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WO2009053732A1 - Nouveau sel - Google Patents

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Publication number
WO2009053732A1
WO2009053732A1 PCT/GB2008/050965 GB2008050965W WO2009053732A1 WO 2009053732 A1 WO2009053732 A1 WO 2009053732A1 GB 2008050965 W GB2008050965 W GB 2008050965W WO 2009053732 A1 WO2009053732 A1 WO 2009053732A1
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WO
WIPO (PCT)
Prior art keywords
tegaserod
dihydrogen phosphate
process according
amorphous
solution
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/GB2008/050965
Other languages
English (en)
Inventor
Abhay Gaitonde
Bindu Manojkumar
Sandeep Sonawane
Dattatrey Kokane
Sinderpal Tank
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 WO2009053732A1 publication Critical patent/WO2009053732A1/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, namely the dihydrogen phosphate salt.
  • the present invention also relates to novel amorphous and crystalline forms of the dihydrogen phosphate salt of tegaserod.
  • the invention further relates to processes for the preparation of the novel salt and the novel amorphous and crystalline forms.
  • the invention also relates to pharmaceutical compositions containing the novel salt or the novel amorphous or crystalline forms, and to uses of said compositions to provide methods of treating patients suffering from gastrointestinal disorders.
  • Tegaserod chemically named 2-[(5-methoxy-lH-indol-3-yl)methylene]-N-pentylhydrazine- carboximidamide, 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 pseudoobstruction, 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.
  • Tegaserod represented by formula (I) was first described in US 5 510 353 as well as processes for its preparation. Also described is the maleate salt of tegaserod, but interestingly a method of manufacturing tegaserod maleate is not disclosed. The only characterizing data is the melting point which is disclosed as 190 0 C for the maleate salt and 124°C for the tegaserod base.
  • 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 dihydrogen phosphate, as well as novel crystalline forms and a novel amorphous form of the dihydrogen phosphate salt of tegaserod.
  • 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 crystalline or amorphous form to another. It is important that stable crystalline or amorphous 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 dihydrogen phosphate or a tautomeric form thereof and/or a pharmaceutically acceptable solvate or hydrate thereof.
  • the tegaserod dihydrogen phosphate 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 - A -
  • 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 novel crystalline form of tegaserod dihydrogen phosphate designated form 1, with a characteristic XRD spectrum having two or more peaks (preferably three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, twelve or more, fifteen or more, twenty or more, twenty-one or more, or all twenty-two peaks) with 2 ⁇ values at 7.6, 10.8, 11.3, 12.9, 15.1, 16.3, 16.7, 17.5, 19.1, 20.0, 20.8, 21.1, 21.8, 22.8, 23.5, 24.0, 24.4, 24.6, 25.7, 26.5, 27.1, 29.2 ⁇ 0.2 °2 ⁇ .
  • the novel crystalline form 1 of tegaserod dihydrogen phosphate has a characteristic XRD spectrum having two or more peaks (preferably three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, twelve or more, fifteen or more, twenty or more, twenty-one or more, or all twenty-two peaks) with 2 ⁇ values at 7.63, 10.78, 11.30, 12.91, 15.07, 16.32, 16.69, 17.46, 19.10, 19.97, 20.83, 21.09, 21.80, 22.78, 23.46, 24.03, 24.38, 24.56, 25.73, 26.47, 27.07, 29.21 ⁇ 0.2 °2 ⁇ .
  • a novel crystalline form of tegaserod dihydrogen phosphate designated form 1, having an XRPD trace substantially as shown in figure 1.
  • a novel crystalline form of tegaserod dihydrogen phosphate designated form 1, characterized by a DSC with an endothermic peak at about 204 0 C ⁇ 2°C, preferably at about 204.06 0 C ⁇ 2°C.
  • a novel crystalline form of tegaserod dihydrogen phosphate designated form 1, having a DSC trace substantially as shown in figure 2.
  • a process for the preparation of tegaserod dihydrogen phosphate crystalline form 1 according to the invention comprising the steps of:
  • step (b) causing tegaserod dihydrogen phosphate form 1 to precipitate from the solution or suspension obtained in step (a);
  • tegaserod dihydrogen phosphate is dissolved in step (a).
  • the solvent used in step (a) is acetonitrile.
  • the acetonitrile is heated to between about 70-90 0 C, preferably about 82°C.
  • the tegaserod dihydrogen phosphate form 1 is caused to precipitate by cooling the solution or suspension obtained in step (a) to between about 20-30 0 C.
  • the tegaserod dihydrogen phosphate form 1 is isolated by filtration.
  • the filtered tegaserod dihydrogen phosphate form 1 is washed, preferably with acetonitrile, preferably about 5 volumes.
  • the tegaserod dihydrogen phosphate form 1 is dried, particularly preferred is drying under vacuum, preferably until a constant weight is achieved.
  • the drying occurs at about 20-40 0 C, preferably about 35°C.
  • a novel crystalline form of tegaserod dihydrogen phosphate designated form 2, with a characteristic XRD spectrum having two or more peaks (preferably three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, twelve or more, fifteen or more, twenty or more, twenty-five or more, or all twenty-seven peaks) with 2 ⁇ values at 7.1, 10.3, 10.8, 11.3, 12.4, 13.0, 14.6, 15.8, 16.2, 16.9, 18.7, 19.4, 19.9, 20.3, 20.5, 21.0, 21.3, 22.9, 23.5, 23.8, 24.0, 24.5, 25.3, 25.9, 26.5, 28.7, 29.3 ⁇ 0.2 °2 ⁇ .
  • the novel crystalline form 2 of tegaserod dihydrogen phosphate has a characteristic XRD spectrum having two or more peaks (preferably three or more, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, twelve or more, fifteen or more, twenty or more, twenty-five or more, or all twenty-seven peaks) with 2 ⁇ values at 7.06, 10.33, 10.80, 11.32, 12.43, 13.0, 14.55, 15.8, 16.20, 16.93, 18.65, 19.44, 19.85, 20.28, 20.54, 21.01, 21.26, 22.93, 23.50, 23.83, 24.01, 24.48, 25.30, 25.90, 26.51, 28.66, 29.31 ⁇ 0.2 °2 ⁇ .
  • a novel crystalline form of tegaserod dihydrogen phosphate designated form 2, characterized by a DSC with an endothermic peak at about 204 0 C ⁇ 2°C, preferably at about 203.76 0 C ⁇ 2°C.
  • a novel crystalline form of tegaserod dihydrogen phosphate designated form 2, having a DSC trace substantially as shown in figure 4.
  • step (b) causing tegaserod dihydrogen phosphate form 2 to precipitate from the solution or suspension obtained in step (a);
  • tegaserod dihydrogen phosphate is dissolved in step (a).
  • the solvent used in step (a) is a C 1 -C 6 alcohol, preferably a C 3 -C 6 alcohol, preferably a secondary or tertiary alcohol, preferably isobutanol.
  • isobutanol Preferably about 25 volumes of isobutanol are used.
  • the isobutanol is heated to between about 80-85 0 C, preferably about 82°C.
  • the tegaserod dihydrogen phosphate form 2 is caused to precipitate by cooling the solution or suspension obtained in step (a), preferably to about 20-30 0 C.
  • the tegaserod dihydrogen phosphate form 2 is isolated by filtration.
  • the filtered tegaserod dihydrogen phosphate form 2 is washed, preferably with isobutanol, preferably about 5 volumes.
  • the tegaserod dihydrogen phosphate form 2 is dried, particularly preferred is drying under vacuum, preferably until a constant weight is achieved.
  • the drying occurs at about 20- 40 0 C, preferably about 35°C.
  • a novel amorphous form of tegaserod dihydrogen phosphate According to a twelfth aspect of the present invention there is provided a novel amorphous form of tegaserod dihydrogen phosphate.
  • a fourteenth aspect there is provided a novel amorphous form of tegaserod dihydrogen phosphate characterized by a DSC with endothermic peaks at about 73°C, about 147°C and about 157°C, preferably at about 73.21°C, about 146.87°C and about 157.27°C, all ⁇ 2°C.
  • amorphous tegaserod dihydrogen phosphate comprising the steps of:
  • step (b) causing amorphous tegaserod dihydrogen phosphate to precipitate from the solution or suspension obtained in step (a);
  • the solvent used in step (a) is a mixture of a C 1 -C 6 alcohol and water, preferably the C 1 -C 6 alcohol is a C 1 -C 2 alcohol, preferably a primary alcohol, preferably methanol. Preferably about 3.3 volumes of methanol are used. Preferably about 3.3 volumes of water are used. Preferably tegaserod and phosphoric acid are used in step (a), preferably about 2 molar equivalents (eq) of phosphoric acid.
  • the amorphous form is caused to precipitate by cooling the solution obtained in step (a), preferably to about 0-5 0 C.
  • the amorphous form is isolated by filtration.
  • the filtered amorphous form is washed, preferably with water preferably chilled and preferably about 5 volumes.
  • the water is chilled to a temperature of between about 0-15 0 C, more preferably about 0-10 0 C, and most preferably about 0-5 0 C.
  • the filtered amorphous form is dried, particularly preferred is drying under reduced pressure, most preferred is drying under vacuum, preferably until a constant weight is achieved.
  • step (b) adding a solution of phosphoric acid in water; (c) causing amorphous tegaserod dihydrogen phosphate to precipitate from the solution obtained in step (b); and (d) isolating the amorphous form of tegaserod dihydrogen phosphate.
  • the solvent used in step (a) is a C 1 -C 6 alcohol, preferably a C 1 -C 2 alcohol, preferably a primary alcohol, preferably methanol.
  • a C 1 -C 6 alcohol preferably a C 1 -C 2 alcohol, preferably a primary alcohol, preferably methanol.
  • Preferably about 3.3 volumes of methanol are used.
  • about 2 molar equivalents (eq) of phosphoric acid in about 3.3 volumes of water are added in step (b).
  • the amorphous form is caused to precipitate by cooling the solution obtained in step (b), preferably to about 0-5 0 C.
  • the amorphous form is isolated by filtration.
  • the filtered amorphous form is washed, preferably with water preferably chilled and preferably about 5 volumes.
  • the water is chilled to a temperature of between about
  • the filtered amorphous form is dried, particularly preferred is drying under reduced pressure, most preferred is drying under vacuum, preferably until a constant weight is achieved.
  • the tegaserod dihydrogen phosphate salt and the crystalline and amorphous forms thereof according to the above described aspects and embodiments have a chemical purity of greater than 90%, 95%, 96%, 97%, 98%, 99% or 99.9% (as measured by HPLC).
  • the crystalline and amorphous forms of tegaserod dihydrogen phosphate according to the above described aspects and embodiments have a polymorphic purity of greater than 90%, 95%, 96%, 97%, 98%, 99% or 99.9% (as measured by XRPD or DSC).
  • the tegaserod dihydrogen phosphate salt and the crystalline and amorphous forms thereof are obtained on an industrial scale, preferably in batches of 0.5kg, lkg, 5kg, 10kg, 50kg, 100kg, 500kg or more.
  • a seventeenth aspect according to the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising tegaserod dihydrogen phosphate or any of the crystalline or amorphous forms of the present invention or prepared by any of the processes of the present invention and one or more pharmaceutically acceptable excipients.
  • the composition is a solid composition, most preferably a tablet or capsule composition.
  • a method of treating or preventing a gastrointestinal disorder selected from the list comprising 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), comprising administering to a patient in need thereof a therapeutically or prophylactically effective amount of tegaserod dihydrogen phosphate or any of the crystalline or amorphous forms of the present invention or prepared by any of the processes of the present invention, or a therapeutically or prophylactically effective amount of a pharmaceutical composition of the present invention.
  • the patient is a mammal, preferably a human.
  • the disorder is irritable bowel syndrome.
  • a twentieth aspect provides the use of tegaserod dihydrogen phosphate or any of the crystalline or amorphous forms of the present invention or prepared by any of the processes of the present invention in the manufacture of a medicament for use in the treatment or prevention of a gastrointestinal disorder.
  • the gastrointestinal disorder is selected from the group comprising 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).
  • Figure 1 describes the XRPD of tegaserod dihydrogen phosphate form 1.
  • Figure 2 describes the DSC of tegaserod dihydrogen phosphate form 1.
  • Figure 3 describes the XRPD of tegaserod dihydrogen phosphate form 2.
  • Figure 4 describes the DSC of tegaserod dihydrogen phosphate form 2.
  • Figure 5 describes the XRPD of amorphous tegaserod dihydrogen phosphate.
  • Figure 6 describes the DSC of amorphous tegaserod dihydrogen phosphate.
  • the term 'reduced pressure' refers to an atmospheric pressure of below about 100 mbar, preferably below about 15 mbar, and the term 'vacuum' as used herein refers to an atmospheric pressure of below about 10 mbar.
  • the terms 'XRD spectrum' and 'X-ray diffraction pattern' are used interchangeably herein and preferably refer to an X-ray powder diffraction (XRPD) trace, spectrum or pattern.
  • the present invention provides the novel dihydrogen phosphate salt of tegaserod and a process for its preparation.
  • the present invention also provides novel polymorphs of tegaserod dihydrogen phosphate, a novel amorphous form of tegaserod dihydrogen phosphate, and processes for their preparation.
  • the present invention further provides compositions comprising said salt or crystalline or amorphous forms.
  • the processes disclosed are simple and amenable to scale up and are capable of providing the salt and novel forms in consistent purity.
  • Particularly preferred embodiments comprise tegaserod dihydrogen phosphate form 1, form 2 or the amorphous form respectively, wherein each of these novel forms according to the invention comprises less than 10%, preferably less than 5%, more preferably less 1%, most preferably less than 0.1% of other forms of tegaserod irrespective of the scale of preparation.
  • the other forms include but are not limited to amorphous forms, hydrates, crystalline forms which are not the subject of this invention and, for example, an embodiment relating to the amorphous form of tegaserod dihydrogen phosphate according to the present embodiment will comprise less than 10%, preferably less than 5%, more preferably less 1%, most preferably less than 0.1% of other forms of tegaserod including tegaserod dihydrogen phosphate form 1 or form 2.
  • a preferred process according to the invention for preparing tegaserod dihydrogen phosphate salt or any of the crystalline or amorphous forms of tegaserod dihydrogen phosphate disclosed herein and as claimed below comprises adding tegaserod dihydrogen phosphate, or tegaserod and phosphoric acid, preferably tegaserod dihydrogen phosphate, to an organic solvent.
  • the solvent type is dependent on the crystalline or amorphous form desired.
  • form 1 is obtained from acetonitrile
  • form 2 is obtained from isobutanol
  • the amorphous form according to the invention is obtained from methanol.
  • the tegaserod dihydrogen phosphate can be completely or only partially dissolved and the process still falls within the scope of the invention.
  • the solvent is heated.
  • the solution is heated until the solution is clear.
  • the novel salt or the novel crystalline or amorphous form according to the invention is caused to precipitate from the tegaserod dihydrogen phosphate solution.
  • the precipitation is caused by cooling the solution until the precipitate is no longer soluble and is forced out of solution and a slurry is formed.
  • the solution is cooled to between about 0-5 0 C.
  • 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 most preferably is washed, preferably with acetonitrile when form 1 is prepared, preferably with isobutanol when form 2 is prepared, and preferably with chilled water of about 0- 10 0 C, preferably about 0-5 0 C, when the amorphous form is prepared, and dried.
  • the product is dried at a temperature that does not induce conversion of the crystalline or amorphous forms respectively or causes the resultant salt or form to degrade.
  • the inventors have found that drying the product at between about 20-40 0 C is advantageous.
  • the solid product is dried under reduced atmospheric pressure, preferably until a constant weight is obtained.
  • the solid product is dried under vacuum.
  • a further embodiment of the invention comprises pharmaceutical compositions of the novel salt or the novel polymorphic or amorphous form(s) according to the invention with one or more pharmaceutically acceptable excipient(s).
  • Another aspect of the present invention is the pharmaceutical compositions containing the novel salt or the novel polymorphic or amorphous form(s) 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 novel salt or the novel polymorphic or amorphous form(s).
  • Illustrative of the invention is a pharmaceutical composition comprising tegaserod dihydrogen phosphate or a novel polymorph or amorphous form of tegaserod dihydrogen phosphate according to the invention and one or more pharmaceutically acceptable excipient(s) .
  • a further embodiment of the invention is a process for preparing a pharmaceutical composition comprising mixing tegaserod dihydrogen phosphate or a novel polymorph or amorphous form of tegaserod dihydrogen phosphate according to the invention and one or more pharmaceutically acceptable excipient(s).
  • Said composition may comprise solid pharmaceutical compositions which in certain embodiments may comprise tablets including for example dispersible tablets, capsules containing pellets, mini-tablets, powders or mixtures thereof, caplets, or any of the solid dosage forms that are within the repertoire of the skilled formulation scientist. These may further include immediate release forms of the above solid dosage forms or controlled release forms of the above including sustained release, delayed release and prolonged release compositions. It is also envisaged that the invention comprises liquid formulations which may be prepared by mixing tegaserod dihydrogen phosphate or the crystalline or amorphous forms according to the invention with a pharmaceutically suitable liquid carrier or solvent.
  • 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 tegaserod dihydrogen phosphate or a novel polymorph of tegaserod dihydrogen phosphate or amorphous form according to the invention.
  • a composition comprising a therapeutically effective amount of tegaserod dihydrogen phosphate or a novel polymorph of tegaserod dihydrogen phosphate or amorphous form according to the invention.
  • the polymorphic purity is in the order of tegaserod dihydrogen phosphate form 1, form 2 or the amorphous form comprising less than 10%, preferably less than 5%, more preferably less 1%, most preferably less than 0.1% of other forms of tegaserod.
  • 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.
  • 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.
  • Eudragit ® polymethacrylates
  • 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-SoI , 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-SoI , Primellose ), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g. Kollid
  • 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 lubiicant 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 crystalline or amorphous 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.
  • Liquid pharmaceutical compositions of the present invention may also contain a viscosity enhancing agent to improve the mouth-feel or organoleptic qualities of the product and/or coat the lining of the gastrointestinal tract.
  • a viscosity enhancing agent include acacia, alginic acid, bentonite, carbomer, carboxymethyl cellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethyl cellulose, gelatin, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth and xanthan gum.
  • Sweetening agents such as sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol and invert sugar may be added to improve the taste.
  • Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxytoluene, butylated hydroxyanisole and ethylenediaminetetraacetic acid may be added at levels safe for ingestion to improve storage stability.
  • a liquid composition may also contain a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate.
  • a buffer such as gluconic acid, lactic acid, citric acid or acetic acid, sodium gluconate, sodium lactate, sodium citrate or sodium acetate.
  • 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 dosage form of the present invention may be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or a soft shell.
  • the shell may be made from gelatin and optionally contain a plasticizer such as glycerine and sorbitol, and an opacifying agent or colourant.
  • the active ingredient and excipients may be formulated into compositions and dosage forms according to methods known in the art.
  • a composition for tableting or capsule filling may be prepared by wet granulation.
  • wet granulation some or all of the active ingredient and excipients in powder form are blended and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules.
  • the granulate is screened and/or milled, dried and then screened and/or milled to the desired particle size.
  • the granulate may then be tableted, or other excipients may be added prior to tableting, such as a glidant and/or a lubricant.
  • a tableting composition may be prepared conventionally by dry granulation.
  • the blended composition of the actives 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 blended composition may be compressed directly into a compacted dosage form using direct compression techniques.
  • Direct compression produces a uniform tablet without granules.
  • Excipients that are particularly well suited for direct compression tableting include microcrystalline cellulose, spray dried lactose, dicalcium phosphate dihydrate and colloidal silica. The proper use of these and other excipients in direct compression tableting is known to those in the art with experience and skill in particular formulation challenges of direct compression tableting.
  • 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 but are not limited to other 5-HT 4 receptor agonists such as prucalopride, RS 67333 (l-(4-amino-5- chloro-2-methoxyphenyl)-3-(l-n-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, tegaserod, SB 205149, SC 53116, BIMU 1, and BIMU 8; proton pump inhibitors such as omeprazole, rabeprazole, pantoprazole, and
  • the starting material comprises Ig of tegaserod dihydrogen phosphate.
  • Tegaserod was dissolved in methanol (3.3 volumes) and a solution of phosphoric acid (2 eq.) in water (3.3 volumes) was added at 25-30 0 C. The clear solution was stirred for 10 minutes and cooled to 0-5 0 C. The slurry was stirred at 0-5 0 C for 30 minutes. The solid obtained was filtered under vacuum, washed with chilled water (5 volumes), and dried at 25-30 0 C under vacuum for 1.5 hours.
  • Tegaserod dihydrogen phosphate was dissolved in 25 volumes of acetonitrile and heated to 82°C. The solution was cooled to between 25-30 0 C for about 15 minutes. The resultant slurry was filtered, washed with 5 volumes of acetonitrile, and dried on a rotavapor under vacuum at 35°C for 30 minutes.
  • Tegaserod dihydrogen phosphate was dissolved in 25 volumes of isobutanol and heated to

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Abstract

La présente invention porte sur un nouveau sel de tegaserode, à savoir le sel de dihydrogénophosphate. La présente invention porte également sur de nouvelles formes amorphes et cristallines du sel de dihydrogénophosphate de tegaserode. L'invention porte aussi sur des procédés de préparation du nouveau sel et des nouvelles formes amorphes et cristallines. L'invention porte enfin sur des compositions pharmaceutiques contenant le nouveau sel ou les nouvelles formes amorphes ou cristallines ainsi que sur leurs utilisations dans des traitements de troubles gastro-intestinaux.
PCT/GB2008/050965 2007-10-24 2008-10-18 Nouveau sel Ceased WO2009053732A1 (fr)

Applications Claiming Priority (2)

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IN2107MU2007 2007-10-24
IN2107/MUM/2007 2007-10-24

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0297651A1 (fr) 1987-06-29 1989-01-04 Duphar International Research B.V Dérivés d'indole annulaires
US5510353A (en) 1991-03-22 1996-04-23 Sandoz Ltd. Certain aminoguanidine compounds, pharmaceutical compositions containing them and their use in treating gastrointestinal motility disorders and disorders associated with cephalic pain
WO1999017755A2 (fr) 1997-10-07 1999-04-15 Glaxo Group Limited Medicaments
WO2006116953A1 (fr) 2005-05-02 2006-11-09 Zentiva, A.S. Procede de preparation de tegaserod et de sels sélectionnés dérivés de ce composé
EP1939176A1 (fr) * 2006-12-22 2008-07-02 Novartis AG Sels de Tegaserod

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0297651A1 (fr) 1987-06-29 1989-01-04 Duphar International Research B.V Dérivés d'indole annulaires
US5510353A (en) 1991-03-22 1996-04-23 Sandoz Ltd. Certain aminoguanidine compounds, pharmaceutical compositions containing them and their use in treating gastrointestinal motility disorders and disorders associated with cephalic pain
WO1999017755A2 (fr) 1997-10-07 1999-04-15 Glaxo Group Limited Medicaments
WO2006116953A1 (fr) 2005-05-02 2006-11-09 Zentiva, A.S. Procede de preparation de tegaserod et de sels sélectionnés dérivés de ce composé
EP1939176A1 (fr) * 2006-12-22 2008-07-02 Novartis AG Sels de Tegaserod

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