JP3254712B2 - Pharmaceutical composition - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION This invention is cimetidine, Kei San'a
It relates to a pharmaceutical composition containing magnesium luminate and aldioxa (hereinafter, referred to as a compounding agent),
Used in the medical field.

[0002]

_2. Description of the Related Art Histamine H ₂ receptor antagonists such as cimetidine (chemical name: 1-cyano-2-methyl-3- [2
-[[(5-Methyl-4-imidazolyl) methyl] thio] ethyl] guanidine) has been sold in more than 100 countries since 1976 for the treatment of peptic ulcers and the like. In Japan, stomach ulcer, duodenal ulcer and the like were approved in 1981 as indications and are sold as ethical drugs. Six years after the approval of cimetidine, a post-marketing drug use-results survey was conducted, confirming its efficacy and safety, paving the way for its development as an over-the-counter drug (over-the-counter). In the development of over-the-counter drugs, it is conceivable to use cimetidine alone, but it is desirable to add a quick-acting effect or the like by blending or using it in combination with other drugs, thereby reducing the dose of cimetidine and further enhancing safety. As a mixture of cimetidine, cimetidine is added to magnesium aluminate silicate (2MgO.Al ₂ O ₃ .SiO
_A compound containing an antacid such as ( ₂ · nH ₂ O) is known, and its usefulness against gastritis and the like due to the combination of an antacid is shown (Clinical Adult Disease, Vol. 21, No. 12, 121-135).
1991). In addition, cimetidine has an aldioxa (chemical name: dihydroxy [(2-hydroxy-5-oxo-2-imidazolin-4-yl)) which is a mucosal protective factor enhancer.
It is also known that ureide] aluminum is used in combination to increase the efficacy against gastritis and the like (diagnosis and new drugs 24).
Vol. 5, No. 35, p. 65-1987, 1987).

[0003]

The above-mentioned combination or combination administration increases the efficacy against gastritis and the like more than the administration of cimetidine alone, but the effects are still satisfactory in terms of rapid efficacy and prevention of recurrence. Nevertheless, a compounding agent that further increases the effect of cimetidine on gastritis and the like was required. Shimechi this invention having such excellent gastritis therapeutic effect
It is intended to provide a compounding agent for gin .

[0004]

Means for Solving the Problems As a result of intensive studies, the inventors of the present invention have succeeded in simultaneously adding magnesium aluminate silicate and aldioxa , which have been conventionally separately or combined with cimetidine , to cimetidine simultaneously. formulated, i.e. cimetidine, magnesium aluminate silicate acid and A
The combination of ludioxa and cimetidine and magnesium silicate aluminate
Than a fixed combination of a fixed combination and cimetidine and aldioxa the Siumu have found that to achieve the therapeutic effects, such as much better gastritis and completed the present invention.

[0005]

[0006]

[0007]

[0008] Cimetidine , ke
The amount of Lee magnesium aluminate and aldioxa are silicate aluminate pike respect cimetidine 1 part by weight
0.5 to 20 parts by weight in magnesium, preferably 0.5 to 5 parts by weight, the aldioxa 0.5
To 10 parts by weight, preferably 0.5 to 3 parts by weight.

The compounding agent of the present invention may further contain additives such as excipients (eg, lactose, corn starch, light anhydrous silicic acid, microcrystalline cellulose, etc.), binders (eg, methylcellulose, carboxylate, etc.). Methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, etc.), disintegrants (eg, carboxymethylcellulose calcium, carboxymethylcellulose sodium, low-substituted hydroxypropylcellulose, etc.), lubricants (eg, magnesium stearate, talc, etc.). Used as an additive. Formulation of this invention, Shimechiji
, Magnesium aluminate silicate and aldioxa , appropriately adding the above-mentioned additives, according to a method known per se, for example, by a method described in the Pharmacopoeia of the Twelfth Revised Japanese Pharmacopoeia, for example, a tablet , Capsules, powders, granules, fine granules and the like can be formulated into dosage forms suitable for oral administration.

[0010] Tablets, granules and fine granules may be coated by a method known per se for the purpose of masking taste and maintaining stability. As the coating agent, for example, hydroxypropylmethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, or the like is used, and a dye such as talc, titanium oxide, or yellow iron sesquioxide may be appropriately added. The preparation thus produced is orally administered to the patient 1 to 3 times a day. The dose is 10 mg to 1000 mg / day, preferably 100 mg to 500 mg / day in the dose of cimetidine .

Test Examples Test Drugs (1) Formulation 1: Six tablets obtained in Example 1 (2) described below were sufficiently pulverized in a mortar and then 15 ml of a 2% arabic gum aqueous solution.
Was prepared by suspension. (2) Formulation A: Six tablets obtained in Reference Example 1 described below were prepared in the same manner as in Formulation 1. (3) Formulation B: Six tablets obtained in Reference Example 2 described later were prepared in the same manner as in Formulation 1. (4) Formulation C: Six tablets obtained in Reference Example 3 described below were prepared in the same manner as in Formulation 1. Dose

[Table 1]

Test Method (1) Histamine Gastric Mucosal Damage Model Male Wistar rats (body weight 168-208 g)
After fasting for 4 hours, histamine dihydrochloride 200 mg / kg dissolved in physiological saline was intraperitoneally administered. Histamine administration 4
After time, the stomach was removed under ether anesthesia. Approximately 12 ml of 1% formalin physiological saline was injected into the stomach that had been removed.
After fixing for -20 minutes, an incision was made along the greater curvature side, and the length of the damage that occurred in the mucosa of the glandular stomach was measured under a stereoscopic microscope at 10 × magnification. The length of injury per rat was the sum of the lengths of the injured portions of the individual. Oral administration of the test drug was performed using a gastric tube at a dose of 5 ml / kg 30 minutes before histamine administration. 2% for the control group not receiving the drug
Gum arabic suspension was similarly administered at a rate of 5 ml / kg. The number of animals in one group was 12 (14 in the control group only). (2) Aspirin gastric mucosal injury model Wistar male rats (body weight 168-208 g)
After fasting for 4 hours, aspirin 300 mg / kg suspended in 0.5% carboxymethylcellulose physiological saline was orally administered. Five hours after aspirin administration, the stomach was removed under ether anesthesia. About 12 ml of 1% formalin physiological saline was injected into the stomach, fixed for 15-20 minutes, cut open along the greater curvature, and the length of damage to the mucosa of the glandular stomach was measured at 10 × magnification using a stereoscopic microscope. did. The length of injury per rat was the sum of the lengths of the injured portions of the individual. Oral administration of the test drug was performed using a gastric tube at a dose of 5 ml / kg 30 minutes before aspirin administration. For the control group not receiving the drug, 5 ml of a 2% gum arabic suspension was used.
/ Kg at the same rate. The number of animals in one group was 12 (14 in the control group only).

Test Results The results are shown in Tables 2 and 3 below. Statistical test for the significant difference between the group of formulation C and the group of formulation 1, formulation A or formulation B
Udent's t-test was used. (1) Histamine gastric mucosa injury model

[Table 2] (2) Aspirin gastric mucosa injury model

[Table 3]

As is apparent from the above test results, the combination preparation of the present invention (formulation 1) was compared with formulation A (combination of cimetidine and aldioxa) and preparation B (combination of cimetidine and magnesium aluminate silicate). And cimetidine,
A much better inhibitory effect on gastric mucosal damage was observed due to the synergistic effect of the combination of the three agents of aldioxa and magnesium silicate.

[0015]

The compounding agent of the present invention comprises cimetidine ,
The synergistic effect of magnesium aluminate silicate and aldioxa , cimetidine and aluminum silicate
Magnesium salt combination and cimetidine and ardioki
It shows much better therapeutic effects, such as gastritis, than the combination of sa . Therefore, the combination drug of the present invention can reduce the dose of cimetidine , so that it is particularly useful as an over-the-counter drug requiring even greater safety as a therapeutic agent for gastric diseases (eg, gastritis, gastric ulcer, etc.). .

[0016]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail with reference to embodiments. Example 1 (1) After sufficiently mixing cimetidine, aldioxa, magnesium aluminate silicate, microcrystalline cellulose and hydroxypropylcellulose, the mixture was granulated with Pharmamatrix (Nara Machinery). Next, the granules were vacuum-dried at 40 ° C., and sized using a double sizing machine (Hata Iron Works). Add magnesium stearate to the granules and add P-
Tableting was performed with an 18 tableting machine (manufactured by Hata Iron Works) to obtain plain tablets having the following component contents per tablet. (Uncoated tablet composition)

(Equation 1) (2) The uncoated tablet obtained in (1) is coated with a coating solution having the following composition per tablet using a Hicoater HCT-55 (manufactured by Freund Corporation) at an air supply temperature of 55 ° C and an exhaust temperature of 40 ° C to form a film coat. I got a tablet. (Coating liquid composition)

(Equation 2)

REFERENCE EXAMPLE Table 4 shows the formulation per tablet of the preparations of Reference Examples 1 to 3 used in the comparative test with the combination preparation of the present invention. These preparations were produced in the same manner as in Example 1.

[Table 4]

──────────────────────────────────────────────────続 き Continued on the front page (58) Fields surveyed (Int. Cl. ⁷ , DB name) A61K 31/4164 A61K 31/4166 A61K 33/06 A61P 1/04 BIOSIS (STN) CAPPLUS (STN) MEDLINE (STN ) EMBASE (STN)

Claims (1)

(57) [Claims] 1. A stomach disease comprising cimetidine, magnesium aluminate silicate and aldioxa.
A pharmaceutical composition for treating a disease .