HU188167B - Process for producing new pharmaceutical compositions against ulcer - Google Patents

Abstract

The present invention relates to a novel anti-ulcer pharmaceutical composition comprising mixing 1 part by weight of cimetidine or its salt, from 0.1 to 10 parts by weight of salicylic acid or its alkali metal salt with a carrier / excipient commonly used in the preparation of pharmaceutical compositions.

Description

This invention relates to novel anti-ulcer pharmaceutical compositions. More particularly, the present invention relates to the preparation of novel gastrointestinal anti-ulcer pharmaceutical compositions.

He opened a new chapter in the research and therapeutic application of anti-ulcer compounds when the existence of the H ₂ receptor in the stomach was described (Natúré 236, 385 (1962)). A few years later, cimetidine [under its chemical name: N-cyano-N'-methyl-N- [2 - {[(5-methyl-1H-imidazol-4-yl) methyl] thio] ethyl] guanidine appeared with significant therapies and market success. Recently, a number of new H ₂ receptor antagonists have been developed and investigated by researchers in clinical trials. Cimetidine is the subject of extensive research. For example, P. Del Soldato et al. Reported that indomethacin-induced rat small intestinal ulcers were not cured by treatment with cimetidine [Br. J. Pharmac. 67, 33 (1979)]. Animal experimental results have recently been supported by human clinical data [WS Mitchell et al., Brit. J. Med. 284: 731 (1982)]. The authors reported that ulcer perforation occurred in several patients when cimetidine and indomethacin were co-administered.

It is known that the new civilization disease, gastrointestinal ulcer, is torturing more and more people. The increasing number of patients is also associated with inflammatory or degenerative musculoskeletal disorders. In this case, the treating physician is facing a practically insurmountable task, as there are currently no known drug combinations that are effective in the given condition and at the same time have no adverse side effects. Currently, the patient should be treated with combination therapy with an anti-ulcer and a non-steroidal anti-inflammatory agent. There is a serious risk of concomitant double treatment with the use of an anti-inflammatory agent to accelerate the perforation of the ulcer. It is an object of the present invention to provide a method of combining drugs which eliminates the above-mentioned adverse effects. It is a further object of the present invention to provide a beneficial effect of potentiating the basic effect of cimetidine.

It is known that the common undesirable side effect of NSAIDs is the ulcer-producing effect. Numerous literature reports indicate that non-steroidal anti-inflammatory drugs may cause ulceration. Several methods are used to reduce this unpleasant side effect. Thus, it is known from our own research (Hungarian Patent No. 170,329) that certain salicylates reduce the adverse effect, but so far the possibility of combining with anti-ulcer drugs has not arisen, in fact, most monographs emphasize that certain salicylates do not undesirably alter gastrointestinal conditions (see, for example, Aspirin and Related Drugs, Their Actions and Uses, edited by KD Rainsford, K. Brown, MW Whitehouse, Birkhauser Verlag Basel and Stuttgart 1977). Although the gastrointestinal cytoprotective effect of sodium salicylate is not associated with acid secretion (Adv. Physiol. Sci., Vol. 29, Gastrointestinal Defense Mechanisms. Pergamon Press, Academic Journal, Budapest, Hungary, 1981).

Thus, the present invention is based on the surprising discovery that the combination of known anti-ulcer cimetidine with sodium salicylate exhibits a remarkable, unexpected synergistic effect in inhibiting acid secretion. This synergism is tabulated in the experimental section.

The invention thus provides a process for the preparation of a novel anti-ulcer pharmaceutical composition comprising 1 part by weight of cimetidine or a salt thereof, 0.1 to 10 parts by weight of salicylic acid or its alkali metal salt, and carriers and / or other excipients commonly used in pharmaceutical formulations.

The present invention may also be carried out using a weight fraction of cimetidine, 0.5 weight% sodium salicylate, and known carriers and / or other excipients.

Testing methods

1. Examination of small intestine ulcers induced by indomethacin.

An intestinal ulcer model induced by indomethacin

Non-fasted 120-150 g female HannoverWistar rats were orally administered 15 mg / kg indomethacin in a suspension of Tween-30 to induce a fatal ulcer. The test substance was also administered orally immediately after indomethacin treatment. Visual evaluation of intestinal ulcers has many sources of error. infusion methods [J. Pharm. Pharmac. 27, 867 (1975)]. The evaluation was as follows: the animals were sacrificed with ether anesthesia, the small intestine was carefully removed, one end ligated, and the other connected to an inflation and pressure recorder via a polyethylene cannula. (Ugo Basile, W + W electronic BP Recorder 8005). The intestine was placed in physiological salt at 37 ° C and the pressure was gradually increased. The tensile strength of the intestinal wall (in mbar) at which the intestinal wall ruptures or falls. bubbles appear in the physiological salt. As the intestinal ulcer induced by indomethacin progresses, the tensile strength of the intestinal wall, or otherwise the intestinal wall resistance (bfr), gradually decreases. For our experiments, animals were sacrificed 48 and 72 hours after indomethacin treatment, respectively.

2. Alcohol-induced gastric necrosis test

The concept of gastrointestinal cytoprotection was introduced by Robert et al. (1979) Gastroenterology 77, 433 in connection with the development of an alcohol necrosis test. Hannover-Wistar Female rats (120-150 g) were fasted for 24 hours and fed with water. For induction of gastric necrosis 0.5 ml (100 g body weight) abs. alcohol was administered to the animals via gastric tube. The test substance was administered 30 minutes earlier (orally) than alcohol. Animals were sacrificed 2 hours after alcohol administration. The stomach was removed, incised along the high curvature, stretched after a gentle wash, and the length of the longitudinal necrotic strips was measured and the average lesion per stomach was measured.

188 in 167 mm. The extent of gastric cytoprotection was reported relative to the control animals.

Investigation of gastric acid secretion in Shay rats

The assays were performed according to Shay et al., Gastroenterology 5, 43-46, 1945. After 24 hours of fasting (120-150 g female rats), the pylorus of the animals was ligated under mild ether narcosis. The test substance was administered intraperitoneally immediately after surgery. Oral treatment was performed 30 minutes before surgery. Animals were sacrificed 4 hours after pylorus ligation. After gastric emptying, the volume and pH of gastric secretion were measured. The HCl content was then titrated with 0.01 N NaOH with phenolphthalein indicator. The amount of acid is given in pmol to 100 g of body weight.

Student's t-test was used to statistically evaluate the results.

Evaluation of experimental results

In the first part of our study, the extent to which cimetidine sodium salicylate prevents small intestinal ulceration induced by 10 mg / kg indomethacin was investigated. Hereinafter, the letter combination "NS" will be used to indicate sodium salicylate. A 2: 1 mixture of cimetidine-NS was found to be optimal. In the following, this mixture ratio was used in our experiments.

The data in Table 2 show that the cimetidine + NS combination is able to inhibit intestinal ulceration at a dose of 15 mg / kg indomethacin.

The data in Table 3 show that indomethacin is induced by a 10 mg / kg oral dose. the combination can stop the non-fatal intestinal ulcer process by triple post-treatment and normalize the tear strength of the intestinal wall.

As shown in Table 4, the 2: 1 mixture of cimetidine-Na-salicylate has a clear dose-dependent gastric cytoprotective effect in abs. alcohol-induced gastric necrosis, whereas cimetidine has no such effect.

According to Table 5, when cimetidine was administered at a dose of 100 mg / kg to animals at a dose of 10 mg / kg indomethacin [oral administration] for three consecutive days, 50% of the animals died due to intestinal perforation. This means that cimetidine treatment is unable to protect or even potentiate the gastrointestinal toxicity of indomethacin. Three times a dose of 100 mg cimetidine + 50 mg Na-salicylate per kg completely prevents the gastrointestinal toxicity of indomethacin and the tear strength of the intestine is close to normal.

Table 6 shows very important experimental data. It shows how it affects gastric acid secretion in the so-called. For Shay rat, it is a 2: 1 mixture of cimetidine, Na-salicylate and the two.

The inhibitory effect of sodium salicylate is negligible at the dose tested. The calculated EDjp values for cimetidine were 54.4 mg / kg ip and for the combination the ED _{m was} 35.6 mg / kg ip. At the 35.6 mg dose of the combination, the cimetidine content was 23.8 mg, the rest being Na-salicylate. 50% inhibition of acid secretion requires 44% less cimetidine in combination. This means that the 2: 1 combination of cimetidine sodium salicylate shows synergism in the inhibition of gastric acid secretion. Similar results were obtained when the animals were treated orally with cimetidine or 30 minutes prior to surgery. with the combination.

In a preferred embodiment of the method of the invention, 200 mg of cimetidine and 100 mg of sodium salicylate are administered as an antiulcer agent per tablet. Alternatively, the additional component may be added in the form of salicylic acid or lithium salicylate.

The pharmaceutical combinations of the invention may be administered orally, rectally and / or parenterally once daily or in divided doses. For oral administration, the composition may be in the form of tablets, preferably film-coated tablets, dragees or capsules. Oral compositions of the present invention generally do not contain a filler, but optionally, the filler may be lactose or starch. Gelatin, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or starch beads may be used as binders or granulating agents. Potato starch or microcrystalline cellulose is preferably used as disintegrant, but ultra-amylopectin or formaldehyde casein, etc. can be used. too. Talc, colloidal silica, stearin, calcium and magnesium stearate, and the like as lubricants and anti-adhesives. It can be used.

For example, the tablet may be prepared by wet granulation followed by compression. The mixed active and excipients, and optionally a portion of the disintegrant, are granulated with an aqueous, alcoholic, or aqueous-alcoholic solution of the binders in a suitable apparatus, and the granules are dried. Next, other disintegrants, glidants and anti-adhesives are mixed with the dried granulate and compressed into a tablet. If desired, the tablet may be provided with a score pad to facilitate dosing. If desired, a gastric juice-resistant film coating such as shellac, cellulose acetate phthalate or a film-forming agent marketed under the name Eudragit-L may be applied to the tablet from an alcoholic solution, preferably isopropanol. Tablets may be prepared by direct compression of a mixture of the active ingredient and suitable excipients and optionally coated with an intestinal solvent film.

If desired, the tablets may be formulated with protective, flavoring or coloring agents commonly used in the preparation of the drug, such as sugar, cellulose derivatives (methyl or ethylcellulose, carboxymethylcellulose sodium, etc.), polyvinylpyrrolidone, calcium phosphate, calcium carbonate, food grade iron, pigments, flavorings, etc. using pellets.

In the manufacture of capsules, the mixture of active ingredients and excipients is filled into a hard gelatin capsule.

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For rectal administration, the composition is prepared in the form of a suppository. Vegetable fats such as hardened vegetable oils or triglycerides of C12-C18 fatty acids, preferably under the trademark Witepsol, may be used. The active ingredient is homogeneously distributed in the molten carrier mass and suppositories are prepared by molding.

For parenteral administration, the composition is prepared by injection. Purine, injection solution ¹⁰ at the active ingredients are oldósközvetítők such as polyoxyethylene sorbitan monolaurate, monooleate or monostearate (Tween 20, Tween 60, Tween 80) in distilled water and / or various organic solvents, such as ¹⁵ in lower aliphatic alcohols or glycol ethers, preferably ethylene glycol monoethyl ether. The solution for injection also contains auxiliaries such as preservatives such as benzyl alcohol, methyl or propyl p-hydroxybenzoic acid, phenylmercuriborate or benzalkonium chloride, and antioxidants such as sodium pyrosulfate, ascorbic acid, tocopherol, a substance such as ethylenediaminetetraacetic acid, and pH-adjusting and buffering agents, and, if desired, a local anesthetic such as lidocaine.

The injection solution containing the pharmaceutical combination of the invention is filtered before being filled into an ampoule and sterilized after filling into the ampoule.

The preparation of the pharmaceutical combination according to the invention is illustrated by the following example, without being limited thereto:

Example I

Cimetidine Sodium Salicylate Tablet Cimetidine 200 mg Sodium Salicylate 100 mg Magnesium Stearate 3 mg Polyvinylpyrrolidone 8 mg Talc 12 mg Potato Starch 27 mg

From the above materials 350 mg tablets are obtained by wet granulation and compression.

As described in the example, other alkali metal salicylates, e.g. lithium salicylate can also be used to make tablets with the same effect.

2nd-4th example

Other combinations

In each case, the procedure described in Example 1 was followed except that the measurements were as follows:

example cimetidine 150 mg Sodium salicylate 150 mg example cimetidine 200 mg Sodium salicylate . 100 mg example cimetidine 100 mg Sodium salicylate 200 mg

No. 1 Cimetidine sodium salicylate combination Table 35

Inhibition of the gut-inducing effect of indomethacin when co-administered at different rates.

Treatment n (Number of animals) Dose mg / kg p. She. V. B. No. No. * 48 hours after treatment in mbarb Intestinal wall resistance is normal % of untreated 30 307.2 100 ' indomethacin 26 10 147.6 48 cimetidine 9 100 301.9 98 Ind. + Address. 10 10 + 100 83.7 27 Ind. + (Address. + NS) 10 10+ (100 + 10) 208.8 68 Ind. + (Address. + NS) 10 10+ (100 + 25) 209.9 68 Ind. + (Address. + NS) 10 10+ (100 + 50) 289.9 94

* = small bowel tensile strength ",,,,

No. 2 spreadsheet

Dose-dependent inhibition of indomethacin-induced small intestinal ulceration with concomitant treatment

Treatment n (Number of animals) Dose mg / kg p. She. Intestinal wall tensile strength 72 hours after treatment in MB Intestinal wall resistance is normal % of untreated 30 307.2 100 Indomethacin (Ind) 26 15 85.2 28 Ind. + (Cim. + NS) 10 15 + (17 + 8) 97.1 32 Ind. + (Cim. + NS) 10 15 + (34 + 16) 275.3 89 Irid. + (Cim. + NS) 10 15 + (68 + 32) 279.3 91

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No. 3 spreadsheet

Inhibition of Non-Fatal Intestinal Ulcerative Induction with Indomethacin 10 mg / kg by Triple Treatment with Cimetidine + NS

Treatment 4, 24 and 48 hours after Ind. Treatment n (Number of animals) Dose mg / kg p. She. Intestinal wall No. 72 hours after Ind. Treatment Mbarek Intestinal wall resistance is normal % of Untreated (normal) 30 307.2 100 Indomethacin Ind. 38 10 186.2 60 Ind. + Cimetidine 10 10+ 3 X 50 138.3 45 Ind. + Cimetidine 10 10 + 3 x 100 230.0 75 Ind. + Cimetidine + NS 10 10 + 3 x 12 168.9 55 Ind. + Cimetidine + NS 10 10 + 3x25 305.2 103 Ind. + Cimetidine + NS 10 10 + 3 * 50 307.0 104 Ind. + NS 10 10 + 3x25 258.0 . 83 Ind. + NS 10 10 + 3x 100 291.2 95

No. 4 spreadsheet

The cytoprotective effect of cimetidine, NS and a combination of the two (2: 1!) Is abs. alcohol-induced gastric necrosis

Treatment n Dose mg / kg p. She. Average lesion nm / stomach Cytoprc tekció %-in t Comment Kontrol 112 - 82.4 + 5.0 Cimetidine (Cim.) 5 6 - 46.0 + 10.0 44 cimetidine 5 12 63.0 18.0 + 24 EDjo not calculated cimetidine 10 25 55.0 + 12.0 33 cimetidine 5 50 34.0 + 10.0 59 cimetidine 12 100 47.0 + 16.0 43 Na-salicylate (NS) 6 12 61.0 + 9.0 26 Sodium salicylate 15 25 39.0 + 10.0 53 EDjo = 28 mg / kg p. She. Sodium salicylate 9 50 * 39.0 13.0 + 53 Sodium salicylate 9 100 9.4 + 2.0 89 Title. + NS 6 8 + 4 79.0 19.0 + 5 Title. + NS 5 16 + 8 49.0 17.0 + 41 Title. + NS 6 32 + 16 15.0 + 5.0 82 EDjo = 30 mg / kg p. She. Title. + NS 7 64 + 32 6.4 + 3.0 93

No. 5 spreadsheet

Development of intestinal ulceration with indomethacin and concomitant treatment. (Treatment three consecutive days, evaluation 24 hours after last treatment.)

Treatment n Dose mg / kg p. She. Intestinal wall in S. No. mbar gut resistance in% of normal mortality %-in untreated 30 - 307.2 100 indomethacin 10 3x10 26.2 9 30 cimetidine 10 3x 100 247.3 80 Ind. + Cimetidine 10 3x (10 + 100) 12.5 4 50 Ind. + Address + NS 10 3x (100 + 50) 299.2 97

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No. 6 spreadsheet

Claims (2)

CLAIMS 1. A process for the preparation of a synergistic anti-ulcer pharmaceutical composition comprising 1 part by weight of cimetidine or a salt thereof and from 0.1 to 10 parts by weight of salicylic acid or an alkali metal salt thereof in admixture with a carrier and / or other excipients. 2. A process according to claim 1, wherein 1 part by weight of cimetidine, 0.5 parts by weight of sodium salicylate and a known carrier and / or other excipients.