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WO2008149136A1 - Bésylate de tégasérod et formes polymorphes - Google Patents

Bésylate de tégasérod et formes polymorphes Download PDF

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Publication number
WO2008149136A1
WO2008149136A1 PCT/GB2008/050392 GB2008050392W WO2008149136A1 WO 2008149136 A1 WO2008149136 A1 WO 2008149136A1 GB 2008050392 W GB2008050392 W GB 2008050392W WO 2008149136 A1 WO2008149136 A1 WO 2008149136A1
Authority
WO
WIPO (PCT)
Prior art keywords
tegaserod
besylate
process according
composition
gastrointestinal disorder
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB2008/050392
Other languages
English (en)
Inventor
Abhay Gaitonde
Bindu Manojkumar
Sandeep Sonawane
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Generics UK Ltd
Mylan Pharmaceuticals Pvt Ltd
Original Assignee
Generics UK Ltd
Mylan Development Centre Pvt Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Generics UK Ltd, Mylan Development Centre Pvt Ltd filed Critical Generics UK Ltd
Publication of WO2008149136A1 publication Critical patent/WO2008149136A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • 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

Definitions

  • the present invention relates to a novel salt of tegaserod, tegaserod besylate, and also to polymorphic forms of this salt.
  • the invention further relates to processes for the preparation of the salt and polymorphic forms.
  • the invention also relates to pharmaceutical compositions comprising the salt, optionally in a polymorphic form, and to uses of said compositions for treating patients suffering from gastrointestinal disorders.
  • Tegaserod chemically named 2-[(5-methoxy-l_FJ-indol-3-yl)methylene]-iV- pentylhydrazinecarboximidamide, is a selective serotonin 4 (5-HT 4 ) receptor agonist, which can be used to treat gastrointestinal disorders such as heartburn, bloating, postoperative ileus, abdominal pain and discomfort, epigastric pain, nausea, vomiting, regurgitation, intestinal pseudo-obstruction, irritable bowel syndrome and gastro-oesophageal reflux.
  • Tegaserod as the maleate salt is marketed for the short-term treatment of irritable bowel syndrome in women whose primary bowel symptom is constipation.
  • WO 2006/116953 describes crystalline forms of the hydrobromide, fumarate and oxalate salts of tegaserod. Also claimed is a process for preparing the hydrochloride, hydrobromide, fumarate, tartrate, citrate, lactate, mesylate, oxalate, succinate, glutarate, adipate, salicylate, sulphate, mandelate, camphor sulphonate and hydrogen sulphate salts of tegaserod from a specific crystalline form of tegaserod base.
  • Another process described is a method of preparing the fumarate, maleate, tartrate, citrate, mesylate, lactate, succinate, oxalate, hydrochloride, salicylate, glutarate, adipate, hydrobromide, sulphate and hydrogen sulphate from a hydrogen halide salt of tegaserod.
  • API active pharmaceutical ingredient
  • the rate of dissolution of an API that has poor aqueous solubility is often problematic.
  • the aqueous solubility is a major influence on the bioavailability of the API such that a poorly soluble API can mean the API is not available to have a pharmaceutical effect on the body.
  • the API can also cause problems during manufacture of a pharmaceutical composition. For example, flowability, compactability and stickiness are all factors affected by the solid state properties of an API.
  • the present invention provides a novel salt of tegaserod, namely tegaserod besylate, as well as a crystalline form of said salt.
  • polymorphism influences every aspect of the solid state properties of an API and one of the important aspects of polymorphism in pharmaceuticals is the possibility of interconversion from one polymorphic form to another. It is important that stable crystalline forms are used in pharmaceutical dosage forms as, for example, conversion from a form showing greater aqueous dissolution and potentially better bioavailability to a less soluble form can potentially have disastrous consequences.
  • a first aspect according to the invention provides the compound tegaserod besylate or a tautomeric form thereof and/or a pharmaceutically acceptable solvate or hydrate thereof.
  • the tegaserod besylate may exist in one or more polymorphic, tautomeric, hydrate and/or solvate forms.
  • the present invention embraces all polymorphic forms and their mixtures, all tautomeric forms and their mixtures, all hydrate forms and their mixtures, and all solvate forms and their mixtures.
  • tegaserod is defined for convenience by reference to one guanidino form only, the invention is not to be understood as being in any way limited by the particular nomenclature or graphic representation employed. - A -
  • a novel polymorphic form of tegaserod besylate is provided with a characteristic XRD spectrum having at least five peaks (preferably at least six, seven, eight, nine, ten, fifteen, twenty, or twenty-six peaks) selected from peaks with 2 ⁇ values at 6.8, 8.8, 10.9, 11.1, 13.1, 13.3, 13.6, 14.8, 15.1, 15.9, 17.8, 19.0, 19.4, 19.7, 20.4, 22.2, 22.6, 23.0, 23.4, 23.8, 24.5, 25.3, 25.7, 26.8, 27.1 and 27.8 ⁇ 0.2 degree.
  • a polymorphic form of tegaserod besylate characterized by a DSC with an endothermic peak at about 193°C, preferably at about 192.65°C.
  • step (a) Preferably tegaserod and benzene sulphonic acid are used in step (a).
  • the reaction mixture obtained in step (a) is stirred to increase the precipitation of the tegaserod besylate salt. It is preferred that the stirring occurs at about 20-30 0 C for about 0.5-2 hours.
  • an anti-solvent can be added to increase the precipitation of the tegaserod besylate salt.
  • a fifth aspect according to the invention provides a pharmaceutical composition comprising tegaserod besylate according to any of the aspects or embodiments described above and one or more pharmaceutically acceptable excipients.
  • the composition is a solid composition, most preferably a tablet or capsule composition.
  • Figure 1 describes the XRPD of tegaserod besylate.
  • Figure 2 describes the DSC of tegaserod besylate.
  • Figure 3 describes the TGA of tegaserod besylate.
  • the present invention provides the novel besylate salt of tegaserod and a process for its preparation.
  • the process disclosed is simple and amenable to scale up and is capable of providing the salt in consistent polymorphic and chemical purity of greater than 95% respectively, preferably greater than 96%, more preferably greater than 97%, particularly preferred is a purity of greater than 98% and most preferred is a purity of greater than 99% irrespective of the scale of preparation.
  • a preferred process according to the invention for preparing tegaserod besylate according to the invention comprises adding tegaserod to methanol.
  • the tegaserod is in the form of the free base.
  • tegaserod can be completely or only partially dissolved and the process still falls within the scope of the invention.
  • benzene sulphonic acid preferably in solution, either in methanol or in alternative embodiments in water.
  • the resulting reaction mixture comprising methanol, tegaserod and the benzene sulphonic acid solution in certain embodiments can be stirred to increase the precipitation of the solid salt. It is preferred that the stirring occurs at about 25°C or approximately room temperature, but it is envisaged that the stirring conditions may be varied and still remain within the scope of the invention.
  • the solid product obtained can then be isolated by any means common in the field or known to the skilled artisan.
  • the solid is obtained by evaporation of the solvent.
  • the solid product is filtered and dried.
  • the product is dried at a temperature that does not induce conversion of the polymorphic form or cause the resultant form to degrade. The inventors have found that drying the product at about 40 0 C is advantageous.
  • the solid product is dried under vacuum until a constant weight is obtained.
  • a further embodiment of the invention comprises pharmaceutical compositions of the tegaserod besylate or a tautomeric form thereof and/or a pharmaceutically acceptable solvate or hydrate thereof with one or more pharmaceutically acceptable excipient(s).
  • Another aspect of the present invention is the pharmaceutical compositions containing the tegaserod besylate in any form according to the invention and uses of the pharmaceutical compositions to provide methods of treating patients suffering from gastrointestinal disorders, comprising providing to a patient a pharmaceutically effective amount of the tegaserod salt.
  • Illustrative of the invention is a pharmaceutical composition made by mixing a tegaserod salt, namely tegaserod besylate according to the invention, and a pharmaceutically acceptable carrier.
  • a further embodiment of the invention is a process for making a pharmaceutical composition comprising mixing the besylate salt according to the invention and a pharmaceutically acceptable carrier.
  • a method for the treatment of a 5-HT 4 receptor mediated disorder in a subject in need thereof comprising administering to the subject a composition comprising a therapeutically effective amount of a tegaserod salt according to the invention.
  • a tegaserod salt according to the invention substantially free of other polymorphic forms, for the preparation of a medicament for treating a 5-HT 4 receptor mediated disorder in a subject in need thereof.
  • the tegaserod besylate may be in amorphous form, or indeed any of a number of crystalline forms.
  • 5-HT 4 receptor mediated disorders comprise gastrointestinal disorders such as heartburn, bloating, postoperative ileus, abdominal pain and discomfort, epigastric pain, nausea, vomiting, regurgitation, intestinal pseudo-obstruction, irritable bowel syndrome and gastro- oesophageal reflux, preferably irritable bowel syndrome.
  • the pharmaceutical compositions of the present invention may contain one or more excipients. Excipients are added to the composition for a variety of purposes. Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle. Diluents for solid compositions include, for example, microcrystalline cellulose (e.g.
  • Avicel microfine cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulphate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, polymethacrylates (e.g. Eudragit ), potassium chloride, powdered cellulose, sodium chloride, sorbitol and talc.
  • Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression.
  • Binders for solid pharmaceutical compositions include acacia, alginic acid, carbomer (e.g. Carbopol ), carboxymethyl cellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenated vegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g. Klucel ® ), hydroxypropyl methyl cellulose (e.g.
  • Methocel liquid glucose, magnesium aluminium silicate, maltodextrin, methyl cellulose, polymethacrylates, povidone (e.g. Kollidon , Plasdone ), pregelatinized starch, sodium alginate and starch.
  • povidone e.g. Kollidon , Plasdone
  • the dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition.
  • Disintegrants include alginic acid, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium (e.g. Ac-Di-Sol ® , Primellose ® ), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollidon ® , Polyplasdone ® ), guar gum, magnesium aluminium silicate, methyl cellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate (e.g. Explotab ) and starch.
  • alginic acid include alginic acid, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium (e.g. Ac-Di-Sol ® , Primellose ® ), colloidal silicon dioxide, croscarmellose sodium, crospovid
  • Glidants can be added to improve the flowability of a non-compacted solid composition and to improve the accuracy of dosing.
  • Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate.
  • a dosage form such as a tablet
  • the composition is subjected to pressure from a punch and dye.
  • Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities.
  • a lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye.
  • Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulphate, sodium stearyl fumarate, stearic acid, talc and zinc stearate.
  • Flavouring agents and flavour enhancers make the dosage form more palatable to the patient.
  • Common flavouring agents and flavour enhancers for pharmaceutical products include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol and tartaric acid.
  • Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
  • liquid pharmaceutical compositions of the present invention the tegaserod salt and any other solid excipients are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerine.
  • a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol or glycerine.
  • Liquid pharmaceutical compositions may further contain emulsifying agents to disperse uniformly throughout the composition an active ingredient or other excipient that is not soluble in the liquid carrier.
  • Emulsifying agents that may be useful in liquid compositions of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer, cetostearyl alcohol and cetyl alcohol.
  • Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar may be added to improve the taste.
  • the solid compositions of the present invention include powders, granulates, aggregates and compacted compositions.
  • the dosages include dosages suitable for oral, buccal, rectal, parenteral (including subcutaneous, intramuscular, and intravenous), inhalant and ophthalmic administration. Although the most suitable administration in any given case will depend on the nature and severity of the condition being treated, the most preferred route of the present invention is oral.
  • the dosages may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the pharmaceutical arts.
  • Dosage forms include solid dosage forms like tablets, powders, capsules, suppositories, sachets, troches and lozenges, as well as liquid syrups, suspensions and elixirs.
  • the blended composition of the active and excipients may be compacted into a slug or a sheet and then comminuted into compacted granules.
  • the compacted granules may subsequently be compressed into a tablet.
  • a capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tableting, however, they are not subjected to a final tableting step.
  • composition of the invention may further comprise one or more additional active ingredients.
  • Further active ingredients may include other 5-HT 4 receptor agonists such as prucalopride, RS 67333 (l-(4-amino-5-chloro-2-methoxyphenyl)- 3-(l-butyl-4-piperidinyl)-l-propanone), RS 67506 (l-(4-amino-5-chloro-2-methoxyphenyl)- 3- [1 - [2- [(methylsulphonyl) amino] ethyl] -4-piperidinyl] - 1 -propanone) , cisapride, renzapride, norcisapride, mosapride, zacopride, SB 205149, SC 53116, BIMU 1, and BIMU 8; proton pump inhibitors such as omeprazole, rabeprazole, pantoprazole, and lansoprazole; 5-HT 3 receptor agonists

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne un nouveau sel de tégasérod, le bésylate de tégasérod, ainsi que des formes polymorphes de ce sel. L'invention concerne également des procédés destinés à la préparation du sel et de ses formes polymorphes. L'invention concerne également des compositions pharmaceutiques comprenant le sel, éventuellement sous une forme polymorphe, ainsi que des usages de ces compositions pour le traitement de patients souffrant de troubles gastro-intestinaux.
PCT/GB2008/050392 2007-06-04 2008-05-30 Bésylate de tégasérod et formes polymorphes Ceased WO2008149136A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1043MU2007 2007-06-04
IN1043/MUM/2007 2007-06-04

Publications (1)

Publication Number Publication Date
WO2008149136A1 true WO2008149136A1 (fr) 2008-12-11

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ID=39737111

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2008/050392 Ceased WO2008149136A1 (fr) 2007-06-04 2008-05-30 Bésylate de tégasérod et formes polymorphes

Country Status (1)

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WO (1) WO2008149136A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0505322A1 (fr) * 1991-03-22 1992-09-23 Sandoz Ltd. Aminoguanidines
WO2005058819A2 (fr) * 2003-12-16 2005-06-30 Teva Pharmaceutical Industries Ltd. Formes polymorphiques de la base du tegaserod et des sels de celui-ci
WO2006116953A1 (fr) * 2005-05-02 2006-11-09 Zentiva, A.S. Procede de preparation de tegaserod et de sels sélectionnés dérivés de ce composé
WO2008077871A1 (fr) * 2006-12-22 2008-07-03 Novartis Ag Sels de tégasérod

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0505322A1 (fr) * 1991-03-22 1992-09-23 Sandoz Ltd. Aminoguanidines
WO2005058819A2 (fr) * 2003-12-16 2005-06-30 Teva Pharmaceutical Industries Ltd. Formes polymorphiques de la base du tegaserod et des sels de celui-ci
WO2006116953A1 (fr) * 2005-05-02 2006-11-09 Zentiva, A.S. Procede de preparation de tegaserod et de sels sélectionnés dérivés de ce composé
WO2008077871A1 (fr) * 2006-12-22 2008-07-03 Novartis Ag Sels de tégasérod

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