JP6310780B2 - Oral composition - Google Patents

Description

  The present invention relates to an oral composition containing activated carbon and lipase. More specifically, the present invention relates to an oral composition for preventing or treating dyslipidemia or digestive symptoms.

  Lipids are an important energy source and are also essential as components constituting living tissues.

  However, lipids take longer to digest than carbohydrates and proteins, so if you consume too much of a diet high in fat, undigested food stays in the stomach and intestines for a long time, causing it to enter the digestive tract. In addition, the digestive function is disturbed and the stomach is leaned, and uncomfortable digestive symptoms such as stomach and abdominal bloating and constipation are likely to occur.

  As an ameliorating agent for unpleasant gastrointestinal symptoms when an excessive intake of fat-rich foods is used, there are a gastrointestinal motility improving agent, a gastric mucosa protective agent, a gastric acid secretion inhibitor, an intestinal regulating agent, and a pharmaceutical compound containing them. However, these drugs do not act directly on food and lipids, and their effects on lipids are not sufficient.

  For the purpose of acting more directly on lipids, lipase, which is a digestive enzyme having an action of degrading lipids, is sometimes taken orally. For the purpose of assisting digestion, it is blended in a medicine such as a gastrointestinal drug (for example, see Non-Patent Documents 1 and 2).

  Lipase is known as a digestive enzyme contained in a digestive juice, and is an enzyme that hydrolyzes an ester bond that constitutes a lipid. Lipases work in the intestinal tract to break down lipids into fatty acids and alcohols. The decomposed fatty acid and alcohol are absorbed into the cell, and the absorbed fatty acid and alcohol are re-synthesized into lipid in the cell and released into the blood. However, in general, it is said that by inhibiting the activity of lipase present in the intestinal tract, it is possible to suppress the degradation and absorption of lipids in the intestinal tract, so that the absorption of lipids is promoted by improving the lipase activity. (For example, refer nonpatent literature 3).

  Furthermore, lipase alone does not have sufficient effects on gastrointestinal symptoms such as stomach upset, stomach / abdominal bloating, and constipation. Therefore, when using lipase, diastase that mainly breaks down carbohydrates and protease that breaks down proteins In addition, digestive enzymes such as cellulase that degrade fiber are used in combination.

  As a direct improvement measure against excessive intake of lipid, there is currently only oral intake of digestive enzymes including lipase. Development of means to prevent and ameliorate gastrointestinal symptoms such as bloating and constipation is desired.

  In addition, due to the penetration of Western diets rich in lipids, not only gastrointestinal symptoms such as stomach upset, but also an increase in dyslipidemia (hyperlipidemia) has become a problem. Dyslipidemia is known as a cause of arteriosclerosis and is also defined as a diagnostic standard for metabolic syndrome, and it is considered important to treat or prevent it.

  So far, factors directly or indirectly related to the cause and treatment of dyslipidemia include exercise, eating habits, body weight, blood glucose level, blood triglyceride or various cholesterol levels, insulin resistance, adiponectin, leptin, AMPK activity, sex hormones such as estrogen, genetic factors and the like are known.

  Currently, effective methods for treating dyslipidemia are weight loss due to exercise and dietary restriction. That is, it promotes energy metabolism and consequently increases the consumption of excess energy in the body and inhibits energy storage, but these practices are too strict for the patient. Therefore, it is desired that the disease can be prevented or treated without forcing such a great effort.

  Activated carbon is widely known as an adsorbent that adsorbs various substances, and is basically produced by carbonizing vegetable matter. Because of its functionality, it is also used in health foods and medicines as an orally taken product.

  Activated carbon is used in ethical drugs for the adsorption of gas produced by peracidosis and fermentation in the digestive tract, the adsorption of poisonous and toxins in the digestive tract, the detoxification of drug addiction, diarrhea, etc. (see, for example, Non-patent Document 1) ). In addition, over-the-counter medicines are blended with drugs for gastrointestinal diseases for the purpose of antistasis and bowel regulation (see, for example, Non-Patent Document 2). However, when taking activated carbon, it causes indigestion such as constipation (for example, see Patent Documents 1 and 2), and adsorbs useful components such as enzymes (for example, see Non-Patent Document 4). There is a problem.

Table 98/03259 Patent No. 54552056

JAPIC “Chemical Drug Collection” 2013 Maruzen Publishing, 2012 JAPIC "Olympic Drugs Collection" 2013 Maruzen Publishing, 2012 How to choose a marketed drug that works well Page 141 Pharmaceutical Information Laboratory / SCI Co., Ltd. 16th revision Japanese Pharmacopoeia C-5017 Ministry of Health, Labor and Welfare

  An object of the present invention is to promote the excretion of ingested lipids outside the body, thereby preventing and ameliorating gastrointestinal symptoms such as stomach stagnation due to the staying of lipids in the digestive tract for a long time. It is an object of the present invention to provide a safe oral composition that significantly improves blood lipids by promoting the excretion of blood.

  The action of adsorbing the wastes that are no longer necessary in the body is well known and put to practical use. However, when activated charcoal is ingested, it has been a problem that activated charcoal causes indigestion such as constipation.

  In general, lipase decomposes lipids into fatty acids and alcohols by its action, and as a result, it has been thought that absorption of lipids is promoted.

As a result of intensive studies over many years in order to solve the above problems, the present inventors have surprisingly found that the combination of activated carbon and lipase promotes the excretion of ingested lipids outside the body. The inventors have found a phenomenon that is contrary to expectations and have completed the present invention.
That is, the present invention relates to the following (1) to (9).
(1) An oral composition containing activated carbon and lipase.
(2) The oral composition according to (1), wherein the activated carbon is medicinal charcoal.
(3) The oral composition according to (1) or (2), wherein the lipase is a lipase produced from an Aspergillus bacterium.
(4) The oral composition as described in any one of (1)-(3) whose compounding ratio of lipase with respect to 1 weight part of activated carbon is 2-0.001 weight part.
(5) The oral composition according to any one of (1) to (4), which is used for prevention or treatment of digestive organ symptoms.
(6) The composition for oral administration according to (5), wherein the digestive symptom is stomach upset, heartburn, stomach / abdominal fullness or constipation.
(7) The composition for oral administration according to any one of (1) to (4), which is used for prevention or treatment of dyslipidemia.
(8) The oral composition according to any one of (1) to (4), which is used for lowering blood triglycerides.
(9) A lipid excretion promoter containing activated carbon and lipase.

  The oral composition containing activated carbon and lipase of the present invention has a safe and excellent effect of promoting the excretion of lipids out of the body, so that not only prevention or treatment of digestive symptoms, but also prevention or treatment of dyslipidemia or It is an oral composition useful for treatment.

C57BL / 6N Jcl mice fed a high fat diet (control group), medicinal charcoal added high fat diet group (medicinal charcoal group), lipase added high fat diet group (lipase group), medicinal charcoal and lipase added high fat diet The blood triglyceride (TG) concentration (unit: mg / dl) in the group (medicinal charcoal + lipase group) is shown. Each value showed the average value of n = 6. High fat diet group for SD rats (control group), high fat diet group with medicinal charcoal (medicinal charcoal group), high fat diet group with lipase (lipase group), high fat diet group with medicinal charcoal and lipase (medicine) It shows the amount of crude fat in feces (unit: mg / g intake) of charcoal + lipase group. Each value showed the average value of n = 6. High fat diet group for SD rats (control group), high fat diet group with medicinal charcoal (medicinal charcoal group), high fat diet group with lipase (lipase group), high fat diet group with medicinal charcoal and lipase (medicine) It shows the amount of cholesterol (unit: mg / g intake) in feces of charcoal + lipase group. Each value showed the average value of n = 6. High fat diet group for SD rats (control group), high fat diet group with medicinal charcoal (medicinal charcoal group), high fat diet group with lipase (lipase group), high fat diet group with medicinal charcoal and lipase (medicine) It shows the amount of free fatty acid in feces (unit: mEq / g intake) of charcoal + lipase group. Each value showed the average value of n = 6. A group of SD rats administered with 0.5% methylcellulose containing medicinal charcoal (control group) and a group of medicinal charcoal + lipase combination preparation suspended in 0.5% methylcellulose (medical charcoal + lipase combination preparation group) It shows the intestinal transport ability 30 minutes after administration. Each value showed the average value of n = 6.

  In the present specification, the “activated carbon” means a porous carbonaceous material having a large specific surface area and adsorption ability. For example, it is listed as a food additive in an existing additive list item list. The activated carbon in the present invention is preferably medicinal charcoal.

  In this specification, “medicinal charcoal” means activated carbon that satisfies the standard of the 16th revised Japanese pharmacopoeia “medicinal charcoal”.

  In the present specification, “lipase” is one of hydrolytic enzymes and means an enzyme that hydrolyzes an ester bond between a fatty acid and an alcohol to liberate the fatty acid and the alcohol. For example, it is listed as a food additive in an existing additive list item list. As the lipase in the present invention, a lipase produced by an Aspergillus bacterium is preferable, and lipase AP12 and lipase AP6 are more preferable.

  In the present specification, “lipid” is a large group of substances that constitute a living body together with proteins and carbohydrates, and means substances that are present in or derived from living bodies such as long-chain fatty acids or derivatives thereof and analogs thereof. . For example, the thing (for example, triglyceride) which the fatty acid and alcohol couple | bonded with ester, its analog (for example, cholesterol ester), etc. are mentioned.

  In the present specification, “digestive symptom” means an unpleasant symptom or disease generally derived from the stomach or intestine. For example, stomach upset, heartburn, stomach / abdominal fullness, indigestion, loss of appetite, stomach pain, stomach weight, burping, vomiting, abdominal pain, constipation, loose stool, gastritis, functional dyspepsia, or reflux esophagitis It is done.

  In this specification, “dyslipidemia” refers to a disease in which too much lipid (cholesterol or triglyceride) is contained in the blood (Ministry of Health, Labor and Welfare, “Welcome to the website of dyslipidemia”, [2012 Search on December 25], “What kind of disease is dyslipidemia?” On the Internet <URL: http://www.mhlw.go.jp/topics/bukyoku/kenkou/seikatu/kousi/index.html> Search on December 25, 2012], Internet <http://www.mhlw.go.jp/topics/bukyoku/kenkou/seikatu/kousi/about.html>).

In the present specification, “triglyceride (TG)” means acylglycerol (triacylglycerol) in which three molecules of fatty acid are ester-bonded to one molecule of glycerol.
As used herein, “treatment” means curing, reducing or ameliorating gastrointestinal symptoms and dyslipidemia by promoting lipid excretion.

  In the present specification, “prevention” means to prevent, suppress, or delay the onset of a disease or symptom of gastrointestinal symptoms or dyslipidemia by promoting lipid excretion.

  The subject to which the oral composition of the present invention is administered is a mammal. Examples include humans, mice, rats, guinea pigs, rabbits, dogs, cats, monkeys, and the like, and humans are more preferable.

  According to one aspect of the present invention, a pharmaceutical composition containing activated carbon and lipase for preventing or treating gastrointestinal symptoms and dyslipidemia is provided, but it may be a supplement or a health food.

  The oral composition of the present invention can be administered in various forms, for example, oral administration using tablets, powders, capsules, suspensions, emulsions, pills, powders, liquids (including syrups), elixirs and the like. Etc. In particular, tablets, powders, and capsules are preferable, but the present invention is not limited thereto.

  As long as the effects of the present invention are not impaired, other auxiliary medicinal ingredients can be blended with the oral composition in addition to activated carbon and lipase. In particular, herbal medicines and digestive enzymes that improve gastrointestinal function are preferred in order for activated charcoal and lipase to be effective in the gastrointestinal tract.

  Examples of the supplementary medicinal ingredients are: ogon, duck, auren, turmeric, keihi, ginger, ginger, dio, carrot, aloe, akagashi, ganoderma, funnel extract, menthol, carnitine, ursodeoxycholic acid, starch digestive enzyme , Protein digestive enzymes, fiber digestive enzymes, live intestinal bacteria components such as lactic acid bacteria, and the like.

  In the formulation of the oral composition of the present invention, excipients, binders, disintegrants, lubricants, stabilizers, preservatives, colorants, surfactants, pH regulators, flavoring agents, and flavoring agents are further included. Commonly accepted pharmaceuticals and food additives such as sweeteners, preservatives, and fragrances can be blended.

  The preparation of the present invention can be produced according to a conventional method such as the method described in the 16th revised Japanese Pharmacopoeia General Formulation, using appropriate additives and base materials suitable for each dosage form.

  The daily use amount of the activated carbon (medicinal charcoal) of the present invention varies depending on the symptom, age, dosage form, etc. of the subject, but is 0.1 to 20 g per day, preferably 0.4 to 5 g per adult. is there. Moreover, the activated carbon (medicinal charcoal) of the present invention is usually taken in 1 to 6 times per day, and preferably taken in 1 to 3 times per day. A preferred combination is to take 0.4-5 g daily for adults in 2 to 3 divided doses.

  The daily use amount of the lipase of the present invention varies depending on the symptom, age, dosage form, etc. of the subject, but is 0.001 to 1 g, preferably 0.01 to 0.2 g per day for one adult. The lipase of the present invention is usually taken in 1 to 6 times per day, and preferably in 1 to 3 times per day. A preferred combination is to take 0.01 to 0.2 g daily for adults in 2 to 3 divided doses.

  In the present invention, the mixing ratio of activated carbon (medicinal charcoal) and lipase is preferably 2 to 0.001 parts by weight of lipase, more preferably 1 to 0. 01 parts by weight.

  The administration period of the oral composition of the present invention is not particularly limited, but administration for a certain period or longer (for example, 3 days or more, or 14 days or longer) is useful.

  EXAMPLES Hereinafter, although an Example and a test example are given and this invention is demonstrated further in detail, the scope of the present invention is not limited to these.

Example 1 Liquid Agent 0.4 g of medicinal charcoal, 60 mg of lipase, 100 g of fructose-glucose liquid sugar, and an appropriate amount of a pH adjusting agent are mixed, and a total amount of 1000 g of the liquid agent is prepared to have a pH of 5 to 7 with purified water.

Example 2 Granules 0.4 g of medicinal charcoal, 60 mg of lipase, 350 g of lactose and 125 g of crystalline cellulose are added and mixed, and a 5% hydroxypropylcellulose aqueous solution is sprayed as a binder to prepare granules.

Example 3 Tablet 0.4 g of medicinal charcoal, 60 mg of lipase, 350 g of lactose and 125 g of crystalline cellulose are added and mixed, and a 5% hydroxypropylcellulose aqueous solution is sprayed as a binder to prepare granulated granules. A plain tablet is prepared by mixing and compressing 49.5 g of the granulated granule with 0.5 g of magnesium stearate.

Formulation Example 1 Granule A granule is produced by following the ingredients of the following (Table 1) in accordance with the section of the Japanese Pharmacopoeia General Rules “Granule”.

Formulation Example 2 Tablets Tablets are produced in accordance with the ingredients of the following (Table 2) according to the section “General Tablet Formulation“ Tablets ”.

Test Example 1 Improvement of blood lipids in obese model mice (1) Test drug As test drugs, medicinal charcoal was manufactured by Nichi-Iko and lipase AP12 manufactured by Amano Enzyme was used.
(2) Animals
5-week-old C57BL / 6N Jcl mice were purchased from CLEA Japan. These mice had a 12-hour light-dark cycle (8-20 hour light period, 20 hour-next 8 hour dark period) at room temperature of 22 ° C ± 3 ° C, high-fat diet (D12451, 45% Kcal + Preliminary breeding with 17% sucrose load (Research Diets) was performed for 1 week.
(3) Administration route and administration period After the completion of the preliminary breeding, the control group (n = 6) fed only with the powdered diet high-fat diet, fed with 2% activated carbon added to the powdered diet high-fat diet Medicinal charcoal group (n = 6), lipase group fed with 2% lipase added to powdered feed high-fat diet (n = 6) 1% medicinal charcoal and 1% lipase fed to powdered high-fat diet Four groups of medicinal charcoal + lipase group (n = 6) fed with the added one were set. The prepared food was fed for 5 days.
(4) Preparation of test sample
After feeding for 5 days, the animals were fasted for 12 hours, and blood was collected from the tail vein to obtain serum. The collected serum was measured for TG concentration using Triglyceride E-Test Wako (Wako Pure Chemical Industries, Ltd.).
(5) Test results (blood TG concentration)
The test results are shown in FIG. From FIG. 1, in the group administered with medicinal charcoal and lipase alone, no significant decrease in TG value was observed, but in the combination administration of medicinal charcoal and lipase, the serum TG concentration was significant compared to the control group. (P <0.05). Furthermore, in the medicinal charcoal and lipase combination group, a significant decrease in the TG value was observed even when medicinal charcoal alone was administered (p <0.05). From this, it became clear that the combination of medicinal charcoal and lipase produces a remarkable blood lipid inhibitory effect.

Test Example 2 Fecal lipid excretion in obese model rats (1) Test drug As test drugs, medicinal charcoal was manufactured by Nichi-Iko and lipase AP12 manufactured by Amano Enzyme was used.
(2) Animals
Six-week-old Slc: SD rats were purchased from Japan SLC. These rats have a high-fat diet (D12451, 45% Kcal +) with a 12-hour light-dark cycle (8-20 hour light period, 20 hour-next 8 hour dark period) at room temperature 22 ° C ± 3 ° C. Preliminary breeding with 17% sucrose load (Research Diets) was performed for 1 week.
(3) Administration route and administration period After the completion of the preliminary breeding, a control group (n = 6) fed only with powdered high-fat diet was fed with 2% medicinal charcoal added to powdered high-fat diet. Medicinal charcoal group (n = 6), lipase group (n = 6) fed with 2% lipase added to powdered feed high-fat diet, medicinal charcoal 2% and lipase 2 to powdered feed high-fat diet Four groups of medicinal charcoal + lipase group (n = 6) to be fed with the addition of% were set. The prepared food was fed for 7 days, and feces from day 5 to day 7 were collected. In addition, food intake during the administration period was measured.
(4) Preparation of test sample Using the collected feces, the fecal crude fat weight (mg / g intake), fecal total cholesterol content (mg / g intake), fecal free fatty acid content (mEq / g intake) It was measured. (Intake indicates the amount of food consumed for 2 days from day 5 to day 7.)
The crude fat weight in the feces is calculated using the Van de Kamer method, the total cholesterol content in the feces is measured using cholesterol E-Test Wako (Wako Pure Chemical Industries, Ltd.), and the free fatty acid content in the feces is calculated using the NEFA C- Measurement was performed using Test Wako (Wako Pure Chemical Industries, Ltd.).
(5) Test results (fecal lipid concentration)
The fecal crude fat weight, fecal total cholesterol content and fecal free fatty acid content are shown in FIGS. 2, 3 and 4, respectively. From FIG. 2, in the group to which medicinal charcoal and lipase were administered alone, there was no significant increase in the weight of crude fat excreted in the feces. The fecal crude fat weight was significantly increased (p <0.01). From FIG. 3, in the group to which medicinal charcoal was administered alone, no increase in the total fecal cholesterol weight was observed, but in the lipase single administration and medicinal charcoal and lipase combination administration, the total fecal cholesterol was compared with the control group A significant increase in weight was observed (lipase alone administration: p <0.05, medicinal charcoal + lipase administration: p <0.01). As shown in FIG. 4, in the group to which medicinal charcoal and lipase were administered alone, there was no significant increase in the free fatty acid weight in feces. A significant increase in fatty acid weight was observed (p <0.01). From these facts, it became clear that lipid excretion into feces was significantly promoted by the combination of medicinal charcoal and lipase.

Test Example 3 Effects on rat intestinal transport (1) Test drug As test drugs, medicinal charcoal (manufactured by Nichi-Iko), lipase AP12 (manufactured by Amano Enzyme) and other ingredients and additives that are not directly related to medicinal effects are actually used as tablets. (Mixing ratio in the preparation: medicinal charcoal 22%, lipase 2.2%), and pulverized powder of this tablet was suspended in 0.5% methylcellulose, and the medicinal charcoal concentration in the solution was adjusted to 1% ( Medicinal charcoal + lipase combination formulation). In the control group, 0.5% methylcellulose suspended to 1% medicinal charcoal was used.
(2) Animals
Five week old Crl: CD (SD) rats were purchased from Charles River, Japan. These rats were preliminarily prepared with solid diet FR-2 (Funabashi Farm) under a room temperature of 23 ° C ± 2 ° C in a 12-hour light-dark cycle (7-19 light period, 19: 00-next dark period). The breeding was carried out for one week.
(3) Administration route and administration period After the preliminary breeding, fast for 16 hours so that the test drug will be 10 mL / kg body weight in the control group (n = 6) and medicinal charcoal + lipase combination drug group (n = 6). Was orally administered.
(4) Preparation of test sample 30 minutes after administration, the rat was exsanguinated under isoflurane anesthesia and the intestine was extracted. The total length (cm) of the excised intestinal tract and the medicinal charcoal powder movement distance (cm) were measured, and the intestinal tract transport capacity [medical charcoal powder movement distance / full length of the intestinal tract x 100 (%)] was calculated.
(5) Test results (intestinal transport ability)
The intestinal transport ability of each group is shown in FIG. From FIG. 5, it was revealed that the intestinal transport ability was significantly increased in the group administered with the medicinal charcoal + lipase combination preparation compared to the group administered medicinal charcoal alone. (P <0.05)

Claims (5)

An oral composition for use in prophylaxis or treatment of gastrointestinal symptoms or prophylaxis or treatment of dyslipidemia, comprising activated carbon and lipase.   The oral composition according to claim 1, wherein the activated carbon is medicinal charcoal.   The oral composition according to claim 1 or 2, wherein the lipase is a lipase produced from an Aspergillus bacterium. The blending ratio of lipase to 1 part by weight of activated carbon is 2 to 0.001 part by weight.
Oral composition of any one of -3. 5. An oral composition for use in the prevention or treatment of digestive symptoms , wherein the digestive symptoms are stomach upset, heartburn, stomach / abdominal fullness, or constipation . The composition for oral administration according to Item 1 .