KR20200110308A - Polymorph of trimebutine maleate and method of use thereof - Google Patents

Abstract

The present invention relates to the pharmaceutical, pharmacology, and chemical and pharmaceutical industries, and in particular to novel polymorphic forms of trimebutine maleate and methods of making and using the same.

Description

Polymorph of trimebutine maleate and method of use thereof

The present invention relates to the pharmaceutical, pharmacology and chemical and pharmaceutical industries, and in particular to novel polymorphic forms of trimebutine maleate and methods for their preparation and use.

In clinical practice, a significant proportion of diseases are functional diseases of the gastrointestinal tract. Functional bowel disorders (or FBD) include a group of heterogeneous clinical diseases that exhibit symptoms in the middle and lower part of the gastrointestinal tract and do not accompany any structural, systemic or metabolic changes. . In spite of the lack of an organic basis, functional disorders lower the patient's quality of life and are indirect indirect indicators of expenditure for medical care and treatment, and indirect damages such as compensation for temporary disability. It causes significant economic damage to society both in terms of indicators.

First of all, these diseases include irritable colon syndrome. Epidemiological studies show that 15-20% of the population suffers from irritable bowel syndrome. There are several forms of this disease: diarrhea predominant subtype, constipation predominant subtype, and mixed form. Other functional bowel diseases such as functional diarrhea, functional constipation, and idiopathic abdominal pain are less common.

Since 1969, many countries have been using trimebutine to treat functional bowel disease, primarily irritable bowel syndrome (IBS). At the end of 2007 it was registered in Russia under the trade name Trimedat ^® . Trimebutin's effectiveness in reducing abdominal pain has been demonstrated in various clinical studies. For a long time, it has been believed that the effects of trimebutine maleate are associated with antispasmodic activity, and are considered mebeverine-a drug that acts like a myotropic antispasmodic. However, later new data, less common in antispasmodics, have been discovered regarding the mechanism of action of trimebutine maleate. In experimental and clinical studies, the modulatory effect of trimebutine maleate on motor function of the gastrointestinal tract (GIT) has been found, which is the GIT motility in the case of therapeutic and surgical pathologies. Was shown to be its normalizing effect on hypokinetic and hyperkinetic diseases. Trimebutin has a significant analgesic effect. During the experimental study, it was found that trimebutin is an opiate receptor agonist, and its modulatory and analgesic effects on GIT motility are related to all types of peripheral opioid receptors-μ, κ and δ- It was confirmed by the non-specific effect of this drug on. Acting on the intestinal enkephalinergic system, it regulates the GIT peristalsis. It works throughout the gastrointestinal tract to reduce pressure in the esophagus sphincter, help empty the stomach and increase intestinal motility, and help to increase colon smooth muscles against food irritants. ) Contributes to the reaction.

2-(dimethylamino)-2-phenylbutyl-3,4,5-trimethoxybenzoate maleate (trimebutine maleate)

The main indications for the use of trimebutine maleate include irritable bowel syndrome, postoperative paralytic ileus, X-ray preparation and endoscopic examinations of GIT.

Typically, trimebutine is administered orally in a variety of solid dosage forms, including tablets, that disintegrate rapidly and have a delayed action. Since trimebutine is hardly soluble in water, a more soluble salt, maleate, has been produced and used in clinical practice to increase bioavailability.

Two different polymorphic forms of trimebutine 3-thiocarbamoylbenzenesulfonate are described in WO2013134869, "Preparation of sulfonate-based trimebutine salts for use as gastrointestinal endoscopic and medical imagining and for the treatment. of visceral pain", publ. 09/19/2013]. Polymorph A is produced by crystallization of a mixture of acetone and methanol while polymorph B is produced by crystallization of methanol. Polymorph B is more thermodynamically stable than polymorph A. Polymorph A melts at a temperature of about 128°C, while polymorph B melts at a temperature of about 180°C. Three other polymorphs of trimebutine p-toluenesulfonate have also been identified. Polymorphs A and B are produced by crystallization of isopropyl alcohol. Polymorph B is produced by crystallization of ethanol. Polymorph C is also produced from ethanol. Polymorph C is more thermodynamically stable than polymorphs A and B. Polymorph A melts at a temperature of about 123°C, polymorph B melts at a temperature of about 142°C, and polymorph C melts at a temperature of about 173°C.

The crystalline structure of trimebutine dimaleate is reviewed [Coquerel G. "Limits of the co-crystal concept and beyond", RSC Drug Discovery Series, 2012, 20 Vol. 16, pp. 300-317].

The synthesis of trimebutine maleate is described, for example, in patent GB1342547, where trimebutine maleate reacts with maleic acid of trimebutine in water when heated by subsequent crystallization. Is manufactured.

However, the preparation of the polymorph of trimebutine maleate and the study of its properties has not been known to date.

It is noted that trimebutine maleate may exist as a new polymorphic crystalline with better properties than trimebutine maleate produced according to the method described in GB1342547, hereinafter referred to as the "prototype". It was discovered unexpectedly by the authors of the present invention.

Definitions of terms used in the description of the present invention are given below.

A "medicinal agent" (a drug substance, a medicinal substance) is a physiologically active synthetic or other (biotechnology, plant, animal, microbial, etc.) substance of origin, and has pharmacological activity. It refers to a substance that becomes an active agent of a pharmaceutical composition used in the production and manufacture of a product (medicinal product) (drug).

"Medicinal drugs (products)" refer to the restoration, correction or alteration of the physiological functions of humans and animals, as well as diagnostics, anesthesia, contraception, and cosmetology. ), substances in the form of tablets, capsules, injections, ointments and other preparations (or mixtures of substances in the form of pharmaceutical compositions), made for the treatment and prevention of diseases in the etc.

"Pharmaceutical composition" refers to a novel polymorph of trimebutine maleate and pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, auxiliary agents, distribution Distributing agents, preservatives as delivery agents, stabilizers, fillers, dispersing agents, moisturizers, emulsifiers, suspending agents, thickeners, sweeteners, At least one component selected from the group consisting of odorants, flavors, antibacterial agents, fungicides, lubricants, and prolonged delivery regulators. As a composition to be included, in this case, the selection and ratio of the ingredients means that they depend on their properties and the method of administration and administration of the composition. Examples of suspending agents include ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide. metahydroxide, bentonite, agar-agar and tragacanth, as well as mixtures of these substances. Protection against the action of microorganisms can be provided by the use of various antibacterial and antifungal agents such as parabens, chlorobutanol, sorbic acid, etc. . The composition may also include isotonic agents, such as sugar, sodium chloride, and the like. A substance whose prolonged action slows the absorption of the active agent. For example, it can be achieved using aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyalcohol as well as mixtures thereof, vegetable oils (such as olive oil) and injection organic esters (ethyl oleate). (such as ethyl oleate). Examples of excipients include lactose, milk sugar, sodium citrate, calcium carbonate, and calcium phosphate. Examples of dispersing and dispersing agents are starch, alginic acid and salts thereof, and silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycol. Alone or in combination with other active agents, the active agents may be oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal ( rectal) may be administered to animals and humans in a standard administration form, mixed with a conventional pharmaceutical carrier. Suitable unit dosage forms include oral forms such as tablets, gelatin capsules, pills, powders, granules, chewable tablets, and oral solutions. Or suspension, sublingual and buccal dosage forms, aerosols, implants, local, transdermal, subcutaneous, intramuscular, intramuscular, intravenous, nasal It includes intranasal or intraocular dosage forms and rectal dosage forms.

"Pharmaceutically acceptable salt" means the relatively non-toxic organic and inorganic salts of acids and bases claimed in the present invention. These salts may be prepared in situ or intentionally through the process of synthesis, separation or purification of the compound. In particular, base salts can be specially prepared based on the purified free base of the claimed compounds and suitable organic and inorganic acids. Examples of the salts thus prepared are hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates. ), valerates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, tosyl Tosylates, citrates, fumarates, succinates, tartrates, mesylates, malonates, salicylates, propionates (propionates), ethanesulfonates, benzenesulfonates, sulfamates, and the like, and preferably maleates.(Detailed description of the properties of these salts is Berge SM, etc. Of "Pharmaceutical Salts" J. Pharm. Sci. 1977, 66: 1-19). Salts can be prepared with amino acids. Acidic amino acids-glutamic acid and aspartic acid-can be used as amino acids.

It is an object of the present invention to provide a polymorph of trimebutine maleate that is stable in storage, non-hygroscopic, easily soluble, economically viable, industrially manufacturable and can be prepared. will be.

The stability in the solid state and the shelf life of the active ingredient are very important factors. Pharmaceutical compounds and compositions containing the same should be able to be stored for long periods of time without showing significant changes in the physicochemical properties of the active ingredient (e.g., its chemical composition, density, hygroscopicity and solubility). In addition, it is also important to present the drug product in the purest form possible. In this respect, amorphous compounds can present significant problems. For example, these compounds have been found to be difficult, often unstable and chemically contaminated, to be incorporated into handling and dosage forms compared to crystalline compounds. Those skilled in the art will understand that the above problem can be solved if the drug product can be easily obtained in a stable crystalline form.

The technical effect of the present invention is the improved properties of the present compounds when used preparatively, in particular a high dissolution rate, increased storage stability and low hygroscopicity.

The following angles in the X-ray powder diffraction pattern: 8.7; 11.6; 13.2; 15.3; 17.6; 20.1; 20.3; 20.8; 21.5; 23.4; 24.7; 25.4; 27.3; 27.9; 30.8; 34.7; 35.8; 39.1; By obtaining a novel polymorph of trimebutine maleate having a characteristic peak at 45.0° (± 0.1°) 2θ, the above object is fulfilled and the technical result is achieved.

In addition, as a pharmaceutical composition for the treatment of irritable bowel syndrome, the treatment of postoperative paralytic ileus, and the preparation of X-rays and endoscopic examinations of GIT, the trimebutine male By providing a pharmaceutical composition containing a therapeutically effective amount of a polymorph of an acid salt and at least one pharmaceutically acceptable carrier, the above-established objectives are met and the stated technical results are achieved.

In addition, as a medical product for the preparation of irritable bowel syndrome, postoperative intestinal obstruction, and endoscopy of X-ray and GIT, tablets and capsules contained in a pharmaceutically acceptable package Or in the form of injections, by providing a pharmaceutical product containing a therapeutically effective amount of a novel polymorph of a trimebutine maleate compound and the pharmaceutical composition of the present invention, the above set object is satisfied and the technical result mentioned Is achieved.

The pharmaceutical composition may contain a pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients are understood as diluents, auxiliary agents and/or carriers used in the pharmaceutical field. The pharmaceutical composition having a novel polymorph of the trimebutine maleate compound according to the present invention may contain other active ingredients, provided it has activity and does not cause undesirable effects.

If the pharmaceutical composition of the present invention is to be used clinically, it can be mixed with a conventional pharmaceutical carrier.

The carrier used in the pharmaceutical composition of the present invention is a carrier used in the pharmaceutical field to prepare common forms; Specifically, binders, lubricants, disintegrants, solvents, diluents, stabilizers, suspending agents, and flavoring agents are oral. used in (oral forms); Antiseptic agents, solubilizers, and stabilizers are used in injection forms; Supports, thinners, lubricants, and preservatives are used in topical forms.

Medicinal agents may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically). I can. The clinical dosage of the substance containing the novel polymorph of the trimebutine meleate compound of the present invention is generally 50-1000 mg, preferably 300-600 mg, in an adult. The therapeutic efficacy and bioavailability of the active ingredients in, their metabolic rates and excretion from the body, as well as the age, sex and disease stage of the patient can be adjusted to the patient. Therefore, in the case of preparing the pharmaceutical drug of the present invention from the pharmaceutical composition, the effective amount should be considered as dosage units, in which case each dosage unit is the trimebutine maleate compound of the present invention. It contains 10-500 mg, preferably 50-300 mg of the novel polymorph. Depending on the doctor's or pharmacist's instructions, these preparations can be taken several times (preferably once to six times) within a certain period of time.

The invention is also illustrated by the accompanying drawings.
1 shows a powder x-ray diffraction pattern of a novel polymorph of trimebutine maleate prepared according to the present invention. The dependence of the intensity I,% of the angle 2θ° (± 0.1°).

The following examples of embodiments of the invention are illustrative and do not limit the invention in any way.

Preparation of polymorph of trimebutine maleate.

10 mg of trimebutine maleate was dissolved in 10 ml of methanol and the mixture was heated to 40°C. 10 ml of water was added dropwise to the prepared solution for 20 minutes at the same temperature, and the prepared mixture was cooled to 5° C. for 24 hours, and then filtered and crystalline material was collected. The crystals were dried at 50[deg.] C. under reduced pressure until the decrease in crystal weight ceased upon further drying; As a result, 9.75 mg of a white solid material having a melting temperature of 132-133°C was prepared.

The presence of trimebutine maleate polymorphs was tested using three detection methods in compliance with the recommendations of the International Conference on Harmonization Q6A (International Conference on Harmonization Q6A): differential scanning calorimetry (DSC) analysis, solid -Solid-state infrared spectrophotometry (FT-IR) and X-ray powder diffraction. Differential scanning calorimetric analysis of trimebutine maleate was performed in Perkin Elmer DSC. Thermograms were recorded in a nitrogen atmosphere at a heating rate of 5°C/min. Three consecutive thermograms showed endothermicity in the range of 105.6°C-105.7°C. The FT-IR spectrum of trimebutine maleate was recorded as a solid state as KBr dispersion using a Shimadzu FT-IR spectrophotometer. The three consecutive IR spectra were identical.

Three consecutive X-ray powder diffraction patterns of trimebutine maleate were obtained using a diffractometer equipped with a horizontal goniometer at θ/2θ.

On the spectrum of the powder X-ray diffraction pattern of the crystalline material (Fig. 1), the characteristic peaks are the following diffraction angles: 8.7; 11.6; 13.2; 15.3; 17.6; 20.1; 20.3; 20.8; 21.5; 23.4; 24.7; 25.4; 27.3; 27.9; 30.8; 34.7; 35.8; 39.1; It was observed at 45.0 ° (± 0.1 °) 2θ (Table 1).

The peak values of the powder X-ray diffraction pattern. Angle 2θ, °

Interplanar distance D,

Relative intensity I,% 8.7 ± 0.1 10.10 ± 0.01 99.9 ± 0.1 10.7 ± 0.1 8.27 ± 0.01 0.2 ± 0.1 11.6 ± 0.1 7.59 ± 0.01 5.4 ± 0.1 13.2 ± 0.1 6.72 ± 0.01 2.1 ± 0.1 15.3 ± 0.1 5.77 ± 0.01 1.4 ± 0.1 16.0 ± 0.1 5.54 ± 0.01 0.2 ± 0.1 16.3 ± 0.1 5.42 ± 0.01 0.5 ± 0.1 17.6 ± 0.1 5.04 ± 0.01 1.4 ± 0.1 17.8 ± 0.1 4.98 ± 0.01 0.6 ± 0.1 18.5 ± 0.1 4.79 ± 0.01 0.4 ± 0.1 18.8 ± 0.1 4.72 ± 0.01 0.4 ± 0.1 19.3 ± 0.1 4.60 ± 0.01 0.3 ± 0.1 20.1 ± 0.1 4.41 ± 0.01 1.1 ± 0.1 20.3 ± 0.1 4.37 ± 0.01 0.8 ± 0.1 20.8 ± 0.1 4.26 ± 0.01 0.8 ± 0.1 21.5 ± 0.1 4.13 ± 0.01 2.5 ± 0.1 22.3 ± 0.1 3.99 ± 0.01 0.6 ± 0.1 23.4 ± 0.1 3.80 ± 0.01 4.9 ± 0.1 24.7 ± 0.1 3.61 ± 0.01 0.9 ± 0.1 25.4 ± 0.1 3.50 ± 0.01 0.9 ± 0.1 25.9 ± 0.1 3.44 ± 0.01 0.4 ± 0.1 26.3 ± 0.1 3.39 ± 0.01 0.5 ± 0.1 26.5 ± 0.1 3.36 ± 0.01 0.4 ± 0.1 27.3 ± 0.1 3.27 ± 0.01 1.0 ± 0.1 27.9 ± 0.1 3.20 ± 0.01 2.2 ± 0.1 28.8 ± 0.1 3.10 ± 0.01 0.3 ± 0.1 29.4 ± 0.1 3.04 ± 0.01 0.3 ± 0.1 30.4 ± 0.1 2.94 ± 0.01 0.3 ± 0.1 30.8 ± 0.1 2.90 ± 0.01 2.1 ± 0.1 31.4 ± 0.1 2.85 ± 0.01 0.3 ± 0.1 32.3 ± 0.1 2.77 ± 0.01 0.2 ± 0.1 34.2 ± 0.1 2.62 ± 0.01 0.3 ± 0.1 34.7 ± 0.1 2.58 ± 0.01 0.9 ± 0.1 35.3 ± 0.1 2.54 ± 0.01 0.4 ± 0.1 35.8 ± 0.1 2.51 ± 0.01 0.7 ± 0.1 36.0 ± 0.1 2.43 ± 0.01 0.3 ± 0.1 36.5 ± 0.1 2.46 ± 0.01 0.3 ± 0.1 37.7 ± 0.1 2.39 ± 0.01 0.2 ± 0.1 38.3 ± 0.1 2.35 ± 0.01 0.4 ± 0.1 39.1 ± 0.1 2.30 ± 0.01 0.7 ± 0.1 40.0 ± 0.1 2.25 ± 0.01 0.3 ± 0.1 42.5 ± 0.1 2.13 ± 0.01 0.2 ± 0.1 43.0 ± 0.1 2.10 ± 0.01 0.3 ± 0.1 43.4 ± 0.1 2.08 ± 0.01 0.3 ± 0.1 44.0 ± 0.1 2.06 ± 0.01 0.5 ± 0.1 45.0 ± 0.1 2.01 ± 0.01 1.7 ± 0.1 45.4 ± 0.1 2.00 ± 0.01 0.3 ± 0.1 47.0 ± 0.1 1.93 ± 0.01 0.3 ± 0.1 47.4 ± 0.1 1.92 ± 0.01 0.3 ± 0.1 48.9 ± 0.1 1.86 ± 0.01 0.2 ± 0.1 49.4 ± 0.1 1.84 ± 0.01 0.2 ± 0.1

Dissolution kinetics of novel polymorphs.

The dissolution kinetics of the novel polymorph of trimebutine maleate prepared in Example 1 was measured by the material content in the solvent medium and compared with the dissolution kinetics of the prototype. The tool for determining the dissolution rate is a 1 liter 3-neck vessel. A thermometer was placed in one of the necks, a glass tube for the sample and their complexation was placed in the second neck, and the main part of the tool-as a cylindrical basket 3.6 cm high and 2.5 cm diameter. A cylindrical basket made of stainless steel in the shape of a mesh with holes having a diameter of 40 mesh (about 0.351 mm)-was placed in the third neck. The basket was mounted on the shaft of the motor.

The solvent medium (1000 ml) was poured into the vessel, and in this experiment it was a 50:50 mixture of ethanol and water, which is one of the common carriers for injections and is often used as a solvent in chemical reaction and biological screening systems. Because it is used. The test samples were placed in a cylindrical basket installed 2 cm from the bottom of the vessel.

For Comparative Sample 1, a novel polymorph of 200 mg of trimebutine maleate was used to prepare a solution containing 200 ppm of trimebutine maleate after complete dissolution; And for Comparative Sample 2, 200 mg of the prototype was used to prepare a solution containing 200 ppm of the prototype after complete dissolution.

During the experiment, the temperature of the solvent medium was kept constant (37 ± 0.5 °C). The rotation speed of the basket in the medium was 200 rpm, and was adjusted to an accuracy of ± 5%. At predetermined time intervals, 1-2 ml samples were taken and analyzed to confirm the content of the medicinal substance. The volume of solvent taken was immediately replenished with fresh.

The results obtained are shown in Table 2 (the value is the amount (ppm) of Sample 1 or 2 in the solution).

Dissolution kinetics of novel polymorphs. Concentration in solution Time in seconds Sample 1, ppm
Novel polymorph of trimebutine maleate Sample 2, ppm
(prototype) 0 0 0 10 18 7 30 50 12 60 75 29 300 132 98 600 180 169 900 200 188 1,200 200 200

These results show that the dissolution rate of the novel polymorph of trimebutine maleate in the water-alcohol mixture is higher than that of the prototype. Specifically, the dissolution time of 50% of the novel polymorph of trimebutine maleate was statistically significantly lower compared to the comparative sample of the prototype.

Stability study of novel polymorphs upon storage.

The stability of the novel polymorph of trimebutine maleate prepared in Example 1 was measured by material content and compared with the stability of the prototype through an accelerated aging method.

All samples were stored in glass vials sealed with rubber stoppers with aluminum caps in a climate chamber under an accelerated test environment. Active substance content was determined by HPLC using the respective criteria.

The "accelerated aging" method is characterized by maintaining at a temperature and humidity that exceeds its storage temperature and humidity during handling of the test medicinal product. At elevated temperatures, in general, the physicochemical processes that take place in pharmaceuticals are accelerated, resulting in undesirable quality changes over time. Thus, at elevated temperatures, the period over which controlled quality indicators of the drug product are preserved within acceptable limits (experimental shelf life) is artificially compared to the shelf life at the storage temperature. Decreases. This makes it possible to significantly reduce the time required to set the validity period.

According to the results obtained in the "accelerated aging" process of pharmaceuticals, it is also possible to solve the inverse problem, ie to set a storage temperature that provides a specific shelf life.

The shelf life (C) at the storage temperature (t _st ) is related to the experimental shelf life (C _E ) at an increased temperature (t _e ) of the experimental storage by the following relationship:

In this case, the correlation coefficient is:

The temperature coefficient of the chemical reaction rate (A) was 2.5. This dependence is based on the Van't-Hoff rule, which states that every 10°C increase in temperature increases the rate of chemical reactions by 2-4 times.

According to GPM.1.1.0009.15, the value of the correlation coefficient (K) according to the selected temperature interval (t _e -t _st ) equal to 30°C is 15.6. The experimental storage period for the selected shelf life of 3 years is 71 days.

Statistical processing of parameters was performed using the statistical software package SPSS Statistics 19.0.

The novel polymorph of trimebutine maleate according to the present invention was found to have a statistically significant increase in storage stability compared to the prototype.

After storage for 71 days under the accelerated aging method, it was found that the novel polymorph of trimebutine maleate according to the present invention has a statistically significant increase in stability and remains chemically pure. The prototype material was kept in a chemically pure state for less than 10 days, and the content of the active material was reduced by more than 3%. That is, the novel polymorph of trimebutine maleate according to the present invention is significantly more stable upon storage compared to the prototype.

Stability evaluation according to the accelerated aging method compared to the prototype. Save time at (t _e -t _st )
= 30°C, days The amount of active substance as measured by HPLC, expressed as a percentage of the theoretical content Novel polymorph of trimebutine maleate prototype 0 100 100 10 100 99.9 20 99.9 99.5 30 99.9 99.2 40 99.9 98.6 50 99.9 98.1 60 99.9 97.5 71 99.8 96.6

Measurement of hygroscopicity.

The reduction in hygroscopicity is a great advantage of the novel polymorph of trimebutine maleate during manufacture and storage of the material.

Hygroscopicity is measured by storing the solid compound in a chamber having a constant relative humidity at room temperature for 96 hours. A comparison of the anhydrous polymorph and prototype of trimebutine maleate at room temperature showed that the prototype was hygroscopic, starting at a relative humidity of 60% and increasing the humidity significantly. The novel polymorph of trimebutine maleate showed no significant increase in humidity except when stored at a relative humidity of 90% or more. The results are shown in Table 4 below.

Hygroscopic evaluation at room temperature compared to the prototype (96 hours). Relative humidity,% Increase (new polymorph of trimebutine maleate),% Increase (prototype),% 0 0.0 0.0 15 0.0 0.0 30 0.0 0.2 45 0.0 0.4 60 0.1 1.5 75 0.3 4.5 90 3.7 9.1 100 6.3 12.5

Manufacture of pharmaceuticals in tablet form

Polymorphs of 1,600 mg of starch, 1,600 mg of crushed lactose, 400 mg of talc, and 1,000 mg of trimebutine maleate compound were mixed and pressed to prepare a bar. The resulting rod was crushed into granules and sieved, collecting 14-16 mesh granules. The granules thus obtained were purified into suitable tablets weighing 560 mg each.

Manufacture of pharmaceuticals in capsule form

The polymorph of the trimebutine maleate compound was carefully mixed with the lactose powder in a 2:1 ratio. The prepared powder mixture was packaged in a gelatin capsule of an appropriate size of 300 mg each.

Preparation of pharmaceuticals in the form of injection compositions for intramuscular, intraperitoneal or subcutaneous injection

500 mg of a polymorph of trimebutine maleate compound was mixed with 300 mg of chlorobutanol, 2 ml of propylene glycol and 100 ml of injection water. The prepared solution was filtered and put into ampoules of 1 ml each, and then sealed.

Study of antispasmodic activity of novel polymorphs.

Experiments were carried out on separate bladder strips of nonlinear female white rats weighing 173 ± 13 g [IV Gerashchenko, NA Mohort "The study of the antispasmodic activity of imidazo [1,2]. -a] azepinium derivatives on isolated rat bladder strips". Experimental and Clinical Pharmacology, 2014, Volume 77, No. 6, p. 24-26]. Animals were kept at a temperature of 22-24°C and humidity of 65-75% with a 14-hour photoperiod with free access to water and standard all-mash ration. Prior to the experiment, animals were placed in cages with no access to feed and water for 1 hour. After weighing, the bladder was separated from the animal and placed on a paraffin surgical table in Krebs buffer solution (mmol/L) having the following composition: NaCl-132; KCl-4.7; NaH ₂ PO ₄ -1.4; NaHCO ₃ - 16.3; CaCl ₂ - 2.5; MgCl ₂ -1.05; Glucose-6.5. Aeration of the solution was performed with a mixed gas (carbogen) (a gas mixture containing 5% CO ₂ /95% O ₂ ).

After washing the bladder fat and connective tissue, the lower part of the bladder was cut and two rings 1 mm wide were cut out. The rings were cut in half to obtain a strip, which was placed in a flow chamber having a temperature of 37±0.5° C. and a flow rate of 1.5 ml/min. The first stretching of the separated strip was performed with a load of 0.25 g.

After stabilizing the response to periodic stimulation with Krebs hyperpotassium solution (KCL 40 mM), the effect of the polymorph of this study on the basal tone of the separated strip was studied. The polymorph of this study was dissolved in dimethyl sulfoxide and Krebs high potassium ion solution was added to prepare a concentration of 10 ^-7 , 10 ^-6 , 10 ^-5 , 10 ^-4 mol/L, and 15 Pumped through the chamber incrementally every minute.

The force of contractile movement was measured in isometric mode using FTC-0.1 capacitive strain gauges. Contractions were recorded with a personal computer using an analog-to-digital converter.

Basal elasticity was measured in grams using a recorded mechanogram. Then, the relaxation rate was calculated, considering the reaction of the strip in the Krebs high potassium ion solution as 100% shrinkage.

Statistical data processing was performed using Origin 7.5 and Microsoft Office Excel 2010 software. Antispasmodic activity was measured by the concentration indicated at the maximum rate of relaxation (￡ _max , %). At a concentration of 10 ^-4 mol/L, the maximum relaxation for the solution background of the new polymorph reached 60%, which shows the high antispasmodic activity of the novel polymorph of the trimebutine maleate compound.

The present invention can be applied to medicine and pharmacology.

Claims (3)

As a polymorph of trimebutine maleate, the following angles in the X-ray powder diffraction pattern: 8.7; 11.6; 13.2; 15.3; 17.6; 20.1; 20.3; 20.8; 21.5; 23.4; 24.7; 25.4; 27.3; 27.9; 30.8; 34.7; 35.8; 39.1; A polymorph of trimebutine maleate, characterized in that it has a characteristic peak at 45.0° (± 0.1°) 2θ.
As a pharmaceutical composition for the treatment of irritable bowel syndrome, the treatment of postoperative paralytic ileus, and the preparation of X-ray and endoscopy of GIT, the composition comprising the trimer of claim 1 A pharmaceutical composition comprising a therapeutically effective amount of a polymorph of butine maleate and at least one pharmaceutically acceptable carrier.
As a medical drug for the treatment of irritable bowel syndrome, postoperative intestinal obstruction, and preparation for X-ray and GIT endoscopy, tablets and capsules contained in a pharmaceutically acceptable package Or in the form of injections, wherein the drug comprises a therapeutically effective amount of the polymorph according to claim 1 or the pharmaceutical composition according to claim 2.

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