JPH03294226A - Pharmaceutical composition for preventing stomach disease resulting from nonsteroidal anti-inflammatory agent - Google Patents

Abstract

PURPOSE: To obtain a medicine composition useful for avoiding gastropathy caused by treatment of NSAIDs, having protecting activity against toxicity caused by NSAIDs, containing zinc acexamate. CONSTITUTION: This composition is a medicine acting by increase in synthesis of viscous fluid, reinforcement of mucosa preventing wall, improvement in microcirculation and inhibition of degranulation of mast cell and increase in prostaglandin synthesis in mucosa cell of stomach, comprising zinc acexamate alone or it and a nonsteroid antiinflammatory drug (NSAIDs) as active ingredients. Each administration unit is 20-500mg of zinc acexamate and 80-2,000mg of zinc acexamate is administered daily.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to non-steroidal anti-inflammatory drugs (hereinafter referred to as rNsAIDsJ).
It relates to a novel use of zinc acexamate) for the prevention of gastric diseases caused by Czinc acexamate).

Conventional technology and its problems The therapeutic benefits of zinc acexamate are already known.

This drug has been shown to be effective against gastric and gastrointestinal ulcers, with high percentages of cure and low recurrence rates on maintenance therapy. However, its effectiveness as an anti-ulcer agent in gastric diseases caused by the drug is not clear at present.

For example, H is a standard treatment for gastric and duodenal ulcers.
2 antihistamines were tested (Kaufman et al., 1979.
Proc, Soc, Exp, Biol, Me
d, 161; 512-4) or clinical trials (Roos et al. 1987° Arch, Jnt, Med,
, 147: 179g-801) do not demonstrate the usefulness of drugs for gastric diseases.

Therefore, it has been suggested that there is a difference in the pathogenesis of gastrointestinal ulcers and the gastric toxicity of NSAIDs (Roos et al.
．． 1987. Arch, Int, Med, 1
47: 1798-801).

Gastric toxicity is one of the most frequent side effects of NSA XDs.

This toxicity has effects ranging from asymptomatic erosive gastritis to hematemesis that can put the patient's life at serious risk. In patients who need to take the preparation for long periods of time, such as rheumatoid patients, iron deficiency anemia is not occasionally observed as a result of chronic loss of gastric blood from the gastrointestinal tract. In addition, the onset of gastrointestinal diseases is
In patients with acute arthritis, treatment may not be definitively indicated.

Despite obvious differences, all N5AIDs
It is agreed that s has a detrimental effect on the gastric organs. Two basic mechanisms have been suggested for the production of this toxicity. First of all, N
The majority of SAIDs are weak acids that can damage cells to the point of destruction, and are believed to be the result of localized effects on mucous membranes caused by direct stimulation by the drug. This would be accompanied by alteration of the gastric mucosal barrier due to increased back-diffusion of hydrogen ions, damaging supramucosal tissue structures. However, since this lesion also occurs when administered parenterally, the local mechanisms described above cannot fully explain the deleterious effects of NSA I DS on gastric tissue. It is therefore conceivable that these drugs will influence the synthesis of gastric mucosal prostaglandins, especially substances that defend against acids and attacking foreign substances. The main prostaglandins in the mucosa are PGI2 and PGE2. These physiological functions include stimulating mucus secretion, reinforcing the mucosal barrier, and improving microcirculation. They can also inhibit acid secretion. Therefore, if their synthesis is inhibited, the stomach becomes more sensitive to the action of irritating factors.

Efforts to reduce the gastric effects of N5AIDs while maintaining their anti-inflammatory effects have been largely unsuccessful.

Both effects occur simultaneously and cannot be separated at this time.

Neither anti-acid nor anti-secretory agents were effective in preventing the residual gastric effects of N5AIDs. This was expected given these special characteristics.

Gastroduodenal ulcer disorder and N treated appropriately with antisecretory agents
The basic differences between gastric pathologies caused by 5AIDs are the initial clinical presentation (little or no symptoms with NSAIDs), demographics (more women than men), and N5A
This is due to the location of lesions induced by IDs (often in the lower part, antrum, and prepyloric region) and the physiopathological mechanism (suppression of prostaglandin synthesis). This is due to the fact that the loin (19
8B, Arch, Intern, Med, 146
: 1075-6) and other authors, NSA ID5f9
This led to a discussion of gastrogenic diseases and clarification of the clinical picture presented by these patients.

As Westerners age, their consumption of N5AIDs increases due to the presence of rheumatic diseases that require the use of N5AIDs. Therefore, many patients are at increased risk of gastric toxicity. In some countries, upper gastrointestinal bleeding
0% was due to salicylate intake, and more than 20% was due to NSA IDs. This is particularly important for patients with rheumatoid arthritis who are forced to take N5AIDs due to the lack of alternative treatments, and there are still no therapeutically useful drugs available to prevent the onset of this condition. Not found.

Zinc acexamate is a new drug that acts by increasing mucus synthesis, reinforcing the mucosal barrier, improving microcirculation, inhibiting mast cell degranulation, and increasing prostaglandin synthesis in gastric mucosal cells (Esbragez et al., 1985). ．．
Eur, J., Pharwacol, 109:145-
51: Esbraguez et al., 1987. Arcb, Int
, Pharmacodyn, Ther, , 290:1
28-37; Navarro et al., 1988. Prostagl
andins, Leukotrjens and Es
5ential Fatty Ac1ds.

33 near 5-80).

Means for Solving the Problems Accordingly, one object of the present invention is to provide a method for treating NSAIDs-induced gastric diseases by producing a composition in which zinc acexamate is the main active ingredient. It is.

Another object of the invention is to provide a pharmaceutical composition containing zinc acexamate.

The composition has protective activity against toxicity due to N5AIDs and is useful for avoiding gastric disorders caused by treatment with NSAIDs.

Yet another object of the present invention is to provide a drug useful for preventing gastric diseases caused by administration of N5AIDs.

The present invention also provides the use of zinc acexamate for the manufacture of a medicament for the prevention or prevention of gastric diseases caused by administration of N5AIDs.

The preventive effect of zinc acexamate (ZAC) on NSA I DS-induced gastric disease is discussed below.

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for the treatment of various pain conditions (Heart,
F. D. et al., 1984). This class of drugs forms a mixed group of compounds with different chemical groups, which have both therapeutic properties and disadvantages of side effects.

Anti-inflammatory drugs known for their harmful effects on the stomach include aspirin, indomethacin, phenylbutacin,
There is a group of so-called aspirin drugs such as ibuprofen (Feifa Shinei, 1982.Dr.
ugs and peptic UIcer, Vol.

11, C,R,C,Press, Inc.).

The effects of these substances on gastric mucosal cells have been extensively studied and are very similar in humans and rats. From a practical point of view, the most interesting aspect of this study is that while preserving the anti-inflammatory activity of N5AIDs,
The aim is to use the results obtained to improve the gastric tolerance to AIDs.

The possibility of suppressing side effects through the protective effect of zinc acexamate (ZAC) was investigated from the viewpoint of serious intolerance to various anti-inflammatory drugs. Therefore, the protective effect on gastric lesions caused by the most representative N5AIDs was investigated. The selected animal was the rat (Sprague
Dawley (Sprague Dawley), which was sacrificed after treatment with ZAC and N5AID.

The stomach was removed and macroscopically and microscopically evaluated. Visual evaluation is performed using the method of Adami (1964, Ar
ch, Int, Pharmacodyn, 147:1
1B-45) with some modifications, the weight and size of the lesions were determined, and a scoring system was used to evaluate the lesions according to their number and/or size.

No lesions Presence of early inflammation or bleeding areas 1 to 5 small ulcers Multiple small ulcers (5 or more) or 1 large ulcer 4 - Multiple large ulcers 5 - Comprehensive evaluation of perforated ulcer lesions: It is obtained by summing the determined lesion values.

An additional anti-ulcer activity index was determined for phenylbutacin, which was obtained by expressing the lesion index by the inhibition rate compared to the control group. A dose-response curve was determined from the inhibition rate, and the theoretical EDso was determined from this curve.

Half of the stomachs of each animal group were removed for histological processing, and the lesions were evaluated on a scale of 0 to 5 by microscopic observation. 0 is mucosa without lesions, 5 is semihemolysis (h
It shows numerous erosions with emorrhagic 5ubfusphons).

The anti-inflammatory drug administration levels and ZAC levels studied for each anti-inflammatory drug group are shown below. Dosing parameters are as follows.

Aspirin: 200 mg/kg was administered orally twice at 12 hour intervals.

Ibuprofen: 200 mg/kg was administered once.

In both cases ZAC, 50, 100 and 150 mg
/kg and the control group received water.

The total dose of phenylbutacin was 80 mg/kg, with half administered at the beginning of the study and the remainder 2 hours later. The dosage of ZAC is 75°150 and 300mg
/kg. Experimental animals were sacrificed 4 hours after the last ZAC administration.

The total dose of indomethacin was 20 mg/k
g, and IQmg/kg was administered twice at 12-hour intervals. The dose of ZAC was 200 mg/kg. Experimental animals were sacrificed 2 hours after the last dose.

Results Example 1 Aspirin-induced disease a) Index control by visual observation ZAC50ZAC100 n 10 10 1
0X±SD 3.4±0.22.3±0.32
．． 1 Shi0.3*Zero** b) Index control by microscopic observation ZAC50ZAC100 n 10 10 10XiSD
3.0shi0.3 1.8+0.2 2. Of
o, 2*** Zero Example 2 Ibuprofen-induced disease a) Index by visual observation ZAC150 0 1,9 ± 0.3 Kimoto ZAC150 0 2,3 Sat 0.2 ** X ± 5D b) Control ZAC50 1010 2 , 4 soil Oi 1.60.4 Index control by Kimoto microscopic observation ZAC50 ZACto.

0 1.7±0.3 ** ZAC 00 ZAC150 0 1,5±0.2 Kimoto ZAC 50 X±SD 5 5 5 52.8 Sat 0.
4 2.2±0.2 2.4±0.2 2.0±0
．． 03I NS **Example 3
Phenylbutacin-induced disease a) Index control by visual observation ZAC75ZAC150 n 10 10 10
X±SD 2.8±0.4 1.3±0.5 0.
4±0.3*Kimoto Example 4 Indomethacin-induced disease a) Index by visual observation ZAC300 0 2,0±0.2 **X+SD Control ZAC200 1010 4,3±0.4 1.8±0.3 ** b) Index control by microscopic observation ZAC 00 X+SD 4.0 +0.7 2.1
±0.2 zero* *p<0.05 book* pro, 01 Statistical analysis Nistupund's t-test was used for comparison.

Results are expressed as standard deviation (SD) above the mean.

From these results, by visual observation and microscopic observation,
The protective effect of zinc acexamate on the studied N5AID-induced gastric diseases was observed.

These results on the prevention of N5AID-induced gastric disease by administration of zinc acexamate directly relate these effects to the anti-ulcer healing effects reported for this substance and other antisecretory or anti-acid substances. This is surprising since it is not possible.

These results provide a new prevention method for N5AID-induced gastric disease.

Indications for which NSAIDs are used, such as pain of various etiologies (headache, earache, toothache, dysmenorrhea, trauma) and rheumatic symptoms (chronic rheumatoid arthritis, osteoarthritis, ankylosing spondylitis) The scope of application is wide and diverse, as it can be considered in a very wide range.

In all cases where N5AIDs are required, especially when administered repeatedly and over a long period of time, N5
It is very useful to administer zinc acexamate in single or divided doses before administration of AIDs or concurrently with administration of N5AIDs.

According to the present invention, as a novel therapeutic application, zinc acexamate can be included as an active ingredient in the formulation, alone or together with anti-inflammatory agents.

Suitable oral administration formulations are prepared as pharmaceutical compositions according to the invention.

For example, if a solid carrier is used, it may be in tablet, powder or granule form in a hard gelatin capsule, troche, or capsule.

If a liquid carrier is used, it can be a syrup, emulsion, soft gelatin capsule, or aqueous or non-aqueous suspension. These pharmaceutical compositions are prepared by conventional methods depending on the required formulation.

The compositions of the invention, depending on the mode of administration, can include other adjuvants useful in forming the formulation or administering it. For example, when administered as a tablet, the composition of the present invention may further contain lubricants, excipients, binders, disintegrants, seasonings, and the like.

When administered as a capsule, it may contain a flocculant, a lubricant, a humectant, a disintegrant, and the like.

Each dosage unit of the composition of the invention contains 200% zinc acexamate.
~500 mg alone or with an effective dose of an anti-inflammatory agent. When containing with N5AID, N5
The usual dosage of AID is 20mg to 300mg.

The particular dosage will depend on the desired effect and the route of administration. For example: - daylight, zinc acexamate 8
0 to 2000 mg may be administered alone or together with an anti-inflammatory agent.

Examples of formulations are shown below.

Formulation Example 1 For Labcel 484.5 mg Zinc acexamate 300 mg Corn starch (flocculant) 70 mg Lactose 50 mg Polyethylene glycol 4000 (humectant) 1 mg Talcum powder (lubricating agent) L5gg Polyvinylpyrrolidone or Plasd.

ne) (flocculant) 10+
ig starch Bricolet Tirado Sodium (Sta
rch Glycollated Sodium) or Explotab (disintegrant)
8mg Tween 80
80) (Moisturizer) 0.5+ag Formulation Example 2 For 466 mg of tablets Zinc acexamate 3001 g Dehydrated calcium sulfate 80 mg Corn starch (flocculant) 50.9 m, g Talc powder (lubricating agent) 2hg Starch Bricollet Sodium (Starch) Glycoll
ated Sodium) or Explotab (Ex
plotab) (disintegrant) 10 m
g Polyvinylpyrrolidone or Plasd.

ne) (flocculant) 5mg
Tween 80 (moisturizer)
0.1mg Formulation Example 3 For one bag of 2000mg foamed powder, zinc acexamate 300mg ibuprofen 200g sucrose
500+wg sodium bicarbonate 500g tartaric acid
445mg powdered orange essence (seasoning) 30mg sodium saccharin (sweetener)
25mg formulation example 4 % w/v

Claims (7)

[Claims] (1) A pharmaceutical composition for the prevention or prevention of gastric diseases caused by administration of a non-steroidal anti-inflammatory agent, characterized by containing zinc acexamate as an active ingredient. (2) The pharmaceutical composition according to claim 1, which contains only zinc acexamate as an active ingredient. (3) The pharmaceutical composition according to claim 1, containing a mixture of zinc acexamate and a non-steroidal anti-inflammatory agent. (4) The pharmaceutical composition according to any one of claims 1 to 3, which is for oral administration. (5) The pharmaceutical composition according to any one of claims 1, 2 and 4, which is administered before treatment with a non-steroidal anti-inflammatory drug. (6) The pharmaceutical composition according to any one of claims 1, 2 and 4, which is administered simultaneously with a non-steroidal anti-inflammatory drug. (7) Unit dosage form is zinc acexamate 80-2000
7. The pharmaceutical composition according to any one of claims 1 to 6, which contains a pharmaceutically acceptable excipient.