Antithrombotic pharmaceutical compositions and antithrombotic processed foods

Abstract

Many pharmaceutical compositions used to prevent or treat thrombosis have side effects, and there has been a demand for drugs and other substances that have fewer side effects and are more effective. [Solution] An antithrombotic pharmaceutical composition containing tricaprin or tricapriline as an active ingredient has virtually no side effects and possesses both the ability to prevent and treat thrombosis, making it suitable for use as an antithrombotic pharmaceutical composition. Furthermore, by consuming it together with a high-fat diet as an antithrombotic processed food, the risk of thrombosis caused by a high-fat diet can be avoided or treated.

Description

Technical Field

[0001] The present invention relates to an antithrombotic pharmaceutical composition and a processed food for antithrombotic use that prevent the formation of thrombi or reduce the formed thrombi.

Background Art

[0002] Supplements and drugs for maintaining vascular health are on the market. However, deaths due to vascular diseases still rank among the top causes of death. Vascular diseases are caused by those originating from the vascular wall and those originating from the blood. Among those caused by the blood, thrombi block blood vessels and cause necrosis of the subsequent cell tissues, thus easily causing a serious condition.

[0003] A thrombus mainly consists of aggregates of platelets and fibrin, which are blood factors. A thrombus is considered to be formed in the first place to block bleeding from blood vessels. When platelets come into contact with the surface of the subendothelial layer, a reaction occurs that generates thrombi and blocks the vascular system. This is a process called so-called hemostasis. This process plays a very important role in preventing bleeding at the wound site.

[0004] However, when a thrombus forms in the blood vessels due to some cause, it becomes the cause of a disease. These are widely called thrombosis and the name changes depending on the site of occurrence. An arterial thrombus causes local occlusion of an artery and brings about a serious disease. Also, a venous thrombus causes embolism. In such cases, a pharmaceutical composition having an antiplatelet aggregation or thrombolytic effect is required.

[0005] Diseases caused by thrombi include myocardial infarction, angina pectoris, thrombophlebitis, arterial embolism, coronary and cerebral artery thrombosis, peripheral vascular or cardiac arrhythmia thrombosis, arterial thrombosis of any blood vessel, venous thrombosis, ischemic cerebral infarction, arteriosclerosis, hypertension, pulmonary hypertension, cerebral infarction, stroke, chronic arterial occlusion, pulmonary infarction, cerebral embolism, renal embolism, thromboembolism, etc.

[0006] As a means of preventing or treating such thrombosis, for example, Patent Document 1 discloses an antiplatelet agent containing chondroitin sulfate oligosaccharide as an active ingredient. Furthermore, Patent Document 2 shows an antithrombotic agent containing wild celery (Oenanthe javanica) extract and one or more antithrombotic agents selected from the group consisting of clopidogrel or a pharmaceutically acceptable salt thereof and cilostazol or a pharmaceutically acceptable salt thereof as active ingredients. [Prior art documents] [Patent Documents]

[0007] [Patent Document 1] Japanese Patent Publication No. 2022-187126 [Patent Document 2] Japanese Patent Publication No. 2022-062186 [Overview of the project] [Problems that the invention aims to solve]

[0008] Many pharmaceutical compositions used to prevent or treat thrombosis have side effects, and there is a demand for drugs and other substances that have fewer side effects and are more effective. [Means for solving the problem]

[0009] This invention was conceived in view of the above-mentioned problems. The inventors of this invention have come up with the invention after confirming that certain triglycerides, which are also found in breast milk and food and are considered to have no problematic side effects based on past experience, have the effect of preventing or treating blood clots.

[0010] More specifically, the antithrombotic pharmaceutical composition according to the present invention is: It is characterized by containing tricaprine or tricaprilin as an active ingredient.

[0011] Furthermore, the present invention can also provide an antithrombotic processed food that has the effect of preventing or treating blood clots.

[0012] More specifically, the antithrombotic processed food according to the present invention is: It is characterized by containing tricaprine or tricaprilin as an active ingredient. [Effects of the Invention]

[0013] Because the present invention uses tricaprine or tricaprylin as an active ingredient, it is readily available and can exhibit good thrombosis prevention and thrombosis treatment effects, as shown in the following examples. [Brief explanation of the drawing]

[0014] [Figure 1] This diagram shows the procedure for creating model animals for thrombosis prevention experiments. [Figure 2] This is a cross-sectional image of a blood vessel showing the results of an experiment to prevent blood clots. [Figure 3] This graph shows the results of an experiment to prevent blood clots. [Figure 4] This diagram shows the procedure for creating model animals for thrombosis treatment experiments. [Figure 5] This is a cross-sectional image of a blood vessel showing the results of a thrombosis treatment experiment. [Figure 6] This graph shows the results of a thrombosis treatment experiment. [Modes for carrying out the invention]

[0015] The antithrombotic pharmaceutical composition and antithrombotic processed food according to the present invention will be described below with reference to drawings and examples. The following description illustrates one embodiment and one example, and the present invention is not limited to the following description. The following description may be modified without departing from the spirit of the present invention.

[0016] In addition, embodiments and examples obtained by appropriately combining the technical means disclosed in different embodiments and examples are also included in the technical scope of the present invention. Also, all the documents described in this specification are incorporated herein by reference. Further, in this specification, when a numerical range is described as "A to B", such description is intended to mean "A or more and B or less".

[0017] The pharmaceutical composition for antithrombosis according to the present invention has both a preventive ability to prevent the formation of thrombi in blood vessels and a therapeutic ability to reduce the formed thrombi. Therefore, the pharmaceutical composition for antithrombosis can also be referred to as a pharmaceutical composition for thrombus prevention or a pharmaceutical composition for thrombus treatment. Similarly, the processed food for antithrombosis can also be referred to as a processed food for thrombus prevention or a processed food for thrombus treatment.

[0018] In the present invention, prevention of thrombi means suppressing the formation of coagulants in blood vessels regardless of arteries or veins. Also, treatment of thrombi means reducing the coagulants formed in blood vessels. Further, the aggregate is an aggregate containing platelets and fibrin that have become immobile in blood vessels due to the beating of the heart. The pharmaceutical composition for antithrombosis and the processed food for antithrombosis can prevent and treat such thrombi.

[0019] The pharmaceutical composition for antithrombosis and the processed food for antithrombosis according to the present invention contain tricaprin or tricaprylin as an active ingredient. Tricaprin (CAS No. 621-71-6) is a triester of three capric acids (C 10 H 20 O2: CAS No. 334-48-5) and glycerin. Tricaprylin (CAS No. 538-23-8) is a triester of caprylic acid (C8H 16 O2: CAS No. 124-07-2) and glycerin. Hereinafter, tricaprin is also represented as "C10-TG", and tricaprylin is also represented as "C8-TG".

[0020] Tricaprine and tricaprilin are used individually, but they may also be mixed. Therefore, the antithrombotic pharmaceutical composition and antithrombotic processed food according to the present invention may contain tricaprine and tricaprilin in a mixing ratio of 0:100 to 100:0.

[0021] When the antithrombotic pharmaceutical composition according to the present invention is used as a pharmaceutical composition for the prevention and treatment of thrombosis, it may contain components other than tricaprylin or tricaprine. For example, carriers, excipients, binders, disintegrants, lubricants, and colorants suitable for the applications of the present invention can be suitably used.

[0022] Examples of carriers and excipients include lactose, glucose, sucrose, mannitol, potato starch, corn starch, calcium carbonate, calcium phosphate, calcium sulfate, and crystalline cellulose.

[0023] Additionally, starch, gelatin, syrup, tragacanth gum, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, hydroxypropyl cellulose, methylcellulose, ethylcellulose, and carboxymethylcellulose can be used as binders.

[0024] Additionally, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, sodium alginate, sodium carboxymethylcellulose, and calcium carboxymethylcellulose can be used as disintegrants.

[0025] Examples of lubricants that can be used include magnesium stearate, hydrogenated vegetable oil, talc, and macrogol.

[0026] Furthermore, the coloring agent used may be one that is permitted to be added to pharmaceutical compositions.

[0027] Furthermore, the pharmaceutical composition for the prevention and treatment of thrombosis of the present invention may be coated with one or more layers of sucrose, gelatin, purified shellac, glycerin, sorbitol, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, cellulose phthalate acetate, hydroxypropylmethylcellulose phthalate, methyl methacrylate, and methacrylic acid polymer, if necessary. In addition, pH adjusters, buffers, stabilizers, and solubilizers may be added as necessary.

[0028] Furthermore, the pharmaceutical composition for the prevention and treatment of thrombosis of the present invention can be provided in any form of formulation. For example, the present invention provides oral formulations such as tablets including sugar-coated tablets, buccal tablets, coated tablets and chewable tablets; capsules including lozenges, pills, powders and soft capsules; granules, suspensions, emulsions and syrups including dry syrups; and liquid formulations such as elixirs.

[0029] Furthermore, the present invention can be a formulation for parenteral administration, such as intravenous injection, subcutaneous injection, intraperitoneal injection, intramuscular injection, transdermal administration, transnasal administration, transpulmonary administration, enteral administration, oral administration, and transmucosal administration. Examples include injectable preparations, transdermal tapes, aerosols, and suppositories.

[0030] Since tricaprylin and tricaprine are hydrophobic oils, it is desirable to add a surfactant to make them hydrophilic when administering them parenterally. Suitable surfactants include those used in pharmaceuticals. Specifically, sodium alkylbenzene sulfonate, sodium lauryl sulfate, sodium polyoxyethylene cetyl ether phosphate, benzalkonium chloride, sucrose fatty acid esters, polyethylene glycol monooleate, polyethylene glycol dioleate, sorbitan sesquioleate, prooleic glycol monostearate, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, glyceryl monostearate, polyoxyethylene glyceryl monostearate, polyoxyethylene lauryl ether, polyoxyethylene nonylphenyl ether, polyoxyethylene oleylamine, coconut oil diethanolamide, ursodeoxycholic acid, purified soy lecithin, and purified egg yolk lecithin are suitable.

[0031] Furthermore, the antithrombotic pharmaceutical composition of the present invention can be manufactured using any method. For example, the antithrombotic pharmaceutical composition of the present invention can be manufactured by mixing tricaprylin or tricaprin with the various materials described above in a desired amount using a known manufacturing method, and then molding it into a desired form of formulation.

[0032] Furthermore, when the antithrombotic pharmaceutical composition of the present invention is administered orally, it is desirable that the composition ratio of tricaprylin or tricaprine in the antithrombotic pharmaceutical composition be 92% by mass or more. In particular, when supplied in capsule form, it is desirable that the composition ratio of tricaprylin or tricaprine in the capsule be 92% by mass or more. This is because a high effect can be obtained by providing the substance in an impurity-free state.

[0033] Furthermore, while the antithrombotic pharmaceutical composition according to the present invention has no risk of side effects, it needs to be taken in large quantities. Therefore, it is preferable not to include ingredients that are harmful to the body when taken in large quantities. For example, lipophilic vitamins (vitamin A, vitamin D, vitamin E, vitamin K) are preferably not included in the antithrombotic pharmaceutical composition of the present invention.

[0034] Furthermore, the antithrombotic pharmaceutical composition of the present invention may be provided as an antithrombotic processed food in the form of food or beverages. The antithrombotic processed food may consist only of the active ingredient tricaprylin or tricaprin. It may also be a general food, a food for specified health uses, a food with nutritional function claims, a nutritional supplement, a functional food, a food for the sick, or a food for the elderly. In addition, the present invention may be, for example, a food or beverage labeled as a food for specified health uses, or a food or beverage labeled as having a thrombosis prevention effect or a therapeutic effect.

[0035] Furthermore, the antithrombotic processed food of the present invention can be added to, mixed with, or used as an antithrombotic food ingredient in other foods. Particularly as a Food for Specified Health Uses, a tablet containing a binder and at least 20% by mass or more of tricaprylin or tricaprine based on the total amount is preferred.

[0036] Furthermore, as will be shown in later examples, blood clots can be attributed to excessive consumption of high-fat foods. Therefore, the processed foods for preventing and treating blood clots according to the present invention are preferably used in Chinese cuisine that uses oil, such as ramen, meat dishes, and fried foods. They are also preferably used in donuts and fried sweets.

[0037] Furthermore, as will be shown in later examples, blood clots can also be attributed to excessive consumption of high-fat foods. Therefore, sauces and pastes (marinades) that are frequently used with high-fat dishes and contain a certain amount or more of tricaprylin or tricaprin are suitably utilized. These processed foods can be prepared by adding a certain amount of tricaprylin or tricaprin to known sauce ingredients or marinade ingredients.

[0038] For example, in barbecue sauce, by including a certain amount (preferably 20% by mass) or more of tricaprylin or tricaprin in the dipping sauce ingredients such as onions, ginger, garlic, soy sauce, sake, sesame oil, miso, sugar, and sesame seeds, it can be made into an antithrombotic processed food.

[0039] Furthermore, as an additive seasoning for Chinese cuisine, which frequently uses oil, it may contain a certain amount (preferably 20% by mass) or more of tricaprylin or tricaprin.

[0040] Furthermore, the antithrombotic processed foods according to the present invention do not include those that inherently contain tricaprylin or tricaprin, such as coconut milk, nor processed foods that use these ingredients. Therefore, it can be said that the processed foods according to the present invention are characterized by containing ingredients that do not contain tricaprylin or tricaprin, and containing 20% ​​by mass or more of tricaprylin or tricaprin. [Examples]

[0041] (Example 1) <Method for creating model animals> Six-week-old (160-180g) male SD rats were used. Five rats were prepared as a control group, five as a tricaprylin (C8-TG) dose group, and five as a tricaprine (C10-TG) dose group. Figure 1 shows the method for creating the model animals. One rat was selected from each group immediately after arrival and euthanized and dissected as a day 0 sample.

[0042] Referring to Figure 1, all rats were initially fed a normal diet for the first week after arrival. During the first week after arrival, the C8-TG and C10-TG groups were given a normal diet and force-fed 1145 mg / kg body weight / day of either C8-TG or C10-TG (each containing 98% caprylic or capric acid). The control group was given a normal diet and force-fed 1145 mg / kg body weight / day of water.

[0043] For the first week after arrival, all rats were fed a high-fat diet. The C8-TG and C10-TG groups were then force-administered either C8-TG or C10-TG at a dose of 1145 mg / kg body weight / day. The control group was force-administered water at a dose of 1145 mg / kg body weight / day.

[0044] Three weeks after arrival, a thrombosis induction procedure was performed. This procedure involves inserting a catheter into the abdominal aorta of the rat and ligating the abdominal aorta along with the inserted catheter.

[0045] For four weeks following the thrombosis induction procedure, the C8-TG and C10-TG groups were given a high-fat diet and continuously received the same amounts of C8-TG and C10-TG as in the second week. The control group was given a high-fat diet and continuously received 1145 mg / kg body weight / day of water. After four weeks had passed since the thrombosis induction procedure (seven weeks after admission), the animals were euthanized and autopsied.

[0046] Figure 2 shows photographs of the anatomical results. All photographs show cross-sections of the blood vessels distal to the ligation point between the catheter and the abdominal aorta (cross-sections perpendicular to the length of the blood vessel), stained with Elastica van Gieson (EVG staining). The side with the scale bar in the photograph is the intima side of the blood vessel. The scale bar represents 50 μm. (a) to (c) under "Day 0" show the results of rats sampled immediately after arrival on day zero. (d) to (f) under "Day 28" show the results of rats 7 weeks after arrival (4 weeks after thrombosis induction treatment). (a) to (c) and (d) to (f) are photographs of the control group, the C8-TG administered group, and the C10-TG administered group, respectively.

[0047] Referring to Day 0, no thrombus was detected in the control group, the C8-TG administration group, or the C10-TG administration group. On the other hand, referring to Day 28, a clear thrombus was detected in the control group. The thrombus is circled with a dotted line. Meanwhile, the thrombus thickness was significantly thinner in the C8-TG administration group and the C10-TG administration group compared to the control group. As with the control group, the thrombus is circled with a dotted line.

[0048] Figure 3 summarizes the above results in a graph. The horizontal axis represents the sample type (control group, C8-TG administration group, C10-TG administration group), and the vertical axis represents the thrombus thickness (μm). The thrombus thickness is measured from the intima of the blood vessel toward the center of the vessel. The blood vessel was observed in a cross-section perpendicular to the length. In Figure 3, "a, b, c" indicates that there is no significant difference (p<0.01) between the same sign, and there is a significant difference between different signs. These statistical analyses were performed using the Tukey-Kramer test.

[0049] Referring to Figure 3, no thrombi were observed in the control group, the C8-TG administration group, or the C10-TG administration group on Day 0 by microscopic cross-sectional observation. On the other hand, the average thickness of thrombi on Day 28 was 101 μm in the control group, 76 μm in the C8-TG administration group, and 46 μm in the C10-TG administration group. These results indicate that thrombus formation can be prevented by administering C8-TG and C10-TG before thrombus treatment.

[0050] (Example 2) <Method for creating model animals> The method for creating the model animals is similar to that in Example 1. The method is shown in Figure 4.

[0051] Referring to Figure 4, all rats were initially fed a normal diet for the first week after arrival. Thrombotic induction was performed one week after the initial feeding period. A high-fat diet was then administered. Because thrombosis induces the development of abdominal aortic aneurysms in the cross-section of the blood vessel distal to the ligation point between the catheter and the abdominal aorta, laparotomy was performed on the 7th day after the thrombosis induction (corresponding to the 2nd week after arrival) to confirm the presence of abdominal aortic aneurysms. Rats in which abdominal aortic aneurysms were confirmed were then divided into a control group and a C10-TG administration group. Five rats were assigned to each group.

[0052] After laparotomy and confirmation of abdominal aortic aneurysm, the control group was given a high-fat diet in addition to 1145 mg / kg body weight / day of water, while the C10-TG (tricaprine) administration group was given a high-fat diet in addition to 1145 mg / kg body weight / day of tricaprine. Water and C10-TG were administered force-fed. Twenty-one days after thrombosis induction (14 days after C10-TG administration: four weeks after admission), the animals were euthanized and autopsied.

[0053] The following are the results of measuring thrombi formed in the portion of the abdominal aorta distal to the ligation point and in the lumen of the vessel on the cardiac side of the ligation point. No thrombi were induced in the vessel on the cardiac side of the ligation point. This portion is called the normal region. The portion where an abdominal aortic aneurysm occurs is called the aneurysm region (AAA region).

[0054] The mean size of thrombi formed in the normal vascular region was 6 μm in the control group and 3 μm in the C10-TG administered group. On the other hand, the mean size of thrombi formed in the abdominal aortic aneurysm region was 112 μm in the control group and 50 μm in the C10-TG group.

[0055] Figure 5 shows cross-sectional images of the blood vessels at that time. Images A and B represent the normal region, and images C and D represent the abdominal aortic aneurysm region (AAA region). The scale bar represents 100 μm. Similar to Figure 2, cross-sections cut perpendicular to the length of the blood vessel were stained with EVG. The arrows indicate the intima and adventitia of the blood vessel. In the abdominal aortic aneurysm region (AAA region) C and D, the thrombus is enclosed by a dotted line.

[0056] Figure 6 shows the results. Referring to Figure 6, the horizontal axis represents the sample type (control group (labeled Control) and C10-TG administration group (labeled C10-TG)). The vertical axis represents the thrombus thickness (μm). "a, b, c" in the figure are the same as in Figure 3.

[0057] In this animal model, thrombosis was observed on the second day after induction treatment, meaning that thrombi had already formed by day 7 when the C10-TG administration group was given. In other words, at that point, it was the same as the control group in the AAA region. However, 14 days later, a significant reduction in thrombus thickness was observed. This result indicates that it was effective even when thrombi had already formed, suggesting the possibility that C10-TG administration can reduce and treat thrombi. [Industrial applicability]

[0058] The antithrombotic pharmaceutical composition and antithrombotic processed food according to the present invention can be suitably used for the prevention and treatment of thrombosis.

Claims

1. An antithrombotic pharmaceutical composition containing tricaprine or tricaprilin as the active ingredient.

2. Antithrombotic processed food containing tricaprine or tricaprylin as the active ingredient.

Images