JP5131895B2 - Lipid metabolism improver derived from Sikhwasher - Google Patents

Description

  The present invention relates to a lipid metabolism improving composition, and more particularly to a lipid metabolism improving agent and a composition thereof for improving a lipid metabolism by a component derived from Seekwasher.

  Sea quashshire (Citrus depressa HAYATA) is one of small citrus fruits native to Japan, and is cultivated in southern islands including Okinawa. This crop is mainly used for the production of fruit juice and is used to add acidity and aroma such as seasonings. Seek washer is manufactured and sold as juice after squeezing and squeezing.

  For example, Patent Document 1 discloses a method of squeezing a washed sequwer, separating a sequwer juice and a squeaker residue, discarding the residue, and then centrifuging the sequwer juice to separate it into a sequwer juice and a sequencer essential oil. ing.

  On the other hand, most of the large amount of residue after being squeezed and squeezed is discarded. For example, Patent Document 2 discloses a technique for roasting a seeker residue and mixing it with goya tea to make a tea pack tea as a technique for using a large amount of the residue after being pressed and squeezed without discarding. ing.

  In addition, for example, in Patent Document 3, dietary fiber, which is the main component of Unshu mandarin orange or Iyokan capsule, binds and adsorbs bile acids, considering Shikuwasa as a citrus fruit. Have been disclosed that amines (sinephrine) reduce lipid absorption (paragraphs “0017”, “0018”, “0022”, etc.).

  Furthermore, Patent Document 4 discloses the content using a citrus fruit film as a raw material. In this patent document 4, it is disclosed that it is produced from a raw material mainly composed of a camphor membrane contained in an orifice discharge effluent, and inhibits pancreatic lipase and reduces lipid absorption (specification paragraph “0001”). ”,“ 0011 ”, etc.).

Lifestyle-related diseases such as hyperlipidemia, hypertension and diabetes have increased remarkably in recent years. Furthermore, it has been recently reported that obesity, particularly visceral fat-type obesity, secondarily and secondarily develops and develops these lifestyle-related diseases and synergistically increases the risk of developing arteriosclerosis. , Also called metabolic syndrome. The onset and progress of these lifestyle-related diseases and metabolic syndrome are closely related to abnormal lipid metabolism. It is known that foods we eat daily contain ingredients that suppress the onset and progression of lipid metabolism abnormalities that lead to these diseases. As its solution, enteric-hepatic circulation of dietary fiber known from the past using citrus capsular membrane as listed in Patent Documents 3 to 5, and the action of amine induction to stimulate fat cells, pancreatic lipase There has been an invention that combines the action of inhibiting lipid and lowering the absorption of lipids, the action of lowering blood pressure, or the action of lowering blood glucose level.
JP 2003-183690 A JP-A-2005-204586 JP 2006-225278 A JP-A-2005-40107 JP 2001-240539 A

  However, the above-mentioned Patent Document 1 relates to the separation of Sikhwasa fruit juice, and the above-mentioned Patent Document 2 uses the Sikhwaser residue as tea, so that the dietary fiber contained in the outer skin and seaweed membrane of Sikhwaser is efficiently used. There was a problem that could not be taken. Moreover, since tea husk is generally discarded, there is a problem that a large amount of residue seeker residue is not fully utilized. Furthermore, since the above-mentioned Patent Documents 3 to 5 cannot completely identify the biochemical action / effect, there are problems relating to its efficacy and safety.

  Accordingly, the present invention has made extensive efforts to solve the above problems and to suppress / prevent the onset and progress of lifestyle-related diseases and metabolic syndrome. It was found to suppress the activity and increase the activity of carnitine acyltransferase. That is, this invention solves the said subject with the lipid-metabolism improving agent which consists of a seek sour residue obtained by squeezing a seek squash.

  According to the present invention, serum cholesterol concentration lowering action, serum HDL cholesterol concentration raising action, serum neutral fat concentration lowering action, serum lipid peroxide concentration lowering action, liver cholesterol concentration lowering action, liver cholesterol esterification rate lowering action , Liver neutral fat concentration lowering effect, white adipose tissue weight lowering effect, fatty adipose tissue weight increasing action through fatty acid β-oxidation, fecal weight increasing effect, fecal total steroid excretion increasing effect Rather, it has the effect of reducing fatty acid synthase activity in the liver and increasing the activity of carnitine acyltransferase, so it can synergistically suppress and prevent the onset and progression of lifestyle-related diseases and metabolic syndrome, Can make full use of Sikhwasher residue.

  The present invention is a lipid metabolism improving agent comprising a seeker shear residue obtained by squeezing seeker shear.

  Thereby, the onset and progress of lifestyle-related diseases and metabolic syndrome can be suppressed / prevented, and a large amount of seek-washer residue after being squeezed / squeezed can be effectively utilized.

  In addition, “seek washer residue” generally refers to something other than fruit juice after squeezing the fruit of shik washer (ie, sand (pulp residue), inner candy peel, outer confectionery peel , And at least one selected from the gills), the “seek washer residue” according to the present invention is a dry residue (that is, after squeezing the fruit of the shik washer fruit) And non-dried residue (that is, the non-dried residue after squeezing Shikwasher fruit and taking out the juice). It is a concept that includes both, and may include some or all fruit juices and seeds.

  The residue of the sikhwasher according to the present invention includes at least one selected from the group consisting of sandwash (fruit pulp residue), inner confectionery skin, outer confectionery skin, and funnel membrane of the sikhwasher. Anything may be used, for example, crushing and crushing with a crusher, a food slicer, and an endless net of about 10 to 20 mesh is rotated between two compression rolls, and the fruits are continuous. Roll press squeezing machine that squeezes with two compression rolls, filter cloth press machine that wraps the fruit in a filter cloth and compresses and squeezes, centrifugal filtration type separation device, in-line squeeze machine Or a residue that has been squeezed or squeezed with a chopper pulper squeezing machine or the like.

  After squeezing the seeker, the seeker residue according to the present invention is dried using vacuum freeze drying, hot air drying, ventilation drying, far-infrared drying, vacuum drying, microwave vacuum drying, heating steam drying, etc. Preferably it is done. The drying method is not particularly limited as long as it does not impair the lipid metabolism improving action of the seeker residue. For example, ventilation drying at 45 to 55 ° C. for 85 to 120 hours or ventilation drying at 40 ° C. for 75 to 120 hours can be mentioned.

  The drying temperature of the seek washer residue according to the present invention is preferably -80 to 100 ° C, more preferably 40 to 70 ° C, and further preferably 45 to 55 ° C. This is because if the drying temperature is less than −80 ° C., efficient drying cannot be expected, and if it is less than 100 ° C., the lipid metabolism improving action may be lost.

  Although the drying time of the seek-washer residue concerning this invention is not limited, Preferably it is 5-120 hours, More preferably, it is 5-100 hours, More preferably, it is 17-95 hours.

  Moreover, it is preferable that the seek squash residue which concerns on this invention is obtained by isolate | separating a seek squash juice and a seek squash residue after squeezing a seek squash.

  Therefore, the seeker residue according to the present invention may be dried by the above method or may not be dried after the seeker juice is separated from the seeker juice after the seeker is squeezed. .

  It is preferable that the seek washer residue according to the present invention suppresses the activity of fatty acid synthase and / or increases the activity of carnitine acyltransferase.

  As a result, the Sikhwasher residue suppresses the activity of fatty acid synthase and / or increases the activity of carnitine acyltransferase, and at the same time, excretion of cholesterol by enterohepatic circulation of dietary fiber contained in the Sikhwasher residue, fat Suppresses / prevents the onset and progression of lifestyle-related diseases and metabolic syndrome by stimulating cells, inhibiting pancreatic lipase and reducing lipid absorption, lowering blood pressure, and lowering blood glucose levels.

  The fatty acid synthase according to the present invention refers to acetyl transfer, malonyl transfer, condensation, 3-oxoacyl reduction, dehydration, enoyl reduction, palmitoyl in the process of synthesizing fatty acids (palmitic acid, myristylic acid, stearic acid, etc.) from citric acid. This refers to a multi-enzyme complex that catalyzes different reactions such as transfer. In this specification, “inhibits fatty acid synthase activity” refers to the production of fatty acids (such as palmitic acid, myristylic acid, stearic acid) from citric acid. Inhibiting, it means inhibiting / inhibiting the reaction of synthesizing fatty acids from acetyl CoA and malonyl CoA with NAD (P) H as a reducing agent. Furthermore, it is preferable to suppress and inhibit fatty acid synthase in the liver.

  In addition, the “carnitine acyltransferase” according to the present invention is an enzyme that exists on the outer side and inner side of the mitochondrial inner membrane in a fatty acid degradation reaction, that is, in the degradation process of fatty acid to acetyl CoA, and includes carnitine acetyltransferase, carnitine octanoyltransferase, The generic name of the three enzymes of carnitine palmitoyltransferase, and “increasing the activity of carnitine acyltransferase” in the present specification means that carnitine palmitoyltransferase is activated to undergo at least β-oxidation performed in mitochondria. Furthermore, it is preferable to increase the fatty acid decomposition reaction in the liver and / or the fatty acid decomposition reaction of the brown adipose tissue.

  The lipid metabolism-improving agent according to the present invention comprises a pharmaceutically acceptable carrier in the form of a squeaker residue obtained by squeezing the squeaker as it is or in a squeaker residue obtained by squeezing the seeker. It can be formulated and administered to patients (including livestock, poultry and mammals such as humans, and fish) as a composition for oral administration or parenteral administration. When the agent is used for oral administration, the seeker residue obtained by squeezing the seeker is used with suitable additives such as lactose, sucrose, mannitol, corn starch, synthetic or natural gum, and Excipients such as crystalline cellulose, starch, cellulose derivatives such as carboxymethylcellulose and methylcellulose, binders such as gum arabic, gelatin and polyvinylpyrrolidone, carboxymethylcellulose calcium, carboxymethylcellulose sodium, starch, corn starch, bicarbonate Disintegrants such as sodium and sodium alginate, lubricants such as talc, magnesium stearate and sodium stearate, and fillers such as calcium carbonate, sodium carbonate, calcium phosphate and sodium phosphate Others can be in solid form of a suitably mixed with such diluents, tablets, powders (powders), such as pills, and granules. Or the lipid metabolism improving agent for oral administration may have the form of a capsule, In this case, a hard or soft gelatin capsule is used as a capsule. These solid preparations may be enteric-coated using a coating base such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, and methacrylate copolymer. Furthermore, the seek washer residue of the present invention is suspended in a generally used inert diluent such as purified water or a glycerin ester such as tricaprin and triacetin or an alcohol such as ethanol. Liquid preparations such as syrups and elixirs can be obtained by appropriately adding wetting agents, emulsifiers, dispersion aids or surfactants, sweeteners, flavors or aromatic substances to the solution.

  When the lipid metabolism-improving agent of the present invention is for parenteral administration, the above-mentioned seek washer residue is purified water, an appropriate buffer solution such as a phosphate buffer solution, physiological saline, Ringer's solution or lock solution. As sterile aqueous or non-aqueous solutions, suspensions, liposomes, or emulsions combined with physiological salt solutions such as ethanol, propylene glycol, glycerin and conventional preservatives, stabilizers and surfactants, etc. It can be made into a liquid formulation. In this case, the liquid preparation preferably has a physiological pH, preferably a pH within the range of 3.5 to 8.5. Further, the lipid metabolism improving agent of the present invention may be formed as a transdermal preparation such as an ointment, lotion or cream using a known method.

  In addition, the lipid metabolism improving agent of the present invention uses, for example, a neutral solution consisting of sodium hydrogencarbonate, boric acid or the like, or a buffer solution having a pH of 5.5 to 8.5, and if necessary, a preservative, a stabilizer, An ophthalmic pressure regulator or the like may be added to form an eye drop.

  Furthermore, the lipid metabolism improving agent of the present invention can be administered as a suppository using a suppository base such as embedding with a pellet or gelatin soft capsule.

  Among the above-mentioned, a preferable dosage form and administration route are selected by the doctor in charge.

  The concentration of the seek washer residue contained in the lipid metabolism-improving agent of the present invention varies depending on the form at the time of administration, the type and severity of the disease, the target dose, etc. The ratio is not particularly limited as long as it exhibits a metabolic improvement effect, and the weight of the seeker residue (dry residue) is 0.5 to 99.5% by weight, preferably 0.5 to the total weight of the raw material. The range is 30% by weight. In particular, when the lipid metabolism improving agent of the present invention is administered orally, the weight of the seeker residue (dry residue) is 0.5 to 10% by weight, more preferably 1 to 4%, based on the total weight of the raw material. In the range of 3% by weight, when administered parenterally, the weight of the seeker residue (dry residue) is 0.1 to 50% by weight, more preferably 0.00%, relative to the total volume of the raw material. The range is preferably 1 to 10% by weight. At this time, if the concentration of the seek seeker residue exceeds the upper limit, a uniform dose cannot be obtained, which is not preferable. On the other hand, if the concentration of the seek-washer residue (dry residue) is less than the lower limit, it is not preferable because the disease state improving effect to be obtained by the present invention cannot be sufficiently expected.

  The dosage of the lipid metabolism improving agent of the present invention varies depending on the age, weight and symptoms of the patient, the intended dosage form and method, therapeutic effect, treatment period, etc., and the exact amount is determined by the doctor. Specifically, when the lipid metabolism-improving agent of the present invention is orally administered, it is usually 0.1 to 5000 mg / kg body weight / time, more preferably when used as a seeker residue (dry residue). Is preferably in the range of 1 to 1000 mg / kg body weight / dose and divided into 1 to 6 times, more preferably 1 to 3 times a day. At this time, when the dose per day is large, it may be divided into a plurality of preparations such as tablets at a time. In addition, when the lipid metabolism-improving agent of the present invention is administered parenterally, it is usually 0.1 to 5000 mg / kg body weight / time, more preferably 0. It is desirable to administer 1 to 6 times a day, preferably 1 to 3 times a day within a dose range of 1 to 500 mgg / kg body weight / time.

  The lipid metabolism-improving agent of the present invention may be used by mixing it with foods, and as foods according to the present invention, dairy products such as yogurt and cheese, kamaboko, chikuwa, hanpen, fried fish cakes, Processed seafood such as starch, processed meat such as sausage, frankfurt, liver paste, tofu, grilled tofu, freshly fried, deep-fried tofu, gandoki, okara, frozen tofu, bean products such as yuba, processed vegetables such as puree, Processed rice cakes such as mashed potato, litter, harusame, konnyaku, shirataki, rice cake, white rice, white rice, rice cake, rice noodles, macaroni, spaghetti, somen noodles, buckwheat noodles, Chinese noodles, processed bread, dried bread, anpan etc. Sweets such as butter, margarine, mayonnaise, dressings and other oils, candy, rice cake, rice cracker, arabe , Castella, Yokan, Monaka, Manju, Daifukumochi, Dango, Uiro, Chocolate, Biscuits, Cookies, Donuts, Cakes, Pies, Ice Cream, Pudding, Bavaria, Gum and other sweets, Tofu, Jelly, Konjac, Agar or Tokoroten All foods that can be eaten normally, such as gel foods such as seaweeds such as kombu, seaweed, seaweed, and prickly pear are included.

  In addition, the lipid metabolism improving agent of the present invention may be used by mixing with feed, and feeds according to the present invention include pigs, cattle, sheep, goats and other livestock, dogs, cats, rabbits, hamsters and other pets, All food for animals normally raised such as poultry and fish is included.

  Since the lipid improving agent of the present invention was originally eaten and is safe, the amount used for foods and feeds is not particularly limited as long as there is no problem in taste and the like.

  One preferred embodiment of the present invention will be described below as an example, but the scope of the present invention is not limited to the following example.

“Measurement of chemical composition of Sikhwasher residue”
Seek washer residue was seed-removed and dried by ventilation at 45 to 55 ° C. for 17 to 19 hours, and then pulverized with a fiber mixer to obtain seeker residue powder.
The chemical composition of this seeker residue powder was as follows.

"Preparation method and evaluation of Seek washer residue"
We investigated the effect of sikhwasher juice residue powder on lipid metabolism in rats.

  Seek washer residue was subjected to ventilation drying at 45 to 55 ° C. for 17 to 19 hours after removing seeds, and then pulverized with a fiber mixer (MX-X103-D, National). Note that an SP-type dryer (SP-A, Sanshu Sangyo Co., Ltd.) was used as an apparatus for drying the seek washer residue.

  Four-week-old male Sprague-Dawley rats (hereinafter referred to as SD rats) were housed in an animal room with a light cycle of room temperature 22 ± 1 ° C., humidity 55 ± 5%, and 8:00 to 22:00 lighting. For the first week, a commercial powdered feed CE-2 was given and preliminary breeding was performed. Thereafter, the rats were divided into groups so that there was no difference in the body weight between the groups, and the following test meals were fed freely for 2 weeks.

  As the test meal, a purified meal based on the AIN-76 composition was used as a control meal. The weight composition (g / kg) of the feed is: casein 200, corn oil 10, lard 140, mineral mixture (AIN-76) 35, vitamin mixture (AIN-76) 10, cellulose 50, choline bitartrate 2, DL-methionine 3. 1000 with corn starch 150 and sucrose.

  To the group to which Seek washer squeezed residue powder was added, 3% of the total weight of Seek washer squeezed residue powder was added to reduce the amount of sucrose added. During the breeding period, food consumption was measured every day and body weight was measured every other day.

  After the rearing, white adipose tissue around the kidney and testicles was extracted, and the weight was measured to calculate the sum. Sikhwasher juice residue powder decreased the white adipose tissue weight of SD rats. Since the seek squash juice residue powder did not affect the final body weight, it is determined to have an action of effectively reducing only body fat.

  Serum high density lipoprotein (HDL) -cholesterol concentration was measured by a colorimetric method using N-Test S (Nittobo Medical). Serum and liver total lipids were extracted by the Folch method, cholesterol in the total lipids was precipitated by the digitonin precipitation method, and the cholesterol concentration was calculated by a colorimetric method. Seekwasher juice residue powder increased the HDL-cholesterol concentration having an arteriosclerosis-inhibiting action without changing the serum total cholesterol concentration of SD rats. Furthermore, the Sikhwasher juice residue powder reduced the liver cholesterol concentration. Moreover, when the serum lipid peroxide density | concentration was measured by the colorimetric method using Detamina-LPO (Yagi separate method, Kyowa Medix), the Sikhwasher juice residue powder reduced the serum lipid peroxide density | concentration. The results are shown in Table 3.

  Neutral fat in serum and liver total lipid was measured by a colorimetric method using the acetylacetone method. As a result, Sikhwasher juice residue powder effectively reduced serum and liver neutral fat concentrations. The results are shown in Table 4.

  Serum and liver neutral fat concentrations are greatly influenced by fat synthesis and degradation in the liver. It is also considered to be affected by the weight of brown adipose tissue, which is a heat-producing organ, and fatty acid degradation. Therefore, the mitochondrial and microsomal fractions of the liver were fractionated by density gradient ultracentrifugation. Fatty acid synthase (FAS) activity of the liver cytosol fraction was calculated from the amount of NADPH consumed by the absorbance method. Carnitine palmitotransferase (CPT) activity in the mitochondrial fraction of liver and brown adipose tissue was calculated by measuring the amount of CoA released from long-chain acyl-CoA and using the molar extinction coefficient. Seekwasher juice residue powder significantly reduced the FAS activity of the liver cytosol fraction involved in fatty acid synthesis and increased the CPT activity of the liver and brown adipose tissue mitochondrial fraction involved in fatty acid degradation. The brown adipose tissue weight was also increased. Sikhwasher juice residue powder suppresses liver fat synthesis by reducing liver FAS activity, and increases fatty acid degradation by increasing CPT activity, thereby increasing the concentration of neutral fat in liver and serum. It became clear that it lowered. The results are shown in Table 5.

  Serum and liver cholesterol levels are affected by cholesterol synthesis in the liver and steroid excretion in the feces. Therefore, the amount of steroid excreted in feces was measured using gas chromatography. Sikhwasher juice residue powder increased the amount of neutral and acidic steroids in feces. The results are shown in Table 6.

  From these results, Sikhwasher juice residue has a body fat reducing action, a serum and liver neutral fat concentration reducing action, an HDL-cholesterol concentration increasing action, a liver cholesterol concentration reducing action, and a serum lipid peroxide concentration reducing action. This suggests that the lipid metabolism improving effect is exhibited.

  Moreover, it turns out that the lipid metabolism improving agent which concerns on this invention suppresses the activity of a fatty-acid synthetase and / or raises the activity of a carnitine acyltransferase as shown in FIGS. The data of serum triglyceride concentration, liver triglyceride concentration, and liver fatty acid synthase activity in FIGS. 1, 3, and 4 were measured using absorbance measurement (Shimadzu Rika Kikai UVmini-1240).

It is a figure which shows the result of the serum triglyceride density | concentration which concerns on this invention. It is a figure which shows the result of the serum lipid peroxide density | concentration which concerns on this invention. It is a figure which shows the result of the liver triglyceride density | concentration which concerns on this invention. It is a figure which shows the result of the liver fatty acid synthase activity based on this invention.

Claims (5)

A lipid metabolism improver comprising a seek washer residue obtained by squeezing seek squash , wherein the seek squash residue suppresses the activity of fatty acid synthase.   The lipid metabolism improving agent according to claim 1, wherein the seek shark residue increases the activity of carnitine acyltransferase. The seek Wah Shah residue after squeezing the seek word Shah, characterized in that it is obtained by drying 5-120 hours at -80 to 100 ° C., lipid metabolism improving agent according to claim 1 or 2.   The said seek squasher residue is obtained by squeezing a seeker shear and then separating the seeker juice and the seeker shear residue, according to any one of claims 1 to 3. Lipid metabolism improving agent.   A composition for improving lipid metabolism, comprising the lipid metabolism improving agent according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier.

Images