JP5842521B2 - Constipation medication - Google Patents

Description

  The present invention relates to a constipation-improving drug containing a large amount of plantago obata and having excellent dosing properties.

  Plantago Obata is a perennial plant of the genus Plantaginaceae (Plantaginaceae), also known as Psyllium or Isagor. In Japan, it is used for food as well as constipation. Plantago obata has the property of swelling when it absorbs water (Non-Patent Document 1), and therefore has the effect of increasing the amount of feces and promoting peristaltic movement of the intestines to improve bowel movements. However, plantago obata has strong cohesiveness as well as swelling property, so it is easy to cause lumps and it is difficult to disperse uniformly. As a means for improving the water dispersibility of plantago obata, a method of modifying the surface by adding saccharides (Patent Document 1), a method of dispersing in fats and oils (Patent Document 2), a water-soluble polymer and a silicate compound There are known a method of adding (Patent Document 3), a method of adding magnesium oxide or the like (Patent Document 4), a method of adding polyoxyethylene polyoxypropylene glycol (Patent Document 5), and the like.

  Several constipation-improving drugs containing plantago obata are on the market, and most of their dosage forms are granules in consideration of ingestion. Constipation may be accompanied by not only digestive symptoms but also rough skin, acne, and abdominal bloating. For these reasons, many products containing a plurality of herbal medicines have been put on the market in preparations containing plantago obata as pharmaceuticals for the purpose of improving various symptoms associated with constipation or constipation.

As a problem of a granulated product containing a plurality of crude drugs, it is known that disintegration is poor. In particular, in the extrusion granulation method, if the screen pore size is small, the herbal medicine has a strong binding property due to compaction, so the disintegration property of the granulated product may be insufficient even if the disintegrant is increased. As means for improving this, a method of adding a sugar alcohol during granulation (Patent Document 6) is known.
These granules are blended with either or both of hydroxypropylcellulose and propylene glycol for the purpose of improving dispersibility and disintegration as well as the base.

Japanese Patent Publication No. 4-30925 Japanese Examined Patent Publication No. 6-72106 JP 2001-220352 A JP 2001-199894 A JP 2010-106008 A

(Non-patent document 1) Alternative Medline Review, 7 (2), 155-159 (2002)

However, the constipation-improving drug containing plantago obata uses the property that plantago obata absorbs water in the intestine and swells, so its daily dose should be as high as 1200 mg or more. , Other herbal medicines, large amounts of disintegrants, binders, excipients, etc. improve disintegration and granulation properties, but increase daily dose and absorb water in plantago and obata There is a problem that the swellability due to decrease.
Accordingly, an object of the present invention is to provide a constipation-improving drug that has excellent water dispersibility, swelling property, and aggregation-inhibiting effect while containing plantago obata and that is excellent in taking and promotes smooth defecation.

  Therefore, in order to solve the above problems, the present inventors have conducted intensive research, and as a result, in addition to plantago obata and senna or an extract thereof, Sankirai or an extract thereof and / or Cascara sagrada or an extract thereof With an extremely small amount of excipient, the active ingredient is quickly dispersed and excellent swelling properties are maintained for a long time, with almost no disintegrant, disintegration aid, binder, etc. As a result, it was found that a constipation-improving drug having excellent dosing properties and defecation promoting effects was obtained, and the present invention was completed.

  That is, the present invention contains (A) plantago obata, (B) senna or an extract thereof, and (C) sankirai or an extract thereof and cascara sagrada or an extract thereof. The present invention provides a constipation-improving drug characterized by the above.

  According to the present invention, a constipation-improving drug that has good water dispersibility and continuous swelling power, not only promotes smooth defecation, but also improves dosage and economics by reducing the amount of additives. It became possible to provide.

2 is a drawing showing the results of a water dispersibility / swelling force test conducted in Test Example 1. FIG. Comparison with Example 1 0.5 hours after the start of the swelling power test calculated based on the water dispersibility / swelling power test conducted in Test Example 1 (Example 1 was set to 100%) is shown. It is a drawing. It is drawing which shows the comparison (Example 1 was made into 100%) compared with Example 1 6 hours after the start of the swelling power test computed based on the water dispersibility and swelling power test performed in Test Example 1. is there.

  In addition to (A) plantago obata (component (A)) and (B) senna or its extract (component (B)), the constipation-improving drug of the present invention comprises (C) Sankirai or its extract and 1 type or 2 types (component (C)) chosen from a scalar sagrada or its extract are characterized by the above-mentioned.

  (A) Plantago / Obata is not limited in use sites such as seeds, stems, leaves, roots, etc. as long as it contains a swellable shallow component (silium gum), but seeds are preferred because of their swellability. When seeds are used, either whole seeds or seed coats may be used, but seed coats or seed coat powders are more preferable from the viewpoint of swelling. Plantago obata physically stimulates the intestinal wall by absorbing water and swells, and increases the amount of stool, thereby causing a coughing action. Therefore, the content of component (A) impairs this effect. Although there is no particular limitation as long as the amount is not limited, the daily dose of the constipation therapeutic agent of the present invention is 500 to 9000 mg, preferably 1000 to 5000 mg, more preferably 3000 mg or more, particularly preferably 3000 to 4400 mg. To be.

(B) The senna is a plant of the family Jackaceae having scientific names such as Cassia angustifolia M. Vahl and Cassia acutifolia Delile. Any part of fruit, leaves, stems, roots or the like or an extract thereof can be used as long as it contains sennoside, which is a colonic stimulant coughing ingredient, but it is preferable to use leaves or an extract thereof. Here, the senna extract is preferably an organic solvent extract such as water or alcohol. Alternatively, sennoside alone may be used. Sennoside (chemical name: Dihydro-dirheinanthrone glucose, molecular formula: C ₄₂ H ₃₈ O ₂₀ , molecular weight: 862.74) is an anthraquinone derivative and includes 10-10 ′ optical isomers, sennoside A and sennoside B. Metabolized in the bacterial flora of the large intestine, this metabolite stimulates the intestinal mucosa and the Auerbach flora, activates the peristaltic movement of the large intestine, and promotes defecation. In the present invention, either sennoside A or sennoside B, a mixture thereof or an extract containing them can be used. It can also be used in the form of a salt, and a calcium salt is particularly preferred. The content of component (B) is such that the daily dose of the therapeutic agent for constipation of the present invention is 100 to 3000 mg, preferably 200 to 2000 mg. When blended as sennoside alone, the daily dose is 1 to 48 mg, preferably 2.5 to 48 mg.

  (C) Sankirai is a plant belonging to the family Smilacaceae and Smilax glabra, and is known to be effective for rough skin and pimples. Since constipation causes rough skin and pimples, the constipation-improving drug of the present invention is more excellent by adding Sankirai or an extract thereof to Plantago obata. Here, the Sankirai extract is preferably an organic solvent extract of Sankirai water or alcohol. The content of Sankirai or its extract is such that the daily dose of the therapeutic agent for constipation of the present invention is 160 to 3500 mg, preferably 170 to 1400 mg in terms of the active ingredient.

  (C) Cascara sagrada is a plant belonging to the family Aceraceae having the scientific name Rhamnus purshizna De Candolle. As long as it contains kansan slanol having an action to promote intestinal peristalsis, there are no particular restrictions on the use site such as leaves, roots, and skin, but it is preferable to use an extract of bark. Here, the Cascara Sagrada extract is preferably an organic solvent extract such as water or alcohol of Cascara Sagrada. Moreover, you may use a kasan slanol simple substance. Cassanthranol is an effective glycoside in Cascara sagrada skin that acts on the large intestine to promote periodic peristaltic motion and promote colonic content transport by combining segmental motion inhibition that impedes content transfer. The constipation-improving drug of the present invention becomes more excellent by blending Cascarsagrada suitable for relaxed constipation in which intestinal peristalsis is reduced or an extract thereof. The content of Cascara sagrada or its extract is such that the daily dose of the constipation therapeutic agent of the present invention is 15 to 5000 mg, preferably 40 to 3125 mg in terms of a crude drug. When blended as a simple substance, the daily dose is 1 to 48 mg, preferably 2.5 to 48 mg.

  In the constipation-improving drug of the present invention, component (A) is plantago obata seed coat or plantago obata seed coat powder, component (B) is sennoside or a salt thereof, and component (C) is a Sankirai extract and A Cascara sagrada extract is preferable from the viewpoints of ingestion, quick water dispersibility, and sustained swelling. The content ratio of these components is 0.011 to 20 parts by mass (more preferably 0.02 to 3.0 parts by mass) of component (B), Sankirai or an extract thereof, relative to 1 part by mass of component (A) 0 to 23.3 parts by mass (more preferably 0.032 to 3.5 parts by mass), and Cascara sagrada or an extract thereof from 0.0017 to 33.3 parts by mass (more preferably 0.003 to 1. 0 parts by mass) is preferable from the viewpoints of ingestion, rapid water dispersibility, and sustained swelling.

  In addition to the above components, the constipation-improving drug of the present invention can contain other components that improve symptoms of constipation, and additives for pharmaceutical preparations that are usually used in pharmaceutical production. However, in the constipation-improving drug of the present invention, the content of the additive should be small from the viewpoint of improving dosage by reducing the dosage and ensuring water dispersibility and swelling of plantago obata. Is preferred. In the present invention, it is surprisingly found that by adding the component (C), granules can be produced with a small additive content, and that the obtained granules have good water dispersibility and swellability. It was. From such a viewpoint, the total content of additives for preparations (excluding fragrances and corrigents) other than the components (A) to (C) of the constipation improving agent of the present invention is preferably 5 to 18% by mass, particularly 5 -15 mass% is preferable. The total content of components (A) to (C) is preferably 80% by mass or more.

  As such an additive, lactose, crystalline cellulose, sucrose, starch, dextrin and the like are preferable, and lactose is particularly preferable. Usually, there is no particular need for blending of a binder, a disintegrant and a disintegration aid used in the production of granules. However, you may contain 5 mass% or less of a fragrance | flavor and a corrigent.

  The dosage form of the constipation-improving drug of the present invention is not particularly limited as long as it is an oral solid preparation such as a fine granule, a capsule, a tablet, or a granule, but is preferably a granule. In the case of granules, lactose is 5 to 15% by mass, and components (A), (B) and (C) in total are 80% by mass or more based on the total amount. And preferred from the viewpoint of sustained swelling.

  The granule production method is preferably wet granulation. That is, components (A) to (C), lactose and the like are mixed, and 800 to 1600 parts by mass, preferably 1000 to 1500 parts by mass of water or hydrous alcohol is added to 100 parts by mass of the mixture, and kneaded. Granulate with a granulator. Here, the alcohol concentration of the hydrous alcohol is preferably 0 to 20%. Thereafter, the particles may be sized and dried.

  As the granulator, a high-speed agitation granulator, a rolling fluidized granulator, a fluidized bed granulator, or the like can be used. In the present invention, extrusion granulation is preferred. At that time, even if the screen pore diameter during extrusion granulation is as small as 0.5 mm or less, the disintegration property and swelling property of the constipation improving agent of the present invention are not inferior. However, if a very small one is selected, a high load is applied to the screen during extrusion, and the screen may be damaged. In addition, if a too large screen is selected, the granule becomes large and the ingestibility and formulation processability are inferior. Therefore, the screen pore diameter is preferably 0.4 mm to 1.5 mm. Further, the screen hole diameter at the time of sizing is desirably 1 mm to 5 mm.

  The constipation-improving drug of the present invention may be taken in divided doses. Various symptoms associated with constipation and constipation can be improved by taking 1 to 3 times a day on an empty stomach.

  The constipation-improving drug of the present invention has rapid water dispersibility and sustained swelling despite the low content of excipients and the like (the total of components (A) to (C) is 80% by mass or more). Therefore, it has an excellent defecation promoting effect and ingestibility. That is, the plantago obata has the action of stimulating the bowel wall and promoting defecation by swelling, so in order to promote defecation more smoothly, at least about 5 to 6 hours after taking the intestinal tract It is necessary to keep a high swelling capacity. However, constipation-improving medicines that contain herbal medicines etc. in conventional plantago and obata swelled once due to strong cohesiveness and their own weight, and the swelling capacity gradually decreases. . On the other hand, the constipation-improving drug of the present invention has quick water dispersibility and sustained swelling as compared with a medicine containing plantago obata and other herbal medicines.

  Hereinafter, the present invention will be described in detail with reference to examples and test examples. However, the present invention is not limited by these.

Examples 1-3 and Comparative Examples 1-4
Each constipation-improving drug was manufactured by the following manufacturing method according to the prescription (for 1 day) shown in Table 1 below.

Example 1 was produced by the following method.
Sennoside calcium 27.8 g, Cascara sagrada extract 83.3 g and lactose 88.9 g were added to 1000 g of plantago / Obata seed coat powder so that the total solid content was 1200 g. After uniform mixing with a stirring and mixing granulator, 1500 mL of the binding solution was added and kneaded for 3 minutes.
The obtained kneaded product was extruded and granulated, and after sizing, dried and mixed with a fragrance to obtain granules. The solvent of the binding liquid is water or a hydrous alcohol.
In addition, in Example 2, the amount of lactose was increased as the blending amount of Cascara sagrada extract decreased, and the total solid content was 1200 g. In addition, Example 3 is Sankirai instead of Cascara Sagrada Extract, Comparative Example 1 is Chimpi, Comparative Example 2 is Peonies, Comparative Example 3 is Licorice, and Comparative Example 4 is Example 1 except that Pepper is blended. Produced in the same manner.

(Test example)
About each constipation improving agent (Examples 1-3 and Comparative Examples 1-3) manufactured in the Example, the water dispersibility and swelling power test and the dosing test were done. The results are shown in FIGS.

Test Example 1 (Water dispersibility / swelling power test)
1.35 g of constipation-improving drug (corresponding to 1 g as plantago obata) was weighed and placed in a 200 mL graduated cylinder. To this was gently poured 200 mL of purified water, and the mixture was shaken for 1 minute and allowed to stand. Then, after 30 minutes, 60 minutes, and 90 minutes, the swelling capacity of plantago obata was read, and the mixture was shaken in the same manner and allowed to stand. After 90 minutes from the start of the test, only the swelling capacity was read, and after 2 hours, the swelling capacity was measured every 1 hour until every 6 hours. A solid preparation excellent in water dispersibility is considered to disintegrate and disperse rapidly after the start of the test and swell. Therefore, the water dispersibility was evaluated based on the swelling power after 30 minutes from the start of the test. In addition, the evaluation of cohesiveness is not only based on the swelling power after 30 minutes from the start of the test, but also how much the swelling power is maintained after a certain time has passed. From the start of the test to the time to reach the intestinal tract, the evaluation was based on the swelling power after 6 hours.
Examples 1, 2, and 3 swell quickly after 30 minutes from the start of the test, while all of the comparative examples had a swelling capacity that was less than half that of Example 3. Moreover, even when 2 hours passed when the swelling power was the highest, all of the comparative examples had a swelling capacity of about 50 to 60% of that of Example 1 (FIG. 1).

Comparison of swelling power 0.5 hours after the start of the test (evaluation of water dispersibility)
In order to verify the dispersibility of each constipation-improving drug, the swelling capacity of Example 1 after 0.5 hours from the start of the test was set to 100% and compared with the others.

(Equation 1)
* Water dispersibility = swelling capacity of each Example or Comparative Example after 0.5 hours from the start of the test
/ Swelling capacity of Example 1 after 0.5 hours from the start of the test

  The water dispersibility of the comparative examples was 18% to 23% as compared with Example 1, whereas Example 3 was 150% as compared with Example 1. Moreover, about Example 2 whose compounding quantity of cascara sagrada is about 1/5 amount of Example 1, water dispersibility was about 44% of Example 1, but still about about Comparative Examples 1-4. Since it has twice the amount of water dispersibility, it was found that Examples 1 to 3 were superior in water dispersibility compared to Comparative Examples 1 to 4, and swelled quickly (FIG. 2).

Comparison of swelling power after 6 hours from the start of the test (evaluation of cohesiveness)
It was verified how much the swelling power of each constipation-improving drug was maintained after 6 hours from the start of the test. The swelling capacity of Example 1 after 6 hours from the start of the test was taken as 100% and compared with others. The higher the swelling power continuity rate, the lower the cohesiveness, and the lower the swelling power continuity rate, the higher the cohesiveness.

(Equation 2)
* Continuation rate of swelling force = swelling capacity of each Example or Comparative Example after 6 hours from the start of the test
/ Swelling capacity of Example 1 after 6 hours from the start of the test

  In each of Examples 2 and 3, the cohesiveness was 80% to more than 100% as compared with Example 1, and the same swelling force as Example 1 was maintained. The cohesiveness of the comparative examples was 50% or less, and a difference of twice occurred between the examples and the comparative examples (FIG. 3). Therefore, Examples 1 to 3 having low cohesiveness can stimulate the intestinal wall more efficiently and smoothly promote defecation.

Test Example 2 (Dosage Feeling Test)
A dosing sensation test was conducted on 12 persons who were aware of constipation on a daily basis. Example 1 or 3 was divided into 3 times a day and taken for 3 days with 1-2 cups of water or lukewarm water, respectively. After taking the drug, the questionnaire was filled in with ease of use, improvement in constipation, and overall satisfaction. It should be noted that after taking the dose feeling test of Example 1, two weeks or more were allowed before the dose feeling test of Example 3 so that the dose of Example 1 would not affect Example 3. The results are shown in Table 2.

  From the above results, the constipation-improving drug of the present invention was excellent in both the feeling of taking and the constipation-improving effect, and was highly satisfactory.

The constipation-improving drug of the present invention can be used to improve various symptoms associated with constipation and constipation.

Claims (2)

(A) plantago obata seed coat or plantago obata seed coat powder , (B) senna , senna extract, sennoside or sennoside salt , and (C) sankirai or extract thereof , cascara sagrada or extract thereof and casantlanol Contains one or two selected ,
As a daily dose,
(A) Plantago obata seed coat or plantago obata seed coat powder 3000-4400 mg,
(B) Senna or senna extract 200-2000 mg,
Sennoside or sennoside salt 2.5-48 mg,
(C) Sankirai or its extract 160-3500 mg,
Cascala Sagrada or its extract 40-3125 mg,
Cassanthranol 2.5-48mg
Contains,
5 to 18% by mass of formulation additives (excluding fragrance and flavoring agent), and the total amount of components (A), (B) and (C) is 80% by mass or more based on the total amount,
A constipation-improving drug characterized by being a granule . Constipation improving drug according to claim 1, wherein those produced by wet granulation.