KR102035106B1 - Composition for preventing or treating of thrombocytopenia or lymphopenia comprising decursinol - Google Patents

Abstract

The present invention relates to a composition for preventing or treating thrombocytopenia comprising decursinol as an active component. As a result of administering solubilized decursinol to a mouse to increase the bioavailability of decursinol, it is confirmed that the number of platelets and lymphocytes in the mouse blood is increased. Therefore, by using solubilized decursinol of the present invention, it is expected to develop a composition that can prevent or treat thrombocytopenia or lymphopenia.

Description

Composition for preventing or treating thrombocytopenia or lymphopenia comprising decursinol}

The present invention relates to a composition for preventing or treating thrombocytopenia or lymphocytopenia comprising decursinol as an active ingredient, and more specifically, comprising decosinol solubilized for increasing the bioavailability of decosinol. It relates to a composition for preventing or treating thrombocytopenia or lymphocytosis.

Blood flows through the blood vessels throughout the body, providing oxygen and nutrients, and transporting waste to be excreted through the kidneys. In addition, it is responsible for the transport of hormones secreted by the endocrine organs, defense against external pathogens and temperature control. The blood is composed of plasma, a liquid component and blood cells, and blood cells are divided into erythrocytes (erythrocytes, red blood cells, RBCs), white blood cells (WBCs), and platelets (platelets, thrombocytes). Red blood cells carry oxygen molecules through a protein called hemoglobin (Hb, hemoglobin), and white blood cells are divided into granulocytes, monocytes, and lymphocytes, and respond to external invasion. Platelets, along with proteins in the plasma, play an important role in blood coagulation. These blood corpuscles are produced by the hematopoiesis process in the bone marrow.

Platelets are fragments of cells involved in blood coagulation and inflammatory reactions produced in megakaryocytes and are nucleated cells present in mammalian blood. Platelets mediate blood clot formation and hemostasis, play an important role in the recovery and regeneration of connective tissue, and release growth factors that promote wound healing. These platelets are derived from pluripotent stem cells of the bone marrow and humoral factors such as thrombopoietin influence the development of megakaryocytes. In normal blood, there are 150,000-400,000 platelets per μl of blood, and the decrease in platelet levels is called thrombocytopenia.

Thrombocytopenia is a phenomenon in which the number of platelets responsible for blood coagulation and hemostasis is reduced, and platelet levels are defined as 150,000 / μl or less (Hwang Min Kim, 2004). In general, mild thrombocytopenia does not cause any special symptoms. However, as platelet decreases, the bleeding tendency increases, which may cause gum bleeding or bruising on the skin. Decrease in platelet counts below 20,000 / μl may cause bleeding in major organs without trauma, requiring stability and treatment.

The main mechanisms for the reduction of platelet levels are a decrease in platelet production and an increase in destruction. Typical examples of decreased production are myelodysplastic disorders such as aplastic anemia, myelodysplastic syndromes, and thrombocytopenia caused by anticancer agents, and increased destruction is due to conditions such as disseminated intravascular coagulation (DIC) and thrombotic microangiopathy. Seems from In addition, platelet sequestration and blood dilution may be a mechanism for platelet count reduction. Platelet sequestration is characterized by the relocation of platelets from peripheral blood to the spleen in congestive splenomegaly caused by portal hypertension. Blood dilution is a case of receiving a colloid, crystalloid or platelet-low blood product due to massive bleeding (Stable fever, et al., 2014).

Thrombocytopenia depends on the cause of the disease or the degree of reduction. Thrombocytopenia caused by infection or drugs can improve after stopping treatment of the infection and taking the medication. However, in the case of thrombocytopenia, which is caused by abnormal immune system, immunosuppressive agents such as steroids are preferentially used, and when the effects of the immunosuppressive agents are not good, an agent such as immunoglobulin may be used or a splenectomy may be considered surgically. In the case of bone marrow diseases such as acute leukemia or aplastic anemia, anticancer drugs or immunosuppressive treatments for the causative disease are required, and in some cases, hematopoietic stem cell transplantation (bone marrow transplantation) may be necessary for cure.

The only currently approved treatment modality for many patients with thrombocytopenia is platelet transfusion or bone marrow transplantation. However, repetitive platelet transfusion may lose the therapeutic effect due to the development of homologous antibodies, and in the case of transfusion, side effects such as infection, hypersensitivity and hemolytic reaction may occur.

Thrombopoietin plays a role in promoting platelet production from megakaryocytes.Recombinant platelet promoters induce antibody production and cross-react with endogenous platelet production factors, causing secondary thrombocytopenia and bleeding. This was discontinued (Li, J., et al., 2001). The cytokines interleukin and granulocyte-macrophage colony-stimulating factor (GM-CSF) are known to be involved in the production of megakaryocytes in animals (Ciurea, SO, et al., 2007), clinical studies It was confirmed that there is a platelet angiogenesis activity. However, each of these has been shown to have side effects such as severe toxicity, which is limited in the treatment of thrombocytopenia. Therefore, there is an urgent need to develop drugs having an excellent preventive or therapeutic effect on thrombocytopenia.

Lymphocytes are divided into T lymphocytes and B lymphocytes. It is difficult to assess the process of lymphocyte production and differentiation because these processes occur in many organs, including the bone marrow, lymph nodes, spleen, and thymus, which circulate through peripheral blood and reenter some organs. Despite many variables affecting lymphocytes, lymphocyte counts in peripheral blood remain constant (normal range 2-4 × 10 ³ / μl).

Lymphopenia is when lymphocytes are reduced to less than 1.5 × 10 ³ / μl, and in severe cases, lymphocyte counts are reduced to less than 0.7 × 10 ³ / μl. Lymphopenia is caused by a variety of causes. The most common case beyond lymphocyte production is proteincalorie malnutrition. Undernourished conditions result in reduced immunity, which increases the risk of infection. Immunosuppressants such as radiation therapy and anti-thymus-globulin, alkylating agents, result in lymphocytosis by inhibiting hematopoietic progenitor cell proliferation and blocking differentiation into lymphocytes. Some viruses cause cell destruction after infection with lymphoid cells, which reduces the number of lymphocytes. This includes measles, polio, and HIV. In the case of physical stress such as bacterial infection, surgery, trauma, bleeding, etc., endogenous glucocorticoids are secreted, thereby rapidly decreasing B lymphocytes and T lymphocytes in circulation. This type of lymphocytosis is a temporary condition that returns to normal within 24 to 48 hours and does not cause a functionally compromised immune system. Steroids administered for therapeutic purposes have the same effect, which is a common iatogenic cause. In patients with autoimmune diseases, including rheumatoid disease, lymphocyte reduction may also occur with anti-lymphocyte antibodies, protein-losing enteropathy, and severe heart failure (Park, SK, 2010).

In many cases, lymphadenopathy occurs as a secondary symptom of the underlying disease, so it is important to find and treat the underlying disease. In patients with lymphopenia with hypomagglobulinemia, intravenous immunoglobulin administration may help to reduce infectious complications. In severe cases, hematopoietic stem cell transplantation or cytokine treatment may be considered, but further research is needed on clinical effects.

Decursinol is a biologically active component of Angelica gigas, and it has been reported to have effects such as analgesic effect, protection against neurotoxicity, prevention of dementia, treatment of sepsis, and antioxidant. Decusinol can be isolated from Angelica gigas , but its content is extremely low and is present in less than other bioactive components decursin and decursinol angelate. Therefore, large amounts of decosinol can be obtained by hydrolysis through bases from decosin and decosinol angelate.

However, decosinol has lower bioavailability due to lower intestinal absorption than oral decosinol and decosinol angelate, and low purity may cause serious problems causing high blood pressure. For the beneficial physiological efficacy of the necessity to prepare a way to increase the bioavailability using a high purity decosinol.

The inventors of the present invention have registered a patent for a method of producing a high purity decosinol in the course of continuous research of Angelica gigas extract (Korean Patent No. 1600961), poorly soluble such as decusin and decosinol angelate Patent registration for the solubilization technology of the material (Korean Patent No. 1717672).

Accordingly, the present inventors can complete the present invention by confirming that solubilizing decosinol to increase bioavailability and increasing the number of platelets or lymphocytes in the blood while conducting experiments using decosinol. there was.

Prior art Korean Patent Nos. 0697212 and 1153436 describe thrombocytopenia treatment effects of compositions containing Angelica extract, but the increase effect of platelet or lymphocyte count of the decosinol of the present invention is not described.

In addition, non-patent prior art Lee, YY, et al. (2003) describes the platelet aggregation inhibitory effect of coumarin-based compounds including decusin and decosinol angelate isolated from the root of Angelica gigas, but the present invention The effect of increasing the platelet or lymphocyte count of Decacinol is not described.

Korean Registered Patent No. 1600961, Suspension for Injection with Decosinol as an Active Ingredient and Manufacturing Method thereof, 2016. 03. 02. Registered. Korean Registered Patent No. 1717672, Injectable or eye drop preparation which is made into a homogeneous solution by solubilizing poorly soluble active pharmacological ingredients, and a preparation method thereof, 2017. 03. 13. Registered. Korean Registered Patent No. 0697212, Hematopoietic accelerator for the treatment of side effects caused by the administration of anticancer agent using the mixed herbal medicine extract of Astragalus and Angelica sinensis as an active ingredient, 2007. 03. 13. Registered. Korean Registered Patent No. 1153436, Composition for preventing or treating hemocytopenia, including the extract of Kamiggye-tang, 2012. 05. 30. 2012. Registered.

Hwang Min Kim, Treatment of Thrombocytopenic Purpura, Korean Journal of Pediatrics, 47 (12), 1262-1265, 2004. Ahn Jung-yeol, et al., Diagnostic Approaches to Thrombocytopenia, The Korean Society of Diagnostic Blood Newsletter, 13, 2014. Ciurea, S.O., et al., Cytokines for the treatment of thrombocytopenia, Semin. Heamtol., 44 (3), 166-182, 2007. Lee Y.Y., et al., Platelet anti-aggregatory effects of coumarins from the roots of Angelica genuflexa and A. gigas, Arch. Pharm. Res., 26 (9), 723-726, 2003. Li, J., et al., Thrombocytopenia caused by the development of antibodies to thrombopoietin, Blood, 98 (12), 3241-3248, 2001. Park, S.K., An interpretation on abnormal finding of CBC, The Korean Journal of Medicine, 78 (5), 531-539, 2010.

It is an object of the present invention to provide a composition for preventing or treating thrombocytopenia or lymphocytosis comprising decosinol as an active ingredient.

The present invention relates to a pharmaceutical composition for preventing or treating thrombocytopenia or lymphocytosis comprising decursinol, surfactants, basic amino acids and polyhydric alcohols.

The present invention also relates to a dietary supplement for improving thrombocytopenia or lymphocytosis comprising decosinol, surfactants, basic amino acids and polyhydric alcohols.

The pharmaceutical composition or health functional food is a first step of preparing a primary mixture by mixing a surfactant in decosinol; A second step of preparing a secondary mixture by adding ethanol to the primary mixture, adding basic amino acid and purified water to dissolve and adding polyhydric alcohol, adjusting the pH to 7.0 to 8.6; And a third step of sterilizing the secondary mixture; It may be prepared through a process consisting of.

The surfactant (detergent) is sodium dodecyl sulfate, polyoxyethylene sorbitan monooleate (Tween-80), polyoxyethylene sorbitan monostearate, Tween- 60), polyoxyethylene sorbitan monopalmitate (Tween-40), polyoxyethylene sorbitan monolaurate (Tween-20), triton X-100 (triton X-100), Nonylphenoxypolyethoxy ethanol (nonyl phenoxypolyethoxylethanol, NP-40), may be at least one member selected from the group consisting of castor oil (poloxamer).

The basic amino acid may be arginine, lysine, histidine or a mixture thereof.

The polyhydric alcohol may be one or more selected from the group consisting of mannitol, sorbitol, sorbitol, xylitol, and lactitol.

The decosinol may be administered at 0.5-10 mg / kg.

The thrombocytopenia may be non-immunologic causes of thrombocytopenia, immunogenic causes of thrombocytopenia or drug-induced thrombocytopenia.

Lymphopenia is immunodeficiency, cancer, viral infection, autoimmune disease, lymphocyte destruction by treatment, lymphocyte loss, lymphoma, Cushing's syndrome, stress, neutrophil increase, immunogenic thrombocytopenia, hepatitis C related thrombocytopenia, It may be that the number of lymphocytes in the blood is reduced to less than 1,500 / μl due to aplastic anemia or a mixture thereof.

Hereinafter, the present invention will be described in detail.

The present invention relates to a composition for preventing or treating thrombocytopenia or lymphocytosis comprising decosinol, a surfactant, a basic amino acid and a polyhydric alcohol.

The decosinol is a pyranocoumarin derivative as a bioactive component of Angelica gigas.

The decosinol can be separated from the Angelica extract. In addition, the decosinol can be obtained by hydrolysis through a base from decursin and decursinol angelate.

Decacinol isolated from the Angelica extract, the lower the purification rate of decosinol can increase the blood pressure during administration. Therefore, the decosinol of the present invention may have a purification rate of 50% or more. Preferably it is 70% or more, More preferably, it is 90% or more. Most preferably at least 99%.

The donkey may be a true donkey, but is not limited thereto.

Meanwhile, the decosinol of the present invention may be prepared according to a conventional method in the art, and may be prepared as a pharmaceutically acceptable salt.

The composition comprises a first step of preparing a primary mixture by mixing a surfactant in decosinol; A second step of preparing a secondary mixture by adding ethanol to the primary mixture, adding basic amino acid and purified water to dissolve and adding polyhydric alcohol, adjusting the pH to 7.0 to 8.6; And a third step of sterilizing the secondary mixture; It can be decosinol solubilized through.

The solubilization refers to a phenomenon in which solubility of a material that is not well dissolved in water is increased, and the solubilization method may be used to increase the bioavailability by increasing the solubility of the decosinol of the present invention which is a poorly soluble material.

The surfactant is sodium dodecyl sulfate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monolaurate, triton X-100, Nonylphenoxypolyethoxylethanol, castor oil and poloxamer may be at least one member selected from the group consisting of.

In the present invention, "castor oil" is a fatty oil extracted from castor seeds and has a unique tackiness and is used as a nonionic surfactant for the purpose of suspending agents of poorly soluble substances which are insoluble in water.

Castor oil of the present invention is for solubilizing decosinol, and is intended to prevent decocinol from agglomerating together with the dispersion of decosinol to precipitate.

The castor oil may be polyoxyl 35 castor oil. The polyoxyl 35 castor oil is a product commercialized under the trade names Kolliphor EL or Cremophor EL, and 35 mol (ethylene) of ethylene oxide and one molecule of castor oil are combined. However, it is not limited thereto.

In the present invention, "poloxamer" is also referred to as pluronics, and is a hydrophilic polymer having polyoxypropylene at the center, polyoxyethylene at both sides, and polyoxypropylene. There are various kinds such as P123 and P407 depending on the molecular weight of and polyoxyethylene.

The poloxamer of the present invention is Pluronic P407, which is a poloxamer having a molecular weight of 4000g / mol of polypropylene and 70% of polyethylene, and Pluronic P407 is the most preferred surfactant. It can be used to increase or to promote micelle formation.

The surfactant is i) sodium dodecyl sulfate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monolaurate, triton X- 100, and at least one selected from the group consisting of nonylphenoxypolyethoxylethanol; ii) castor oil; And iii) poloxamer; It can be used by mixing. These mixtures are i) sodium dodecyl sulfate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monolaurate, triton X- 100, and at least one selected from the group consisting of nonylphenoxypolyethoxylethanol; ii) pizza horse oil; And iii) poloxamer; 1: 0.1 to 1: 1 may be mixed in a weight ratio. If it is out of the weight ratio, nonspecific itching by castor oil may appear, which is not preferable.

The surfactant may be added at 0.01% by weight or more based on the total weight of the composition. Preferably it is 0.01-1 weight%. When the surfactant is less than 0.01% by weight relative to the total weight of the composition, it is difficult to solubilize the decosinol, and when it exceeds 1% by weight, excessive use of the surfactant may cause vomiting, and may cause cell lysis. Not desirable

The basic amino acid is used as a dissolution aid, and may be arginine, lysine, histidine or a mixture thereof, preferably arginine, lysine or a mixture thereof.

The basic amino acid may contain 0.1 to 4% [w / v] based on the composition. If the content of basic amino acid is less than 0.1% [w / v], it is difficult to aid solubility and does not have a practical effect. If it exceeds 4% [w / v], gelation may occur due to excessive viscosity, and economical Also not preferred.

In the present invention, "polyalcohol" is a sugar type containing two or more hydroxyl groups, the polyalcohol of the present invention has a property of intercalating between poorly soluble materials to prevent the poorly soluble materials from agglomerating with each other, Even in this case, unit molecules can be prevented from sticking together.

The polyhydric alcohol may be at least one selected from mannitol, maltitol, galactitol, erythritol, sorbitol, xylitol, lactitol, propylene glycol, glycerol, butylene glycol, and the like. Preferably it is 1 or more types chosen from mannitol, sorbitol, xylitol, and lactitol.

The polyhydric alcohol may be added at 100% by weight or more relative to the decosinol. If the polyhydric alcohol is less than 100% by weight, precipitates are formed in the composition, resulting in poor stability of the composition and difficulty in maintaining uniformity.

In addition, the polyhydric alcohol may not exceed at most 2% by weight relative to the total weight of the composition. When the polyhydric alcohol exceeds 2% by weight relative to the total weight of the composition, it is not preferable because it causes pain.

The composition may not only increase the number of platelets or lymphocytes, but also increase the number of white blood cells.

The composition provides a pharmaceutical composition for preventing or treating thrombocytopenia or lymphocytosis comprising the solubilized decosinol and a pharmaceutically acceptable excipient.

The solubilized decosinol may be added in an amount of preferably 0.001 to 50% by weight, more preferably 0.001 to 40% by weight, and most preferably 0.001 to 30% by weight based on the total weight of the pharmaceutical composition.

The pharmaceutical composition may be used in the form of powder, granules, tablets, capsules, suspensions, emulsions, syrups, solutions, aerosols and the like, oral formulations, suppositories, and sterile injection solutions, respectively, according to a conventional method. have. Carriers, excipients and diluents that may be included in the pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose , Methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. When formulated, diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, surfactants, sweeteners, and acidifying agents are usually used. Solid form preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, which form at least one excipient such as starch, calcium carbonate, water, and solubilized decosinol of the present invention. Prepared with a mixture of cross or lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral use include suspensions, solvents, emulsions, and syrups. In addition to the commonly used simple diluents, water and liquid paraffin, various excipients such as wetting agents, sweeteners, fragrances, preservatives, and acidulants are included. May be included. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate and the like can be used. As the base of the suppository, witepsol, macrogol, tween-61, cacao butter, laurin butter, glycerogelatin and the like can be used.

The dosage of the pharmaceutical composition of the present invention will vary depending on the age, sex, weight of the subject to be treated, the specific disease or pathology to be treated, the severity of the disease or pathology, the route of administration and the judgment of the prescriber. Dosage determination based on these factors is within the level of those skilled in the art, and generally dosages range from 0.01 mg / kg / day to approximately 500 mg / kg / day. Preferred dosages are from 0.1 mg / kg / day to 200 mg / kg / day, and more preferred dosages are from 1 mg / kg / day to 200 mg / kg / day. Administration may be administered once a day or may be divided several times. The dosage does not limit the scope of the invention in any aspect.

The pharmaceutical composition of the present invention can be administered to mammals such as rats, livestock, humans, etc. by various routes. All modes of administration can be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or cerebrovascular injections and skin application. Decacinol of the present invention has little toxicity and side effects, and therefore is a drug that can be used with confidence even for prolonged administration for prophylactic purposes.

The composition provides a dietary supplement for improving thrombocytopenia or lymphocytosis comprising the solubilized decosinol and a food supplement acceptable food supplement.

The health functional food may be added in an amount of preferably 0.001 to 50% by weight, more preferably 0.001 to 30% by weight, and most preferably 0.001 to 10% by weight based on the total weight of the solubilized Decasinol health functional food. have.

The health functional food includes tablets, capsules, pills, or liquids, and the like to which the solubilized decosinol of the present invention may be added, for example, various foods, beverages, gums, teas, Vitamin complexes and health functional foods.

In the present invention, "thrombocytopenia" is a phenomenon in which the number of platelets is reduced and means a state in which platelet levels are 150,000 / μl or less based on human platelet count.

The thrombocytopenia may be non-immunologic causes of thrombocytopenia, immunologic causes of thrombocytopenia or drug-induced thrombocytopenia.

The non-immunogenic thrombocytopenia includes disseminated intravascular coagulation, thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome, pregnancy addiction, preeclampsia (pregnancy addiction). pre-eclampisa, HELLP syndrome, thrombocytopenia caused by massive blood transfusion, thrombocytopenia due to liver disease, thrombocytopenia due to infection or thrombocytopenia due to hematopoietic deficiency hematinic deficiencies).

The immunogenic thrombocytopenia may be alloantibody-mediated thrombocytopenia or autoantibody-mediated thrombocytopenia.

The alloantibody-mediated thrombocytopenia may be neonatal alloimmune thrombocytopenia or post-transfusion purpura.

The autoantibody-mediated thrombocytopenia may be idiopathic thrombocytopenic purpura, immune throbocytopenic purpura, chronic immune thrombocytopenic purpura, or secondary immune thrombocytopenia. .

The drug-induced thrombocytopenia may be heparin-induced thrombocytopenia or other drugs causing immune-mediated platelet destruction.

Other drugs that cause immune-mediated platelet destruction include anticancer agents, quinidine, quinine, quinine, gold salts, valproic acid, rapamycine, and sulfa antibiotics. And so on. However, it is not limited thereto.

In the present invention, "lymphopenia" is a case where the number of lymphocytes in peripheral blood is absolutely reduced, and the number of lymphocytes is reduced to less than 1500 / μl, and in severe cases, it decreases to less than 700 / μl.

The lymphocytosis may be caused by immunodeficiency, cancer, viral infection, autoimmune disease, destruction by treatment, lymphocyte loss, lymphoma, Cushing syndrome, stress, neutrophil increase, and the like.

In addition, the lymphocytosis may be caused by immunogenic thrombocytopenia, hepatitis C-related thrombocytopenia, aplastic anemia and the like.

The immunodeficiency syndrome may be congenital immunodeficiency syndrome or acquired immunodeficiency syndrome (AIDS). The congenital immunodeficiency syndrome includes Di George's syndrome, Wiskott-Aldrich syndrome, ataxia telangiectasia, agammmaglobulinemia and severe complex immunodeficiency syndrome (agamma globulinemia). severe combined immunodeficiency (SCID).

Lymphocytosis caused by the cancer is caused by lymphocyte reduction by immunosuppressive substances produced by tumor cells.

Lymphocytosis caused by the viral infection is the destruction of lymphocytes by infected measles, polio, human immunodeficiency virus (HIV).

Lymphocytosis caused by the autoimmune disease is systemic lupus erythematosus, and lymphocytes are destroyed by antilymphocyte autoantibodies.

Lymphocyte depletion caused by the above treatment is disrupted by administration of anticancer drugs, radiation, steroids, and the like.

The lymphocyte loss may be proteomic gastrointestinal disorder or pneumonia drainage.

The present invention relates to a composition for preventing or treating thrombocytopenia or lymphocytosis comprising decursinol as an active ingredient, the result of administering solubilized decosinol to mice to increase the bioavailability of decosinol, An increase in the number of platelets or lymphocytes in the blood of rats was confirmed.

Through this, it is expected that the solubilized Decacinol of the present invention can be used to develop a composition capable of preventing or treating thrombocytopenia or lymphocytosis.

Figure 1 shows the results confirming the increase in platelet count (A) and lymphocyte count (B) in the blood of rats by administration of solubilized decosinol of the present invention.

Hereinafter, a preferred embodiment of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, the information provided herein is to be thorough and complete, and to fully convey the spirit of the present invention to those skilled in the art.

Example 1 Preparation of Solubilized Decacinol

Decosinol is a poorly soluble substance and has low bioavailability. Thus, in order to increase the bioavailability of decosinol, solubilized decosinol was prepared by referring to the method described in Korean Patent No. 1917672. At this time, the decosinol was used to produce a large amount of decosinol having a purification rate of 99% or more, referring to the method of preparing decosinol of the present inventors Korean Patent No. 1600961.

0.8 g of polyoxyethylene sorbitan monooleate and 0.2 g of polyoxyethylene sorbitan monolaurate were added and mixed uniformly in 0.1 g of decosinol, and then 1 ml of 95% [v / v] ethanol was added and mixed. 1.5 g of basic amino acid lysine or arginine and about 90 ml of purified water were added to the mixture, and 0.4 g of mannitol was added and adjusted to pH 8.6 using 6 M HCl or 6 M NaOH. Thereafter, purified water was added to a total volume of 100 ml, and the solution was subjected to steam sterilization to prepare solubilized decosinol.

Even when polyoxyethylene sorbitan monolaurate or polyoxyethylene sorbitan monolaurate is used alone instead of the polyoxyethylene sorbitan monooleate and polyoxyethylene sorbitan monolaurate, Confirmed.

< Example  2. Solubilized Dekersinol  Check the effect on blood cells>

Blood analysis was performed after administration to rats to determine the effect of solubilized decosinol of the present invention on blood cells such as platelets, lymphocytes, and the like.

23-week-old SD (Sprague Dawley) mice were purchased and acclimated for one week in the animal room, and then randomly divided into the experimental groups of Table 1 below. In the case of the control group, 1 ml of saline solution was administered orally for 3 weeks once a day, and the remaining experimental groups were intraperitoneally administered for 1 week, 1 ml of the composition corresponding to Table 1 below. One day before administering the composition, rats were fasted and blood was collected. After administration of the composition for 3 weeks, the mice were anesthetized, blood was collected, and blood analysis was performed. The results are shown in Table 2 and FIG. 1. Blood analysis was performed using the automated blood analyzer of Pusan National University's anti-aging industry development center.

Deckerin of Table 1 was purchased from Core Science of China, and the Angelica extract was directly extracted using the dried Angelica Angelica inventor. In addition, the solubilized Angelica extract and Decasin were used solubilized using the same method as the solubilization method of Decusinol of Example 1.

Experimental group Treatment method Control Saline solution Experimental group 1 Angelica Extract 10mg / ml Experiment group 2 Decusin 10mg / ml Experiment group 3 Decosinol 10mg / ml Experimental Group 4 Solubilized Angelica Extract 10mg / ml Experimental group 5 Solubilized Decasin 10mg / ml Experimental Group 6 Solubilized Decacinol 10 mg / mL of Example 1

Experimental group Blood analysis after 3 weeks of administration Red blood cells
(× 10 ⁶ cells / μl) leukocyte
(× 10 ³ cells / μl) Platelets
(× 10 ³ cells / μl) Lymphocyte
(× 10 ³ cells / μl) Monocytes
(× 10 ³ cells / μl) Control 9.22 6.12 892 3.69 0.40 Experimental group 1 9.20 6.50 950 3.90 0.39 Experiment group 2 9.20 7.00 950 5.50 0.40 Experiment group 3 9.20 6.10 890 3.70 0.39 Experimental Group 4 9.50 8.00 1050 5.80 0.40 Experimental group 5 9.21 7.89 1048 5.62 0.39 Experimental Group 6 9.20 28.90 1705 5.23 0.40

As shown in FIG. 1 and Table 2, it was confirmed that the number of platelets increased in the experimental group 6 administered the solubilized decosinol of Example 1 compared to the control group, and the administration of unsolubilized decosinol In Experiment 3, it was confirmed that the number of platelets was similar to that of the control group. In addition, it was confirmed that the experimental group 6 administered the solubilized decosinol of Example 1 increased the number of leukocytes and lymphocytes as well as platelets as compared to the control group, while not affecting the red blood cells and monocytes.

It was predicted that the solubilization of decosinol increased the in vivo absorption of decosinol, which increased the pharmacological activity of decosinol, which increased the number of platelets, lymphocytes and white blood cells in the blood. I could see that.

Preparation Example 1. Pharmaceutical Formulations

Formulation Example 1-1. Manufacture of tablets

200 mg of solubilized decosinol of the present invention was mixed with 175.9 g lactose, 180 g potato starch and 32 g colloidal silicic acid. 10% gelatin solution was added to the mixture, which was then ground and passed through a 14 mesh sieve. It was dried and the mixture obtained by adding 160 g potato starch, 50 g active and 5 g magnesium stearate to this was made into a tablet.

 Formulation Example 1-2. Preparation of Injection

100 mg of solubilized decosinol, 0.6 g sodium chloride and 0.1 g ascorbic acid of the present invention were dissolved in distilled water to make 100 ml. The solution was bottled and sterilized by heating at 20 ° C for 30 minutes.

Preparation Example 2 Preparation of Health Functional Food

Formulation Example 2-1. Preparation of Health Functional Food

2 g of solubilized decosinol of the present invention, a vitamin mixture amount, 70 μg of vitamin A acetate, 1.0 mg of vitamin E, 0.13 mg of vitamin B1, 0.15 mg of vitamin B2, 0.5 mg of vitamin B6, 0.2 μg of vitamin B12, vitamin C 10 mg, Biotin 10μg, nicotinic acid amide 1.7mg, folic acid 50μg, calcium pantothenate 0.5mg, mineral mixture appropriate amount, ferrous sulfate 1.75mg, zinc oxide 0.82mg, magnesium carbonate 25.3mg, potassium monophosphate 15mg, calcium diphosphate 55 mg, potassium citrate 90 mg, calcium carbonate 100 mg, magnesium chloride 24.8 mg mixed to prepare a granule, but can be prepared by modifying the formulation in a variety of formulations. In addition, the composition ratio of the above-mentioned vitamin and mineral mixture may be arbitrarily modified, and it may be prepared by mixing the above components according to a conventional health functional food manufacturing method.

Formulation Example 2-2. Preparation of Health Functional Drink

1 g of solubilized Decacinol, 0.1 g citric acid, 100 g of fructooligosaccharide, and 900 g of purified water of the present invention were mixed to prepare a beverage by stirring, heating, filtration, sterilizing, and refrigerating according to a conventional beverage preparation method.

Claims (13)

In the pharmaceutical composition for preventing or treating thrombocytopenia, comprising decursinol, a surfactant, a basic amino acid, and a polyhydric alcohol, the thrombocytopenia may be non-immunogenic thrombocytopenia, immunogenic thrombocytopenia or drug- Pharmaceutical composition for preventing or treating thrombocytopenia, characterized in that the induced thrombocytopenia. The method of claim 1,
The pharmaceutical composition,
A first step of preparing a primary mixture by mixing a surfactant with decosinol;
A second step of preparing a secondary mixture by adding ethanol to the primary mixture, adding and dissolving basic amino acid and purified water, and adding a polyhydric alcohol to adjust the pH to 7.0 to 8.6; And,
The third step of sterilizing the secondary mixture; Thrombocytopenia preventing or treating pharmaceutical composition, characterized in that it is prepared through the process consisting of. The method according to claim 1 or 2,
The surfactant may be sodium dodecyl sulfate, polyoxyethylene sorbitan monooleate (Tween-80), polyoxyethylene sorbitan monostearate (Tween-60), Polyoxyethylene sorbitan monopalmitate (Tween-40), polyoxyethylene sorbitan monolaurate (Tween-20), triton X-100, nonylphenoxy Pharmaceutical composition for preventing or treating thrombocytopenia, characterized in that at least one selected from the group consisting of polyethoxylethanol (non-40phenoxypolyethoxylethanol, NP-40), castor oil, and poloxamer. The method according to claim 1 or 2,
The basic amino acid is arginine, lysine, histidine or a mixture thereof, characterized in that thrombocytopenia preventing or treating pharmaceutical composition. The method according to claim 1 or 2,
The polyhydric alcohol is mannitol (mannitol), sorbitol (sorbitol), xylitol (xylitol) and lactitol (lactitol) is a pharmaceutical composition for preventing or treating thrombocytopenia, characterized in that at least one selected from the group consisting of. The method according to claim 1 or 2,
The decosinol is a pharmaceutical composition for preventing or treating thrombocytopenia, characterized in that administered at 0.5 ~ 10mg / kg. delete delete In a dietary supplement for improving thrombocytopenia, comprising decosinol, a surfactant, a basic amino acid and a polyhydric alcohol, the thrombocytopenia may be non-immunogenic thrombocytopenia, immunogenic thrombocytopenia or drug-induced thrombocytopenia. Health functional foods for improving thrombocytopenia, characterized in that. The method of claim 9,
The health functional food,
A first step of preparing a primary mixture by mixing a surfactant with decosinol;
A second step of preparing a secondary mixture by adding ethanol to the primary mixture, adding and dissolving basic amino acid and purified water, and adding a polyhydric alcohol to adjust the pH to 7.0 to 8.6; And,
A third step of sterilizing the secondary mixture; thrombocytopenia improving health functional food, characterized in that it is prepared through the process consisting of. The method of claim 9 or 10,
The surfactant may be sodium dodecyl sulfate, polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monolaurate, triton X-100, Nonylphenoxypolyethoxylethanol, castor oil, and poloxamer Health functional food for improving thrombocytopenia, characterized in that at least one member selected from the group consisting of. The method of claim 9 or 10,
The basic amino acid is arginine, lysine, histidine or a mixture of these, thrombocytopenia improving health functional food. The method of claim 9 or 10,
Wherein the polyhydric alcohol is mannitol, sorbitol, xylitol and lactitol is a health functional food for improving thrombocytopenia, characterized in that at least one selected from the group consisting of.

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