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CN111432811A - Polymorphs of trimebutine maleate and methods of use thereof - Google Patents

Polymorphs of trimebutine maleate and methods of use thereof Download PDF

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CN111432811A
CN111432811A CN201880074646.0A CN201880074646A CN111432811A CN 111432811 A CN111432811 A CN 111432811A CN 201880074646 A CN201880074646 A CN 201880074646A CN 111432811 A CN111432811 A CN 111432811A
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trimebutine maleate
polymorph
trimebutine
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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
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Abstract

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.

Description

Polymorphs of trimebutine maleate and methods of use thereof
The present invention relates to the fields of medicine, pharmacology, and the chemical and pharmaceutical industry, and in particular to novel polymorphs of trimebutine maleate and methods of making and using the same.
In clinical practice, a considerable proportion of the diseases are functional diseases of the gastrointestinal tract. Functional bowel disorders (or FBDs) comprise a heterogeneous group of clinical disorders that manifest as lower-middle gastrointestinal disorders, without any structural, systemic, or metabolic changes. Despite the lack of organic basis, functional diseases, both in terms of direct indicators of medical care and treatment expenditure and in terms of indirect indicators such as temporary disability compensation, can reduce the quality of life of patients and cause huge economic losses to society.
First, these diseases include irritable bowel syndrome. According to epidemiological studies, 15-20% of people suffer from irritable bowel syndrome. There are several forms of this disease: a diarrhea-predominant subtype, a constipation-predominant subtype, and a mixed subtype. Other functional colon diseases such as functional diarrhea, functional constipation, idiopathic abdominal pain, etc. are less common.
Since 1969, trimebutine has been used in many countries to treat functional bowel disorders, mainly in the case of Irritable Bowel Syndrome (IBS). At the end of 2007, it came
Figure BDA0002496842770000011
Trademarks are registered in russia. The effectiveness of trimebutine maleate in reducing abdominal pain has been demonstrated in various clinical studies. It has long been thought that the effect of trimebutine maleate is related to its spasmolytic activity and is thought to be similar to mebeverine (mebeverine), a myotropic antispasmodic drug. However, new data was later discovered regarding the mechanism of action of trimebutine maleate, which is not commonly found in anticonvulsant drugs. In experimental and clinical studies, the modulatory effects of trimebutine maleate on gastrointestinal tract (GIT) motor function have been shown to manifest in therapeutic and surgical pathologies as a normalization of hypo-and hyperactivity disorders of GIT motility. Trimebutine has obvious analgesic effect. In experimental studies, trimebutine was found to be an opioid agonist and its nonspecific effects on all types of peripheral opioid receptors- μ, κ, andGIT movement and analgesic modulation. It acts on the enkephalinase system of the intestine and regulates GIT peristalsis. It acts throughout the gastrointestinal tract, reducing esophageal sphincter pressure, helping to empty the stomach and increase bowel motility, and helping to smooth the colon muscles' response to food stimulation.
Figure BDA0002496842770000021
3,4, 5-Trimethoxybenzoic acid (2-dimethylamino-2-phenyl) butyl maleate (trimebutine maleate)
The main indications for the use of trimebutine maleate include irritable bowel syndrome, post-operative paralytic ileus and X-ray and endoscopic examinations in preparation for GIT.
Generally, trimebutine is administered orally in various solid dosage forms (including tablets) which disintegrate rapidly and have a delayed action. Because trimebutine is poorly soluble in water, its more soluble salt, maleate, is prepared and put into clinical practice to improve its bioavailability.
Two different polymorphs of trimebutine 3-thiocarbamoylbenzenesulfonate are identified in the literature [ WO2013134869, "Preparation of sulfate-based trimebutine salts for use as organic and physical imaging and for the present of viral pain", publ.09/19/2013 ]. Polymorph a crystallizes from a mixture of acetone and methanol, whereas polymorph B crystallizes from methanol. Polymorph B is thermodynamically more 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 different polymorphs of trimebutine p-toluenesulfonate were also identified. Polymorphs a and B were crystallized from isopropanol. Polymorph B was crystallized from ethanol. Polymorph C is also produced from ethanol. Polymorph C is thermodynamically more stable than polymorphs a and B. Polymorph a melts at a temperature of about 123 ℃, polymorph B melts at a temperature of about 142 ℃, and polymorph C melts at a temperature of about 173 ℃.
The crystal structure of trimebutine dimaleate is described in a review [ Coquerel G. "L images of the co-crystal concept and beyond", RSCDUG Discovery Series,2012,20Vol.16, pp.300-317 ].
For example, the synthesis of trimebutine maleate is described in patent GB1342547, wherein trimebutine maleate is prepared by the heated reaction of trimebutine base with maleic acid in water and subsequent crystallisation. However, to date, no report has been made on the generation and study of the properties of polymorphic forms of trimebutine maleate.
The authors of the present invention have unexpectedly found that trimebutine maleate can exist in a new polymorphic crystalline form with properties superior to trimebutine maleate (hereinafter the "prototype") produced according to the process described in GB 1342547.
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
Example 1 preparation of polymorphs of trimebutine maleate
10mg trimebutine maleate are dissolved in 10ml methanol and the mixture is heated to 40 ℃. To the resulting solution was added dropwise 10ml of water at the same temperature over 20 minutes, and the resulting mixture was cooled to 5 ℃ for 24 hours, followed by filtration and collection of crystalline material. Drying the crystals at 50 ℃ under reduced pressure until further drying does not reduce the weight of the crystals; as a result, 9.75mg of a white solid substance having a melting point of 132-133 ℃ was obtained.
The presence of polymorphic forms in trimebutine maleate was detected using three assays in accordance with the International Conference on harmony (International Conference) Q6A recommendation: differential Scanning Calorimetry (DSC) analysis, solid-state infrared spectrophotometry (FT-IR) and X-ray powder diffraction).
Differential scanning calorimetry of trimebutine maleate was performed in a Perkin Elmer DSC. The thermograms were recorded at a heating rate of 5 ℃/min under nitrogen atmosphere. The thermograms of the three series show endotherms in the range 105.6-105.7 ℃.
The FT-IR spectrum of trimebutine maleate was recorded in solid KBr dispersion using a Shimadzu FT-IR spectrophotometer. The infrared spectra of these three series are identical.
Three series of X-ray powder diffraction patterns of trimebutine maleate were obtained using a diffractometer equipped with a theta/2 theta goniometer.
On the powder X-ray diffraction pattern (fig. 1) of the crystalline substance, characteristic peaks were observed at the following diffraction angles 2 θ, ° (± 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. (Table 1).
Table 1 peaks of the powder X-ray diffraction pattern.
Figure BDA0002496842770000071
Figure BDA0002496842770000081
Example 2. determination of the dissolution kinetics of the novel polymorph.
The dissolution kinetics of the novel polymorph of trimebutine maleate prepared in example 1 was evaluated by the content of substances in the solvent medium and compared with the dissolution kinetics of the prototype. The apparatus for determining the dissolution rate was a 1 liter three-necked vessel (three-neck vessel). A thermometer was inserted into one of the necks, a glass tube for collecting the sample and its complex was inserted into the second neck, and the main part of the instrument, a cylindrical basket 3.6cm high and 2.5cm in diameter, made of stainless steel, and having a mesh shape with a hole diameter of 40 mesh (about 0.351mm), was inserted into the third neck. The basket is mounted on the shaft of the motor.
The solvent medium (1000ml) was poured into a container, in this experiment a 50:50 mixture of ethanol and water, which is commonly used as a solvent in chemical reactions and biological screening systems because it is one of the commonly used carriers in the injection form. The sample was placed in a cylindrical basket mounted 2cm from the bottom of the vessel.
For comparative sample 1, after complete dissolution, 200mg of the novel polymorph of trimebutine maleate was used to prepare a solution containing 200ppm of trimebutine maleate; for comparative sample 2, after complete dissolution, a solution containing 200ppm of the prototype was prepared using 200mg of the prototype.
During the experiment, the temperature of the solvent medium was kept constant (37. + -. 0.5 ℃). The rotational speed of the basket in the medium was adjusted to an accuracy of + -5%, which was 200 rpm. At defined time intervals, 1-2ml samples were taken for analysis to determine the content of the pharmaceutical substance. The volume of solvent taken was immediately replenished with fresh solvent.
The results obtained are shown in Table 2 (wherein the values are the amount (ppm) of sample 1 or 2 in the solution).
Table 2 dissolution kinetics of the novel polymorph.
Figure BDA0002496842770000091
These results indicate that the new polymorph of trimebutine maleate has a higher dissolution rate in water-alcohol mixtures than the prototype. In particular, the time to dissolve 50% of the novel polymorph of trimebutine maleate was statistically significantly less than the prototype comparative sample.
Example 3. stability study of the novel polymorph in storage.
The stability of the novel polymorph of trimebutine maleate prepared in example 1 was evaluated by substance content and compared with the stability of the prototype by accelerated ageing.
All samples were stored under accelerated test conditions in glass vials sealed with rubber stoppers with aluminium lids in climatic chambers the active substance content was determined by HP L C using the corresponding standard.
The "accelerated aging" method is to maintain the test drug at a temperature and humidity exceeding its storage temperature and humidity during the treatment. Generally, at elevated temperatures, the physicochemical processes occurring in the pharmaceutical agent are accelerated, resulting in undesirable changes in quality over time. Thus, at elevated temperatures, the time period to preserve the controlled quality indicator of the medicament within acceptable limits (experimental shelf life) is artificially shortened compared to shelf life at storage temperatures. This can greatly shorten the time required to determine the expiration period.
Depending on the results obtained during "accelerated ageing" of the pharmaceutical agent, the problem can also be solved in reverse, i.e. setting a storage temperature that provides a defined shelf life.
Storage temperature (t)st) Shelf life (C) and elevated experimental storage temperature (t)e) Experimental shelf life (C)E) The relationship of (a) to (b) is as follows:
C＝K·CE
wherein the correlation coefficient is:
Figure BDA0002496842770000101
the temperature coefficient of the chemical reaction rate (A) was taken to be 2.5. This dependence is based on the Van't-Hoff rule that the rate of chemical reaction increases 2-4 fold when the temperature is increased by 10 ℃.
According to GPM.1.1.0009.15, depending on the temperature interval (t) chosen equal to 30 ℃e–tst) The value of the correlation coefficient (K) was 15.6. The shelf life of the experiment was selected to be 3 years with a storage period of 71 days.
The statistical processing of the parameters is performed by using an SPSS Statistics 19.0 statistical software package.
The results show that the novel polymorph of trimebutine maleate according to the invention has a statistically significantly improved storage stability compared to the prototype.
The novel polymorph of trimebutine maleate according to the invention was determined to have a statistically significant increased stability and to retain chemical purity after 71 days of storage under accelerated ageing. The chemical purity of the prototype substance was maintained for less than 10 days, and then the content of active substance was reduced by more than 3%. That is, the novel polymorph of trimebutine maleate according to the invention is significantly more stable in storage compared to the prototype.
Table 3. stability evaluation by accelerated aging compared to the prototype.
Figure BDA0002496842770000111
Example 4 determination of hygroscopicity.
The reduced hygroscopicity is a great advantage of the novel polymorph of trimebutine maleate during manufacture and storage.
Hygroscopicity was evaluated by storing the solid compound at room temperature in a room with constant relative humidity for 96 hours. Comparing the anhydrous polymorph of trimebutine maleate with the prototype at room temperature, the results show that the prototype is hygroscopic and shows a large increase in humidity starting from a relative humidity of 60%. The novel polymorph of trimebutine maleate does not show any significant increase in humidity, except when stored at a relative humidity above 90%. The results are shown in Table 4 below.
Table 4 moisture absorption at room temperature (96 hours) was evaluated compared to the prototype.
Figure BDA0002496842770000121
Example 5. production of a pharmaceutical agent in the form of a tablet.
1600mg of starch, 1600mg of crushed lactose, 400mg of talc and 1000mg of the polymorphic form of trimebutine maleate compound were mixed and compressed into a stick. The resulting rods were crushed into granules and sieved, and 14-16 mesh granules were collected. The granules thus obtained were compressed into a suitable tablet form weighing 560mg each.
Example 6 production of a medicament in the form of a capsule.
Combining a polymorph of trimebutine maleate compound with a lactose powder in a ratio of 2: 1 are carefully mixed. The resulting powder mixture was packaged in gelatin capsules of appropriate size, 300mg per capsule.
Example 7. production of a medicament in the form of an injectable composition for intramuscular, intraperitoneal or subcutaneous injection.
500mg of the polymorph of trimebutine maleate compound is mixed with 300mg of chlorobutanol, 2ml of propylene glycol and 100ml of water for injection. The resulting solution was filtered and put into ampoules, 1ml per ampoule, and then sealed.
Example 8. investigation of the novel polymorph for spasmolytic activity (antipassamic activity).
The experiments were performed on bladder isolation strips from non-linear female white mice of 173. + -.13 g [ I.V.Gerashchenko, N.A.Mohort "The study of The antisense activity of imidazole [1,2-a]azepinium derivatives on isolated rat bladder strips".Experimental and Clinical Pharmacology,2014,Volume 77,No.6,p.24-26]The animals were exposed to light for 14 hours at a temperature of 22-24 ℃ and humidity of 65-75% in the case of standard full meal ration, and water was freely available, before the experiment, the animals were placed in cages where food and water were unavailable for 1 hour, after weighing, the bladders were separated from the animals and placed in a number of Krebs buffer solutions (expressed as mmol/L) with the following composition on a paraffin surgical table (NaCl-132; KCl-4.7; NaH)2PO4-1.4；NaHCO3-16.3；CaCl2-2.5；MgCl2-1.05; glucose-6.5. Carbon gas (containing 5% CO) for solution2/95％O2Gas mixture of (ii) is aerated.
After removal of the fat and connective tissue bladder, the bladder was excised at the bottom and then two 1mm wide rings were cut. The ring was cut in half to obtain strips, which were placed in a flow chamber at a flow rate of 1.5ml/min and a temperature of 37. + -. 0.5 ℃. The preliminary drawing of the separator was performed under a load of 0.25 g.
The effect of the investigated polymorph on the basal tension of the isolated strips (basal tone) was investigated after stabilizing its response to periodic stimuli with Krebs high potassium solution (KCl 40 mM). The polymorph under investigation was dissolved in dimethyl sulfoxide and added to Krebs high potassium solution to yield 10-7、10-6、10-5、10-4These solutions were pumped through the chamber cumulatively for 15 minutes each.
The force of the contraction movement was measured in isometric mode using a capacitance strain gauge model FTC-0.1. The contraction is recorded by the personal computer using an analog-to-digital converter. The basis tension is measured in grams using a recorded mechanical map. Then, the strips were taken to react in Krebs high potassium solution for 100% shrinkage and the percent relaxation was calculated.
Statistical data processing was performed using Origin 7.5 and Microsoft Office Excel 2010 software. At the maximum percent relaxation (£ c) at the specified concentrationmaxAnd%) evaluation of spasmolytic activity. At a concentration of 10-4maximum relaxation of 60% in the context of the new polymorph solution of mol/L indicates that the new polymorph of trimebutine maleate compound has high spasmolytic activity.
The invention has application in medicine and pharmacology.

Claims (3)

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.
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CN1226162A (en) * 1996-08-07 1999-08-18 帕克－戴维斯公司 Coated trimebutine maleate tablet
CN102188389A (en) * 2010-03-18 2011-09-21 杭州赛利药物研究所有限公司 Trimebutine Maleate suspension and preparation method thereof
EP2481403A1 (en) * 2011-02-01 2012-08-01 Deva Holding Anonim Sirketi Pharmaceutical combination of otilonium and trimebutine
CN104254517A (en) * 2012-03-12 2014-12-31 吉卡尔制药公司 Novel sulfonate-based trimebutine salts

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CA967977A (en) * 1971-03-12 1975-05-20 Dieran R. Torossian Preparation of esters of amino alcohols
CN1226162A (en) * 1996-08-07 1999-08-18 帕克－戴维斯公司 Coated trimebutine maleate tablet
CN102188389A (en) * 2010-03-18 2011-09-21 杭州赛利药物研究所有限公司 Trimebutine Maleate suspension and preparation method thereof
EP2481403A1 (en) * 2011-02-01 2012-08-01 Deva Holding Anonim Sirketi Pharmaceutical combination of otilonium and trimebutine
CN104254517A (en) * 2012-03-12 2014-12-31 吉卡尔制药公司 Novel sulfonate-based trimebutine salts

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