JPH0333126B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION This invention relates to novel pharmaceutical compositions useful in the treatment of inflammation and ulcers of the gastrointestinal tract. Certain derivatives of glycyrrhetinic acid, such as the disodium salt of glycyrrhetinic acid hemisuccinate, have excellent anti-inflammatory activity and are useful in the treatment of gastric ulcers and duodenal ulcers as well as in the treatment of agonistic esophagitis. It has been known. Although there is no doubt that these derivatives have beneficial efforts, the conventionally used derivatives of glycyrrhetinic acid have certain undesirable side effects, such as urinary suppressive activity and a decrease in body potassium levels. It is true that several glycyrrhetinic acid derivatives have been used successfully for many years. However, although it has been reported that the disodium salt of glycyrrhetinic acid hemisuccinate increases the amount of prostaglandins, the exact mechanism of its action is unknown. Theophylline, theobromine, caffein, and their non-toxic salts have been used for many years as diuretics, cardiotonic agents, and mild muscle relaxants. Furthermore, these three xanthine derivatives are adenosine 3′,5′-cyclic monophosphate (CAMP).
can increase the intestinal concentration of
CAMP is known to be associated with increased synthesis of prostaglandins. Therefore, the inventors of the present invention investigated whether the diuretic efficacy of these three known xanthine derivatives would overcome the known diuretic suppressive effect of the known glycyrrhetinic acid derivatives. The possibility of its use in combination with glycyrrhetinic acid derivatives was investigated. As a result of research, the inventors of this invention discovered the above three
The two xanthine derivatives have such a synergistic enhancing effect on these glycyrrhetinic acid derivatives that their advantageous efficacy can be obtained at significantly reduced doses such that their known undesirable side effects no longer appear. He made the surprising discovery that it works. Thus, the present invention comprises at least one glycyrrhetinic acid derivative and at least one of the three xanthine derivatives, each optionally in the form of a non-toxic salt, and the weight ratio of the glycyrrhetinic acid derivative to the xanthine component is 2:1~
5:1, preferably 2.5:1 to 3.5:1. The glycyrrhetinic acid derivatives used in the present invention include 3-0-acyl derivatives of glycyrrhetinic acid, especially those having a carboxyl group in the acyl group, such as glycyrrhetinic acid hemisuccinate, glycyrrhetinic acid propionate, and their salts and esters (British Patent No. 843133), 3-(2-carboxy-cis-cyclohexane-carbonyl)-18β-glycyrrhetinic acid and their salts and esters (see Japanese Patent No. 1155013); esters of glycyrrhetinic acid, such as geranyl ester , cinnamyl ester, ester of the 3-0-acyl derivative of glycyrrhetinic acid, such as geranyl (or cinnamyl) 3-
0-acetyl-glycyretitate (Japanese Patent No.
975632); 2-(ω-carboxy-alkanoyl (or -carboxycycloalkanoyl)oxymethyl)glycyrrhetinic acid derivatives, such as 2-carboxybutyroxy (or carboxyhexanoyloxy)methyl-18α-
Glycyrrhetinic acid, its salts and esters (patent application)
51-12132). If the glycyrrhetinic acid derivative has one or more free carboxy groups, the carboxy groups are salted;
For example, it is preferably used in the form of an alkali metal salt, with sodium salt being particularly preferred. Among the many glycyrrhetinic acid derivatives that can be used in the present invention, preferred is the disodium salt of glycyrrhetinic acid hemisuccinate [carbenoxolone sodium].
sodium)], the disodium salt of mono-(glycyreth-3-yl)-cis-cyclohexane-1,2-dicarboxylic acid, and cinnamyl glycyrrhetate. The xanthine derivatives theophylline, caffein and theobromine can be used as such or in the form of their non-toxic salts. Thus, for example, caffeine can be used in the form of non-toxic acid addition salts such as the phosphate, citrate, acetate or hydrochloride salts, and theobromine and theophylline can be used in the form of non-toxic base salts such as the sodium salt. It can be used in any form. The novel pharmaceutical compositions of this invention can be administered orally to treat inflammation and ulcers of the gastrointestinal tract. For this purpose, these compositions preferably contain the active ingredients described above in admixture with known pharmaceutically acceptable diluents and carriers and may be in solid or liquid form. However, for ease of administration, the compositions of the invention are preferably in the form of tablets, dragees or capsules. Although the dosage of the active ingredients varies depending on the patient's age, sex, weight, symptoms, etc., the total amount of glycyrrhetinic acid derivative and xanthine derivative in the above weight ratio is 50 to 300 mg.
is administered 2 to 3 times per day. To illustrate the efficacy of the novel synergistic mixture of this invention, Derelanko and Long (Derelanko and Long)
and Long) method (Proc.Soc.Expl.Biol.Med.,
The experiment was conducted using an improved method of 166394/1981). 8 Wistar rats (weighing approximately 170g)
Several groups were fasted for 20 hours.
However, they had free access to drinking water. Water was not provided from 1 hour before the start of the experiment until the end of the experiment, and all rats were housed in groups of 8 in wire mesh cages during the experiment. The experiment was started by orally administering the test substance in 0.75 ml of water per test animal, and 15 minutes later each test animal was orally administered 1 ml of absolute ethanol. After an additional hour, the test animals were dissected and the stomach was cut out and treated with 2% formal saline solution.
The length of the eroded area was measured and expressed in mm. The effect on ethanol-induced gastric gangrene for test animals was calculated as follows. Inhibition degree % = 100 - (average length of lesion in treated animals / average length of lesion in untreated animals) ×
100 The test results are shown in Table 1 below. [Table] Efficacy test method and test results of a mixture of theophylline sodium and carbenoxolone on water-induced diuresis in Wistar rats The experiment was conducted with the following groups of 5 male Wistar rats each weighing approximately 250 g. I went. A Control 1 ml/rat, Vehicle B Theophylline sodium 20 mg/Kg C Carbenoxolone sodium 70 mg/Kg D Theophylline sodium + 20 mg/Kg Carbenoxolone sodium 70 mg/Kg Test animals were fasted overnight before use. Experiment 1
On Day 1 and Day 2, diuresis was performed by orally giving 50 ml/Kg of water, and urine was collected 2 and 6 hours later. This experiment allows one to obtain baseline values for the rat prior to treatment with the test compound.
On the seventh day, test compounds were prepared in distilled water;
A third dose was given orally with water, and urine samples were collected 2 and 6 hours after treatment with the drug. Urine volume was measured and sodium, potassium and chloride concentrations were determined. The results obtained are shown in Table 2. [Table] Oral administration of 20mg/Kg of theophylline sodium was found to have a diuretic effect. Oral administration of carbenoxolone sodium at 70 mg/Kg appears to have no effect on electrolyte excretion;
The volume of urine collected for 2 hours decreased slightly. A mixture of theophylline sodium (20 mg/Kg) + carbenoxolone sodium (70 mg/Kg) when administered orally has no effect on water excretion. However, in this case, although the excretion of sodium and potassium increases somewhat, only theophylline sodium 20
It is smaller than the amount excreted by mg/Kg administration. Therefore, these results indicate that the mixture of theophylline sodium + carbenoxolone sodium decreased the diuretic efficacy of theophylline sodium and the antidiuretic efficacy of carbenoxolone sodium, as indicated by urine volume. I understand that. The three xanthine derivatives also enhance the protective effect of carbenoxolone, with theophylline still having the highest efficacy. As a result of a series of experiments, the ratio of theophylline to carbenoxolone was approximately 1:3 (3:10 mg/Kg and 20:70 mg/Kg).
Kg) gave the best synergistic effect. In most animal studies, theophylline was administered in a solution of its sodium salt. A comparative study of the efficacy of theophylline and theophylline sodium on an ethanol-induced ulcer model revealed no difference in the efficacy of these two compounds. Also, the mixture of theophylline sodium and carbenoxolone sodium was not ulcerogenic and did not affect gastrointestinal motility. A mixture of theophylline (20 mg/Kg) and carbenoxolone (70 mg/Kg) was found to have no central nervous system activity by the leptazol convulsion test and perbiturate sleep time test in mice. However, although this mixture showed significant peripheral analgesic activity in the rat carrageenan-induced hyperalgesia test, it did not show significant peripheral analgesic activity in the rat carrageenan-induced hyperalgesia test;
syndrome test) showed no significant activity. A mixture of theophylline (20 mg/Kg) and carbenoxolone (70 mg/Kg) had no significant anti-inflammatory efficacy against rat edema formation induced by carrageenan or sodium urate. However, in a dextran-induced anaphylaxis study in rats, oral administration of theophylline (20 mg/Kg), carbenoxolone (70 mg/Kg), and their mixture all resulted in a significant reduction in edema. Moreover, the mixture had greater potency than a single drug. Regarding passive cutaneous anaphylaxis in rats, oral administration of theophylline (20 mg/Kg) alone or a mixture with carbenoxolone (70 mg/Kg) had a significant suppressive effect, but carbenoxolone alone had no activity. Toxicity The acute toxicity of carbenoxolone and theophylline to mice was unchanged when high doses of either drug were administered simultaneously. Theophylline 150-200mg/Kg intraperitoneal administration or
The acute toxicity of carbenoxolone when administered orally at 350 mg/Kg (approximately the LD ₅₀ value of theophylline according to each administration method) did not change even when carbenoxolone was orally administered at 600 mg/Kg at once. Similarly, the LD ₅₀ value (2g/Kg) for oral administration of carbenoxolone is 100.
Concomitant oral administration of mg/Kg theophylline did not change the effect. Interactions Oral administration of theophylline sodium (35 mg/Kg) to male rats had no effect on the absorption or excretion of orally administered ^3-3H carbenoxolone sodium (100 mg/Kg). Oral administration of carbenoxolone sodium (100 mg/Kg) to male rats delayed the absorption of orally administered ( ^8-14C ) theophylline (35 mg/Kg) but did not affect theophylline excretion. , the final absorption amount was similar. Preliminary protein binding studies
Protein binding studies) showed no interaction between carbenoxolone and theophylline. Next, the present invention will be explained by examples, but the present invention is not limited to the following. Example 1 Tablets containing the following ingredients were prepared in a conventional manner. Glycyrrhetinic acid hemisuccinate disodium salt 20mg Theophylline sodium 7mg Povidone 4.5mg Horsetail oil 0.5mg Lactose 63mg Corn starch 180mg Magnesium stearate 2.5mg Example 2 Tablets containing the following ingredients were prepared in a conventional manner. Disodium salt of mono-(glycylleth-3-yl)-cis-cyclohexane-1,2-dicarboxylic acid 22mg Sodium theobromine 7mg Povidone 0.5mg Horsetail oil 0.5mg Lactose 63mg Corn starch 180mg Magnesium stearate 2.5mg Example 3 Below Tablets containing the ingredients were prepared in a conventional manner. Disodium salt of glycyrrhetinic acid hemisuccinate 20mg Caffeine phosphate 8mg Povidone 4.5mg Horsetail oil 0.5mg Lactose 63mg Corn starch 180mg Magnesium stearate 2.5mg Example 4 Tablets containing the following ingredients were prepared in a conventional manner. Glycyrrhetinic acid hemisuccinate disodium salt 20 mg Theophylline 7 mg Microcrystalline cellulose 51 mg Ultrafine lactose 119 mg Ac-di-sol (Ac-di-sol) 2 mg Magnesium stearate 1 mg The tablets described in the above examples are suitable for treating ulcers of the gastrointestinal tract. and can be administered orally to humans for the treatment of inflammation, especially gastric ulcers. Clinical Trial Six patients with an initial diagnosis of benign gastric ulcer were treated for 4 weeks as follows. That is, two tablets containing 20 mg of British Pharmacopoeia carbenoxolone sodium and 7 mg of British Pharmacopoeia theophylline were administered three times per day for one week, and then one tablet was administered three times per day for three weeks. One patient was later found to have adenocarcinoma and was excluded within a week. In the other patient, adenocarcinoma was confirmed 4 weeks later, when the ulcer had shrunk from 6 cm to 2 cm in diameter. Three patients were cured in 4 weeks. One patient's ulcer had shrunk significantly in 4 weeks (from 3 x 3 cm)
(up to 0.5 x 2 cm) and was not completely cured until an additional 4 weeks of administration of carbenoxolone sodium at 50 mg three times per day. None of the five patients who completed 4 weeks of treatment had any changes in electrolytes or blood pressure. In the patient who continued treatment with carbenoxolone sodium, serum potassium decreased during that period (4.0 mmol/day at the start of treatment and 4.0 mmol/day after 4 weeks).
, 2.5 mmol/after 8 weeks). The results obtained are shown in Tables 3 and 4 below. [Table] [Table]

Claims (1)

[Scope of Claims] 1. 3-0-acyl derivatives of glycyrrhetinic acid, esters of glycyrrhetinic acid, 3-0-acyl derivatives of glycyrrhetinic acid in which the acyl group optionally has a carboxy group,
esters of 0-acyl derivatives, 2-(ω-carboxy-alkanoyl (or -cycloalkanoyl)-oxymethyl)-glycyrrhetinic acid and salts of said glycyrrhetinic acid derivatives having one or more free carboxyl groups. It contains at least one glycyrrhetinic acid derivative and at least one xanthine derivative selected from theophylline, theobromine and caffein, each optionally in the form of a non-toxic salt, and the weight ratio of the glycyrrhetinic acid derivative to the xanthine derivative is An anti-inflammatory anti-ulcer composition having a ratio of 2:1 to 5:1. 2 Glycyrrhetinic acid derivative is disodium salt of glycyrrhetinic acid hemisuccinate, mono(glycyreth-3-yl)-cis-cyclohexane-1,
The composition according to claim 1, which is a disodium salt of 2-dicarboxylic acid or cinnamyl glycylate. 3. The composition according to claim 1, wherein the weight ratio of the glycyrrhetinic acid derivative to the xanthine derivative is 2.5:1 to 3.5:1.