WO2019098883A1 - Formes polymorphes de maléate de trimébutine et procédés d'utilisation - Google Patents

Formes polymorphes de maléate de trimébutine et procédés d'utilisation Download PDF

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Publication number
WO2019098883A1
WO2019098883A1 PCT/RU2018/000729 RU2018000729W WO2019098883A1 WO 2019098883 A1 WO2019098883 A1 WO 2019098883A1 RU 2018000729 W RU2018000729 W RU 2018000729W WO 2019098883 A1 WO2019098883 A1 WO 2019098883A1
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Prior art keywords
trimebutine maleate
polymorphic form
trimebutine
maleate
ray
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PCT/RU2018/000729
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English (en)
Russian (ru)
Inventor
Кирилл Константинович Сыров
Владимир Викторович НЕСТЕРУК
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Общество С Ограниченной Ответственностью "Валента-Интеллект"
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Priority to UAA202003442A priority Critical patent/UA124755C2/uk
Priority to EA202091237A priority patent/EA202091237A1/ru
Priority to CN201880074646.0A priority patent/CN111432811B/zh
Priority to KR1020207016962A priority patent/KR102509190B1/ko
Priority to BR112020010135-4A priority patent/BR112020010135A2/pt
Publication of WO2019098883A1 publication Critical patent/WO2019098883A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C219/18—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated and containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C219/20—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • C07C219/22—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings

Definitions

  • the invention relates to the field of medicine, pharmacology and chemical-pharmaceutical industry, namely, new polymorphic forms of trimebutine maleate and methods for their preparation and use.
  • Functional intestinal disorders include a group of heterogeneous clinical conditions that manifest symptoms from the middle and lower parts of the gastrointestinal tract and are not accompanied by any structural, systemic or metabolic changes.
  • functional diseases reduce the quality of life of patients and cause great economic damage to society both in terms of direct costs of medical care and treatment, as well as indirect indicators, including compensation for temporary disability.
  • the first of these diseases include irritable bowel syndrome. According to epidemiological studies, 15–20% of the population suffers from irritable bowel syndrome. There are several forms of this disease: diarrhea variant, constipation variant, mixed form. Other functional bowel diseases, such as functional diarrhea, functional constipation, idiopathic abdominal pain, etc., are less common.
  • trimebutin is used to treat functional bowel disorders, mainly in irritable bowel syndrome (IBS). In Russia, at the end of 2007, it was registered under the trade name Trimedat®.
  • Trimedat® The effectiveness of trimebutine maleate in reducing abdominal pain has been demonstrated in various clinical studies. For a long time it was believed that the effect of trimebutine maleate is associated with its spasmolytic activity and it was believed that this drug acts like myotropic spasmolytic mebeverin. However, later, new data were discovered concerning the mechanism of action of trimebutine maleate, uncharacteristic for antispasmodic drugs.
  • trimebutin has a significant analgesic effect.
  • trimebutin is an agonist of opiate receptors and its modulating effect on gastrointestinal motility and analgesic effect is determined by the nonspecific effect of this drug on all classes of peripheral opiate receptors - m, k and d. Acting on the enkephalinergic system of the intestine, regulates gastrointestinal peristalsis. Acts throughout the gastrointestinal tract, reduces the pressure of the esophageal sphincter, promotes gastric emptying and increased intestinal motility; promotes the response of the smooth muscles of the colon to food stimuli.
  • trimebutine maleate used in the main indications include irritable bowel syndrome, postoperative paralytic intestinal obstruction, preparation for X-ray and endoscopic studies of the gastrointestinal tract.
  • trimebutin is prescribed orally in the form of various solid dosage forms, including tablets, both rapidly disintegrating and with delayed action. Since trimebutin is poorly soluble in water, for In order to increase its bioavailability, its more soluble salt, maleate, was obtained and introduced into clinical practice.
  • Polymorphs A and B were obtained by crystallization from isopropyl alcohol.
  • Polymorph B was obtained by crystallization from ethanol.
  • Polymer C is also derived from ethanol.
  • Polymorph C is more stable thermodynamically than polymorphs A and B.
  • Polymorph A melts at about 123 ° C
  • polymorph B melts at about 142 ° C
  • polymorph C melts at about 173 ° C.
  • trimebutin dimaleate The crystal structure of trimebutin dimaleate is described in the review [Coquerel G. “Limits of the co-crystal concept and beyond”, RSC Drug Discovery Series, 2012, vol.16, pp. 300-317].
  • trimebutine maleate is described, for example, in patent GB 1342547, where trimebutine maleate is obtained by reacting the base of trimebutine with maleic acid in water when heated, followed by crystallization.
  • trimebutine maleate can exist in a new polymorphic crystalline form, which has better properties than trimebutine maleate, obtained according to the method described in GB 1342547, hereinafter referred to as "prototype".
  • drug principle drug substance, drug substance
  • drug substance means a physiologically active substance of synthetic or other (biotechnological, plant, animal, microbial, etc.) origin, which has pharmacological activity and is the active principle of the pharmaceutical composition used for the manufacture and manufacture of a medicinal product ( ).
  • Drug (drug) a substance (or a mixture of substances in the form of a pharmaceutical composition) in the form of tablets, capsules, injections, ointments and other ready-made forms, designed to restore, correct or change the physiological functions in humans and animals, as well as treatment and prevention of diseases, diagnosis, anesthesia, contraception, cosmetology and others.
  • “Pharmaceutical composition” means a composition comprising a new polymorphic form of trimebutine maleate and at least one of the components selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible excipients, solvents, diluents, carriers, auxiliary, dispensing agents, means delivery, such as preservatives, stabilizers, fillers, dispersing agents, moisturizers, emulsifiers, suspending agents, thickeners, sweeteners, fragrances, flavors, en tibacterial agents, fungicides, lubricants, prolonged delivery regulators, the choice and ratio of which depends on their nature, the method of administration of the composition and dosage.
  • suspending agents examples include ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ether, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures of these substances. Protection against the action of microorganisms can be provided with a variety of antibacterial and antifungal agents, such as parabens, chlorobutanol, sorbic acid, and similar compounds.
  • the composition may also include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged action of the composition can be achieved with the help of agents slowing down the absorption of the active principle, such as, for example, aluminum monostearate and gelatin.
  • suitable carriers solvents, diluents, and delivery vehicles are water, ethanol, polyalcohols, and mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate).
  • suitable carriers solvents, diluents, and delivery vehicles are water, ethanol, polyalcohols, and mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate).
  • fillers are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate, and the like.
  • dispersing agents and dispensing agents are starch, alginic acid and its salts, silicates.
  • lubricants are magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycol.
  • a pharmaceutical composition for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, local or rectal administration of the active principle, alone or in combination with another active principle, can be administered to animals and humans in a standard administration form, as a mixture with traditional pharmaceutical carriers.
  • Suitable standard forms of administration include oral forms such as tablets, gelatin capsules, pills, powders, granules, chewable tablets and oral solutions or suspensions, sublingual and transbukkalny forms of administration, aerosols, implants, local, transdermal, subcutaneous, intramuscular, intravenous, intranasal or intraocular forms of administration and rectal forms of administration.
  • “Pharmaceutically acceptable salt” means relatively non-toxic organic and inorganic salts of acids and bases, as claimed in the present invention. These salts can be obtained in situ during the synthesis, isolation or purification of compounds, or obtained specifically. In particular, salts of the bases can be obtained specifically, starting from the purified free base of the claimed compound and a suitable organic or inorganic acid.
  • salts thus obtained are hydrochlorides, hydrobromides, sulphates, bisulphates, phosphates, nitrates, acetates, oxalates, valeriates, oleates, palmstats, stearates, laurates, borates, benzoates, lactates, tosylates, citrates, fumarates, succinates, tartrates. malonates, salicylates, propionates, ethanesulfonates, benzenesulfonates, sulfamates and the like, preferably maleates (A detailed description of the properties of such salts is given in Berge SM, et al., Pharmaceutical Salts ”J. Pharm. Sci. 1977, 66: 1-19 ).
  • Can be salts with amino acids are obtained.
  • the amino acids can be used acidic amino acids - glutamic and aspartic acid.
  • the present invention is to develop a stable during storage, non-hygroscopic, highly soluble, economically viable, industrially marketable preparative polymorphic form of trimebutine maleate.
  • Stability in solid state and shelf life of active ingredients are very important factors.
  • the medicinal compound and compositions comprising it must be able to be stored for considerable periods of time without showing significant changes in the physicochemical properties of the active component (for example, its chemical composition, density, hygroscopicity and solubility).
  • amorphous compounds can present significant problems. For example, such compounds are more difficult to handle and incorporate into dosage forms as compared to a crystalline compound, and it often turns out that they are unstable and chemically contaminated.
  • the person skilled in the art will understand that if the drug can be easily obtained in a stable crystalline form, then the above problems can be solved.
  • the technical result of the present invention is to improve the properties of this compound during its preparative use, in particular a higher dissolution rate, increased storage stability and low hygroscopicity.
  • the task is carried out, and the technical result is achieved by obtaining a new polymorphic form of the trimebutine maleate, which has characteristic peaks on an X-ray powder diffractogram at the following 2Q angles, ° ( ⁇ 0.1 °): 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; 45.0.
  • the problem is solved, and the claimed technical result is also achieved by creating a pharmaceutical composition for the treatment of irritable bowel syndrome, postoperative paralytic intestinal obstruction, preparation for X-ray and endoscopic studies of the gastrointestinal tract, containing a therapeutically effective amount of the above-mentioned polymorphic form of the trimebutine maleate compound, and at least one pharmaceutically acceptable carrier.
  • the task is solved, and the claimed technical result is also achieved by creating a drug for treating irritable bowel syndrome, postoperative paralytic intestinal obstruction, to prepare for X-ray and endoscopic studies of the gastrointestinal tract in the form of tablets, capsules or injections, placed in a pharmaceutically acceptable package containing therapeutically effective the amount of the mentioned new polymorphic form of the compound trimebutine maleate or pharmaceutical composition the present invention.
  • compositions may include pharmaceutically acceptable excipients.
  • Pharmaceutically acceptable excipients are diluents, auxiliary agents and / or carriers used in the pharmaceutical field.
  • the pharmaceutical composition, along with a new polymorphic form of the trimebutine maleate compound of the present invention, may include other active substances, including those with activity, provided that they do not cause undesirable effects.
  • the use of the pharmaceutical composition of the present invention in clinical practice it can be mixed with traditional pharmaceutical carriers.
  • the carriers used in the pharmaceutical compositions of the present invention are carriers that are used in the pharmaceutical field to produce common forms, in particular, in oral forms, binders, lubricants, disintegrating agents, solvents, diluents, stabilizers, suspending agents, flavoring agents are used. ; antiseptic agents, solubilizers, stabilizers are used in injection forms; in local forms, bases, diluents, lubricants, antiseptic agents are used.
  • Drugs can be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically).
  • Clinical the dosage of the agent containing the new polymorphic form of the trimebutine maleate compound of the present invention can be adjusted in patients depending on the therapeutic efficacy and bioavailability of the active ingredients in the body, their exchange rate and elimination from the body, and also depending on the age, sex and stage of the patient's disease while the daily dose in adults is usually 50-1000 mg, preferably 300-600 mg.
  • each dosage unit of the preparation should contain 10-500 mg of a new polymorphic form of the trimebutine maleate compound of the present invention, preferably 50-300 mg .
  • these drugs can be taken several times during certain periods of time (preferably from one to six times).
  • FIG. 1. shows the powder x-ray diffractogram of a new polymorphic form of the trimebutine maleate obtained according to the present invention.
  • trimebutine maleate was investigated using three detection methods, corresponding to the recommendations of the International Q6 A Harmonization Conference: differential scanning calorimetry (DSC) analysis, solid state infrared spectrophotometry (FT-IR) and powder X-ray diffraction).
  • DSC differential scanning calorimetry
  • FT-IR solid state infrared spectrophotometry
  • powder X-ray diffraction powder X-ray diffraction
  • FT-IR spectra of trimebutine maleate were recorded in the solid state as a dispersion of KBr using a Shimadzu FT-IR spectrophotometer.
  • the IR spectra of the three series are identical.
  • the X-ray powder diffraction patterns of the three series of trimebutine maleate were obtained using a diffractometer equipped with a horizontal qoniometer goniometer.
  • Table 1 The values of the peaks of the powder x-ray diffraction pattern.
  • Example 2 Determination of the kinetics of dissolution of a new polymorphic form.
  • the kinetics of dissolution of the new polymorphic form of the trimebutine maleate obtained in Example 1 was evaluated by the content of the substance in the solvent medium and compared with the dissolution kinetics of the prototype.
  • the device for determining the rate of dissolution is a three-neck vessel with a capacity of 1 l.
  • a thermometer was introduced into one of the tubes, a glass tube for taking samples and their integration into the other, and the third part — the main component of the instrument — a cylindrical basket 3.6 cm high and 2.5 cm in diameter, made of stainless steel in the form of a grid with holes. 40 mesh in diameter (about 0.351 mm).
  • the basket was mounted on the motor axis.
  • a dissolving medium 1000 ml was poured into the vessel, in this experiment a mixture of ethanol and water was 50:50, since it is one of the most common carriers for injection forms and is often used as a solvent in chemical reactions and biological screening systems.
  • the sample was placed in a cylindrical basket, which was placed at a distance of 2 cm from the bottom of the vessel.
  • Example 3 The study of stability during storage of a new polymorphic form.
  • Example 1 The stability of the new polymorphic form of trimebutine maleate obtained in Example 1 was evaluated by the content of the substance and compared with the stability of the prototype by the method of accelerated aging. All samples were stored in glass vials, sealed with rubber stoppers with aluminum caps, in a climatic chamber under accelerated testing conditions. The content of the active substance is determined by HPLC using standards.
  • the method of "accelerated aging” is to maintain the tested drug at temperatures and humidity exceeding the temperature and humidity of its storage during circulation.
  • elevated temperatures physicochemical processes occurring in drugs, as a rule, accelerate, leading to undesirable changes in quality over time.
  • the period of time during which the controlled indicators of the quality of the medicinal product are kept within acceptable limits is artificially reduced in comparison with the shelf life at storage temperature. This can significantly reduce the time required to establish the shelf life.
  • the inverse problem can also be solved, i.e. set the storage temperature to ensure any desired shelf life.
  • the shelf life (C) at the storage temperature (t xp ) is associated with the experimental shelf life (Ce) at elevated temperature of the experimental storage (t 3 ) by the following relationship:
  • the temperature coefficient of the chemical reaction rate (A) is assumed to be 2.5.
  • the dependence is based on the Van't Hoff rule about a 2-4-fold increase in the rates of chemical reactions with a temperature increase of 10 ° C.
  • the value of the conformity coefficient (K), depending on the selected temperature range (t 3 -t xp ), equal to 30 ° ⁇ , is 15.6.
  • the experimental storage period with a selected shelf life of 3 years is 71 days.
  • trimebutine maleate according to the present invention After 71 days of storage under the conditions of the method of accelerated aging, it was established that a new polymorphic form of trimebutine maleate according to the present invention has a statistically significantly increased stability and remains chemically pure.
  • the substance of the prototype remains chemically pure for less than 10 days, then the content of the active substance is reduced by more than 3%. That is, a new polymorphic form of trimebutine maleate according to the present invention is much more stable during storage compared to the prototype.
  • Reduced hygroscopicity is a great advantage of the new polymorphic form of trimebutine maleate in the preparation and storage of the substance.
  • Hygroscopicity was evaluated when storing a solid compound in chambers with constant relative humidity at room temperature for 96 hours.
  • a comparison of the anhydrous polymorphic form of the trimebutine maleate and the prototype at room temperature showed that the prototype is hygroscopic and reveals a large increase in humidity, starting at 60% relative humidity.
  • a new polymorphic form of trimebutine maleate does not detect any significant increase in moisture except for storage at a relative humidity above 90%.
  • Example 5 Getting the drug in pill form.
  • Example 6 Getting the drug in the form of capsules.
  • the polymorphic form of the trimebutine maleate compound was thoroughly mixed with lactose powder in a 2: 1 ratio.
  • the resulting powder mixture was packaged in 300 mg each into gelatin capsules of suitable size.
  • Example 7 Obtaining a medicinal product in the form of injection compositions for intramuscular, intraperitoneal or subcutaneous injections.
  • 500 mg of the polymorphic form of the trimebutine maleate compound were mixed with 300 mg of chlorobutanol, 2 ml of propylene glycol and 100 ml of injection water.
  • the resulting solution was filtered and placed in 1 ml ampoules, which were sealed.
  • Example 8 The study of the antispasmodic activity of a new polymorphic form.
  • the bladder was separated from the animals and placed on a paraffin surgical table in the thickness of the Krebs buffer solution of the following composition (in mmol / l): NaCl — 132; KS1 — 4.7; NaH 2 P0 4 -l, 4; NaHC0 3 - 16.3; CaCl 2 -2.5; MgCl 2 -l, 05; glucose - 6.5.
  • Aeration of the solution was carried out with carbogen (gas mixture of 5% C0 2 /95% 0 2 )
  • the effect of the studied polymorphic form on the basal tone of the isolated strips was studied after stabilization of their response to a periodic stimulation with Krebs hyperkalium solution (KS1 40 mM).
  • the studied polymorphic form was dissolved in dimethyl sulfoxide and added to the Krebs hyperkalium solution with the creation of concentrations of 10 7 , 10 6 , 10 5 , 10 4 mol / l, which were pumped through the chamber accumulatively, each 15 min.
  • the force of contractile movements was measured in isometric mode using capacitive strain gauges FTK-0, l.
  • the abbreviations were recorded by a personal computer using an analog-to-digital converter.
  • Basal tone was measured in grams using the recorded mechanogram. Next, the relaxation percentage was calculated, taking the reaction of the strips in Krebs hyperkalium solution as 100% contraction.
  • the invention can be used in medicine, pharmacology.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Emergency Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicinal Preparation (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne le domaine de la médecine humaine, de la pharmacie et d'industrie chimico-pharmaceutique et notamment de nouvelles formes polymorphes de maléate de trimébutine et des procédés de leur production et utilisation.
PCT/RU2018/000729 2017-11-20 2018-11-08 Formes polymorphes de maléate de trimébutine et procédés d'utilisation WO2019098883A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
UAA202003442A UA124755C2 (uk) 2017-11-20 2018-11-08 Поліморфні форми тримебутину малеату і спосіб застосування
EA202091237A EA202091237A1 (ru) 2017-11-20 2018-11-08 Новые полиморфные формы тримебутина малеата, способ получения и применения
CN201880074646.0A CN111432811B (zh) 2017-11-20 2018-11-08 马来酸曲美布汀的多晶型物及其使用方法
KR1020207016962A KR102509190B1 (ko) 2017-11-20 2018-11-08 트리메부틴 말레산염의 다형체 및 이의 사용방법
BR112020010135-4A BR112020010135A2 (pt) 2017-11-20 2018-11-08 formas polimórficas de maleato de trimebutina e método de usar as mesmas

Applications Claiming Priority (2)

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RU2017140269 2017-11-20
RU2017140269A RU2706166C2 (ru) 2017-11-20 2017-11-20 Новые полиморфные формы тримебутина малеата, способ получения и применения

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RU2752086C1 (ru) * 2020-04-27 2021-07-22 Общество С Ограниченной Ответственностью "Валента-Интеллект" Новое соединение [2-(диметиламино)-2-фенилбутил]-3,4,5-триметоксибензоата 4-метил-2н-хромен-2-он-7-илсульфат и его применение

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EA001506B1 (ru) * 1996-08-07 2001-04-23 Парк-Давиз Таблетка малеата тримебутина, покрытая оболочкой
EP2481403A1 (fr) * 2011-02-01 2012-08-01 Deva Holding Anonim Sirketi Combination pharmaceutique de l'otilonium et trimebutine

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FR2131804B1 (fr) * 1971-03-12 1974-03-22 Jouveinal Sa
CN102188389B (zh) * 2010-03-18 2014-04-02 杭州赛利药物研究所有限公司 马来酸曲美布汀干混悬剂及其制备方法
KR101220829B1 (ko) * 2010-07-16 2013-01-10 안국약품 주식회사 트리메부틴 함유 서방성 정제
RU2014138619A (ru) * 2012-03-12 2016-05-10 Джикеа Фарма Инк. Новые соли тримебутина на основе сульфонатов

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
EA001506B1 (ru) * 1996-08-07 2001-04-23 Парк-Давиз Таблетка малеата тримебутина, покрытая оболочкой
EP2481403A1 (fr) * 2011-02-01 2012-08-01 Deva Holding Anonim Sirketi Combination pharmaceutique de l'otilonium et trimebutine

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RU2017140269A3 (fr) 2019-05-20
CN111432811A (zh) 2020-07-17
CN111432811B (zh) 2023-06-23
KR102509190B1 (ko) 2023-03-14
KR20200110308A (ko) 2020-09-23
UA124755C2 (uk) 2021-11-10
RU2017140269A (ru) 2019-05-20
EA202091237A1 (ru) 2020-08-17
BR112020010135A2 (pt) 2021-03-23
RU2706166C2 (ru) 2019-11-14

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