JP4355967B2 - Pharmaceutical composition - Google Patents

Description

  TECHNICAL FIELD The present invention relates to a pharmaceutical composition having few side effects due to Kazetsu-san, particularly a pharmaceutical composition having an effect of improving constipation, anti-obesity and liver function.

  In recent years, due to changes in dietary habits and stress, etc., constipation accompanied by symptoms such as a decrease in the number of defecations and difficulty in defecation, and excessive accumulation of fat has caused lifestyle diseases such as diabetes, hyperlipidemia, and arteriosclerosis. As a result, various pharmaceutical compositions for improving constipation and obesity have been developed.

  Conventionally, Fufutsu Seisaku, a Chinese medicine, has a defecation promoting action and is known to be effective against constipation. Such an effect is thought to be due to sennoside, a component of Daio contained in Fukatsu-Don Seisaku. Sennoside is a kind of anthraquinone compound and is absorbed from the small intestine and is said to promote defecation by stimulating the mucous membrane of the large intestine in a hematogenous manner. However, sennoside has a large problem that the defecation promoting action is too strong and abdominal pain is likely to occur, and that the effect is attenuated if a high concentration is used for a long time (Patent Document 1, Non-Patent Document 1). See).

  In addition, it is known that Fengtsu Sansho is effective for anti-obesity, particularly the reduction of internal fat (see, for example, Non-Patent Documents 2 and 3). Care should be taken when using Fengtsu Sansho for obese people who are included and tend to have impaired liver function.

  As described above, Fukatsutsu Seisaku has various effects, but cannot avoid side effects.

  Panthetin is known to promote peristaltic movement of the intestinal tract (Non-Patent Document 4), and acts on the parasympathetic nervous system to promote peristaltic movement of the intestine. was there.

  In addition, pantethine is known to have an effect of promoting lipid metabolism such as a cholesterol reduction effect and a neutral fat reduction effect (see, for example, Non-Patent Documents 5 and 6), but the effect is slow and sufficient. It wasn't.

  Furthermore, although pantethine is known to be effective in reducing visceral fat (see Non-Patent Document 7), it has not been known to reduce even subcutaneous fat.

  As described above, pantethine was known to have a peristaltic exercise promoting effect and a lipid metabolism promoting effect, but a sufficient effect could not be obtained.

That is, in the past, side effects were unavoidable when trying to ensure the effects of promoting defecation and anti-obesity. From such a background, there has been a demand for a pharmaceutical composition that has few side effects, and is excellent in constipation improving effect, anti-obesity effect, and liver function improving effect.
JP-A-8-310960 Plzenide (registered trademark) lock (manufactured by Novartis Pharma KK) package insert Fiscal 2002 Science and Technology Research Fund Regional Leading Research Research Results Report Abstracts of Annual Meeting of the Pharmaceutical Society of Japan (issued March 5, 2003) Medical treatment and new drugs (medical publishing company) 13 (2) 247 (1976) Geriatrics 18 (9) 1275 (1980) Geriatrics 18 (7) 967 (1980) Journal of Atherosclerosis and Thrombosis, 2000 vol.7 55-58

  The main object of the present invention is to provide a pharmaceutical composition containing Fufutsu Seisaku, which has few side effects and is excellent in constipation improving effect, anti-obesity effect and the like. Another object of the present invention is to provide a method for reducing the side effects caused by taking Fufutsu Seisaku.

  The present inventor has intensively studied to solve the above problems, and by using a combination of Fengtsu Sansho and Panthetins, an excellent defecation promoting effect, that is, a constipation improving effect can be obtained. It has been found that abdominal pain that tends to occur due to enhanced defecation promoting action is reduced.

  In addition, the present inventor exhibits excellent anti-obesity effect, weight gain inhibitory effect, free fatty acid and serum triglyceride increase inhibitory effect, liver function improving effect, etc. by combining Fufutsu Seisan and panthetins I found out.

  Furthermore, the present inventor has found that the amount of ketone bodies in the serum, which may lead to acidemia (ketoacidosis), increases due to the taking of Fengtsu Seikisan, and It was found that it can be effectively suppressed by combining with.

  The present invention has been completed as a result of further research based on such findings.

The present invention provides the following pharmaceutical composition and a method for reducing the side effects of Fukatsu Sansho.
Item 1. (A) component:
(B) Component: A pharmaceutical composition comprising at least one pantethine selected from pantethine, pantethine salt, pantothenic acid, pantothenic acid salt, pantethein and panthenol.
Item 2. Item 2. The pharmaceutical composition according to Item 1, wherein the blending ratio of component (B) to 1 part by weight of sennoside in component (A) is 2 to 800 parts by weight.
Item 3. Item 3. The pharmaceutical composition according to Item 1 or 2, which is used for improving constipation.
Item 4. Item 3. The pharmaceutical composition according to Item 1 or 2, which is used for anti-obesity. Item 6. The pharmaceutical composition according to Item 1 or 2, which is for improving liver function. Side effects of Fengtsu Seiki, characterized by using Panthetin, pantethine salt, pantothenic acid, pantothenic acid salt, pantethein and panthenol in combination with at least one type of panthetin Mitigation method.
Item 7. Item 7. The method according to Item 6, wherein the side effect of Feng Shui-san is abdominal pain and / or an increase in serum ketone bodies.

  The pharmaceutical composition of the present invention can exhibit an excellent defecation promoting action (ie, constipation improving action) and the like, although there are few side effects.

  Ingredient (A) of the present invention: Fengtsu Sansho is abdominal pain when used in a large amount to promote defecation, and its effect diminishes when used continuously. As a result, habitual use is necessary. The vicious circle of becoming was a problem. However, according to the pharmaceutical composition of the present invention, an excellent defecation promoting effect can be realized by combining the component (B): panthetins, and there is no abdominal pain. It is suitable for. Furthermore, panthetins act on the parasympathetic nerves to promote natural defecation, and therefore, according to the pharmaceutical composition of the present invention, there is low concern about addictive properties and excellent safety. Moreover, when Fengtsu Sansho and pantethine are used in combination, the effect of promoting defecation is exerted more strongly by constipation-prone persons and constipation patients, and is therefore effective as a constipation-improving drug.

  In addition, the pharmaceutical composition of the present invention significantly suppresses an increase in body weight due to excessive intake of lipids. In addition, the pharmaceutical composition of the present invention is also useful as an anti-obesity pharmaceutical composition because of its excellent inhibitory effect on the increase in free fatty acids and serum triglycerides.

  In the case of obesity, the function of the liver is likely to deteriorate due to, for example, fatty liver. Also, Fengtsu Sansho includes ougon, which may cause liver dysfunction. Care must be taken when using Fengtsu Sansho for obese people who tend to have impaired liver function. However, according to the present invention, it is possible to exert an excellent liver function improvement effect by using a combination of Fengtsu Sansho and Panthetins, so it can be used with peace of mind even for obese people whose liver function tends to decrease it can.

  Thus, the present invention is an extremely excellent pharmaceutical composition that can effectively improve the side effects and problems caused by taking Fengtsu Sansho in addition to the effects of improving bowel movement and anti-obesity. is there. In particular, it is excellent in reducing the side effects such as abdominal pain and increased serum ketone body caused by taking Fukatsutsu Seisaku. That is, it is not limited to uses such as improvement of constipation, but has an excellent effect of reducing side effects in all pharmaceutical compositions containing Fufutsu Seisaku.

  In addition, the present invention also provides a method for reducing the side effects of Fukatsu-san-san by using Fukutsu-san-san together with panthetins.

  The pharmaceutical composition of the present invention is mainly characterized by containing (A) component: Fufutsu Seisaku and (B) component: panthetins. The configuration of the present invention will be described below.

(A) Windproof Tsushosan The component (A) of the present invention is Windproof Tsushosan. Wind-proof sangsan used in the pharmaceutical composition of the present invention includes: Toki, Peonies, Senkyu, Sanshi, Forsythia, Hakka, Pepper, Keigai, Bowfu, Maou, Daio, Bowshaw, Sandalwood, Kyokyo, Ogon, Ganzo, Gypsum And an extract of a mixture of Kasseki.

  The preparation of Fengtsu Sansho, which is the component (A) of the present invention, is in accordance with the “Guide to General Kampo Prescription” (supervised by the Ministry of Health and Welfare, Pharmacy Bureau, edited by the National Pharmacopoeia Specialist Committee, published by Yakuho Hokpo). Can be done. Moreover, as for the plant raw material which can be used for a wind-proof tsusan, use site | part is prescribed | regulated by the Japanese Pharmacopoeia, and a use site | part can be selected suitably according to this.

  In addition, Fufutsu Seisaku, which is the component (A) of the present invention, is defined in the `` Basic Handling Policy of Kampo Preparations '' established by the Kampo Herbal Medicine Research Committee. The Kampo prescriptions (herbal medicine blends) described in the letter and extracts obtained from these Kampo prescriptions are included.

  As the component (A) of the present invention, an extract preparation of Fengtsu Seisan can be used. For the preparation of the extract preparation, the extract obtained by the above-mentioned method is concentrated under reduced pressure to obtain a dry extract by a spray drying method, or an adsorbent suitable for a soft extract with an increased concentration of the extract (for example, anhydrous For example, silicic acid, starch, etc.).

  Specifically, for example, in terms of dry weight, Toki 1.2 (parts by weight, the same applies hereinafter), Peonies 1.2, Senkyu 1.2, Sanshishi 1.2, Forsythia 1.2, Hakka 1.2, Show 1.2, Kei-Gai 1.2, Bow-Fu 1.2, Maou 1.2, Daio 1.5, Bow-show 1.5, Sandalwood 2.0, Kyo-Ju 2.0, Ogon 2.0, Kanzo 2.0 , Gypsum 2-3, casseki 3-5, and in principle, this is extracted with 20 times its weight (and hence 560-620 parts by weight) hot water, then concentrated to 1/2 volume, What remove | excluded solid content (extract) can be used as a wind-proof Tsushosan extract.

  Here, depending on the letter, in the above ingredients, those that do not contain peanuts (for example, “Experimental Kampo Prescription Quantity Collection”, Takatsuka Otsuka and Michiaki Yahaichi, published by Nippon Shokudo Co., Ltd.), those that do not contain Ogon (for example, "Sequential Kampo this and that", edited by Osaka Yomiuri Shimbun, published by Naniwasha), 1.2 parts by weight in the above amount are all 1.5 parts by weight (for example, "Myoken Kampo Prescription", Kazuo Nishioka, Shintaro Takahashi, Some of them have slightly different ingredients and component ratios.

  In addition, the method for producing the extract of Fuyutsu Seisaku also adds 400 parts by weight of water to each of the above components other than bowsho, decocts up to 200 parts by weight, removes residue, and then adds bowsho (for example, “Wakan” Some of them are slightly different from the above, such as “Yaku Handbook”, Michinori Kubo, Kenzo Moriyama, published by Yoikusha.

  In the present invention, these differences are not particularly limited, and any of these differences is included as a windbreaking sansho.

  Examples of the extract preparations of Fukatsutsu Seisaku are, for example, Fudotsu Seisaku Dry Extract A, Fadotsu Seisaku Dry Extract AM, Fadotsu Seisaku Dry Extract E, and Fudotsu Seisaku Dry Extract EM (all of which are Nippon Powder Co., Ltd.) ), And Fudotsu-san-san dried extract-C and Fado-san-san-san dried extract-F (both manufactured by Alps Pharmaceutical Co., Ltd.) are known as products, and can also be obtained commercially. .

  Daio used in the preparation of Fengtsu Sanseong contains sennoside which causes abdominal pain. As sennoside, sennoside A which is easily hydrolyzed and sennoside B which is hardly hydrolyzed (both are glycosides and activated by bacteria in the large intestine) are known.

  The blending ratio of the component (A) in the pharmaceutical composition of the present invention is not particularly limited as long as the effects of the present invention are exhibited. However, the component (A) is usually 0. It is about 0001 to 20% by weight, preferably about 0.001 to 20% by weight, and more preferably about 0.001 to 15% by weight.

  In the pharmaceutical composition of the present invention, the blending ratio of the component (A) can be appropriately set with reference to the blending ratio converted to the sennoside. In the composition, usually about 0.01 to 95% by weight, preferably about 1 to 90% by weight, more preferably about 5 to 90% by weight, still more preferably about 10 to 90% by weight, particularly preferably 30 to 80% by weight. %, Particularly preferably about 50 to 65% by weight.

  The content of sennoside in the pharmaceutical composition of the present invention can be measured according to a quantitative method known to those skilled in the art.

(B) Panthetins The component (B) of the pharmaceutical composition of the present invention includes at least one pantethine selected from the group consisting of pantethine, pantethine salt, pantothenic acid, pantothenic acid salt, pantethein and panthenol Can be used singly or in combination of two or more, preferably pantethine.

  Panthethine is represented as bis (2- {3-[(2R) -2,4-dihydroxy-3,3-dimethylbutanoylamino] propanoylamino} ethyl) disulfide, and pantothenic acid (vitamin B5) Also called derivatives or active vitamin B5.

  Further, pharmaceutically acceptable pantethine or pantothenic acid salt can be used as component (B), for example, alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; Examples thereof include mineral acid salts such as hydrochloride, nitrate and sulfate; and organic acid salts such as acetate, citrate and benzoate.

  The component (B) is a known compound and can be synthesized according to a conventionally known method. For example, products such as pantethine A (Daiichi Sankyo Propharma Co., Ltd.) are also known, It can also be obtained commercially. The compounds used as the component (B) other than pantethine are also known and can be obtained according to conventional methods.

  In the pharmaceutical composition of the present invention, the blending ratio of the component (B) is not particularly limited as long as the effects of the present invention are exhibited, but is usually about 0.0001 to 95% by weight, preferably 0.001 to 80% in terms of pantethine. About 0.1% by weight, more preferably about 0.01 to 60% by weight, still more preferably about 0.1 to 45% by weight, and particularly preferably about 0.1 to 15% by weight.

  The pantethine content in the pharmaceutical composition of the present invention can be measured in accordance with the quantitative method described in the Japanese Pharmacopoeia Pharmaceuticals Articles / Chemical Drug “Panthetine”.

  The blending ratio of the component (A) and the component (B) in the pharmaceutical composition of the present invention is not particularly limited as long as the effects of the present invention are achieved.For example, when effectively promoting defecation and reducing side effects, the cause Component (B) component (in terms of pantethine) is about 2 to 800 parts by weight, preferably about 10 to 700 parts by weight, more preferably 10 to 600 parts by weight, based on 1 part by weight of sennoside in component (A). Part, more preferably about 20 to 500 parts by weight. In the case where the component (A) is Fufutsu Seisaku Extract, the blending ratio of the component (A) and the component (B) can be appropriately set with reference to the blending ratio converted to the sennoside, for example, the component (A) (Total amount of dry extract) About 100 to 30 parts by weight of component (B) (converted to pantethine) is about 0.1 to 30 parts by weight, preferably 0.1 to 25 parts by weight, more preferably 0.2 to 25 parts by weight. About parts by weight. According to this blending ratio, even when Fengtsu Sansho is used, promotion of defecation and reduction of side effects can be effectively obtained, and the pharmaceutical composition is particularly excellent in anti-obesity effect and liver function improving action. be able to.

(C) Other components The composition of the present invention is a liquid preparation (suspension agent) such as a liquid (including syrup) according to a conventionally known method together with pharmaceutically acceptable excipients, carriers and the like. And oral preparations in the form of solid preparations such as tablets, pills, powders, granules, and capsules (including soft capsules). The composition of the present invention is preferably in the form of tablets or capsules such as film-coated tablets, sugar-coated tablets, sweetener-coated tablets, and sublingual tablets.

  When the composition of the present invention is a liquid preparation, it can be stored frozen, or it may be stored after removing moisture by lyophilization or the like. Freeze-dried preparations, dry syrups and the like are used by adding sterilized water and dissolving them again at the time of use.

  When preparing the composition of the present invention as a solid preparation, for example, in the case of a tablet, conventionally known carriers can be widely used in this field. Such carriers include, for example, excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, silicic acid; water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin Binders such as solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, crystalline cellulose, hydroxypropylcellulose, hypromellose, sodium alginate; dry starch, agar powder, laminaran powder, sodium bicarbonate, polyoxyethylene sorbitan fatty acid Disintegrating agents such as esters, sodium lauryl sulfate, monoglyceride stearate, starch, crospovidone, povidone, low-substituted hydroxypropylcellulose; stearin, cocoa butter, water Disintegration inhibitors such as additive oils; Absorption accelerators such as quaternary ammonium salts and sodium lauryl sulfate; Moisturizers such as glycerin; Adsorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid; Purified talc, stearic acid Lubricants such as salt, boric acid powder and polyethylene glycol can be used. Further, the tablets can be made into tablets with ordinary coatings as necessary, for example, sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multilayer tablets. Moreover, the composition containing the said active ingredient can be filled into the conventionally well-known capsule which uses gelatin, pullulan, starch, gum arabic, hydroxypropyl methylcellulose (HPMC), etc. as a raw material, and can be set as a capsule.

  Moreover, when preparing in the form of a pill, a conventionally well-known thing can be widely used as a support | carrier in this field | area. Examples thereof include excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin and talc, binders such as gum arabic powder, tragacanth powder, gelatin and ethanol, and disintegrants such as laminaran and agar. Can be used.

  In addition to the above, for example, surfactants, absorption promoters, adsorbents, fillers, preservatives, stabilizers, emulsifiers, solubilizers, salts that regulate osmotic pressure, dosage units of the preparations obtained It can be appropriately selected and used according to the form.

  Moreover, you may contain other active ingredients, such as an amino acid, vitamins, and organic acid salts. Examples of other active ingredients include valine, leucine, isoleucine, threonine, methionine, phenylalanine, tryptophan, lysine, glycine, alanine, asparagine, glutamine, serine, cysteine, cystine, tyrosine, proline, hydroxyproline, aspartic acid, glutamic acid Amino acids such as hydroxy lysine, arginine, ornithine and histidine; vitamins such as vitamin A1, vitamin A2, carotene, lycopene (provitamin A), vitamin B6, vitamin B1, vitamin B2, ascorbic acid, nicotinamide and biotin; Examples include alkali metal salts such as sodium chloride and potassium chloride, and organic acid salts such as citrate, acetate and phosphate.

  The pharmaceutical composition of the present invention can be prepared in the form of powders, fine granules, granules, tablets, capsules and the like. These forms can be prepared by using ordinary methods in the art. For example, tablets can be appropriately added with components (A), (B) and other excipients necessary for obtaining tablets, It can be obtained by tableting after mixing and dispersing well. In addition, the powder can be obtained by appropriately adding the components (A), (B) and other excipients necessary for obtaining the powder, and pulverizing them by a suitable method.

  The daily intake when the pharmaceutical composition of the present invention is prepared into various preparations can be appropriately changed according to the patient's condition and the degree of symptoms, but the daily dose for one adult (body weight 60 kg) is ( The amount of sennoside of component A) is usually about 0.01 to 50 mg, preferably about 0.1 to 40 mg, more preferably about 0.1 to 30 mg, still more preferably about 0.1 to 15 mg, particularly preferably 0.1. About 10 mg, most preferably about 0.1 to 8 mg. According to the pharmaceutical composition of the present invention, the dose of sennoside having side effects such as strong abdominal pain can be reduced, and nevertheless, sufficient defecation promoting effect, constipation improving effect, and anti-obesity effect are exhibited. Can do. In the case of using Fufutsu Seikisan extract as the component (A), the dry extract is usually about 0.1 to 10 g, preferably about 1 to 8 g, more preferably about 1.5 to 6 g. The pharmaceutical composition of the present invention is usually used in the form of oral administration divided into 1 to 3 times a day. The dose time is not particularly limited, but is preferably before meals, between meals or before going to bed. According to the pharmaceutical composition of the present invention, side effects such as strong abdominal pain and an increase in the amount of ketone bodies in serum can be suppressed, and sufficient defecation promoting effect, constipation improving effect, and anti-obesity effect can be exhibited. .

  The pharmaceutical composition of the present invention can be used to promote defecation, and is particularly useful for preventing constipation, improving symptoms, and treating it. Here, constipation, as defined by the Japan Society of Internal Medicine, means “a state in which there is no bowel movement for 3 days or more, or even if there is a bowel movement every day, the feeling of residual stool does not go away.” In many cases, the number of flights decreases In addition to hard stools, residual stool feeling, abdominal pain, abdominal distension, vomiting, and anorexia are accompanied.

  In addition, the pharmaceutical composition of the present invention is also useful as an anti-obesity pharmaceutical composition because it is excellent in the effect of increasing body weight due to excessive intake of lipids and the effect of suppressing the increase in free fatty acids and serum triglycerides.

  Furthermore, the pharmaceutical composition of the present invention also has an effect of improving liver function. Since Ougong, which may cause liver dysfunction, is included in Fengtsu Sanseiki, it is not desirable to take Fengtsu Sanse to obese people whose liver function tends to decrease. However, the pharmaceutical composition of the present invention can be used with peace of mind even for such obese people.

  Fengshutsu Seisaku has side effects such as abdominal pain and increased ketone body in serum when taken alone, but the pharmaceutical composition of the present invention reduces these side effects and Or it can be prevented. Therefore, the present invention also provides a pharmaceutical composition for reducing and / or preventing side effects of Fukatsutsu Seisaku. Each component used in the method for reducing side effects of Fukatsutsu Seisaku, its blending amount, and the like are as described above.

  Hereinafter, the present invention will be described in more detail with reference to test examples and formulation examples, but the present invention is not limited thereto.

Test Example 1 Effect of improving constipation in rats [subjects]
SD rats (4 weeks old) males were acclimated for 1 week with the normal diet “CE-2” (manufactured by CLEA Japan, Inc.) (average weight at acclimation: 180 g).

  The acclimated rats were divided into 5 groups ((i) normal group, (ii) control group, (iii) Fengtsu Sansho group, (iv) pantethine group, (v) windbreak) according to the test drug administration components listed in Table 2. Tsushosan / pantethine group) (9 / group), and each group was reared for 85 days with a normal feed or a high fat / low dietary fiber feed of the mixing ratio shown in Table 1 (during the breeding period, rats Were given free access to food and water). Each group was orally administered once a day with test substances (pantethine, sennoside, Fufutsu Seisaku) shown in Table 2. Distilled water was administered to the control group.

  Normal feed is “CE-2” (manufactured by Clea Japan Co., Ltd.), pantethine is 80% by weight pantethine aqueous solution “Panthetine A” (manufactured by Daiichi Fine Chemical Co., Ltd.), lard and corn starch Each was used. The amount of pantethine in the table is a value calculated from the pantethine content of pantethine A (80% by weight).

  In this test example, the wind-proof tsusan-san is converted to dry weight as Toki 1.2 (parts by weight, the same applies hereinafter), Peonies 1.2, Senkyu 1.2, Sanshi 1.2, Forsythia 1.2, and mint. 1.2, Show 1.2, Kei-Gai 1.2, Bow Fu 1.2, Maou 1.2, Daio 1.5, Bow Show 1.5, Sandalwood 2.0, Kyo 2.0, Ogon 2.0, Licorice 2.0, Gypsum 2.0 and Kasseki 3.0 were extracted with 20 times the weight of water (560 parts by weight) at about 100 ° C. for 1 hour, centrifuged to obtain an extract, and concentrated under reduced pressure. Then, using “drying tsushosan extract” (spray dryer drying was performed by dropping the extract into an atomizer with a rotational speed of 10000 rpm and supplying hot air at 150 ° C.) It was.

  Furthermore, sennoside was pulverized in a mortar using “Pruzenide (registered trademark) tablet” (12 mg as sennoside) manufactured by Novartis Pharma, and orally administered according to Table 2.

  On the 21st and 42nd days from the start of breeding with a high-fat diet, feces for one day were collected and weighed, and the weight of feces per body weight was calculated. The results are shown in Table 3 below.

  As shown in Table 3, a decrease in the amount of defecation was observed in the control group compared to the normal group due to a decrease in fiber intake, confirming constipation symptoms. In the pantethine group, no significant improvement was observed in the symptoms of constipation, but in the sennoside group, the sennoside / pantethine group, the Fufutsu Seiki group, and the Fufutsu Seisan / Pantethine group, an improvement was observed in the decrease in stool volume.

  In addition, when the improvement was evaluated as a ratio to the amount of defecation in the control group, the sennoside group, the sennoside / pantethine group, and the Fufutsu Seiki group showed a decrease in the degree of improvement in constipation after long-term use for 42 days. In the Fengtsu Sansho / Pantethine group, there was a tendency to maintain and improve the effect of improving constipation during the test period.

  It is known that in the use of a constipation drug, resistance and habituation to the drug occur in the long-term use, and the effect of the drug becomes difficult to be exerted, and as a result, the effect of improving constipation is attenuated. However, from these results, it was shown that such a decrease in constipation-improving effect was not observed by using Fufutsu Seisan and Panthetin together.

Test Example 2 Improvement of constipation in humans (I)
Five groups ((i) take pantethine in advance) so that the number of defecations, defecation amount, etc. are evenly distributed among 50 men (average age: 31.8 years old) who are not constipated in a questionnaire about defecation status Panthetin group, (ii) Fengtsu Seikisan group taking Fengtsu Seikisan, (iii) Fufutsu Seikisan and Pantethine group taking Panthetin, (iv) Sennoside group taking sennoside, ( v) Sennoside and pantethine group taking sennoside and pantethine).

  Each group was recorded for the number of bowel movements, bowel movements and bowel movement for 5 days. The number of defecations was recorded for several golf balls.

  Thereafter, for 5 days, three times a day, between meals or before meals, each test drug was taken and observation records were similarly recorded regarding defecation. In addition, abdominal pain was observed every day during the observation period.

  The windproof sansho and sennoside used in this test example are the same as those in Test Example 1. As pantethine, Daiichi Sankyo's “Pantosine Tablet 100” (100 mg as pantethine) was used, and the dose per administration was 1 tablet. Table 4 summarizes the test drugs and doses administered to each test group. The results are shown in Tables 5 and 6 below.

  As is clear from Table 5, in the pantethine group, there was no significant change in the number of stool and the amount of stool before and after pantethine administration. The frequency and defecation amount were significantly increased compared to before pantethine. As described above, it was confirmed that the combination of sennoside or Fukatsu-san and pantethine improved the defecation promotion effect, but the effect was higher than that of the sennoside / pantetin group. Was even higher.

  In addition, as is apparent from Table 6, when taking only sennoside or Fengtsu Sansho, 90% and 70% of the subjects had abdominal pain as a side effect, respectively. % And 20%. Here, the rate of decrease in abdominal pain was 2.25 (= sennoside group / sennoside / pantethine group) when sennoside and pantethine were used in combination, while Fengtsu Seiki and pantethine were used together. It was possible to increase to 3.50 (= Fengtsu Seiki group / Fengtsu Seiki group / Pantetin group), and combining Panthetin with Fengtsu Seiki group was more effective in reducing abdominal pain. In addition, as for the degree of abdominal pain (severity of abdominal pain), the Fengtsu Seiki / Pantethine group was lighter than the Sennoside / Pantethine group.

  In the sennoside / pantethine group, the sennoside dose (daily dose) was 0.5 mg (sennoside: pantethine = 1: 600), 0.6 mg (sennoside: pantethine = 1: 500), 1 mg (sennoside: pantethine). = 1: 300), 3 mg (sennoside: panthetin = 1: 100), 5 mg (sennoside: panthetin = 1: 60), 10 mg (sennoside: panthetin = 1: 30), 15 mg (sennoside: panthetin = 1: 20), In the case of 20 mg (sennoside: pantethine = 1: 15) and 30 mg (sennoside: pantethine = 1: 10), and in the group of Fufutsu Seiki and Pantethine, 1000mg (Fengtsu Seiki: Pantechin = 100: 30), 1200mg (Fengtsu Seiki: Panthechi = 100: 25) and 3000 mg (Fukatsu Tsushosan: Pantethine = 100: 10), the effect of promoting defecation by using pantethine in the same manner as in Test Example 2 is significantly improved, Compared with the sennoside / pantethine group, the Fengtsu Sansei / Panthetine group was more effective in promoting defecation and reducing abdominal pain.

  As for side effects (abdominal pain), the dose of sennoside tended to increase from 15 mg (sennoside: pantethine = 1: 20) or more, but the level was lower than when taking 15 mg of sennoside alone. In other words, the preferred blending ratio of sennoside and pantethine that provides a defecation promoting effect and a side effect mitigating effect was about 10 to 600 parts by weight, more preferably about 20 to 500 parts by weight with respect to 1 part by weight of sennoside.

  Here, the same tendency was observed when calcium pantothenate was used instead of pantethine.

Test Example 3 Improvement of constipation in humans (II)
Preliminary questionnaire on defecation status for 30 men with constipation (mean age: 32.3 years) Panthetin group, (ii) Fengtsu Seikisan group to take Fudotsu Seiki, (iii) Fudotsu Seikisan and Pantethine group to take Fudotsu Seikisan and Pantethine, (iv) Sennoside group to take Sennoside, ( v) Sennoside and pantethine group taking sennoside and pantethine).

  Each group was observed in the same manner as in Test Example 2. The results are shown in Table 7 below.

  As is clear from Table 7, the number of defecations and the amount of defecation increased significantly compared with those before pantethine combination in the same manner as in Test Example 2 by using sennoside or Fufutsu Seisan and pantethine in combination with those with a tendency to constipation . In addition, the bowel movement rate (number of bowel movements / number of bowel movements) was significantly increased by using pantethine together. In other words, it was recognized that sensation can be improved by combining sennoside or Fufutsu Seisan with pantethine.

  Even for constipated people, the combination of sennoside and pantethine was excellent in reducing the number of defecations, the amount of defecation, and the side effects, but the effect of using Fufutsu Seisan and pantethine was even better.

  In addition, the incidence and level of abdominal pain were the same as in Test Example 2.

  Further, in the sennoside / pantethine group, the sennoside dose (daily dose) was 0.5 mg (sennoside: pantethine = 1: 600), 0.6 mg (sennoside: pantethine = 1: 500), 1 mg (sennoside: pantethine). = 1: 300), 3 mg (sennoside: panthetin = 1: 100), 5 mg (sennoside: panthetin = 1: 60), 10 mg (sennoside: panthetin = 1: 30), 15 mg (sennoside: panthetin = 1: 20), In the case of 20 mg (sennoside: pantethine = 1: 15) and 30 mg (sennoside: pantethine = 1: 10), and in the group of Fengtsu Seiki / Pantethine, 1000 mg (Fengtsu Seikisan: Pantechin = 100: 30), 1200 mg (Fukatsutsu Seiki: Pante Even if it is a case where it is set to 100 mg = 100: 25) and 3000 mg (Fengtsu Seikisan: Pantethine = 100: 10), the defecation promoting effect due to the combined use of pantethine is remarkably improved as in Test Example 3, and As compared with the sennoside / pantethine group, the Fengtsu Sanse / pantethine group was more effective in promoting defecation and reducing abdominal pain.

  As for side effects (abdominal pain), the dose of sennoside tended to increase from 15 mg (sennoside: pantethine = 1: 20) or more, but the level was lower than when taking 15 mg of sennoside alone. In other words, the preferred blending ratio of sennoside and pantethine that provides a defecation promoting effect and a side effect mitigating effect was about 10 to 600 parts by weight, more preferably about 20 to 500 parts by weight with respect to 1 part by weight of sennoside.

  Here, the same tendency was observed when calcium pantothenate was used instead of pantethine.

  According to the present invention, it is possible to improve the defecation promoting effect without increasing the dose of Fufutsu Seisaku. Moreover, the effect which reduces the side effect (abdominal pain) of a wind-proof Tsushosan to pantethin was confirmed. That is, according to the pharmaceutical composition of the present invention, it was shown that the desired defecation can be realized and the side effects (abdominal pain) of Fengtsu Sansho can be reduced.

  From the results obtained in Test Examples 2 and 3, the rate of increase in the effect on constipation persons in each group was calculated for the number of defecations per day and the amount of defecation per day. The results are shown in Table 8 below.

  From the results shown in Table 8, the number of defecations was improved in the pantethine group only for constipated persons, but in the sennoside group, the sennoside pantethine group, the Fufutsu Seisan group and the Fufutsu Seisan / Pantethine group Improved in both constipated and non-constipated people. Among them, the Fufutsu Seisan / Pantetin group improved 3.33 times before and after taking constipation, and 1.89 times that of non-constipation, and was particularly effective against constipation. Demonstrated.

  Regarding the amount of defecation, synergistic effects were shown in both non-constipated and non-constipated groups in the groups other than the pantethine group. The improvement effect was 22 times, 1.22 times that of non-constipated persons, and the effect was excellent for constipated persons.

Test Example 4 Abdominal pain suppression effect in humans Preliminary questionnaire on defecation status for 50 men (average age: 31.4 years) who are not constipated in 5 groups ((i) magnesium oxide group taking magnesium oxide, (ii) pantethine Pantethine group to be taken, (iii) Fudotsu Seiki group to take Fudotsu Seiki, (iv) Fudotsu Seiki and Magnesium oxide group to take Fudotsu Seiki and magnesium oxide, (v) Fudotsu Seiki And sennoside and pantethine group taking pantethine). The dose per time in each group is shown in Table 9 below. Each group was given the test drugs shown in Table 7 for 5 days, 3 times a day, between meals or before meals, and answered whether there was abdominal pain.

  Both Fukatsu Seisan and Panthetin used in this test were the same as in Test Example 2, and “3A Magnesia” manufactured by 3A Calcium Co., Ltd. was used as the magnesium oxide. The results are shown in Table 10.

  From the results shown in Table 10, when magnesium oxide, which is known to have an effect on constipation, was used in combination with Fukatsu-san, the abdominal pain due to Fukatsu-san could not be effectively reduced. On the other hand, when pantethine was combined with Fufutsu Seisaku, abdominal pain could be reduced. That is, in order to reduce the abdominal pain of Fukatsu-san, the combined use of magnesium oxide is insufficient, and panthetins are useful.

Test Example 5 After the end of Liver Function Elevating Effect Test Example 1 in rats, a 85-day long-term administration test was conducted under the same test conditions. On day 85, blood was collected and dissected, and the AST value in serum was measured and the liver was visually observed by autopsy. The results are shown in Tables 11 and 12 below.

  The serum AST value can be used as an evaluation factor for liver function because the value in the blood increases abnormally as hepatocyte destruction (disorder) progresses. The smaller the value, the lower the risk of liver damage. Further, in the naked eye observation, it is possible to estimate the progression of fatty liver and liver damage by fading of the liver.

  As shown in Table 11, the control group showed an increase in the AST value compared to the normal group when fed the diet of high fat and low dietary fiber. In the pantethine group, there was no change in the AST value, and in the Fufutsu Seisaku group, a slight decreasing tendency was seen. In addition, the value was significantly decreased in the Fengtsu Sansei / Pantetine group. When this value is compared with the control group being 1, a significant decrease in the AST value is seen in the Fengtsu-san-san / pantethine group, and it is considered that hepatic function is improved by the combined use of Fado-san-san and panthetin.

Further, as shown in Table 12, in the macroscopic observation of the liver, the fading of the liver is observed in the control group as compared with the normal group, but the fading is suppressed in the Fufutsu Seisan / Pantetin group. From the properties of the liver, the effect of combined use of Fukatsutsu Seisan and Panthetin was confirmed.

Test Example 6. Anti-obesity effect in rats SD rats (6 months old) were acclimated for 1 week with a normal diet “CE-2” (manufactured by CLEA Japan, Inc.) (average weight at acclimation: 563 g).

  The acclimated rats were divided into 5 groups ((i) normal group, (ii) control group, (iii) Fengtsu Seiki group, (iv) Pantethine group, (v) Fukatsu sansho) according to the diet shown in Table 13. -Panthetin group) (8 animals / group), and each group was reared for 40 days on a high-fat diet with the mixing ratio shown in Table 13 (during the breeding period, rats were allowed to freely feed and feed) )

  Blood was collected on the 32nd day from the start of the breeding, and the amounts of neutral fat, free fatty acid and ketone bodies in the serum were measured according to the enzyme method. Moreover, the visceral fat rate and the body fat rate were measured using CT apparatus LaTheta LCT-100 (made by Aroka Co., Ltd.) on the 40th day from the start of breeding with a high fat feed.

  Here, in the table, Fufutsu Seisaku Extract is the same as Test Example 1.

  Normal feed is “CE-2” (manufactured by Clea Japan Co., Ltd.), pantethine is 80% by weight pantethine aqueous solution “Panthetine A” (manufactured by Daiichi Fine Chemical Co., Ltd.), lard and corn starch Each was used. The amount of pantethine in the table is a value calculated from the pantethine content of pantethine A (80% by weight).

  The results are shown in Table 13 below. Moreover, the weight change of each group is shown in Table 14 and FIG. 1, and the measurement results of serum neutral fat, free fatty acid, and ketone body are shown in Table 15 and FIG. 2, respectively.

  From Tables 14 and 15, a synergistic increase-inhibiting effect was seen in body weight, neutral fat, free fatty acid, visceral fat rate, and subcutaneous fat rate by combining Fengtsu Seisaku and Pantethine. These effects are drastically increased compared to the case where Fukatsutsu Seisan and Pantethine are used alone.

  In addition, the increase in the amount of ketone bodies in serum, which was observed when using Fukatsu-Seisan alone, was effectively suppressed by using pantethine together.

  An increase in the amount of ketone bodies indicates that ketone bodies made from lipids in the body are not used as energy well, and if the amount of ketone bodies continues to increase, acidemia (ketoacidosis) can occur. Therefore, the suppression of the increase in the amount of ketone body is very preferable as efficient lipid metabolism and prevention of acidemia.

<Prescription example>
Formulation examples are shown below, but the present invention is not limited thereto.

  According to the prescription described in Prescription Examples 1 to 14, tablets were produced by a conventional method.

10 is a graph showing the weight change of rats in Test Example 6. It is a graph showing the result of the measured value of the neutral fat in rat serum, the free fatty acid, and the ketone body in Test Example 6.

Claims (2)

(A) component:
(B) Component: A pharmaceutical composition comprising at least one pantethine selected from pantethine, pantethine salt, pantothenic acid, pantothenic acid salt, pantethein and panthenol. The pharmaceutical composition according to claim 1, which is used for improving constipation.

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