prepared by mixing at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin, etc., into the composition. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, syrups and the like, and various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included in addition to water and liquid paraffin which are commonly used simple diluents. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As the suppository base, witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like can be used.

In another embodiment of the present invention, the pharmaceutical composition for preventing or treating radiation-induced fibrosis containing alpha lipoic acid or a pharmaceutically acceptable salt thereof as an active ingredient may be formulated into granules, powders, It may be formulated into tablets, coated tablets, tablets, pills, capsules, suppositories, gels, syrups, juices, suspensions, emulsions, drops or liquids.

According to one embodiment of the present invention, the medicinal composition may be administered orally, intraarterally, intraperitoneally, intramuscularly, intraarterally, intraperitoneally, intrasternally, transdermally, nasally, inhaled, topically, rectally, ≪ / RTI > can be administered to the subject in a conventional manner.

The preferred dosage of the alpha-lipoic acid or its pharmaceutically acceptable salt may vary depending on the condition and body weight of the subject, the type and degree of disease, the drug form, the administration route and the period, and may be appropriately selected by those skilled in the art. According to one embodiment of the present invention, the daily dose may be 0.01 to 200 mg / kg, specifically 0.1 to 200 mg / kg, more specifically 0.1 to 100 mg / kg, though it is not limited thereto. The administration may be performed once a day or divided into several times, and thus the scope of the present invention is not limited thereto.

In the present invention, the 'subject' may be a mammal including a human, but is not limited thereto.

The present invention also provides a cosmetic composition for preventing or improving radiation-induced fibrosis containing alpha lipoic acid as an active ingredient.

As can be seen from the following Examples, the alpha-lipoic acid of the present invention has an effect of suppressing epidermal inflammation and tissue entanglement in an animal model of radial dermal fibrosis mouse, and is useful as a cosmetic composition for preventing or improving the inflammatory response of radiation- .

In one embodiment of the present invention, the cosmetic composition may contain, in addition to the alpha-lipoic acid, additives commonly used in cosmetics such as vitamins, surfactants, emulsifiers, perfumes, colorants, stabilizers, preservatives, antioxidants, And at least one additive selected from the group consisting of chelating agents.

According to one embodiment of the present invention, the cosmetic composition in which the cosmetic composition is used is not limited to the formulation, but may be, for example, a softener, a nutritional lotion, a massage cream, a nutritional cream, a pack, a gel, Base, foundation, lotion, ointment, gel, cream, cleansing, cleanser, soap, shampoo, rinse, treatment and serum. Such cosmetics may contain conventional ingredients such as aqueous vitamins, oily vitamins, high molecular weight peptides, polymeric polysaccharides, sphingolipids and the like, and may be easily prepared according to techniques well known to those skilled in the art.

According to an embodiment of the present invention, the content of the alpha-lipoic acid component may be, but not limited to, 0.001 to 20% by weight, 0.001 to 5% by weight, or 0.001 to 1% by weight based on the total weight of the cosmetic composition.

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are intended to illustrate the contents of the present invention, but the scope of the present invention is not limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

< Example  1> Radiation of alpha-lipoic acid Dermal fibrosis  Review treatment effect

Balb / c male mice were used for radiation induced fibrosis-induced animal models. Bleomycin (12 mg / kg) was subcutaneously injected into the right femur in a Balb / c (male, 7 weeks old) mouse, and 22 Gy of radiation (linear accelerator, Clinac, Varian, Palo Alto, , And a radiation-induced dermal fibrosis model was prepared. Administration of bleomycin The following day, the group was divided and the candidate substance was administered orally. Alpha-lipoic acid was administered at a dose of 800 mg / kg once a day for 15 days.

The leg shrinkage was measured using the acrylic fixture shown in FIG. The mice were anesthetized and then placed in a fixed frame and the tail was fixed. The length of the legs was measured by pulling the legs vertically, and the degree of shrinkage of the legs induced by fibrosis was expressed as% when the left leg was taken as 100%. The results are shown in Fig.

Referring to FIG. 2, after 14 weeks, the shrinkage of the legs of the radiation-induced fibrosis mice was 82.4 ± 8.4% while that of the alpha-lipoic acid group was 92.7 ± 0.2% Of the total number of radiation-induced fibrosis.

FIGS. 3 and 4 are photographs showing the comparison of the leg lengths of the radiation-induced fibrosis-induced mice. Referring to FIGS. 3 and 4, although the leg lengths of the mice in which apparently radicular fibrosis was induced were significantly different on both sides, the legs of the group administered with the alpha-lipoic acid of the present invention did not show much difference, Can be confirmed. In addition, the degree of inflammation and tissue necrosis of the epidermis was also reliably inhibited by the alpha-lipoic acid-treated group.

< Example  2> Effects of Alpha-Lipoic Acid on Radiation Pulmonary Fibrosis

Radiological pulmonary fibrosis models were constructed using Balb / c male mice. Balb / c (male, 7 weeks old) The chest of the mouse was irradiated with 12 Gy of radiation, and other organs other than lung were shielded with lead. At the end of the experiment, the mouse was sacrificed and the lung tissue was fixed with formalin, stained with masson's trichrome, and collagen accumulation and inflammatory cell deposition were observed. The results are shown in Fig.

Referring to FIG. 5, in a mouse in which pulmonary fibrosis was induced by radiation, a large amount of collagen (blue dyeing) accumulated around the organs, inflammatory cells were distributed throughout the lung, and lung hardening proceeded appear. However, alpha-lipoic acid effectively inhibited it.

The number of inflammatory cells and collagen accumulation were scored and evaluated. The results are shown in Fig. Referring to FIG. 6, it was found that inflammatory cells were accumulated in a large number of radiation pulmonary fibrosis animals, while alpha lipoic acid was significantly inhibited and collagen accumulation was also significantly decreased.

As shown in the above results, alpha-lipoic acid effectively inhibited radiation-induced dermal fibrosis as well as pulmonary fibrosis.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that such detail is solved by the person skilled in the art without departing from the scope of the invention. will be. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (6)

A pharmaceutical composition for preventing or treating radiation-induced fibrosis comprising alpha lipoic acid or a pharmaceutically acceptable salt thereof as an active ingredient. The method according to claim 1,
Wherein the radiation-induced fibrosis is radiation-induced dermal fibrosis or pulmonary fibrosis. The method according to claim 1,
At least one additive selected from the group consisting of carriers, excipients, disintegrants, sweeteners, coating agents, swelling agents, lubricants, lubricants, flavors, antioxidants, buffers, bacteriostats, diluents, dispersants, surfactants, Or a pharmaceutically acceptable salt thereof, for the prophylaxis or treatment of radiation-induced fibrosis. The method according to claim 1,
The pharmaceutical composition for preventing or treating radiation-induced fibrosis may be selected from the group consisting of granules, powders, coated tablets, tablets, pills, capsules, suppositories, gels, syrups, juices, suspensions, emulsions, Induced fibrosis. &Lt; / RTI &gt; A cosmetic composition for preventing or improving radiation-induced fibrosis containing alpha lipoic acid as an active ingredient. 6. The method of claim 5,
Wherein the cosmetic composition further comprises at least one additive selected from the group consisting of vitamins, surfactants, emulsifiers, flavors, pigments, stabilizers, preservatives, antioxidants, ultraviolet screening agents, pH adjusters and chelating agents.

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