阅读说明：本技术 马来酸曲美布汀的多晶型物及其使用方法 (Polymorphs of trimebutine maleate and methods of use thereof ) 是由 基里尔·康斯坦丁诺维奇·瑟罗夫 弗拉基米尔·维克托罗维奇·涅斯捷鲁克 于 2018-11-08 设计创作，主要内容包括：本发明涉及医药、药理学以及化学和制药工业领域,尤其涉及马来酸曲美布汀的新型多晶型物及其生产和使用方法。(The present invention relates to the fields of medicine, pharmacology, and the chemical and pharmaceutical industries, and in particular to novel polymorphs of trimebutine maleate and methods of making and using the same.)

1. A polymorph of trimebutine maleate, characterised in that it has characteristic peaks in the X-ray powder diffraction pattern at the following angles: 2 theta, (± 0.1 °) 8.7; 11.6; 13.2; 15.3; 17.6; 20.1; 20.3; 20.8 of the total weight of the mixture; 21.5; 23.4; 24.7; 25.4 of the total weight of the mixture; 27.3; 27.9; 30.8 of the total weight of the mixture; 34.7; 35.8 of; 39.1; 45.0.

2. a pharmaceutical composition for the treatment of irritable bowel syndrome, post-operative paralytic ileus and for X-ray and endoscopic examinations in preparation for GIT, characterized in that it comprises a therapeutically effective amount of the polymorphic form of trimebutine maleate according to claim 1 and at least one pharmaceutically acceptable carrier.

3. A medicament for the treatment of irritable bowel syndrome, post-operative paralytic ileus and for X-ray and endoscopic examinations in preparation for GIT in the form of tablets, capsules or injections placed in a pharmaceutically acceptable package, characterized in that: the medicament comprising a therapeutically effective amount of the polymorph of claim 1 or the pharmaceutical composition of claim 2.

The terms used in the description of the present invention are defined as follows.

"agent" (drug substance, pharmaceutical substance) refers to a physiologically active substance of synthetic or other (biotechnological, plant, animal, microbial, etc.) origin that has pharmacological activity and is an active agent of a pharmaceutical composition for the production and preparation of a pharmaceutical product (drug).

"drug (product)" is a substance (or a mixture of substances in the form of pharmaceutical compositions) in the form of tablets, capsules, injections, ointments and other preparations, which is intended to restore, correct or modify the physiological functions of humans and animals and for the treatment and prevention of diseases in terms of diagnosis, anesthesia, contraception, cosmetology and the like.

"pharmaceutical composition" means a novel polymorph comprising trimebutine maleate and at least one of the components selected from the group consisting of: pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, adjuvants, distribution agents, delivery agents, such as preservatives, stabilizers, fillers, dispersants, humectants, emulsifiers, suspending agents, thickening agents, sweeteners, flavoring agents, antibacterial agents, fungicides, lubricating oils, prolonged delivery modulators, the selection and proportions of which depend on their nature, the method of administration and the dosage of the composition. Examples of suspending agents are ethoxylated isostearyl alcohols, polyoxyethylene, sorbitol and sorbitol ethers, microcrystalline cellulose, aluminum metahydroxide (aluminum metahydroxide), bentonite, agar-agar and tragacanth (tragacanth) and mixtures of these substances. A variety of antibacterial and antifungal agents (e.g., such as parabens, chlorobutanol, sorbic acid, and the like) can be used to provide protection against the action of microorganisms. The composition may also contain isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged action of the composition can be achieved by the use of agents which slow the absorption of the active agent, such as aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents and delivery vehicles are water, ethanol, polyols and mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Examples of excipients are lactose, bovine lactose (milk sugar), sodium citrate, calcium carbonate, calcium phosphate, and the like. Examples of dispersing and partitioning agents are starch, alginic acid and its salts, silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc and high molecular weight polyethylene glycols. Pharmaceutical compositions for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, topical or rectal administration of active agents, alone or in combination with another active agent, can be administered to animals and humans in standard administration forms in admixture with conventional pharmaceutical carriers. Suitable unit dosage forms include oral forms such as tablets, gelatin capsules, pills, powders, granules, chewable tablets and oral liquids or suspensions, sublingual and buccal administration forms, aerosols, implants, topical, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular administration forms and rectal administration forms.

"pharmaceutically acceptable salts" refers to the relatively non-toxic organic and inorganic salts of the acids and bases claimed in this invention. These salts may be generated in situ, or intentionally generated, by the synthesis, isolation or purification of the compound. In particular, base salts can be specifically produced based on the purified free base of the claimed compounds and a suitable organic or inorganic acid. Examples of Salts thus produced are hydrochloride, hydrobromide, sulphate, bisulphate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, tosylate, citrate, fumarate, succinate, tartrate, mesylate malonate, salicylate, propionate, ethanesulphonate, benzenesulphonate, sulphamate and the like, preferably maleate (detailed description of the properties of these Salts is found in Berge SM, et., "Pharmaceutical Salts" j.pharm. sci.1977,66:1-19) Salts can be produced from amino acids. Acidic amino acids-glutamic acid and aspartic acid-can be used as amino acids.

The invention aims to provide a preparation type polymorphic substance of trimebutine maleate, which is stable in storage, non-hygroscopic, easy to dissolve, economic and feasible, and can be industrially produced and prepared.

The stability and shelf life of the active ingredient in the solid state are very important factors. Pharmaceutical compounds and compositions containing such compounds must be capable of long-term storage without significant changes in the physicochemical properties of the active ingredient (e.g., its chemical composition, density, hygroscopicity and solubility). Furthermore, it is also important to provide the drug in as pure a form as possible. In this regard, amorphous compounds can present significant problems. For example, such compounds are more difficult to handle and incorporate into dosage forms than crystalline compounds, and they often prove unstable and chemically contaminated. It will be appreciated by those skilled in the art that the above problems can be solved if the drug can be readily obtained in a stable crystalline form. The technical effect of the present invention is to have improved properties when the compound is prepared for use, in particular higher dissolution rate, increased storage stability and low hygroscopicity.

The above objects are achieved and technical results obtained by obtaining a new polymorph of trimebutine maleate, having characteristic peaks on the X-ray powder diffraction diagram at the following angles: 2 theta, (± 0.1 °) 8.7; 11.6; 13.2; 15.3; 17.6; 20.1; 20.3; 20.8 of the total weight of the mixture; 21.5; 23.4; 24.7; 25.4 of the total weight of the mixture; 27.3; 27.9; 30.8 of the total weight of the mixture; 34.7; 35.8 of; 39.1; 45.0.

the set objects as well as the technical effects described are achieved by providing a pharmaceutical composition comprising a therapeutically effective amount of the polymorphic form of trimebutine maleate compound as defined above and at least one pharmaceutically acceptable carrier for the treatment of irritable bowel syndrome, post-operative paralytic ileus and for the preparation of X-ray and endoscopic examinations of the GIT.

The stated objects as well as the stated technical effects are achieved by providing a pharmaceutical product comprising a therapeutically effective amount of this novel polymorph of trimebutine maleate compound or pharmaceutical composition according to the invention in the form of tablets, capsules or injections placed in a pharmaceutically acceptable package for the treatment of irritable bowel syndrome, post-operative paralytic ileus and for the preparation of X-ray and endoscopic examinations of the GIT.

The pharmaceutical composition may include a pharmaceutically acceptable excipient. Pharmaceutically acceptable excipients are understood to be diluents, adjuvants and/or carriers used in the pharmaceutical field. The pharmaceutical compositions of the novel polymorphic forms of trimebutine maleate compound according to the invention may comprise other active substances, including those having activity, as long as they do not cause adverse effects.

If the pharmaceutical composition of the present invention must be used in clinical practice, it may 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 for producing a usual form; in particular, binders, lubricants, disintegrating agents, solvents, diluents, stabilizers, suspending agents, flavoring agents, used in oral form; preservatives, solubilizers, stabilizers used in the form of injections; a support agent, a diluent, a lubricant, a preservative for topical use.

Pharmaceutical agents (Medicinal agents) can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically). The clinical dose of the medicament containing the novel polymorph of trimebutine maleate compound of the present invention may be adjusted in the patient according to the therapeutic effect and the bioavailability of the active ingredient in the patient's body, its metabolic rate and the amount excreted from the body, as well as the age, sex and disease stage of the patient, whereas the daily dose for an adult is usually 50-1000mg, preferably 300-600 mg. Thus, when preparing the medicament of the present invention from a pharmaceutical composition, the above effective dose must be taken as dosage units, each containing 10-500mg, preferably 50-300mg, of the novel polymorph of trimebutine maleate according to the invention. These formulations may be taken multiple times (preferably one to six times) over a period of time, as instructed by the physician or pharmacist.

The invention is also illustrated by the accompanying drawings.

Figure 1 shows the powder X-ray diffraction pattern of the novel polymorph of trimebutine maleate prepared according to the present invention. Intensity I,% dependence on angle 2 θ, ° (± 0.1 °).

The following examples of embodiments of the present invention are illustrative, and not limiting of the invention in any way.

Examples