JP2002205939A - Antiulcer agent composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject composition having higher effectiveness than that of a conventionally known combination for noninfectious peptic ulcer represented by drug-induced ulcer and stress ulcer, or the like, regarded as modern diseases in aging society and stress society. SOLUTION: This antiulcer agent composition comprises plaunotol and one or more kinds selected from the group consisting of Phellodendri bark, ranitidine, an antacid and Cinnamomi Cortex.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to an antiulcer composition comprising plaunotol and one or more selected from the group consisting of oak, ranitidine, antacids and cinnamon.

[0002]

2. Description of the Related Art The occurrence of peptic ulcers is caused by an imbalance between the digestive power of gastric juice and the defense power of mucous membranes. And those caused by Helicobacter pylori infection, and the like. For the treatment of peptic ulcers, antacids that neutralize gastric acid, attack factor inhibitors such as histamine H2 receptor antagonists and proton pump inhibitors that suppress acid secretion, and protective factor enhancers for gastrointestinal mucosa alone or alone The drug is administered in combination, and if the cause is Helicobacter pylori, eradication treatment with antibiotics is also performed.

Praunitol is an anti-ulcer agent that enhances gastric mucosal protective factor, and an antacid that neutralizes gastric acid and ranitidine, a histamine H2 receptor antagonist, are anti-ulcer agents that suppress attack factors. In addition, it is known that oubaku has an anti-ulcer effect by suppressing a decrease in prostaglandin E2 in gastric mucosa in indomethacin-administered rats (Japanese Journal of Pharmaceutical Sciences, Vol.10, No.1 1993 p. 47-5
3). In addition, cinnamaldehyde, the main component of Caffeine, is known to have an inhibitory effect on the formation of gastric damage in mice immersed in water immersion stress (Progress in Medicine,
Vol.17 No.4 1997 p.887-893).

[0004] As a well-known matter of the two-drug combination, a drug combining ranitidine and an antacid is known (Japanese Patent Application Laid-Open No.
In clinical practice, histamine H2 receptor antagonists and antacids are often used in combination (for example, gastrointestinal drugs and their use in clinical practice, 1995, Nanzando). This can be interpreted as complementation by the combined use of aggressor inhibitors having different pharmacological mechanisms of action.

[0005] It is known that the combined use of ranitidine and pranotol improves the treatment results of peptic ulcer (for example, medical care and new drugs, Vol. 29 No. 7, 1992).
p.1619-1635). This can be interpreted as an increase in efficacy due to the combined use of an aggressive factor inhibitor and a protective factor enhancer.

Further, as a more advanced combination, a combination of an aggressive factor inhibitor having a different pharmacological action mechanism and / or a mucosal protective factor enhancer having a different pharmacological action mechanism can be considered. In this case, the number of possible individual drug combinations will be enormous, but there will be no way to determine whether the combination enhances, invariably, or attenuates other than examining each combination in detail. .

[0007] As a three-drug combination, in a drug-induced gastric mucosal injury animal model, a histamine H2 receptor antagonist, cimetidine and an antacid, two aggressor inhibitors and aldioxa, a mucosal defense factor enhancer, were used. It is known that the combined use improves the damage suppression effect (Japanese Patent Application Laid-Open No. H5-24684).
8). However, since the data of each component alone is not sufficiently disclosed in this specification, it is not clear whether the combined use has increased the usefulness more than expected. In addition, although the name of ranitidine is mentioned as a histamine H2 receptor antagonist in this specification, there is no specific disclosure,
Plaunotol is not named as a mucosal protective factor enhancer. Therefore, ranitidine, praunitol,
The grounds by which the combined use of antacids can be expected to be as effective as the effective examples presented in the specification are not clear from the disclosure of the specification.

[0008] This study has been made in view of the above situation, and is directed to non-infectious peptic ulcers represented by drug ulcers and stress ulcers which can be said to be modern diseases in an aging society and a stressed society. It is an object of the present invention to provide a composition which is more effective than conventionally known combinations.

[0009]

DISCLOSURE OF THE INVENTION The present inventors have conducted intensive studies on a composition having an even better anti-ulcer effect than existing anti-ulcer agents.
A composition containing at least one selected from the group consisting of oak, ranitidine, an antacid, and cinnamon,
The present inventors have found that they have a remarkable anti-ulcer effect which cannot be inferred from the known information so far, and completed the present invention.

[0010]

DISCLOSURE OF THE INVENTION The present invention is an antiulcer composition comprising plaunotol and one or more selected from the group consisting of oak, ranitidine, antacids and cinnamon.

Plaunotol (chemical name: (Z, E, E)
-2- (4,8-dimethyl-3,7-nonadienyl)-
6-methyl-2,6-octadiene-1,8-diol) is a compound represented by the following formula, and its production method is described in JP-A-52-62213 and JP-A-52-131.
507 etc., but it is easily available because it is available.

[0012]

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Ranitidine (chemical name: N- (2-(((5
-((Dimethylamino) methyl) -2-furanyl) methyl) thio) ethyl) -N'-methyl-2-nitro-1,
1-ethenediamine is a compound represented by the following formula, and its production method is described in JP-A-53-18557, JP-A-56-103171, JP-A-57-134475, and the like. Although it is commercially available, it can be easily obtained.

[0014]

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[0015] The term "oakaku" refers to extracts such as oak powder and oak extract.

[0016] Caffeine refers to extracts such as powdered cabbage powder and cabbage extract. The anti-ulcer agent shows an anti-ulcer effect on peptic ulcer.

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION In the case where the antiulcer composition of the present invention is a solid preparation, the weight percentage of praunitol is contained.
Is usually 0.5 to 50%, preferably 2 to 2%.
5%, and the weight percentage of oak powder is usually 1 to 80%, preferably 15 to 50% in the case of oak powder, and 0.3 to 60% in the case of oak extract. %, Preferably 7 to 30%, and the weight percentage of cinnamon powder is generally 1 to 80%, preferably 15 to 50% for cinnamon powder, and , Usually 0.3 to 60%, and preferably 7
Antacid is usually 0.1 to 50%, preferably 1 to 20%, and ranitidine is usually 1 to 70%. And preferably 3 to 50%.

An antacid can be added to the composition of the present invention for the purpose of formulation in addition to the medicinal effect. Examples of such an antacid include dried aluminum hydroxide gel, magnesium aluminate silicate, and the like. Magnesium silicate, Synthetic aluminum silicate, Synthetic hydrotalcite, Magnesium oxide, Magnesium hydroxide alumina, Aluminum hydroxide gel, Aluminum hydroxide / sodium hydrogen carbonate coprecipitation product, Aluminum hydroxide / magnesium carbonate mixed dry gel, Water Aluminum oxide / magnesium carbonate / calcium carbonate co-precipitated product, magnesium hydroxide, sodium hydrogen carbonate, magnesium carbonate, precipitated calcium carbonate, magnesium aluminate metasilicate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, squid bone, ishiseki Akira, Volley etc. Rukoto can, preferably a magnesium oxide.

Specific dosage forms of the antiulcer composition of the present invention include, for example, tablets, fine granules (including powders), capsules and the like. It can be produced according to a usual method described in the Japanese Pharmacopoeia or the like, using a base material as appropriate.

In each of the above dosage forms, various commonly used additives can be used according to the dosage form.

For example, in the case of tablets, lactose, crystalline cellulose and the like are used as excipients, magnesium metasilicate aluminate and the like as stabilizers, hydroxypropyl cellulose and the like as coating agents, and magnesium stearate and the like as lubricants. In the case of fine granules and capsules, lactose, purified sucrose and the like as excipients, magnesium metasilicate aluminate and the like as a stabilizer,
Maize starch or the like as an adsorbent, hydroxypropyl cellulose, polysorbate or the like as a binder,
In each of the above dosage forms, if necessary, a disintegrating agent such as crospovidone; an adsorbent such as calcium silicate; a coloring agent such as iron sesquioxide and caramel; a pH adjusting agent such as sodium benzoate; Fragrances can also be added.

[0022]

EXAMPLES (Example 1) Tablet (1) Ingredient

[0023]

[Table 1] ---------------------------------------------- ----------------- <Magnesium oxide> <Ohaku> <Ranitissin + cinnamon> 6 out of 6 tablets 6 out of 6 tablets (1440mg) (1560mg) (1440mg) --- -------------------------------------------------- ---------- Flaunotol 240mg 240mg 240mg ranitissin--120mg oak powder-600mg-cinnamon powder--200mg magnesium oxide 400mg--magnesium magnesium silicate 144mg-144mg crystalline cellulose 120mg 75mg 75mg corn starch-140mg 140mg Human peroxyfluorocellulose 60mg 48mg 48mg croscarmellose sodium 15mg 15mg 15mg macnesium stearate 24mg 24mg 24mg triacetin 6mg 6mg 6mg lactose qs qs qs ----------------------- ----------------------------------------

[0024]

[Table 2] ---------------------------------------------- ----------------- <Ranitishin + Ohaku><Ranitishin + Macneadium Oxide> 6 tablets out of 6 tablets (1560mg) (1440mg) ---------- -------------------------------------------------- --- Furanotol 240mg 240mg Ranitisin 120mg 120mg Oak powder 600mg-Magnesium oxide-400mg Macinecesium aluminate metasilicate 144mg-Microcrystalline cellulose 120mg 75mg Corn starch-140mg Human oxyfluorocellulose 60mg 60mg Croscarmellose sodium 15mg 15mg Stecerin 6mg 24mg Lactose appropriate amount appropriate amount ----------------------------------------------- ---------------- (2) Manufacturing method Take the above components and amounts, and manufacture tablets according to the “Tablets” section of the Japanese Pharmaceutical General Regulations. (Example 2) Fine granule (1) Component

[0025]

[Table 3] ---------------------------------------------- ----------------- <Magnesium oxide> <Ohaku> <Ranitissin + cinnamon> 3 in 3 3 in 3 (4500mg) (4500mg) (4500mg) --- -------------------------------------------------- ---------- Flaunotol 240mg 240mg 240mg ranitidine--120mg oak powder-600mg-Caesium powder--200mg magnesium oxide 400mg--magnesium magnesium silicate 144mg--Purified sucrose 1400mg 1600mg 1600mg Extracted product -16mg 16mg corn starch 1200mg 1200mg 1200mg polysorbate 80 80mg 48mg 48mg magnesium stearate 24mg 24mg 24mg lactose qs qs qs --------------------------- ------------------------------------

[0026]

[Table 4] ---------------------------------------------- ----------------- <Ranitishin + Ohaku><Ranitishin + magnesium oxide> 3 in 3 (4500mg) (4500mg) ---------- -------------------------------------------------- --- Furanotol 240mg 240mg Ranitissin 120mg 120mg Oax powder 600mg-Magnesium oxide-400mg Magnesium aluminate metasilicate 144mg 144mg Refined sucrose 1400mg 1600mg Stea Extracted product-16mg Corn sulphacin 1200mg 1200mg phosphoric acid -------------------------------------------------- ------------- (2) Manufacturing method The above components and amounts are taken, and a fine granule is manufactured in accordance with the section of the Japanese Pharmacopoeia General Rules for Granules. Example (3) Capsule (1) Component

[0027]

[Table 5] ---------------------------------------------- --------------------- <Magnesium oxide> <Owaku> <Ranitissin + Caffeine> 6 out of 6 capsules 6 out of 6 capsules -------- -------------------------------------------------- --------- Flaunotol 240mg 240mg 240mg Ranitissin--120mg Oohaku powder-600mg-Caffeine powder--300mg Magnesium oxide 400mg--Maize protein 720mg 630mg 630mg Polyphosphate 80 80mg 48mg 48mg 24mg of magnesium stearate 24mg of magnesium stearate 24mg of magnesium stearate 24mg of magnesium stearate Appropriate amount Appropriate amount ------------------------------------------------ ----------------- Subtotal 2070mg 2130mg 2070mg Capsule 480mg 480mg 480mg Total 2550mg 2610mg 2550mg --------------------- --------------------------------------------

[0028]

[Table 6] ---------------------------------------------- ------------------- <RUNITISHIN + OHAKAK><RUNITISHIN + MACHINEUM OXIDE> Out of 6 capsules Out of 6 capsules -------------- -------------------------------------------------- -Furanotol 240mg 240mg Ranitissin 120mg 120mg Oax powder 600mg -Magnesium oxide -400mg Maize protein 720mg 630mg Polysolate 80 80mg 48mg Magnesium stearate 24mg 24mg Lactose Suitable amount ------------------- ---------------------------------------------- Subtotal 2130mg 2070mg Capsule 480mg 480mg Total 2610mg 2550mg --------------------------------------------- -------------------- (2) Production method Fine ingredients were prepared according to the Japanese Pharmaceutical Preparations General Regulations “Granules” taking the above ingredients and amounts. Thereafter, the capsules are filled to produce hard capsules. (Test method) (1) Test substance Plaunotol was prepared by adding 1% Tween80, mixing well, and then sonicating. Ranitidine, oak, cinnamon, magnesium oxide and aspirin
The suspension was dissolved or dissolved in a 1% tokaperant solution and prepared on the day before or on the day of the test. In the single agent administration test, oral administration was performed at a ratio of 0.5 mL / 100 g body weight. In addition, 0.25mL / 100g in the case of two agents combination
Body weight was orally administered at a ratio of 0.17 mL / 100 g body weight in the case of a combination of three drugs. (2) Test animals Wistar-Imamichi male rats, 5 weeks old, were purchased and used after pre-breeding for 5 to 9 days. The test used 5 animals per group. (3) Test method Aspirin ulcer Aspirin was orally administered to a rat that had been fasted for 16 hours, and 3 hours and a half later, the carotid artery was exsanguinated under ether anesthesia, the stomach was removed, and the length of the ulcer was observed under a stereoscopic microscope. did. Here, an animal having an ulcer length of 4 or more having a length of 0.5 mm or more is defined as positive, and a dose (UD ₁₀₀ : mg / K) at which the positive rate is 100%
g). Maximum no-effect level Test substance is orally administered, and 30 minutes later, aspirin UD ₁₀₀
The dose was orally administered, and three and a half hours later, the total length of the major axis expressed in the gastric mucosa was measured by the method described above. Aspirin monotherapy UD
_{Using the 100} dose as a control, the ulcer suppression rate at each dose of the test substance was determined. The maximum dose that did not produce an ulcer-suppressing effect was defined as the maximum no-effect level. 50% ulcer inhibitory amount (ID ₅₀ ) in the two-drug combination The ulcer inhibition rate was determined by the same method as described above when a certain amount of the maximum inactive amount of magnesium oxide, oak or caffeine was added irrespective of the dose of pranotol. determined, and regression method of least squares from the dose, 50% ulcer inhibition dose (ID _50: mg /
Kg) was calculated. 50% ulcer-inhibiting amount of 3 blending the determined (ID ₅₀₎ Puraunotoru and ID ₅₀ of ranitidine, the I
Was prepared a mixture blended Puraunotoru and ranitidine in a ratio of D _50. Regardless of the dose of this combination, a certain amount of the maximum inactive amount of magnesium oxide, oak or cinnamon was added, and a 50% ulcer-inhibitory dose (ID ₅₀ : mg / Kg) in the three-drug combination was added in the same manner as described above. ) Was calculated.

The gastric disorder caused by aspirin is erosion of the gastric mucosa accompanied by bleeding, which is generally described as an ulcer in the literature, and was followed. (Test results) (1) Antiulcer effect of the combination of two drugs on aspirin ulcer The results are shown in Table 7. Here, “without concomitant drug” is the ID ₅₀ (50% ulcer-inhibiting dose) of praunitol alone. In addition, with combination, the maximum amount of magnesium oxide that does not show anti-ulcer effect by a single agent, when combined with oak or calyx,
It is the dose of pranotol required for ID50.

[0030]

[Table 7] ---------------------------------------------- -------------------- Necessary dose of plaunotol for concomitant drug ID ₅₀ (mg / Kg) --------------- -------------------------------------------------- -None 231 Magnesium oxide (maximum no-effect level) 73 Oubaku extract (maximum no-action level) 86 Caffeine powder (maximum no-action level) 225 -------------------- ---------------------------------------------- Anti-ulcer effect When an unshown amount of magnesium oxide, oak extract or cinnamon is used in combination, the ID ₅₀ of plaunotol should not be changed. However, surprisingly, it can be seen from Table 7 that when combined with magnesium oxide or oak, ID ₅₀ is achieved with significantly lower praunitol levels than with the single agent. (2) Antiulcer effect of the combination of the three drugs on aspirin ulcer The results are shown in Table 8. Here, “without concomitant drug” is the ID ₅₀ (50% ulcer-inhibitory dose) of the combination of praunitol and ranitidine. In addition, the combination is the dose of praunitol and ranitidine combination required for ID ₅₀ when the maximum amount of magnesium oxide, oak or cinnamon which does not show an anti-ulcer effect by a single agent is used in combination.

[0031]

[Table 8] ---------------------------------------------- ------------------- Concomitant drug The required dose of pranotol and ranitidine for ID ₅₀ (mg / Kg) ----------- -------------------------------------------------- ---- None 65 Magnesium oxide (maximum no-effect level) 31 Oubaku extract (maximum no-action level) 43 Caffeine powder (maximum no-action level) 50 ----------------- ------------------------------------------------ Table 7 Similarly to the above, when an amount of magnesium oxide, oak extract or cinnamon which does not show an anti-ulcer effect is used in combination, the ID ₅₀ of the combination of praunitol and ranitidine should not change. However, the combination of two drugs, pranotol and ranitidine, whose usefulness was previously known,
Further, it can be seen from Table 8 that the combination of the three agents to which magnesium oxide, oak or cinnamon is added results in a more useful composition.

[0032]

The pranotol of the present invention and oak,
An anti-ulcer agent composition comprising one or more selected from the group consisting of ranitidine, antacids and cinnamon has excellent anti-ulcer activity against non-infectious peptic ulcers Therefore, it is useful as an anti-ulcer agent.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme court ゛ (Reference) A61P 1/04 A61P 1/04 (72) Inventor Ippei Shimizu 3-5-1 Nihonbashi Honcho, Chuo-ku, Tokyo Inside Sankyo Co., Ltd. (72) Inventor Tatsuhito Kondo 3-5-1 Nihonbashi Honcho, Chuo-ku, Tokyo Inside Sankyo Co., Ltd. (72) Inventor Masato Nakayama 3-5-1 Nihonbashi Honcho, Chuo-ku, Tokyo Sankyo Co., Ltd. (72) Inventor Yasuhiro Torizumi 3-5-1 Nihonbashi Honcho, Chuo-ku, Tokyo F-term in Sankyo Co., Ltd. 4C084 AA19 MA02 NA14 ZA682 4C086 AA01 AA02 BA03 MA03 MA04 ZA68 4C088 AB33 AB62 MA02 ZA68 4C206 AA01 AA02 CA08 MA02 MA03 MA04 ZA68

Claims (2)

[Claims] (1) An anti-ulcer composition comprising praunitol, oak and / or an antacid. 2. A method according to claim 1, wherein (a) pranotol and ranitidine are:
(B) An anti-ulcer composition comprising at least one selected from the group consisting of antacids, oak and cinnamon.