JPH052652B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a lipid-lowering agent that is useful for lowering (reducing or inhibiting increase in) lipids such as triglycerides (neutral fats) and cholesterol, and in particular, does not cause side effects when administered for a long period of time, and does not cause diarrhea, abdominal pain, etc. when administered in large doses. The present invention relates to a lipid-lowering agent that can exhibit an outstanding blood lipid-lowering effect at a low dosage without causing side effects, and also exhibits a hepatic lipid-lowering effect. More specifically, the present invention has an intrinsic viscosity [η] of 0.29.
The present invention relates to a lipid-lowering agent characterized by containing a partially degraded dextran of ~1.1 as an active ingredient. In recent years, hyperlipidemia due to an increase in blood lipids has attracted attention as one of the important factors related to arteriosclerosis, which has become a problem as an adult disease, and the need to lower blood lipids has been recognized. has been done. Recently, many dietary fibers have been used to lower lipid levels, and it is known that this effect is particularly strong with water-soluble dietary fibers such as pectin, glucomannan, and guar gum. However, the effective amount of these dietary fibers is generally 10 to 30 g/Kg in animal experiments.
Body weight/day, 50-500mg/Kg- even in clinical applications
body weight per day, resulting in nausea,
In addition to side effects such as diarrhea and abdominal pain,
At present, these dietary fibers cannot necessarily be said to be satisfactory lipid-lowering agents because of the risk of vitamin and mineral deficiencies. Hitherto, a proposal has been made for a hypoglycemic agent characterized by containing as an active ingredient a saccharide selected from the group consisting of indigestible polysaccharides, oligosaccharides, and derivatives thereof, including dextran (Japanese Patent Application Laid-Open No. 1983-1999).
No. 146713) is known. In addition to native dextran, this proposal also discloses the use of partially decomposed dextran, with a molecular weight of 60,000 (intrinsic viscosity [η] approximately
0.22) ~ 90000 (intrinsic viscosity [η] approx.
It has been disclosed that dextran (equivalent to 0.275) showed hypoglycemic effects. However, the proposal in JP-A-57-146713 does not mention the blood sugar-lowering effect of partially decomposed dextrans with molecular weights other than dextrans with molecular weights of 60,000 to 90,000, and also does not mention the effect of lowering blood sugar levels on lipids such as triglycerides and cholesterol in the blood. There is no mention of the effect of dextran on. Therefore, as a matter of course, no knowledge or suggestion is disclosed regarding the relationship between the effect of dextran on lipids and the molecular weight or intrinsic viscosity of the dextran. Furthermore, New Food Industry, Vol.25, No.3
(1983), pp. 13-15, also reports on α-1,6-linked polysaccharides including dextran under the title ``Development of sugars containing substances that control blood sugar levels''. This literature states that the molecular weight of approx.
70,000 (corresponding to an intrinsic viscosity [η] of approximately 0.23) added to sugar and administered to rats suppresses the rise in blood sugar, and the most effective amount of dextran to be added to sugar is 1/1000. is listed. However, this document does not mention partially decomposed dextran with a molecular weight other than the above-mentioned molecular weight, and furthermore, the effect of dextran on lipids in the blood, the effect of dextran on lipids, and the molecular weight or limit of the dextran. There is no mention or suggestion of any relationship with viscosity. On the other hand, US Pat. No. 3,148,114 (published September 8, 1964) discloses a method for lowering blood cholesterol. This proposal lists a large number of mucilaginous substances that are chemically significantly different as mucilaginous substances that exhibit blood cholesterol-lowering effects. The dextran produced is illustrated. However, in this proposal, there is no mention of the molecular weight or intrinsic viscosity [η] of the dextran used, but for example,
Native dextran such as dextran produced by the action of sucrose by Leuconostoc dextranicum is exemplified.
Usually Leuconostoc dextranicum or Leuconostoc
Native dextran obtained by the action of mecenteroids is said to have a molecular weight on the order of about 4 million to about 10 million. Furthermore, this proposal exemplifies the dosage of mucilaginous substances in doses ranging from 50 to 500 mg/Kg - body weight/day, and also the administration of mucilaginous substances to food in amounts ranging from 5 to 30 g/Kg - food. Although it is stated that the addition of native dextran promotes the maximum reduction in blood cholesterol, administration of native dextran in amounts such as those exemplified above may be accompanied by side effects such as diarrhea and abdominal pain. Furthermore, this proposal makes no mention of the effect of dextran and other mucilaginous substances on triglycerides. Also, in this proposal, there is no mention at all of the partially decomposed dextran with the intrinsic viscosity [η] specified in the present invention. No knowledge or suggestion regarding the relationship between the molecular weight or intrinsic viscosity of dextran is disclosed. The present inventors have conducted research to develop a lipid-lowering agent that does not have side effects due to long-term administration or dosage by using dextran, which is safe in terms of toxicity. As a result, it was discovered that there is a close correlation between the action of dextran on lipids and the intrinsic viscosity [η] of the dextran. Further research based on this discovery revealed that partially degraded dextran with a specific range of intrinsic viscosity [η] can reduce blood triglycerides and cholesterol levels at low doses without causing long-term administration or dose-related side effects. It has been discovered that it exhibits a remarkable effect in suppressing the decrease or increase in . According to the research conducted by the present inventors, partially decomposed dextrans which belong to a region with an intrinsic viscosity [η] of 0.29 to 1.1, which is different from the region of intrinsic viscosity [η] of dextran proposed in the prior art as described above, have a
40mg/Kg-body weight/day, preferably 4-30mg/Kg-
When administered orally at a low dose per body weight per day, it shows a remarkable effect on lowering or suppressing the increase in triglycerides and cholesterol in the blood, and there is no risk of side effects even with long-term administration. The researchers discovered that it is a unique lipid-lowering agent that is also highly effective in lowering blood pressure. Therefore, an object of the present invention is to provide an excellent lipid-lowering agent. The above objects and many other objects and advantages of the present invention will become more apparent from the following description. The lipid-lowering agent of the present invention has an intrinsic viscosity [η] of 0.29.
Contains ~1.1 partially degraded dextran as an active ingredient. Such partially degraded dextrans are known per se, for example Leuconostoc
Native dextran produced from sucrose can be obtained by partial hydrolysis using known strains such as mecenteroids, Leuconostoc dextranicum, etc., by a method known per se. , also available on the market. In the present invention, a partially decomposed dextran having an intrinsic viscosity [η] of 0.29 to 1.1 (corresponding to a molecular weight of about 100,000 to about 1,500,000) is selected and used. The toxicity (LD ₅₀ ) of such partially degraded dextran is extremely low at 10 g/Kg or more when administered orally (in mice), and it can be used safely. In the present invention, the intrinsic viscosity [η] of partially decomposed dextran is measured and calculated as follows. Measurement and calculation of intrinsic viscosity [η]: - Dissolve 0.05 to 0.2 g of dextran in water to make exactly 100 ml and use it as the sample solution. Using an Ubbelohde viscometer, measure the flow time at 25°C ± 0.02°C for each of the sample solution and the water used, and calculate and determine the limiting viscosity [η] using the following formula. Intrinsic viscosity [η] = ln Sample solution flow time (seconds) / Water flow time (seconds) / Sample amount (g) From the above intrinsic viscosity, the weight average molecular weight ( M w) of the sample dextran can be calculated using the above formula. You can ask for it. [η] = 9.00×10 ⁴ M w ^0.50 The lipid-lowering agent of the present invention containing partially decomposed dextran having an intrinsic viscosity [η] of 0.29 to 1.1, preferably 0.3 to 1.06 as an active ingredient can reduce triglyceride and cholesterol at low doses. It is possible to exhibit an excellent lowering effect on , without any observable side effects. Examples of the dosage include a low dosage (oral administration) of 3 to 40 mg/Kg body weight/day, preferably 4 to 30 mg/Kg body weight/day of the active ingredient. Furthermore, the active ingredient of the present invention not only exhibits an excellent lowering effect on not only blood cholesterol but also triglycerides, it also exhibits a remarkable lowering effect on hepatic lipids. According to the study by the present inventors, native
Dextran (molecular weight on the order of about 4 million to about 10 million) does not have a practical lowering effect on triglycerides at low doses, and when the dose is increased, there is a risk of untoward side effects such as diarrhea and abdominal pain. However, the active ingredient of the present invention exhibits an excellent lowering effect on blood triglycerides and cholesterol at a low dose as mentioned above, and also shows an excellent lowering effect on liver lipids. It has the advantage of having no side effects. The lipid-lowering agent of the present invention can be in any oral dosage form, such as soft capsules.
capsulae, hard capsules, granules, pills, pulveces, tabellae, syrupi, trochis, elixiria The following dosage forms can be exemplified. Means for preparing such dosage forms are well known to those skilled in the art and can be utilized in the present invention. The lipid lowering agent of the present invention has an intrinsic viscosity [η] of 0.29.
In addition to containing the partially degraded dextran of ~1.1 as an active ingredient, it can be in the form of a composition that further contains a pharmaceutically acceptable diluent or carrier. In such a form, the content of the active ingredient can be appropriately selected. The content can be suitably selected and changed depending on the dosage form, but for example, the content may be about 1 to about 99% by weight, preferably about 5 to about 95% by weight, based on the weight of the composition. I can do it. Examples of diluents or carriers utilized in such compositions include karaya gum, acacia, tragacanth, guar gum, carrageenin, sodium alginate, casein, gelatin, gluten, potato starch, wheat starch, corn starch, rice starch, and sweet potato. starch, agar,
Shellac, glucomannan, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, polyethylene glycol, methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, carboxymethylstarch, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, carbonic acid Sodium hydrogen, magnesium oxide, calcium lactate, calcium carbonate, calcium phosphate, synthetic aluminum silicate, magnesium stearate, magnesium aluminate metasilicate, silicic acid, talc, boric acid, calcium sulfate, benzoic acid, citric acid, succinic acid, tartaric acid , gluconic acid, glycerin, sucrose, mannitol,
Examples include glucose, sorbitol, lactose, fructose, saccharin, water, and ethanol. The lipid-lowering agent of the present invention can be orally administered in the above-mentioned amount to humans who have or are at risk of hyperlipidemia. Hyperlipidemia can be primary, familial or idiopathic, such as arteriosclerosis (ischemic heart disease, myocardial infarction), cerebral arteriosclerosis (cerebral infarction, cerebral thrombosis), and hyperlipidemia. It may be a cause of liver disease, or it may be secondary hyperlipidemia induced by obesity, diabetes, abnormal glucose metabolism, hyperinsulinemia, etc. Furthermore, the partially degraded dextran of the present invention can be administered to the above-mentioned diseases that may induce secondary hyperlipidemia and to humans (including healthy individuals) who may be at risk of hyperlipidemia. It can also be administered. Next, the lipid-lowering effect of dextran will be described. Test Example 1 Male Wistar rats weighing around 105 g were fed ad libitum with a high sucrose diet (high sucrose diet vs. dextran = 500:1) containing dextran with an intrinsic viscosity [η] of 0.11 to 1.72. Let me,
After rearing for 14 days, serum triglyceride (TG), serum total cholesterol (TC), and blood sugar were determined by standard methods. The results are shown in Table 1.

[Table] As shown in Table 1, the test group fed a high-sucrose diet containing dextran had higher TG and TC compared to the control group fed a high-sucrose diet without dextran.
The increase was suppressed. In particular, the intrinsic viscosity [η]
TG in the group containing 0.30-1.06 dextran
and the increase in TC was significantly suppressed. On the other hand, no effect on blood sugar was observed. Test Example 2 Male Wistar rats weighing around 105 g were fed ad libitum with a high sucrose diet containing various proportions of dextran with an intrinsic viscosity [η] of 0.63, and after being reared for 14 days, TG , TC and hepatic lipids were quantified. The results are shown in Table 2. The liver lipids were determined by adding 30 times the amount of acetone to the liver wet weight and homogenizing the liver, evaporating the centrifuged supernatant to dryness, and weighing it.

[Table] As shown in Table 2, in each test group fed feed containing 0.5 to 5 g of dextran with an intrinsic viscosity [η] of 0.63 per 1 kg of high sucrose diet, the high sucrose diet without dextran Compared to the control group given
Increases in TG, TC, and hepatic lipids were significantly suppressed. The composition of the high sucrose diet used in Test Examples 1 and 2 is as follows. Composition of high sucrose diet Sucrose 69.9% Casein 25% Mixed vitamins (Panvitan powder) 0.85% Mixed salt (Harper's salt) 4% Choline chloride 0.15% Corn oil 0.1% Test example 3 Wistar male weighing around 110g Rats were fed a high-fat diet containing dextran with an intrinsic viscosity [η] of 0.53 (high-fat diet vs. dextran =
After breeding for 14 days with ad libitum intake of 500:1),
TG and TC were quantified by conventional methods. 3rd result
Shown in the table.

[Table] As shown in Table 3, the test group fed a high-fat diet containing dextran with an intrinsic viscosity [η] of 0.53 had lower TG and TC levels compared to the control group fed a high-fat diet containing no dextran. The increase was significantly suppressed. The composition of the high-fat food used in Test Example 3 is as follows. Composition of high-fat diet Sugar 61% Casein 22% Mixed vitamins (Panvitan powder) 0.85% Mixed salt (Harper's salt) 4.0% Choline chloride 0.15% Corn oil 1.0% Cholesterol 1.0% Lard 10% Example 1 Tablets with the following composition ( 400 mg/tablet) was prepared in a conventional manner. Dextran ([η] = 0.53) 25% Cane sugar 25% Lactose 48.5% Hydroxypropyl cellulose 0.5% Magnesium stearate 1% Example 2 Mix the ingredients with the following composition, fill it into No. 1 gelatin capsule, and make a capsule. Agent (200mg/capsule)
And so. Dextran ([η]=0.63) 80% Calcium hydrogen phosphate 19% Magnesium stearate 1% Example 3 Granules having the following composition were produced by a conventional method. Dextran ([η]=0.75) 50% Lactose 48% Hydroxypropylcellulose 2% Example 4 Tablets (250 mg/tablet) having the following composition were made into sugar-coated tablets by a conventional method. Dextran ([η] = 0.80) 40% Wheat starch 4.5% Crystalline cellulose 10% 10% potato starch paste 45% Talc 0.5% Example 5 A solution with the following composition was dispensed into a suitable container and sterilized to form a liquid. . Dextran ([η]=0.30) 15% Cane sugar 3% Glucose 5% Distilled water 77% Example 6 A lozenge (1 g/tablet) having the following composition was produced by a conventional method. Dextran ([η]=1.06) 15% Starch syrup 25% Cane sugar 57% Gum arabic powder 3% Distilled water Appropriate amount Example 7 A powder having the following composition was produced by a conventional method. Dextran ([η] = 0.41) 70% Corn starch 19% Lactose 20% Magnesium stearate 1% Example 8 Dextran ([η] = 0.53) was filled into No. 1 gelatin capsules at 200 mg each to form capsules. And so. Clinical Example 1 Ten patients with hypertriglyceridemia were given dextran ([η] = 0.53) filled in capsules before each meal, three times a day for 4 weeks. TG before and after taking dextran was as shown in Table 4.

[Table] As shown in Table 4, when dextran with an intrinsic viscosity [η] of 0.53 was administered to 10 patients with hypertriglyceridemia at 2 to 50 mg/Kg - body weight/day, the results were 4 to 50 mg/Kg. - body weight/day of patients taken
TG decreased, particularly in patients taking 4-30 mg/Kg body weight/day. Furthermore, in patients taking 2 to 30 mg/Kg body weight/day, no side effects were observed due to taking dextran, but in some patients taking 50 mg/Kg body weight/day, a tendency towards loose stools was observed.

Claims (1)

[Scope of Claims] 1. A lipid-lowering agent characterized by containing partially decomposed dextran having an intrinsic viscosity [η] of 0.29 to 1.1 as an active ingredient. 2. The lipid-lowering agent according to claim 1, comprising a partially decomposed dextran having an intrinsic viscosity [η] of 0.29 to 1.1 and a pharmaceutically acceptable diluent or carrier.