JP2011201904A - Salicylic acid-containing oral composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an oral composition alleviated in gastric mucosa disorder caused by aspirin, wherein aspirin is a non-steroidal antipyretic analgesic antiphlogistic agent (NSAID), has the medicinal action mechanism of suppressing biosynthesis of prostaglandin and is known to inevitably cause the gastric mucosal disorder as the side effect.SOLUTION: There is provided an oral composition alleviated in gastric mucosal disorder by containing 1-8 pts.wt. erythritol and 1 pt.wt. aspirin. As the oral formulation, tablets, fine granules, capsules and syrups are preferable.

Description

  The present invention relates to a salicylic acid-containing oral composition in which gastric mucosal damage caused by salicylic acids is reduced by containing optimal amounts of various sugars.

  Aspirin, a salicylic acid, is an antipyretic anti-inflammatory analgesic that has been taken worldwide for over 100 years since its launch in 1899. In the latter half of the 1970s, aspirin's inhibitory effect on platelet aggregation became known, and is currently recommended as a standard drug for suppressing myocardial infarction and stroke in major countries in Europe and the United States. In Japan, this new indication was approved in 2000, and it was released the following year.

  In addition to the platelet aggregation inhibitory effect, aspirin is known to inhibit arteriosclerosis by inhibiting the proliferation of vascular endothelium and smooth muscle and promoting NO (nitrogen monoxide) production (see, for example, Non-Patent Document 1). ).

  In addition, prevention of lung cancer, esophageal cancer, stomach cancer, colorectal cancer, rectal cancer, breast cancer, and other cancers originated from the epidemiological fact that there are few cancer patients among those who take aspirin or other nonsteroidal antipyretic analgesics (For example, see Non-Patent Document 2). Furthermore, cerebrovascular dementia (for example, see non-patent document 3), Alzheimer's disease (for example, refer to non-patent document 4), reflux esophagitis (for example, refer to non-patent document 4), osteoporosis (for example, non-patent document 5). There are also reports that it is effective for alveolar bone reduction (see Non-Patent Document 6), pregnancy toxemia (see Non-Patent Document 7, for example), and the like.

On the other hand, aspirin is a non-steroidal antipyretic analgesic / anti-inflammatory agent (NSAID) and has a pharmacological action mechanism that suppresses the biosynthesis of prostaglandins, and is therefore known to inevitably cause the side effect of gastric mucosal damage. Among them, aspirin, which is a salicylic acid-based drug, has a serious drawback that it causes the largest gastric mucosal damage compared to other types of NSAIDs (see, for example, Non-Patent Document 8). In order to alleviate this gastric mucosal disorder, the following three methods are generally widely known.
(1) Concomitant use of an antacid, gastric mucosa protective agent, proton pump inhibitor, histamine H2 receptor antagonist, etc.
(2) Making enteric or sustained release preparations, and (3) Changing administration routes by suppositories, injections, transdermal preparations, and the like.

However, in the above known avoidance technique,
In the method (1), there is a problem of an increase in medical cost and a decrease in compliance due to combined use.
In the method (2), the upper gastrointestinal disorder can be remarkably reduced, but the immediate effect is sacrificed, and the lower gastrointestinal disorder is newly concerned (Non-patent Document 9 and Patent Document 10) and the method (3) However, there are problems such as rectal ulcer, injection pain, medication cost, shock, percutaneous absorption, skin irritation and the like, and it cannot be said that it is not suitable for long-term administration.

  In addition, there is a report that lactose (equivalent administration) suppressed the formation of lesions due to the direct damaging action of aspirin on the gastric mucosa (see Non-Patent Document 11).

In addition, as preparations in which saccharides are added to aspirin, orally disintegrating tablets (see Patent Document 1), preparations with reduced drug unpleasant taste (see Patent Document 2), techniques for improving tableting properties (see Patent Document 3) Etc. are reported. However, these use saccharides as excipients, binders, taste-masking (sweetening) agents or crystalline powder as an anti-adhesion agent at the time of tableting, and erythritol is one of many listed ingredients. Only xylitol, fructose, sucrose or lactose are mentioned.
Furthermore, none is formulated or implied for the purpose of reducing gastric mucosal damage of aspirin.

  The combination of trehalose and aspirin is not known.

JP 2000-508649 A, JP 2002-87965 A JP 49-92220 A, JP 2001-89396 A JP-A-10-59842

“Medical Tribune” Vol. 35, no. 10, 2002, p22. “Ayumi of Medicine” Vol. 204, no. 1,2003, p105-110. “Clinics and Research” Vol. 79, no. 6, 2002, p60. “Pharmacology & Toxicology” Vol. 8 1, no. 4, 1997, p152. “J. of Bone and Mineral Research” Vol. 11, no. 1, 1996, Table 1 and 2. “Journal of Japanese Society of Periodontology” Vol. 35, no. 3, 1993, p4 84. “Drugs” Vol. 34, 1987, p518. “Japan Newsletter” No. 3930, 1999, Table 1. "Internal Medicine" Vol. 38 No. 3 1999 p. 219 “Medical Tribune” Vol. 35 No. 7 2 002 p. 36 (Fig. 3) “Inflammation” VOL. 14, no. 6, 1994, p533.

  In order to effectively utilize various pharmacological actions possessed by salicylic acids such as aspirin, techniques for reducing gastric mucosal damage caused by salicylic acids are indispensable. In addition, when long-term administration is necessary, serious gastric mucosal damage may occur even if the dose is small.

  Further, in the known avoidance technique, since some problems remain as described above, the present inventor aims to newly find a simple and inexpensive avoidance measure for gastric mucosal damage caused by oral administration of salicylic acids. So I started this research.

For this purpose, a promising pharmaceutical additive that is necessary or usable in a normal formulation process is searched for, and it has an effect of reducing or reducing gastric mucosal damage compared to the above-mentioned other known methods. If it can be realized, it has been judged to be a means that meets this objective.
Therefore, first, research was started in order to find a combination with an additive that is even better than the gastric mucosal disorder alleviation effect seen in the known mixed dose administration of aspirin and lactose.
However, in the confirmation test in the previous stage, surprisingly, it was found that the gastric mucosal disorder alleviating effect was not always manifested at any content ratio of aspirin and lactose, and the content ratio at which the alleviating effect was expressed. First revealed. Furthermore, the present inventors have found that some saccharides may worsen the gastric mucosa damage reducing effect rather than appear. For example, Patent Documents 1 to 3 describe examples of the inclusion of sucrose, sorbitol, maltose or maltitol, but it has been found that when these are contained in aspirin, gastric mucosal damage is enhanced.

  On the other hand, in the combination of the specific saccharides disclosed in the present invention, in particular, erythritol and aspirin, it was found that significant gastric mucosal mitigating action that is unpredictable by the results in lactose appears, which is known gastric mucosa. It was confirmed that the method is equivalent to or better than the obstacle avoidance method, and the present invention has been completed.

  An object of the present invention is to provide a salicylic acid-containing oral composition in which gastric mucosal damage caused by salicylic acids is reduced by containing various sugars.

The present invention
(1) A salicylic acid-containing oral composition containing one or more sugars selected from the group consisting of erythritol, xylitol, fructose, sucrose, lactose and trehalose, and salicylic acids,
(2) A salicylic acid-containing oral composition that reduces gastric mucosal damage caused by salicylic acids by containing the sugar according to (1) above and salicylic acids,
(3) The oral composition according to any one of (1) to (2), which contains 0.2 parts by weight or more of erythritol with respect to 1 part by weight of salicylic acids,
(4) selected from the above (1) to (2) containing 0.7 part by weight or more of one or more sugars selected from the group consisting of xylitol, fructose and sucrose with respect to 1 part by weight of salicylic acids The oral composition according to any one of the above,
(5) The oral composition according to any one of (1) to (2), which contains at least 0.8 part by weight of lactose or trehalose with respect to 1 part by weight of salicylic acid,
(6) Any one selected from the above (1) to (5), wherein the salicylic acid is one or more selected from aspirin, aspirin aluminum, sodium salicylate, salicylamide, sazapyrine, diflunisal, and etenzamide. Oral composition according to paragraph,
(7) The oral composition according to any one of (1) to (5), wherein the salicylic acid is aspirin,
(8) Antipyretic, analgesic, inflammatory treatment, cold treatment, or reflux esophagitis in which gastric mucosal damage due to salicylic acid is reduced by containing the sugar according to (1) above and salicylic acid Therapeutic agent.
(9) An antipyretic agent, an analgesic agent, an inflammatory treatment agent, or a cold treatment agent for reducing gastric mucosal damage caused by salicylic acid, for administering the saccharide according to (1) and salicylic acid separately or every other time.
(10) A therapeutic or prophylactic agent for ischemic cerebrovascular disorder, treatment of ischemic heart disease, wherein gastric mucosal damage due to salicylic acid is reduced by containing the sugar according to (1) and salicylic acid Agent or preventive agent, therapeutic agent or preventive agent for dementia, therapeutic agent or preventive agent for cancer, therapeutic agent or preventive agent for bone loss disease, or therapeutic agent or preventive agent for pregnancy toxemia.
(11) A therapeutic or preventive agent for ischemic cerebrovascular disorder in which gastric mucosal damage due to salicylic acid is reduced, for administering the saccharide according to (1) above and salicylic acid separately or at intervals. A therapeutic agent or preventive agent for ischemic heart disease, a therapeutic agent or prophylactic agent for dementia, a therapeutic agent or prophylactic agent for cancer, a therapeutic agent or prophylactic agent for bone loss disease, or a therapeutic agent or prophylactic agent for pregnancy toxemia.
(12) The therapeutic or preventive agent for ischemic cerebrovascular disorder according to any one of (10) to (11), wherein the ischemic cerebrovascular disorder is cerebral infarction.
(13) The therapeutic or preventive agent for ischemic heart disease according to any one of (10) to (11), wherein the ischemic heart disease is angina or myocardial infarction.
(14) The therapeutic or preventive agent for dementia according to any one of (10) to (11), wherein the dementia is cerebrovascular or Alzheimer type dementia.
(15) The therapeutic or preventive agent for cancer according to any one of (10) to (11), wherein the cancer is lung cancer, esophageal cancer, stomach cancer, colon cancer, rectal cancer, or breast cancer.
(16) The therapeutic or prophylactic agent for osteopenia according to any one of (10) to (11), wherein the osteopenia is osteoporosis and alveolar osteopenia.
(17) Any one selected from the above (8) to (16), wherein the salicylic acid is one or more selected from aspirin, aspirin aluminum, sodium salicylate, salicylamide, sazapyrine, diflunisal, and etenzaamide. The therapeutic agent or prophylactic agent according to Item.
(18) The therapeutic or prophylactic agent according to any one of (8) to (16), wherein the salicylic acid is aspirin.
Furthermore, the present invention provides
(19) An antipyretic method, an analgesic method, an inflammation treatment method, a cold treatment method, by using one or more sugars selected from erythritol, xylitol, fructose, sucrose, lactose and trehalose in combination with salicylic acids, Or reflux esophagitis treatment method,
(20) A method for treating or preventing ischemic cerebrovascular disorder by using one or more sugars selected from erythritol, xylitol, fructose, sucrose, lactose and trehalose in combination with salicylic acid, ischemic A method of treating or preventing heart disease, a method of treating or preventing dementia, a method of treating or preventing cancer, a method of treating or preventing bone loss disease, or a method of treating or preventing pregnancy toxemia,
(21) The method for treating or preventing ischemic cerebrovascular disorder according to (20) above, wherein the ischemic cerebrovascular disorder is cerebral infarction,
(22) The method for treating or preventing ischemic heart disease according to (20) above, wherein the ischemic heart disease is angina or myocardial infarction,
(23) The method for treating or preventing dementia according to (20) above, wherein the dementia is cerebrovascular or Alzheimer type dementia,
(24) The method for treating or preventing cancer according to (20) above, wherein the cancer is lung cancer, esophageal cancer, stomach cancer, colon cancer, rectal cancer or breast cancer,
(25) The method for treating or preventing bone loss disease according to (20) above, wherein the bone loss disease is osteoporosis and alveolar bone loss disease,
(26) The salicylic acid is selected from the above (19) to (25), which is one or more selected from the group consisting of aspirin, aspirin aluminum, sodium salicylate, salicylamide, sazapyrine, diflunisal, and etenzamide. The method according to any one of (1) and (27), the method according to any one of (19) to (25), wherein the salicylic acid is aspirin.

  In the present invention, “salicylic acids” are aspirin (acetylsalicylic acid), aspirin aluminum, sodium salicylate, salicylamide, sazapyrine, diflunisal or etenzamide, salts thereof or hydrates thereof, and preferably aspirin.

  In the present invention, “erythritol” and “xylitol” are sugar alcohols obtained by reducing sugar, “fructose” is a monosaccharide contained in fruits, and “sucrose” is a disaccharide composed of sucrose and fructose. “Lactose” is an oligosaccharide contained in milk, and “trehalose” is a disaccharide in which one of two sucrose is transferred and bound.

  If the saccharides specified in the present invention are contained in an amount exceeding 1% by weight of the salicylic acid, the gastric mucosal damage caused by the salicylic acid is reduced, and if it is less than that, the gastric mucosal damage reducing action is attenuated. Or conversely, gastric mucosal damage increases.

  In the present invention, “gastric mucosal disorder” refers to gastric mucosal lesions (eg, hemorrhoids, bleeding, edema) and gastric ulcers resulting from acute and chronic gastritis, and disorders of the upper gastrointestinal tract including the duodenum, which is the adjacent site of the stomach. is there.

  An oral composition containing salicylic acid with reduced gastric mucosal damage characterized by containing a specific saccharide at a critical content ratio or more with respect to 1 part by weight of salicylic acid according to the present invention. Remarkably suppressed. Furthermore, depending on the content ratio, it has an ulcer suppression effect equivalent to or better than that of conventional buffering agents (containing antacids such as dialuminate preparations), and depending on the saccharide contained and its ratio, gastric mucosa is equivalent to enteric preparations. It can be expected to reduce damage and has an immediate effect not found in enteric preparations.

  That is, when saccharides are used as excipients, binders, and taste-masking (sweetening) agents in the formulation process of aspirin, if the specific saccharides according to the present invention are used, a remarkable ulcer suppressing effect can be obtained at the same time. is there.

Fig. 1 is a graph showing the effect of the content ratio of aspirin and lactose on the ulcer suppression rate (%), with the horizontal axis representing the content ratio of aspirin and lactose and the vertical axis representing the ulcer suppression rate (%). is there. Figure 2 shows the content ratio of aspirin and various sugars, with the horizontal axis representing the content ratio of aspirin and various sugars (lactose, erythritol, xylitol, fructose, sucrose, and trehalose), and the vertical axis representing the ulcer inhibition rate (%). The graph shows the effect of the ratio on the ulcer suppression rate (%).

  Aspirin, aspirin aluminum, sodium salicylate, ethenamide, fructose, sucrose (sucrose), lactose and xylitol are listed in the Japanese Pharmacopoeia XIV.

  Salicylamide, sazapyrine and diflunisal are listed in the Japanese Pharmacopoeia Standard 2002.

  Erythritol is listed in the Pharmaceutical Additives Standard 1998.

  Trehalose is listed in the existing additive list (1996).

  The single dose of salicylic acid varies depending on the indication, purpose of use and age, but is usually 1 to 30 mg / Kg, and this is administered 1 to 3 times a day.

  In the case where the composition of the present invention is a solid preparation, the content of salicylic acid is usually 10 mg to 2000 mg, preferably 30 mg to 1500 mg.

  The content of erythritol is 0.2 to 50 parts by weight, preferably 0.5 to 15 parts by weight per 1 part by weight of salicylic acid.

  The content of xylitol, fructose or sucrose is 0.7 to 10 parts by weight, preferably 0.8 to 4 parts by weight, based on 1 part by weight of salicylic acids.

  Furthermore, the content of lactose or trehalose is 0.8 to 50 parts by weight, preferably 0.9 to 20 parts by weight per 1 part by weight of salicylic acids.

  When the composition of the present invention is a liquid preparation, the content of salicylic acid contained is usually 1 mg / mL to 300 mg / mL, preferably 10 mg / mL to 150 mg / mL.

  In the present invention, in addition to the above components, caffeine, antacid, mucosal protective agent, proton pump inhibitor, histamine H2 receptor antagonist, antitussive, expectorant, antihistamine, antiallergy as necessary Drugs, sympathomimetic drugs, parasympatholytic drugs, anti-inflammatory enzymes, vitamins, minerals, herbal medicines, hyperlipidemia drugs, vasodilators, anti-dementia drugs, anticancer drugs, osteoporosis drugs, etc. It can contain in the range which does not impair the effect of invention.

  Specific dosage forms of the oral salicylic acid-containing composition of the present invention include, for example, tablets, fine granules (including powders), capsules, liquids (including syrups), and the like. It can be produced according to a conventional method described in Japanese Pharmacopoeia, using additives and base materials suitable for the shape as appropriate.

  In the above dosage forms, various commonly used additives can be used depending on the dosage form.

  For example, in the case of tablets, crystalline cellulose or the like is used as an excipient, magnesium aluminate or magnesium oxide as a stabilizer, hydroxypropyl cellulose or the like as a coating agent, magnesium stearate or the like as a lubricant In the case of fine granules and capsules, magnesium aluminate metasilicate or magnesium oxide can be used as a stabilizer, corn starch or the like as an adsorbent, and hydroxypropyl cellulose or the like as a binder. it can.

  In each of the above dosage forms, a disintegrant such as crospovidone; a surfactant such as polysorbate; an adsorbent such as calcium silicate; a colorant such as iron sesquioxide and caramel; a stabilizer such as sodium benzoate; A pH adjuster; a fragrance, etc. can also be added.

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

(Example 1) Tablet (1) Component (Table 1) (Unit: mg)
1 tablet out of 6 out of 6 tablets ―――――――――――――――――――――――――――――――――――――――
Aspirin 100 500 −
Aspirin aluminum-900
Erythritol 300 − −
Lactose or trehalose-2000-
Xylitol, fructose or sucrose-900
Polyvinyl alcohol 60 120 180
Hydroxypropyl cellulose 50 150 200
Magnesium stearate Suitable amount Suitable amount Suitable amount ―――――――――――――――――――――――――――――――――――――――
(2) Manufacturing method Take the above ingredients and quantities, and manufacture tablets according to the section “General Tablets” “Tablet”.

(Example 2) Fine granule (1) component (Table 2) (unit: mg)
1 package 1 package 1 package 1 ―――――――――――――――――――――――――――――――――――――――
Aspirin 100 500 −
Aspirin aluminum-900
Erythritol 300 − −
Lactose or trehalose-2000-
Xylitol, fructose or sucrose-900
Hydroxypropylcellulose 150 200 200
Magnesium stearate 10 15 20
Low substituted hydroxypropylcellulose
Appropriate amount Appropriate amount Appropriate amount ―――――――――――――――――――――――――――――――――――――――
(2) Production method Take the above ingredients and quantities, and produce a fine granule according to the section “Granule” of the General Rules for Preparations.

Example 3 Capsule (1) Component (Table 3) (Unit: mg)
1 capsule 6 capsules 6 capsules ―――――――――――――――――――――――――――――――――――――――
Aspirin 100 500 −
Aspirin aluminum-900
Erythritol 300 − −
Lactose or trehalose-2000-
Xylitol, fructose or sucrose-900
Polysorbate 80 10 20 20
Corn starch Appropriate amount Appropriate amount Appropriate amount ―――――――――――――――――――――――――――――――――――――――
(2) Manufacturing method Take the above components and the amount, and make a fine granule according to the section of the Japanese Pharmacopoeia General Rules “Granule”, then fill the capsule to make a hard capsule.

(Example 4) Syrup (1) component (Table 4) (unit: mg)
In 10 mL in 30 mL in 50 mL --------------
Aspirin 100 500 −
Aspirin aluminum-900
Erythritol 300 − −
Lactose or trehalose-2000-
Xylitol, fructose or sucrose-900
Sodium benzoate 100 150 200
Citric acid 40 90 70
Concentrated glycerin 500 750 900
Polyvinyl alcohol 60 100 140
Purified water Appropriate amount Appropriate amount Appropriate amount ―――――――――――――――――――――――――――――――――――――――
(2) Manufacturing method Take the above components and quantities, and make a syrup according to the Japanese general formulation “Syrup” section, then fill it into a brown glass bottle to make a syrup.

(Test Example 1)
Inhibitory effect of various sugars on gastric mucosal damage of aspirin (1) Test substance Aspirin was manufactured by Sigma, Japanese lactose was manufactured by Nippon Pharmaceuticals (Kokai Pharmaceutical), and sucrose was manufactured by Kanto Chemical. In addition, fructose, sucrose, erythritol, xylitol, lactitol, sorbitol, maltitol and maltose were manufactured by Wako Pure Chemical Industries, and trehalose was manufactured by Hayashibara.

  Each test substance was prepared by suspending or dissolving in 0.5% tragacanth solution on the test day. The administration volume was orally administered at 5 mL per 1 kg body weight, and the same amount of 0.5% tragacanth was administered to the control group.

(2) Animals Environmental control breeding equipment purchased from Wistar-Imamichi male rats (Animal Breeding Research Institute) at 5 weeks of age and controlled at a temperature of 20 to 26 ° C., a humidity of 30 to 70%, and a lighting time of 7:00 to 19:00 (Japan) 5-6 animals were placed in a stainless steel rat breeding gauge, and the animals were fed with feed (mouse / rat breeding F-2, Funabashi Farm) and tap water freely passed through a water filter. After preliminary breeding for 8 days, the health condition was observed macroscopically on the day before the test, and after selecting good animals, the animals were randomly divided into 5 groups per group.

(3) Method In advance, a dose of 100% gastric mucosal damage in a single aspirin agent was determined (a dose in which there was no rat that did not develop ulcers. A dose that would definitely cause ulcers). Went.

  The test substance was orally administered to animals fasted from 16:00 on the day before the test, and 3.5 hours later, the carotid artery was exsanguinated under ether anesthesia, and the stomach was removed. The stomach was cut along the large vagina, washed lightly with physiological saline, and then observed for the presence of bleeding spots under a stereomicroscope (Olympus 10 × 10 times).

  As the ulcer index, the major axis of bleeding spots was measured in units of 0.5 mm, and the total of each animal was determined. Based on the ulcer index of the aspirin single administration group and the ulcer index of the sugar combination group, the ulcer suppression rate was calculated from the following equation.

(Equation 1)
Ulcer inhibition rate (%) = [1-B / A] × 100
A: Ulcer index of aspirin alone administration group B: Ulcer index of sugar combination group

(4) Test results Tables 5 to 8 and FIGS. 1 to 2 show the results of the ulcer suppression rates of the obtained combination groups.

(Table 5)
Test substance (mg / Kg) Content ratio Ulcer inhibition rate (%)
―――――――――――――――――――――――――――――――――――――――
Aspirin (75) + lactose (9.375) 0.125-7
Aspirin (75) + lactose (18.75) 0.25-17
Aspirin (75) + lactose (37.5) 0.5-40
Aspirin (75) + lactose (56.25) 0.75 -9
Aspirin (75) + Lactose (75) 1.0 14
Aspirin (75) + Lactose (150) 2.0 24
Aspirin (75) + lactose (300) 4.0 40
Aspirin (75) + lactose (600) 8.0 27
―――――――――――――――――――――――――――――――――――――――.

  Fig. 1 is a graph showing the effect of the content ratio of aspirin and lactose on the ulcer inhibition rate (%) with the content ratio of aspirin and lactose on the horizontal axis and the ulcer inhibition rate (%) on the vertical axis. is there.

  From Table 5 and Fig. 1, the addition of lactose to aspirin does not necessarily suppress gastric ulcer, but there is a critical content ratio (lactose / aspirin ≒ 0.8). In addition, it was found that the ulcer suppression rate increases with an increase in the content ratio even when the content ratio is higher than the critical content ratio, but reaches a peak near the content ratio 4 and starts to decrease when the content ratio is higher.

(Table 6)
Test substance (mg / Kg) Content ratio Ulcer inhibition rate (%)
―――――――――――――――――――――――――――――――――――――――
Aspirin (75) + erythritol (75) 1 48
Aspirin (75) + xylitol (75) 1 39
Aspirin (75) + fructose (75) 1 32
Aspirin (75) + sucrose (75) 1 30
Aspirin (75) + lactose (75) 1 14
Aspirin (75) + trehalose (75) 1 12
Aspirin (75) + lactitol (75) 1 2
Aspirin (75) + sorbitol (75) 1-15
Aspirin (75) + maltitol (75) 1-17
Aspirin (75) + sucrose (75) 1-19
Aspirin (75) + maltose (75) 1-35
―――――――――――――――――――――――――――――――――――――――.

  From Table 6, it was found that in the combined use of aspirin and erythritol, xylitol, fructose or sucrose, an ulcer suppressing effect far superior to the ulcer suppressing effect of a known equivalent mixture of aspirin and lactose was exhibited. On the other hand, it has been found that the combined use of aspirin and lactitol, sorbitol, maltitol, sucrose or maltose does not exhibit an ulcer suppressing action or worsens the ulcer.

(Table 7)
Test substance (mg / Kg) Content ratio Ulcer inhibition rate (%)
―――――――――――――――――――――――――――――――――――――――
Aspirin (75) + fructose (37.5) 0.5 -28
Aspirin (75) + sucrose (37.5) 0.5-22
Aspirin (75) + trehalose (37.5) 0.5-15
―――――――――――――――――――――――――――――――――――――――
Aspirin (75) + erythritol (37.5) 0.5 12
Aspirin (75) + erythritol (18.8) 0.25 10
―――――――――――――――――――――――――――――――――――――――
Aspirin (75) + xylitol (37.5) 0.5-18
Aspirin (75) + xylitol (56.3) 0.75 50
―――――――――――――――――――――――――――――――――――――――.

(Table 8)
Test substance (mg / Kg) Content ratio Ulcer inhibition rate (%)
―――――――――――――――――――――――――――――――――――――――
Aspirin (75) + erythritol (300) 4 59
Aspirin (75) + xylitol (300) 4 14
Aspirin (75) + fructose (300) 4 25
Aspirin (75) + sucrose (300) 4 -1
Aspirin (75) + trehalose (300) 4 32
―――――――――――――――――――――――――――――――――――――――
Aspirin (75) + erythritol (600) 8 43
Aspirin (75) + Trehalose (600) 8 33
―――――――――――――――――――――――――――――――――――――――.

  Figure 2 shows the content ratio of aspirin and various sugars with the content ratio of aspirin and various sugars (lactose, erythritol, xylitol, fructose, sucrose and trehalose) on the horizontal axis and the ulcer inhibition rate (%) on the vertical axis. The graph shows the effect on ulcer suppression rate (%).

  From Table 8 and FIG. 2, in the case of the combined use of lactose and aspirin, the ulcer enhancing action at a critical content ratio (less than about 0.8) is generally observed even in combination with other sugars, but depending on the type of sugar. The critical content ratio is slightly different. The critical content ratio of trehalose is approximately 0.8 which is almost the same as the critical content ratio of lactose, the critical content ratio of xylitol, fructose and sucrose is 0.5 to 0.75, and the critical content ratio of erythritol is 0. ~ 0.25.

  As the saccharide content ratio increases from the critical content ratio, the ulcer suppression rate rapidly increases and then decreases. In trehalose, a clear maximum value of the ulcer suppression rate due to a change in the content ratio is not recognized, but it is expected that the content ratio is about 8. Moreover, in lactose and erythritol, the maximum value exists in the content ratio of 4 vicinity. On the other hand, fructose, xylitol, and sucrose have a peak ulcer suppression rate in the vicinity of a content ratio of 1, and sucrose loses the ulcer inhibitory action in a content ratio of around 4.

  Table 11 shows that 84 healthy volunteers were randomly assigned to 4 groups of commercially available aspirin enteric-coated tablets, buffered tablets, uncoated tablets and controls, and 325 mg / day was continuously administered for 12 weeks. The ulcer suppression rate based on a result (refer "Medical Tribune" Vol.35 No.7 2002 p.36) is shown.

(Table 11)
Test substance Gastric mucosal endoscope score Ulcer inhibition rate (%)
―――――――――――――――――――――――――――――――――――――――
Aspirin uncoated tablet 2.33 0
Aspirin buffer tablet 1.60 31
Aspirin enteric-coated tablet 0.90 61
―――――――――――――――――――――――――――――――――――――――.

  Although it cannot be said that the above clinical results and the results of this study can be directly compared, from FIG. 2, the composition of the present invention is equivalent to a buffer (containing an antacid such as a dial aluminate preparation) depending on the content ratio. It can be inferred that the above ulcer suppression rate is brought about.

  Furthermore, when the content ratio is 4 with erythritol, it can be expected to bring about an ulcer suppression rate equivalent to that of the enteric preparation (see FIG. 2). In the composition of the present invention, there is no potential concern about the lower gastrointestinal tract disorder of the enteric preparation, and it is immediately effective and advantageous.

Claims (1)

An oral composition characterized by reducing gastric mucosal damage by containing 1 to 8 parts by weight of erythritol per 1 part by weight of aspirin.