CS237705B1 - Anti-ulcer, spasmolytic and locally anesthetic drug - Google Patents

Abstract

The invention relates to a drug with antiulcer, spasmolytic and local anesthetic effects, intended for oral administration, which contains as an active ingredient trans-2/1-pyrrolidinyl/cyclohexyl ester of 3-n-pentyloxycarbanilic acid or its salt with a pharmaceutically acceptable inorganic or organic acid, preferably hydrochloride, together with a physiologically harmless vehicle and/or antacid component. The drug according to the invention in a daily dose of 10 to 200 mg prevents the formation of ulcers, slows their spread and shortens the healing time, in doses where drugs of a similar type do not show such an effect. The combination with antacid substances is particularly advantageous.

Description

The invention relates to a drug with antiulcer, spasmolytic and local anesthetic effects, intended for oral administration.

In the treatment of peptic ulcer disease, a number of drugs are used, especially from the group of so-called histamine-Hg receptor blockers, for example cimetidine and its derivatives, plrenzepine and other derivatives from the group of anxiolytics /S. Kobayashi et al.: Arzneim. -Forseh. 31, 679, /1981/, from the group of intestinal antiphlogistics, for example carbenoxolone /F. Tárnok: Drugs exp. clin.Ses. 5, 157, /1979/ and proglumide /S. E. Uiederer et al.: Drugs exp. clin. Rea. 5, 205, /1979/ and paraeinopathic and anticholinergic agents, such as oxyphenonium bromide, propanthelinium bromide, drotaverinium chloride, scopolamirium bromide, or atropine chloride, as well as substances isolated from natural sources, such as extract from Olycyrrhiza glabra or substances of the polyisoprenoid type /M. Uurakaml et al.: Arzneim.-Forseh, 31, 799, /1981/. In a mixture with antacid suspension, the local anesthetic oxethakaln is also used /J. Seifert et al.: Proc. Soc. Exp. Biol. Med. 109, 664, /1962/ or procaine /F. Švec: Farmakodynamika liakov I, SAV Bratislava /1953/.

The disadvantage of the substances mentioned so far used are their side effects, for example damage to the gastric mucosa, as is the case with cimetidine and its derivatives /M. Ouelandi: Int.

J. Clin. Pharmakol. 18, 140 /1980/, adverse effects on motility and little or no reduction in acidity and others /V. Jirásek: Farmakotherap. zprávy no. 4, 43, /1980/.

The aforementioned disadvantages are eliminated by a drug with antiulcer, spasmolytic and local anesthetic effects, intended for oral administration, according to the invention, the essence of which lies in the fact that it contains, as an active ingredient, trans-2/1-pyrrolidinyl/cyclohexyl ester of 3-n-pentyloxycarbamyl acid of the formula

NHCOOΪ _Z Ò _X

OC ₆ H _fl or its salt is a pharmaceutically acceptable inorganic or organic acid, preferably the hydrochloride, together with a physiologically innocuous vehicle and/or antacid component.

The active ingredient of the drug according to the invention, i.e. trans-2/1-pyrrolidinylcyclohexyl ester of 3-n-pentyloxycarbanilic acid or its hydrochloride, is a known substance, prepared in connection with the study of carbanic acid derivatives and locally anesthetic effects /patent no. 125 666 and 126 102/. The complex of pharmacodynamic effects of the substance consisting in general membrane stabilizing, locally anesthetic and spasmolytic efficacy and the ability to maintain the effect at low pH values is a significant and confirmed prerequisite for the antiulcer effect.

The drug according to the invention exhibits higher antiulcer activity than similar drugs used so far, in the conditions of formation of experimental ulcers induced by acute stress, while it has a significant protective effect even after a single application. It exhibits previously known local anesthetic and spasmolytic effects /P. Švec et al.: Farm. obzor 45, 355, /1976/.

The nature of the effect, its onset, development, duration, disappearance and preservation of local anesthetic activity even in an environment with a reduced pH value to the acidic range /S. Štolo et al.: Brat. Lék. Listy 70, 297, /1978/, _; low acute toxicity, especially after oral administration and minimal side effects and toxicity found with one-month oral administration, are excellent prerequisites for the treatment of gastric ulcers.

The active ingredient of the drug according to the invention, i.e. tran-[1-pyrrolidinyl]cyclohexyl ester of 3-n-pentyloxycarbanilic acid, administered in doses of 1.0 and 10.0 seg.kg- ¹¹ to Wistar rats 30 min. before the start of acute stress induced by swimming, which lasted 30 min. and was repeated 3 times with intervals of 90 min, showed a significant protective effect with regard to the frequency of ulcer occurrence, the size of gastric lesions and ulceration indices.

Under these conditions, the active ingredient of the drug according to the invention in single doses of 1.0 to 10.0 mg.kg" ¹ in rats compared to the control group of animals reduced the incidence of ulcers by 27 or 33 16; its repeated doses 5 times at 2 mg.kg" ¹ . ,«> 5 times at 10 mg-řkg ⁵ reduced the number of animals with ulcers by 30 or 37 16. The average size of gastric lesions after single and repeated administration of the active ingredient according to the invention was significantly reduced depending on the dose. Under the same experimental conditions, oxethacaine used for comparison did not affect the size of gastric lesions, on the contrary, in some cases it increased it.

The active substance according to the invention in a comparative test with oxethacaine _with atropine and control significantly reduced the ulceration index value. With repeated application, only the dose ^of 10 mg.kg was effective. Oxethacaine, on the other hand, does not affect or even increases the ulceration index.

In experiments under the same arrangement, monitoring the action of the active substance according to the invention, antacid preparations and a combination of the active substance according to the invention with antacid gel containing aluminum phosphate and pectin (gel 1) and with a commercial preparation containing aluminum and magnesium hydroxide gel together with oxethacaine, the combination of the active substance according to the invention with gel X showed the greatest inhibition of the formation and size of gastric lesions, reaching 73 and 78% inhibition, respectively. This combination is most effective even after repeated administration in doses of 5 times 2 mg.kg ¹ and 5 times IQ mg.kg ⁵ , when up to 80% inhibition is achieved.

The control group was given 5 ml of distilled water per kg of rat weight. Because when determining the ulceration index value, the effect of the combination was the most pronounced.

When determining the acute toxicity of the active substance according to the invention, expressed as mg/ ^kg , the following values were found:

Animal ^type

intravenous subcutaneous intraperitoneal oral H strain mice At 125 57.5 815 Wistar rats 12.4 289 72.5 1 Q7Q rabbits 2.9 150 46.5 ·» guinea pigs - 73.2 - -

In monitoring the one-month toxicity in Wistar rats after oral administration in doses of 0.1, 1.0 and 10.0 mg.kg ^-5 , no signs of toxic effects on animal behavior or weight were detected, with the exception of the two highest doses, after which weight gains were in some cases lower than the average daily weight gains. At the end of the experiment, the percentage of weight gains did not differ significantly. Analysis of the weight of the monitored organs revealed only a rare increase in the weight of the adrenal glands and kidneys, which was dependent on the dose. Hematological changes did not show signs of toxic effects, on the contrary, the number of erythrocytes and hemoglobin content was more favorable after the end of the experiment than at the beginning. Likewise, biochemical parameters do not indicate signs of toxic effects. According to the results of histological examination, most of the findings are indistinguishable from the control group. Vacuolar dystrophy and other types of reversible dystrophies occur rarely, in which a return to normal can be expected after the removal of the causative agent.

Examination of local irritant effects during intradermal and intramuscular application did not show any unusual irritating effects.

The drug according to the invention can be prepared by dissolving the appropriate salt of the active substance in water or other pharmaceutically acceptable liquids and semi-liquid bases, or the base of the active substance in a suitable solvent, and preferably in ether, further in the form of a solid solution form, for example tablets, with the addition of conventional excipients. For liquid solution forms, common stabilizing additives can be mentioned, for example phosphate buffer, emulsifiers /eorbia acrogels/, stabilizers of suspensions or aw-liquids /for example cellulose esters, hydrated silicon dioxide, bentonite, etc./, for solid forms, for example starches, lactose, methylcellulose, gelatin, doziran, magnesium stearate, microcrystalline cellulose, etc. Given the expected therapeutic daily dose in the range of 1 to 50 mg, there is no effect on the solution form base, an increase in the disintegration rate, etc.

The starting active substance according to the invention is available, as already mentioned above, under Czech Patent Nos. I25 666 and 126 102.

The drug according to the invention can be applied in all indications for peptic ulcer disease or disorders characterized by stomach pain of neurogenic origin, in the usual application forms, tablets, semi-solids, or liquids in a daily dose of 10 to 290 mg for humans, or divided into several smaller doses. It is also possible to use it in veterinary medicine, for example to reduce neurogenically caused damage to the gastric mucosa in farm animals.

In the following examples, two possible forms of administration of the drug according to the invention are presented for illustration, without however limiting the invention to them.

* ? í k 1 a d í drug with antiulcer effect in the form of tablets the active substance in an amount of 10 g is mixed with 90 g of lactose, 138 g of starch and moistened with a suitable amount of* Starch hydrogel. After granulation and homogenization of this mixture, magnesium stearate is added and tablets with an approximate weight of 250 mg and a diameter of 5 mm are pressed. One tablet corresponds to 10 g of the active substance.

Similarly, tablets containing 5 mg of the active substance are prepared. ř # i U a č 2

Anti-ulcer drug in the form of a suspension >

The active substance in the amount of 0.01 g is dissolved in 20 ml of distilled or deionized water and mixed with a suspension prepared from 14.55 g of aluminum hydroxide and 4.90 g of magnesium hydroxide. The prepared suspension contains 1 mg of active substance, 291 mg of aluminum hydroxide and 98 mg of magnesium hydroxide in 5 ml.

Claims (1)

THE INVENTION OF THE INVENTION Medicament and anti-ulcer, spasoolytic and locally enesthetic action, for oral administration, characterized in that it contains, as active ingredient, the trans-2/1-pyrrolidinyl / cyclohexyl ester of the 3-n-pentyloxycarbonyl acid of formula or a salt thereof with a pharmaceutically acceptable inorganic or organic acid , preferably the hydrochloride, together with a physiologically acceptable vehicle and / or an antacid component.