Title of Invention	A METHOD OF PREPARING A SOLID ORAL PHARMACEUTICAL COMPOSITION
Abstract	A method of preparing a solid oral pharmaceutical composition comprising the successive steps of: i) pre-mixing 0.5% to 15% by weight of Compound A or a pham1aceutically acceptable salt thereof with 60 to 98% of the diluent (in an amount based on the total weight of the composition from 10 to 50% by weight), and then sieving the resulting mixture; ii) mixing purified water with a binder (in an amount based on the total weight of the composition from 1 % to 10% by weight), ctlld stirring until dissolution; iii) adding a surfactant (in an amount based on the total weight of the composition from 0.1 % to 10% by weight) to the solution of ii) and stirring until dissolution; iv) adding a disintegrant (in an amount based on the total weight of the composition from 20% to 60%), the remaining diluent and 50 to 70% of a first lubricant (together with a second lubricant in an amount based on the total weight of the composition from 1 % to 20% by weight) to the pre mixture of i) and mixing; . v) wetting the mixture of step iv) with the granulating solution from step iii) while mlxmg; vi) granulating the mixture of step v) by mixing; -vii) drying the granulate; viii) sizing the granulate by sieving; ix) mixing the sized granulate with the rest of the fIrst lubricant and the second lubricant (together with the fIrst lubricant in an amount based on the total weight of the composition from 1 % to 20% by weight); and x) compressing the mixture obtained in step ix) into tablets.

Title of Invention

A METHOD OF PREPARING A SOLID ORAL PHARMACEUTICAL COMPOSITION

Abstract

A method of preparing a solid oral pharmaceutical composition comprising the successive steps of: i) pre-mixing 0.5% to 15% by weight of Compound A or a pham1aceutically acceptable salt thereof with 60 to 98% of the diluent (in an amount based on the total weight of the composition from 10 to 50% by weight), and then sieving the resulting mixture; ii) mixing purified water with a binder (in an amount based on the total weight of the composition from 1 % to 10% by weight), ctlld stirring until dissolution; iii) adding a surfactant (in an amount based on the total weight of the composition from 0.1 % to 10% by weight) to the solution of ii) and stirring until dissolution; iv) adding a disintegrant (in an amount based on the total weight of the composition from 20% to 60%), the remaining diluent and 50 to 70% of a first lubricant (together with a second lubricant in an amount based on the total weight of the composition from 1 % to 20% by weight) to the pre mixture of i) and mixing; . v) wetting the mixture of step iv) with the granulating solution from step iii) while mlxmg; vi) granulating the mixture of step v) by mixing; -vii) drying the granulate; viii) sizing the granulate by sieving; ix) mixing the sized granulate with the rest of the fIrst lubricant and the second lubricant (together with the fIrst lubricant in an amount based on the total weight of the composition from 1 % to 20% by weight); and x) compressing the mixture obtained in step ix) into tablets.

Full Text	New Oral Formulation The present invention relates to a pharmaceutical composition, in particular to a composition for administering active agents which are poorly soluble in aqueous mecia and/or which are acid sensitive. More particularly, the present invention relates to a pharmaceutical composition for administering active agents acting on the gastro-intestinal system. The present invention also relates to a process for manufacturing such compositions. The term "pharmaceutical" also covers veterinary use. Pharmaceutical compositions containing active agents which are poorly soluble in aqueous media and/or acid sensitive are difficult to manufacture. One of the problems that may occur concerns adsorption of the active agent on the process equipment during the manufacturing process. Due to the poor solubility of such active agents it is also difficult to obtain pharmaceutical compositions which upon administration have a good dissolution rate. As a further problem, active agents may be degraded, e.g.. chemically, during a manufacturing prccess using acidic conditions or during the storage of the composition. The present invention provides compositions and processes which avoids or minimise one or more of the above problems. We have now surprisingly found that it is possible to produce a pharmaceutical composition for administering of active agents which are poorly soluble in aqueous media, e.g., pure water, and/or acid sensitive, and which upon administration has good dissolution properties, a good bioavailability and is surprisingly efficacious. The present invention provides in one aspect a solid oral pharmaceutical composition, e.g., a tablet, comprising an active agent which is poorly soluble in aqueous media, and/or acid sensitive, and a disintegrant, e.g., a super-disintegrant, which is present in an amount of at least 15% by weight based on the total weight of the composition. By "poorly soluble" is meant an active agent having a solubility in aqueous media more than 0.001% and less than 10%, e.g., less than 1 %, e.g., less than 0.1%, e.g., less than 0.05%, e.g., less than 0.02%, at room temperature, e.g., 25°C. Ey "acid sensitive" is meant an active agent which under even slightly acidic conditions, e.g., at pH 6, may be transformed to a significant extent in a degradation product, e.g., by chemical degradation, which may have no or changed activity, e.g., within 2 hours. Examples of compounds are known in the art and may be ascertained by routine experimentation. Bv "disintecrant" is meant a substance or mixture of substance added to a solid pharmaceutical composition, e.g., a tablet, to facilitate its break-up or disintegration after administration in order that the active ingredient is released from the composition as efficiently as possible to allow for its rapid dissolution (see e.g. "Remington's Pharmaceutical Science"1 18th edition (1990), The Theory and Practice of Industrial Pharmacy' Lachman et al. Lea & Febiger (1970)). We have also found difficulties on producing stable commercially acceptable formulations, e.g., tablets, of compounds such as those disclosed in EP505322 (herein incorporated by reference) and which are useful as 5-HTa receptcr agonists or partial agonists. A preferred 5-H74 partial agonist disclosed in 5P505322 is Tegasercd (3-{5-methcxy-1H- . J> ■ ;ndcl-3-yl-methylene)-N-pentylcarbazimidamide) (example 13) of formula which is referred hereinafter as Compound A, or a pharmaceutical^ acceptable salt form thereof, e.g., the hydrogen maleate (hereinafter Timf) salt. Compound A has a solubility of about 0.02% at 25°C in water and is acid sensitive. We have found that compositions may be produced which give good absorption even in the stomach. We have also found that Compound A may be adsorbed by certain excipients so that its dissolution upon administration may be substantially reduced. Little has been published in detail en 5-HT4 receptor agonists, partial agonists or antagonists bicpharmaceutical properties, e.g., their site of action is not known. The present invention provides in a further aspect pharmaceutical compositions allowing a complete dissolution cf 5-nT4 receptor agonists, partial agonists or antagonists, e.g., Compound A, when administered ic humans, e.g., patients, in need thereof. These compositions allow a good bioavailability and are surprisingly efficacious. Moreover, they are stable and weil reproducible. A process for their preparation is also provided. Active agents which may be used in compositiens according to the present invention are more generally those acting en the gastro-lntestinal system, e.g., serotonergic active agents, e.g., full agonists, partial agonists and antagonists of 5-HT4 receptcrs to the extent they are pooriy soluble and/or acid sensitive. They are preferably in salt form, e.g., hydrogen maleate or hydrochloride, and may be in free form. The 5-HT4 receptor is a cloned species cf the serotonin receptor family which comprises at least 14 distinct G protein-coupled receptors (the receptor iencphcre of the 5-HT3 subtype excluded). Four splice variants of the human receptor, 5-HT4A , 5-HT4B . 5-HT4c , and 5-r.Tcc, have been identified which differ in the length and sequence of the protein's C terminus (Elcndel et al.( FE3S Letters (1SS7) *2:465-474; Blondel et al., J, Neurcchem. (1SS8) 70: 2252-2261). Biochemical characterisation of 5-HT4 receptors revealed a positive coupiing to adenylyi cyclase. 5-HT4 receptor expression in man has been found in the brain, the gut, the atria, the urinary bladder and kidneys. Compounds capable of acting on the serotonin receptor are substituted benzamides, e.g., cisapride, renzacride, zaccpride, ciebopride, cinitapride, mesapride, lintoprice, metocicpramide, or benzoic esters, e.g., RS 23597-190, SB 2G4070, SB ^207710, or aminoguanidines, zacopride, prucalopride, SB 205149, SC 53116, RS 67333, RS 67506, BIMU 1, BIMU 8, (S)-RS 56532, Tropisetron, Alosetron, GR113808, GR125487, SB 207266, RS 23597, RS 39604, RS 100235, DAU 6285, SC 53606, 3-(5-hydroxy-7- methyl-1H-indGl~3-yl- methyIene)-N-pentyl-N-methyl-caitazimidamide^ indazpIe-3- carboxamides, 2-oxobenzamidazoIe-3-carboxamides (as disclosed in EP 908 459 which is herein incorporated by reference) etc. 5-HT.t receptor agonists are considered as compounds which can activate 5-HTi receptors under quiescent/resting conditions (complete or partial activation). As 5-H74 receptor full agonists or partial agonists one may cite (S)-zacopride, cisapride, prucaiopride. SB 205149, SC53115, RS 67333, RS 67506, EIMU1, EIMU 3, (S)-RS 56532 and Compound A, particularly its hydrogen maieate salt. 5-HT4 receptor antagonists are considered as compounds which do not activate 5-HT4 receptors but act as inhibitors of agonists at 5-HT4 receptors. As 5-HT4 receptor antagonists one may cite GR 113808, GR 125487, S3 203186, SB 204070, S3 207266, RS 23597, RS 39604, RS 100235, DAU 62S5, SC 53606, 3-(5-hydroxy-7-methyl-1H-indol-3-yl-methyleneJ-N-pentyl-N-methyl-carfcazimidamide. 5-HT4 receptor-agonists are useful for the prevention and treatment of gastro-intestinai motility disorders, e.g., Irritable Ecwei Syndrome (IBS), Gastroesophageal Reflux Disease (GERD), Functional Dyspepsia (FD) and Post Operative Ileus (POI). In a preferred embodiment, the composition of the invention comprises 20 to 60%. e.g., 30 to 50%, e.g. 40% by weight cf cisintecrant based on the total weight of the composition. We have observed that the use cf such a high percentage of disintegrant further improves the dissolution rate in aqueous media, but also prevents the active agent from adsorbing en excipients. As disintegrants the composition of the invention may comprise : - crospovidone (molecular weight >10°)f e.g., Folyplasdone XL®, Kollidcn CL® , PclypIasdoneXL-10®, - pregelatinised starch (MW : 30 000 -120 000), e.g., starch 1500®, STA-Rx 1500®, - sodium starch glycolate (MW : 500 000 -1 000 000), e.g. Primojef®, - carboxymethyicellulose calcium (CMC-Ca), - carboxymethyicellulose sodium (CMC-Na) (MW: 90 000 - 700 000), e.g., Ac-Di-Sol®, - sodium alginate, or a mixture thereof. Preferably, the disintegrant is crospovidone which is preferably water insoluble. Preferably it rapidly exhibits high capillary cr pronounced hydration capacity with little tendency :c gel formation. Preferably the panicle size is from about 1 to 5G0 micrcmeters. Preferred panicle size distribution is less than -100 micrometers, e.g., for Poiyplasdone XL3, less than SO micrometers, e.g., less than 7- micrometers for, e.g., Poiyplasdone XL-1C The pharmaceutical composition of the invention may funher comprise one cr mere excipients. The composition may funher comprise one or more lubricants, e.g., in an amount within the range of from, e.g., 1 to 20%, e.g., from 5 to 15%, e.g., 10% by weight of the composition. Examples of such lubricants include - glyceryl mono fatty acid, e.g., having a molecular weight of frcm 200 to SCC, e.g.. giyesr/i mencstearate (e.g., Myvaplex3, USP quality) - polyethylene glycol (PEG), having a molecular weight of frcm ICO to 1CCC0, e.g., 1CCC to SCCO, e.g., 2000 to 6000, e.g., 2500 to 5000, e.g., Macrogci 4000 (Pulver) EF( - hydrogenated caster oil (e.g., Cutina'), and the like or a mixture thereof. In a preferred composition the lubricant is glyceryl monostearate. The lubricant properties of such preferred composition may be improved by adding polyethylene glycol (PEG), e.g., Macrcgol 4000 (Pulver) EP. The composition of the invention may comprise one or more surfactants, e.g., in an amount in the range of from 0.1 to 10%, e.g., 1 to 5%, e.g. 2% by weight of the total composition. Pharmaceutical^ suitable surfactants may be non-ionic or anionic. As non-ionic surfactants one may use: - polyoxyethylene-sorbitan-fatty acid esters (polysorbates; MW: 500 to 2000), e.g., mono- and tri- lauryl, palmityl, stearyl and oleyl esters, e.g., Tween®, e.g., Tween 80®; - pciyoxyethylene fatiy acid esters (MW : 500 to 5000), e.g., Myrfor Cetiof3; - polyoxyethylene-poiycxyprccylene co-polymers, e.g., having a molecular weight of from 1CC0to20 000, e.g., 6 0C0 to 15 000, e.g., 7 000 to 10 000, e.g., Pluronic3 cr Emkalyx3; - oolyoxyethylene-polycxyprcpyiene bicck co-polymers e.g., having a molecular weight of from 1000 to 20 COO. e.g., 6 CC0 to 15 000, e.g., 7 000 to 10 000, e.g., Folcxamer 1383; - reaction products cf a natural or hydrogenated caster oil and ethylene oxide, e.g., Cremophcr9; - dicctylsuccinate or ci-[2-ethylhexyl]- succinate; - prcpyleneglyccl mono- and ci-fatty acid (e.g. C5-Cg) esters, e.g., Miglyci"2; or mixtures thereof. As suitable anionic surfactants one may use, e.g., sodium laurylsulfate or docusate sodium. Unless where otherwise stated fatty acid or carbon containing chain is from about 3 to 22 carbon atoms, e.g., C«a. The composition cf the invention may comprise one or more binders, e.g.. in an amount in the range of from 1 to 10%, e.g., 2 to 6%, e.g., 5% by weight. One may particularly use : - hydroxypropylmethyiceiiuicse, e.g., having a molecular weight of from 10 CC0 to 1 500 000, e.g., HPMC-3 (3mFa-s} (e.g. Fharmacoat®, Methocel®), - polyvinylpyrrolidone, e.g., having a molecular weight of from 2500 to 3 0CC CC0, e.g., 8 000 to 1 000 000, e.g., 10 000 to 400 000, e.g., 30 000 to 50 000 (e.g., Kciliricn Plasdone®), - potato starch, wheat starch, corn starch, e.g., having a molecular weight cf from 30 CCO to 120 000, or a mixture thereof. The composition of the invention may comprise one or more diluents such as lactose, mannitol, sucrose, calcium sulphate, calcium phosphate, microcristalline cellulose (Avicef®) in an amount within the range of from, e.g., 10 to 70%, e.g., 20 to 50%, e.g., 30% by weight of the composition. Preferably, the diluent is lactose, e.g., lactose 200 mesh (e.g., from DMV® or Alpavit ®), e.g., the monohydrated form. Other conventional excipients which may optionally be present in the composition'of the invention include preservatives, stabilisers, anti-adherents or silica flew conditioners or giidants, e.g., silicon dioxide (e.g., Sylcid'3, Aeros.T3) as well as FD&C colours such as ferric oxides. Other excipients disclcsed in the literature, as for instance in Fiedlers "Lexicon e'er Hiifstoffe", 4th Edition, ECV Aulendcrf 19S6 and "Handbook of Pharmaceutical Excipients3 Wade and Weller Ed.(1994), the contents of which are incorporated herein by reference, may be used in the pharmaceutical compositions according to the invention. The invention is particularly useful fcr pharmaceutical compositions containing an active agent, e.g., an 5H74 receptor agonist, partial agonist or antagonist, e.g., compound A, e.g., the hydrogen maleate salt, which is present in an amount within the range of from about 0.2% to about 20%,'e.g. 0.5 to 15%, and preferably from about 1% to about 10% by weight of the composition. A preferred composition cf the invention may comprise from about 0.5 to about 15% by weight of active agent, e.g.. a 5H7 receptor agonist, e.g., compound A, e.g., the hydrogen maieate salt, from 20 tc 60% by weight of disintegrant, e.g., crcspovidone, from 1 to about 20% by weight of a lubricant, e.g., mcncgiycerylstearate, from 0.1 to about 10% by weight of a surfactant, e.g., pclcxalkcl, from about 10 to 50% by weight of a diluent, e.g., lactose, and from 1 to 10% by weight cf a binder, e.g., hydroxypropylmethyl cellulose (e.g. HPMC-3). From 1 to 10% by weight cf PEG may also be added. The weight ratio cf the active agent tc the disintegrant may be from 1:1 to 1:400, e.g., 1:5 to 1:100,1:8 to 1:50, e.g., 1:16 to 1:20. In a further aspect the present invention provides a pharmaceutical oral, e.g., tablet, composition comprising one of the active agents cited above, e.g., a 5-HT4 agonist, partial agonist or antagonist, e.g., Tegaserod, said composition having dissolution characteristics in water or in USP buffers pH 6.8 and 7.5 of: For example a ccmpcsiticn according to the invention, e.g., comprising Tegssercd as the active agent, may have dissolution characteristics in water or in US? buffers pH 6.3 and 7.5 cf: In a further aspect the present invention provides a pharmaceutical crai, e.g., tablet; composition comprising one cf the active agents cited above, e.g., a 5-HT.i agonist, partial agonist or antagonist, e.g., Tegasercd, wherein in use 80% cf said active agent is released in water or in USF buffers pH 6.3 and 7.5 within 5 minutes. in a further aspect, the present invention provides the use of at least 15% by weight of a cisintegrant in the manufacturing of pharmaceutical composition for the administration cf an acid sensitive and/cr poorly soluble, e.g., in aqueous media, active agent, e.g., a 5-HT4 receptor agonist, e.g., compound A, e.g. the hydrogen maleate salt. The pharmaceutical compositions of the present invention are useful in the known indications of the particular active agent incorporated therein. Tne exact amounts of active agent and of the formulation to be administered depend en a number of factors, e.g. the condition to be treated, the desired duration of treatment and the rate of release of active agent. For example, the amount of the active agent required and the release rate thereof may be determined on the basis of conventional in vitro or in vivo techniques, determining how long a particular active agent concentration in the blood plasma remains at an acceptable level for a therapeutic effect The pharmaceutical composition of the invention comprising a 5-ri74 receptcr agonist, partial agonist or antagonist is particularly useful for improving sensor/ perception cf rectal distension, e.g. for the treatment of anal incontinence, or for preventing, modulating or treating visceral pain cr discomfort. 5-HT4 receptor agonists, partial agonists cr antagonists, e.g. as disclosed in EP-A1-5C5.322, en the basis cf observed activity, e.g. stimulatory effect en the peristaltic reflex in the isolated guinea-cic :ieum, e.g. as described in EP-A1-505.222. have been found to be useful fcr the treatment of gastrc-intestinal motility disorders, for example to normalise cr to improve the gastric emptying and intestinal transit in subjects having a oisturbec motility, e.g. in irritabie bev/ei syndrome. in accordanca with the present invention, it has now surprisingly been found that 5-HT4 receptor agonists, partial agonists or antagonists have a beneficial effect, e.g. they exert modulating effects, on the sensor/ perception of rectal distension and en visceral sensitivity cr perception. It is admitted that receptor properties are net uniform throughout the cut and that thg type of afferent innervation reflects the quality of sensations originating from a particular organ. Fcr example, the rectum belongs to those parts of the gastro-intestinai tract from which also non-painful sensations arise, in contrast to the colon from which only painful sensations emanate. Anal incontinence may be due to functional disturbances of the main anal continence mechanisms. Anal continence appears to be based on a co-ordinated functioning of the 1.3. A method fcr stimulating 5-HT4 receptors present en afferent r.er/e terminals, particularly en extrinsic neurones cf the cut, in a subject in need thereof, which method comprises administering to said subject an effective amount of a 5-KT4 receptor agonist or partial agonist or a pharmaceutical^ acceptable salt thereof. 1.4. A method fcr modulating visceral sensitivity, discomfort or pain via stimulation of 5- HT4 receptors present on afferent nerve terminals, particularly on extrinsic neurones of the gut, in a subject in need thereof, which method comprises administering to said subject an effective amount of a 5-HT4 receptor agonist or partial agonist or a pharmaceutical^ acceptable salt thereof. 3. A 5-HT4 receptor agonist, paniai agonist or antagonist cr a pharmaceutical^ acceptable salt thereof for use in the manufacture cf a pharmaceutical composition for use in a method as defined under 1.1 to 1.7 above; cr 4. A pharmaceutical composition for use in a method as defined under 1.1 to 1.7 above comprising a 5-HT4 receptor agonist, partial agonist or antagonist cr a pharmaceutical acceptable salt thereof, together with one cr mere pharmaceutical/ acceptable diiuents or carriers therefor, e.g. a composition such as disclosed hereinabove. Preferred compounds for use in accordance with the invention include e.g. those listed hereinabove, particularly 5-HT4 receptor full agonists or partial agonists, e.g. (S)-zacopride, cisapride, prucaiopride, SB 205149, SC 53116, RS 67333, RS 67506, BIMU1, BIMU8, (S)-RS 56532, especially Compound A and particularly its hydrogen maleate salt, more After obtaining 2 distension profiles (5 rnin each) and/cr 10 rnin cf peristalsis under centre! conditions, a 5-HTi receptor agonist, partial agonist cr antagonist, e.g., Compound A, cr vehicle is applied i.v. and the protocol is repeated. Subsequently, the activity of additional units is recorded in the presence of a 5-HT4 receptor agonist, partial agonist or antagonist, e.g., Compound A, or vehicle according to the distensicn/peristaisis protocol. In this assay, the firing rate cf the rectal afferents is reduced after administration cf a 5-HT4 receptor agonist or partial agonist at a dose range of from 0.1 to 3 mg/kg i.v., at distension pressures above 20 mmHg. With Compound A, administered i.v. in incremental doses from 0.15 to 1.2 severity of the condition to be treated. An indicated daily dose is in the range of from about 0.05 to about 30 .no, e.g., from about 0.05 to about 5 mg for parenteral use, and of from about 0.1 to about 20 mg for oral use, conveniently aoministered once or in civided dosages 2 to -x/cay, or In sustained release form. Unit dosage forms for crai administration accordingly comprise from about 0.5 to about 30 mg of 5-HT4 receptcr agcnist, partial agonist cr antagonist, e.g., Compound A, or a pharmaceuticaily acceptable sait thereof, admixed with an appropriate sciid or iicuid, pharmaceuticaily acceptable diiuent cr carrier therefor. Furthermore, it has also been found that a 5-HT4 receptcr agonist or partial agcnist-e.g., Compound A, have a beneficial effect in the prevention cr treatment of gastrc-intestinal mctiiity disorders, e.g. a stimulatory effect on gastrointestinal motility, in horses and cattle. Accordingly, there is also provided: 5.1. A method for preventing cr treating gastrointestinal motility disorders, e.g. by stimulating the mctiiity of the gastro-lntestinai tract in horses cr cattle in need thereof, which method comprises administering to the horses cr cattie an effective amount of a 5-HT4 receptcr agonist or partial agonist, e.g.. Compound A, cr a pharmaceuticaily acceptable salt thereof. 5.2. A methcd for preventing or treating gastrc-intestinal mctiiity disorders, e.g. after colic surgery, e.g. post-operative Ileus, in horses or cattle in need thereof, which method comprises administering to the horses or cattle an effective amount of a 5-HT4 receptcr agonist or partial agcnist, e.g., Compound A, cr a pharmaceuticaily acceptable salt thereof. 6. A 5-HT4 receptcr agcnist or partial agcnjst, e.g., Compound A, cr a pharmaceuticaily acceptable salt thereof, for use as a veterinary pharmaceutical e.g. for horses or cattle, e.g. in any of the method 5.1 or 5.1 indicated above cr for use in the manufacture of a veterinary pharmaceutical e.g. for use in a methcd as defined under 5.1 or 5.2. 7. A pharmaceutical composition for veterinary use, e.g. in horses cr cattle, e.g. in any of the method 5.1. or 5.2. as indicated above, comprising a 5-HT4 receptor agonist or partial agonist, e.g., Compound A, or a pharmaceutical/ acceptacie sait thereof, tcgether with a pharmaceutical^ acceptable diluent cr carrier therefor, e.g. a composition as discicsec hereinabove. Preferred 5-H74 receptor agonists or partial agonists for use in horses or cattle in accordance with the invention include e.g. these listed hereinabove, e.g. (S)-zacopride, prucalcpride, SE2Q514S, SC 53116, RS 67333, RS 57506, 5IMU 1, EIMU 8, (S)-RS 56532, especially Compound A and particularly its hydrogen maleate salt, mere preferably a selective 5-H74 receptor agonist or partial agonist. Utility of a 5-HT4 receptor agonist or partial agonist, e.g., Compound A, in the treatment of pest-operative Ileus as well as utility in treating conditions as hereinabove specified in hcrses or cattle, mav be demonstrated in accordance with the method hereinafter described. 20 hcrses having colic syndrome are submitted to abdominal surgery. During surgery s-ccccrdve therapy is applied to thenr. At the end of surgery, a specific 5-HT4 receptor agonist cr partial agonist, e.g., Compound A, is administered Lv. or i.m., e.g. at a dose of from 0.01 to 10 mg/kg. This dose is repeated ever/ 8 to 24 h until spontaneous defecation is observed. Gastro-intestinai motility is evaluated based e.g. on the presence cr absence of gastric reflux as determined by nasogastric intubation, occurrence of borborygmi and timing of defecation after the first injection of the test compound. In this test, the compounds tested, e.g. Compound A, are effective in restoring normal motility function of the equine intestine. Daily dosages required in practising the veterinary method of the present invention will vary depending upon, for example, the particular compound employed, the mode of administration and the severity of the condition to be treated. An indicated daily dose is in the range of from about 0.01 to about 10 mg/kg, e.g., from about 0.05 to about 5 mg/kg for parenteral use, conveniently administered once or in divided dosages 2 to 4x/day, or in sustained release form. In a further aspect the invention provides a method for preventing or treating gastrointestinal motility disorders in a subject, e.g., a human or an animal, in need of such a therapy comprising administering to this subject an effective amount of a composition according to the present invention. in a further aspect the invention a process is provided for improving dissolution properties in aqueous media of a pharmaceutical composition containing an acid sensitive and/cr poorly soluble in aqueous media active agent, e.g., a 5-HT4 receptor agonist, more particularly compound A, e.g. the hydrogen maleate salt. The pharmaceutical composition of the invention may be prepared by any conventional method known in the art, e.g., by mixing an appropriate amount of the active agent, e.g., a 5-HT4 receptor agonist, with at least 15%, e.g., from 20 to 60%, e.g., from 30 to 50%, e.g., 40%, by weight of a disintegrant based on the total weight of the composition. It is preferred to formulate in solid form, e.g., unit dosage form. Typical form include capsules and preferably compressed forms such as tablets. Tne pharmaceutical composition according to the invention may be prepared by e.g., a wet, e.g., water based, granulation manufacturing process (the process equipment, as glass material, may be pre-treated with a siliconizing agent) comprising the successive steps of: i) pre-mrxing the acid sensitive and/or poorly soluble in water active agent, e.g., a 5-HT4 receptor agonist, e.g., compound A, e.g. the hydrogen maleate salt with 60 to 98% of the diluent, and then sieving the resulting mixture, ii) mixing purified water with the binder in a weight ratio of from 1:20 to 3:20, and stirring • until dissolution, iii) adding the surfactant to the solution of ii) and stirring until dissolution, iv) adding the disintegrant, the remaining diluent and 50 to 70% of the first lubricant to the pre mixture of i) and mixing v) wetting the mixture of step iv) with the granulating solution from step iii) while mixing Examples The fcllcwina examoles illustrate the manufacturina, en an industrial scale. :f ccmcositicns comprising comccund A hml using a wet aranuiaticn process as discicsed accve. Example 1 A 2 mc tablet formulation mav be prepared as described hereinafter. a) Preparation of the Granulated material Premixinc step 1. 4.432 kg cf compound A hml and 23.583 kg of lactose menchycrate are mixed with an intensive mixer (Colette Gral^ 300 I or Fielder3) ; mixer speed setting : 1; chopper speed setting : 1) for approximately 1.5 minutes, or with a free fall mixer (Turbuia3, Scneco^ or Rchnracf^) 2. The pre-mixture from step 1 is then sieved (oscillating granuiatcr, e.g., Frewitt3 cr Er.veka; mesh size: 0.8 millimetres). 2. "The pre-mixture is divided into two peniens ci 16.560 kg. Preparation of the cranulatinc solution -. Approximately 40 kg of purified water are weighed out. 5. 3.500 kg cf methyihycroxyprcpylceiiulose 3 maps are added to the purified water frcm step 4 and this is stirred until dissolution. 6. 1.440 kg of poloxamer 188 are added to the solution frcm step 5 whiie stirring until dissolution. Granulating steo 7. 23.800 kg of crespovidene, 10.080 kg of lactose menchycrate and ^.320 kg cf Glyceryl menpstearate are weighed cut. 8. One portion of the premixture from step 3 is added to the excipients from step 7 and this is mixed with the intensive mixer, e.g., Colette Graf 300 I or Fielder3 (mixer speed setting : 1; chopper speed setting : 1) for approximately 2 minutes. 9. The mixture from step 8 is wetted with the granulating solution frcm step 6 while mixing with the intensive mixer, e.g., Colette Gral® 300 I or Fielder^ (mixer speed setting : 1; chopper speed setting : 0; pumping rate approximately : 4 kg/minute) for approximately 12 minutes. 10. Approximated 2 kg of cunfied water are weighed out. 11. The vessel from step 6 is rinsed with the purified water from step 10 and this is added to the mixture from step 3 whiie mixing. 12. The mass is granuiatec by mixing with the intensive' mixer, Colette Graf5 300 I or Fielder3 (mixer speed setting : 1: chopper speed setting : 1) for approximately 2.5 minutes. Drying step 12. The granulate from step 12 is dried in a fluidised air bed drier (e.g., Glatt3 or Aeromatic3) for approximately 65 minutes (inlet air temperature approximately 70°C) to reach the required less on crying (LCD) for the tabletting mixture, i.e., until LCD 14. The granulate sized by sieving (0.3 miilimetres) with an oscillating sieve granulatcr, e.g., Frewitt3 or Er«veka3. 15. Steps 4 to 14 are repeated with the ether portion of step 2. ■ b) Preparation of the tabletting mixture 16. 8.640 kg of polyethylene glycoi 40C0 and 5.760 kg of glyceryl monostearate are sieved (oscillating granulatcr, e.g., Frewitt® or Erweka®; mesh size: 0.8 miilimetres) 17. The ingredients from step 16 are added to the total mass of granulated material and this is mixed with a free fail mixer, e.g., Soneco® or Rchnracf®, for approximately 20 minutes (10 rpm) to obtain the desired final tabletting mixture. c^ Compression steo 13. The tabletting mixture from step 17 is pressed into tablets using compression pressures of 11, 14 or 17 KN on a rotary tabletting machine, e.g., Fette®, Korsh®, Kelian® or Coarty® (temperature Example 2 : Composition of a 2 ma tablet (1 ma of base corresponds to 1.385 ma of the hvdroaen maleate salt of compound A) Compound A hml 2.77 (2mg base) Fciyplasdone XL USP/NF 36.00 Glyceryl mcncstearate USP/NF 9.00 Lactose 200 mesh 30.52 HrMCScFs 4.50 Fclvethvlenecivcoi 40C0 SAG Water adsorbed 2.C0 Total 92 mc Example 3 A 6 mg tablet formulation may be prepared by the manufacturing process described hereinafter. a) Preparation of the oranuiatec material Preparation of the granulating solution 1. Approximately 40 kg of purified water are weighed out. 2. 3.600 kg of methylhydrcxyprcpyiceilulose 3 maps are added to the purified water from step 1 while stirring untii dissolution. 3. 1.440 kg of poloxamer 188 are added to the solution from step 2 while stirring untii dissolution (mixing tank under stirring). Granulating step 4. 4.787 kg of compound A hml and 23.800 kg of crospoviccne, 21.853 kg of lactose monohydrate and 4.320 kg of glyceryl monostearate are weighed out. 5. The ingredients from step 4 are mixed with the intensive mixer, e.g., Colette Graf® 300 I or Fielder® (mixer speed setting: 1; chopper speed setting : 1) for approximately 2 minutes. 6. The mixture from step 5 is wetted with the granulating solution from step 3 while mixing with the intensive mixer, e.g., Colette Gral® 300 I or Fielder® (mixer speed setting: 1; chopper speed setting : 0; pumping rate approximately 4 kg/minute) for approximately 12 minutes. 7. Approximately 2 kg of purified water are weighed out. 8. The vessel from step 3 is rinsed with the purified water from step 7 and this is added to the mixture from step 6 while mixing. S. The mass is granulated by mixing with the intensive mixer, e.g., Colette Graf3 300 i or Fielder® (mixer speed setting: 1; chopper speed setting : 1) for approximately 2.5 minutes. Drying step 10. The granulate from step 9 is dried in a fluidised air bed drier, e.g., Glatt® or Aeromatic®) for approximately 65 minutes (Inlet air temperature approximately 70°C) to reach the desired loss en drying (LOD) for the tabletting mixture, i.e., until LOD 11. The granulate sized by sieving (0.3 millimetres) with an csciilating sieve granulator (Frewitt® or Erweka®) 12. Steps 1 to 11 are repeated. b) Preparation of the tabletting mixture 13. 8.640 kg of polyethylene glycol 4000 and 5.760 kg of glyceryl mencstearate are sieved with an oscillating sieve granulator, e.g., Frewitt® or Erweka® (0.8 millimetres) 14. The ingredients from step 13 are added to the total mass of granulated material and this is mixed with a free fail mixer, e.g., Soneco® or Rohnrad®, for approximately 20 minutes (10 rpm) in the desired final tabletting mixture. c^ Compression step » 15. The tabietting mixture from step 14 is pressed into tablets using compression pressures of 13, 16 or 1S KN on a rotary tabletting machine, e.g., Fette®, Keren5, Kelian® or Coarty®(temperature Example 4 : Composition of a 6 mq tablet (1 mq of base corresponds to 1.385 mo of hydrogen maleate of compound A): Compound A hml 8.31 (6mg base) Polyplasdone XL USP/NF 50.00 Glyceryl monostearate USP/NF 12.50 Poioxalkol 2.50 Lactose 200 mesh 37.94 HPMC 3cPs 5.25 Poiyethyleneglycol ^000 7.50 Water adsorbed 3.00 Total 128 mg Example 5 A 0.5 mg tablet formulation may be prepared by the manufacturing process described hereinafter. a) Preparation of the cranulaied material Premixing step 1. 1.994 kg of compound A hml and 31.126 kg of lactose monohydrate are mixed with an intensive mixer (Colette Graf® 300 I or Fielder®) ; mixer speed setting : 1; chopper speed setting : 1) for approximately 1.5 minutes, or with a free fall mixer (Turbula®, Soneco® or Rohnrad®) 2. The premixture from step 1 is then sieved (csciilating granulatcr, e.g., Frewitt® cr Erweka®; mesh size: 0.8 millimetres). 3. The premixture is divided into two portions of 16.560 kg. Preparation of the granulating solution 4. Approximately 43 kg of purified water are weighed cut. 5. 3.600 kg of methyihydroxyprcpylcellulose 3 maps are added to the purified water from step 4 and this is stirred until dissolution. 6. 1.440 kg of poloxamer 188 are added to the solution from step 5 while stirring until dissolution. Granulating step 7. 28.800 kg of crospovidcne, 10,080 kg of lactose monohydrate and 4.320 kg of glyceryl moncstearate are weighed out. 8. One portion of the premixture from step 3 is added to the excipients from step 7 and this is mixed with the intensive mixer, e.g., Colette Gral® 300 I or Fielder® (mixer speed setting : 1; chopper speed setting : 1) for approximately 2 minutes. 9. Tne mixture from step 8 is wetted with the granulating solution from step 6 while mixing with the intensive mixer, e.g., Colette Gral® 300 I or Fielder^ (mixer speed setting : 1; chopper speed setting : 0; pumping rate approximately : 4 kg/minute) for approximately 12 minutes. 10. Approximately 2 kg of purified water are weighed out 11. The vessel from step 6 is rinsed with the purified water from step 10 and this is added to the mixture from step 9 while mixing. 12. Tne mass is granulated by mixing with the intensive mixer, Colette Grai3 300 I or Fieider'2 (mixer speed setting : 1; chopper speed setting : 1) for approximately 2.5 minutes. Drying step 13. The granulate frcm step 12 is dried in a fluidised air bed drier (e.gM Giatf5 or Aeromatic®) for approximately 60 minutes (inlet air temperature approximately 70°C) to reach the required loss on drying (LOD) for the tabletting mixture, i.e. until LOD 14. The granulate sized by sieving (0.8 millimetres) with an oscillating sieve granuiator, e.g., Frewitt® or Erweka. 15. Steps 4 to 14 are repeated with the other portion of step 3. b^ Preparation of the tabletting mixture 16. 8.640 kg of polyethylene glycol 4000 and 5.760 kg of glyceryl mcnostearate are sieved (oscillating granuiator, e.g., Frewitt® or Erweka®; mesh size: 0.8 millimetres) 17. The ingredients from step 16 are added to the total mass of granulated material and this is mixed with a free fall mixer, e.g., Soneco® or Rohnrad®, for approximately 20 minutes (10 rpm) to obtain the desired final tabletting mixture. c) Compression step 18. The tabletting mixture from step 17 is pressed into tablets on a rotary tabietting machine, e.g., Fette®, Korsh®, Kelian® or Coarty9 {temperature Example 6 : Composition of a 0.5 mq tablet (1 ma of base corresponds to 1.385 mo of the hydrogen maleate salt of compound A) Compound A hml 0.6925 (0.5mg base) Polyplasdone XL USP/NF 20.00 Glyceryl monostearate USP/NF 5.00 Poloxalkol 1.00 Lactose 200 mesh 17.8075 HPMCScPs 2.50 Polyethyleneglycoi 4000 3.00 Water adsorbed 1.00 Total 51 mg Example 7 : Composition of a 12 mo tablet (1 ma of base corresponds to 1,385 mg of the hvdroaen maleate salt of compound A) The manufacturing process is similar to the process used for the Smg tablets. Compound A hml 16.62 (12mg base) Polyplasdone XL USP/NF 72.00 Glyceryl monostearate USP/NF 13.00 Poloxalkol . 3.60 Lactose 200 mesh 49.98 HPMC 3cPs 9.0 Polyethyleneglycoi 4000 10.8 Water adsorbed 4.00 Total 184 mg WE Claims 1. A method of preparing a solid oral pharmaceutical con: josilion comprising a) 0.2 to 20% by weight of Compound A or its salts; and b) a disintegrant which is present in an amount of at least 15% by weight based on the total weight of the composition. 2. The method of preparing a composition of claim 1 cornj:rising a disintegrant which is present in an amount of at least 15% by weight based en the total weight of the con' position, wherein the disintegrant is a member selected from the group consisting of crospovidene, sodium starch glycolate, caibcxyniethylceiluiose sodium. sodium alignate, and a mixture thereof. 3. The method of preparing a composition accotding to claims 1 or 2 in which Compound A is in the form of its hydrogen maleate (hm»; salt. 4. The method of preparing a composition according to any preceding claims characterized in that the disintegrant is present in an arrount of 20 to 60% by weight based on tne total weight of the composition. 5 The method of preparing "a composition according to csims 1 to 3 characterized in that the disintegrant is present in an amount of 40% Uy weight based on the total weight of the composition. 3. The method of preparing a composition according to any proceeding claims characterized in that the disintegrant is crospovidone. 7. The method of preparing a composition accurd-inc; to aity proceeding claims comprising from 1 to 20% by weight of a lubricant. i3. The method of preparing a composition according to t.xtn 7 characterised ,n that the lubricant comprises a glyceryl mono fatty acid. 9. The: metnod of preparing a composition according lc ci Him 8 characterized in that the lubricant comprises a mixture of glyceryl monosiearate and polyethylene glycol. "0. The method of preparing a composition according to a;sy proceeding claims comprising from 0.1% to 10% by weight of a surfactant. 11. The method of preparing a composition according to ;iaim SO characterized in that the surfactant comprises poloxamer. 12. The method of preparing a composition according to claim 11, having dissolution characteristics in water of:

Full Text

New Oral Formulation
The present invention relates to a pharmaceutical composition, in particular to a composition for administering active agents which are poorly soluble in aqueous mecia and/or which are acid sensitive. More particularly, the present invention relates to a pharmaceutical composition for administering active agents acting on the gastro-intestinal system. The present invention also relates to a process for manufacturing such compositions. The term "pharmaceutical" also covers veterinary use.
Pharmaceutical compositions containing active agents which are poorly soluble in aqueous media and/or acid sensitive are difficult to manufacture. One of the problems that may occur concerns adsorption of the active agent on the process equipment during the manufacturing process. Due to the poor solubility of such active agents it is also difficult to obtain pharmaceutical compositions which upon administration have a good dissolution rate. As a further problem, active agents may be degraded, e.g.. chemically, during a manufacturing prccess using acidic conditions or during the storage of the composition.
The present invention provides compositions and processes which avoids or minimise one or more of the above problems.
We have now surprisingly found that it is possible to produce a pharmaceutical composition for administering of active agents which are poorly soluble in aqueous media, e.g., pure water, and/or acid sensitive, and which upon administration has good dissolution properties, a good bioavailability and is surprisingly efficacious.
The present invention provides in one aspect a solid oral pharmaceutical composition, e.g., a tablet, comprising an active agent which is poorly soluble in aqueous media, and/or acid sensitive, and a disintegrant, e.g., a super-disintegrant, which is present in an amount of at least 15% by weight based on the total weight of the composition.
By "poorly soluble" is meant an active agent having a solubility in aqueous media more than 0.001% and less than 10%, e.g., less than 1 %, e.g., less than 0.1%, e.g., less than 0.05%, e.g., less than 0.02%, at room temperature, e.g., 25°C.

Ey "acid sensitive" is meant an active agent which under even slightly acidic conditions, e.g., at pH 6, may be transformed to a significant extent in a degradation product, e.g., by chemical degradation, which may have no or changed activity, e.g., within 2 hours. Examples of compounds are known in the art and may be ascertained by routine experimentation.
Bv "disintecrant" is meant a substance or mixture of substance added to a solid pharmaceutical composition, e.g., a tablet, to facilitate its break-up or disintegration after administration in order that the active ingredient is released from the composition as efficiently as possible to allow for its rapid dissolution (see e.g. "Remington's Pharmaceutical Science"1 18th edition (1990), The Theory and Practice of Industrial Pharmacy' Lachman et al. Lea & Febiger (1970)).
We have also found difficulties on producing stable commercially acceptable formulations, e.g., tablets, of compounds such as those disclosed in EP505322 (herein incorporated by reference) and which are useful as 5-HTa receptcr agonists or partial agonists.
A preferred 5-H74 partial agonist disclosed in 5P505322 is Tegasercd (3-{5-methcxy-1H-
. J> ■
;ndcl-3-yl-methylene)-N-pentylcarbazimidamide) (example 13) of formula

which is referred hereinafter as Compound A, or a pharmaceutical^ acceptable salt form thereof, e.g., the hydrogen maleate (hereinafter Timf) salt. Compound A has a solubility of about 0.02% at 25°C in water and is acid sensitive. We have found that compositions may be produced which give good absorption even in the stomach. We have also found that Compound A may be adsorbed by certain excipients so that its dissolution upon administration may be substantially reduced.

Little has been published in detail en 5-HT4 receptor agonists, partial agonists or antagonists bicpharmaceutical properties, e.g., their site of action is not known.
The present invention provides in a further aspect pharmaceutical compositions allowing a complete dissolution cf 5-nT4 receptor agonists, partial agonists or antagonists, e.g., Compound A, when administered ic humans, e.g., patients, in need thereof. These compositions allow a good bioavailability and are surprisingly efficacious. Moreover, they are stable and weil reproducible. A process for their preparation is also provided.
Active agents which may be used in compositiens according to the present invention are more generally those acting en the gastro-lntestinal system, e.g., serotonergic active agents, e.g., full agonists, partial agonists and antagonists of 5-HT4 receptcrs to the extent they are pooriy soluble and/or acid sensitive. They are preferably in salt form, e.g., hydrogen maleate or hydrochloride, and may be in free form.
The 5-HT4 receptor is a cloned species cf the serotonin receptor family which comprises at least 14 distinct G protein-coupled receptors (the receptor iencphcre of the 5-HT3 subtype excluded). Four splice variants of the human receptor, 5-HT4A , 5-HT4B . 5-HT4c , and 5-r.Tcc, have been identified which differ in the length and sequence of the protein's C terminus (Elcndel et al.( FE3S Letters (1SS7) **2:465-474; Blondel et al., J, Neurcchem. (1SS8) 70: 2252-2261). Biochemical characterisation of 5-HT4 receptors revealed a positive coupiing to adenylyi cyclase. 5-HT4 receptor expression in man has been found in the brain, the gut, the atria, the urinary bladder and kidneys.
Compounds capable of acting on the serotonin receptor are substituted benzamides, e.g.,
cisapride, renzacride, zaccpride, ciebopride, cinitapride, mesapride, lintoprice,
metocicpramide, or benzoic esters, e.g., RS 23597-190, SB 2G4070, SB ^207710, or
aminoguanidines, zacopride, prucalopride, SB 205149, SC 53116, RS 67333, RS 67506,
BIMU 1, BIMU 8, (S)-RS 56532, Tropisetron, Alosetron, GR113808, GR125487,
SB 207266, RS 23597, RS 39604, RS 100235, DAU 6285, SC 53606, 3-(5-hydroxy-7-
methyl-1H-indGl~3-yl- methyIene)-N-pentyl-N-methyl-caitazimidamide^ indazpIe-3-
carboxamides, 2-oxobenzamidazoIe-3-carboxamides (as disclosed in EP 908 459 which is herein incorporated by reference) etc.

5-HT.t receptor agonists are considered as compounds which can activate 5-HTi receptors under quiescent/resting conditions (complete or partial activation). As 5-H74 receptor full agonists or partial agonists one may cite (S)-zacopride, cisapride, prucaiopride. SB 205149, SC53115, RS 67333, RS 67506, EIMU1, EIMU 3, (S)-RS 56532 and Compound A, particularly its hydrogen maieate salt.
5-HT4 receptor antagonists are considered as compounds which do not activate 5-HT4 receptors but act as inhibitors of agonists at 5-HT4 receptors. As 5-HT4 receptor antagonists one may cite GR 113808, GR 125487, S3 203186, SB 204070, S3 207266, RS 23597, RS 39604, RS 100235, DAU 62S5, SC 53606, 3-(5-hydroxy-7-methyl-1H-indol-3-yl-methyleneJ-N-pentyl-N-methyl-carfcazimidamide.
5-HT4 receptor-agonists are useful for the prevention and treatment of gastro-intestinai motility disorders, e.g., Irritable Ecwei Syndrome (IBS), Gastroesophageal Reflux Disease (GERD), Functional Dyspepsia (FD) and Post Operative Ileus (POI).
In a preferred embodiment, the composition of the invention comprises 20 to 60%. e.g., 30 to 50%, e.g. 40% by weight cf cisintecrant based on the total weight of the composition. We have observed that the use cf such a high percentage of disintegrant further improves the dissolution rate in aqueous media, but also prevents the active agent from adsorbing en excipients.
As disintegrants the composition of the invention may comprise :
- crospovidone (molecular weight >10°)f e.g., Folyplasdone XL®, Kollidcn CL® ,
PclypIasdoneXL-10®,
- pregelatinised starch (MW : 30 000 -120 000), e.g., starch 1500®, STA-Rx 1500®,
- sodium starch glycolate (MW : 500 000 -1 000 000), e.g. Primojef®,
- carboxymethyicellulose calcium (CMC-Ca),
- carboxymethyicellulose sodium (CMC-Na) (MW: 90 000 - 700 000), e.g., Ac-Di-Sol®,
- sodium alginate,
* or a mixture thereof.

Preferably, the disintegrant is crospovidone which is preferably water insoluble. Preferably it rapidly exhibits high capillary cr pronounced hydration capacity with little tendency :c gel formation. Preferably the panicle size is from about 1 to 5G0 micrcmeters. Preferred panicle size distribution is less than -100 micrometers, e.g., for Poiyplasdone XL3, less than SO micrometers, e.g., less than 7- micrometers for, e.g., Poiyplasdone XL-1C The pharmaceutical composition of the invention may funher comprise one cr mere excipients.
The composition may funher comprise one or more lubricants, e.g., in an amount within the range of from, e.g., 1 to 20%, e.g., from 5 to 15%, e.g., 10% by weight of the composition.
Examples of such lubricants include
- glyceryl mono fatty acid, e.g., having a molecular weight of frcm 200 to SCC, e.g.. giyesr/i mencstearate (e.g., Myvaplex3, USP quality)
- polyethylene glycol (PEG), having a molecular weight of frcm ICO to 1CCC0, e.g., 1CCC to SCCO, e.g., 2000 to 6000, e.g., 2500 to 5000, e.g., Macrogci 4000 (Pulver) EF(
- hydrogenated caster oil (e.g., Cutina'*), and the like or a mixture thereof.
In a preferred composition the lubricant is glyceryl monostearate. The lubricant properties of such preferred composition may be improved by adding polyethylene glycol (PEG), e.g., Macrcgol 4000 (Pulver) EP.
The composition of the invention may comprise one or more surfactants, e.g., in an amount in the range of from 0.1 to 10%, e.g., 1 to 5%, e.g. 2% by weight of the total composition. Pharmaceutical^ suitable surfactants may be non-ionic or anionic.
As non-ionic surfactants one may use:
- polyoxyethylene-sorbitan-fatty acid esters (polysorbates; MW: 500 to 2000), e.g., mono-
and tri- lauryl, palmityl, stearyl and oleyl esters, e.g., Tween®, e.g., Tween 80®;

- pciyoxyethylene fatiy acid esters (MW : 500 to 5000), e.g., Myrfor Cetiof3;
- polyoxyethylene-poiycxyprccylene co-polymers, e.g., having a molecular weight of from 1CC0to20 000, e.g., 6 0C0 to 15 000, e.g., 7 000 to 10 000, e.g., Pluronic3 cr Emkalyx3;
- oolyoxyethylene-polycxyprcpyiene bicck co-polymers e.g., having a molecular weight of from 1000 to 20 COO. e.g., 6 CC0 to 15 000, e.g., 7 000 to 10 000, e.g., Folcxamer 1383;
- reaction products cf a natural or hydrogenated caster oil and ethylene oxide, e.g.,
Cremophcr9;
- dicctylsuccinate or ci-[2-ethylhexyl]- succinate;
- prcpyleneglyccl mono- and ci-fatty acid (e.g. C5-Cg) esters, e.g., Miglyci"2; or mixtures thereof.
As suitable anionic surfactants one may use, e.g., sodium laurylsulfate or docusate sodium.
Unless where otherwise stated fatty acid or carbon containing chain is from about 3 to 22 carbon atoms, e.g., C«a.
The composition cf the invention may comprise one or more binders, e.g.. in an amount in the range of from 1 to 10%, e.g., 2 to 6%, e.g., 5% by weight. One may particularly use :
- hydroxypropylmethyiceiiuicse, e.g., having a molecular weight of from 10 CC0 to 1 500 000, e.g., HPMC-3 (3mFa-s} (e.g. Fharmacoat®, Methocel®),
- polyvinylpyrrolidone, e.g., having a molecular weight of from 2500 to 3 0CC CC0, e.g., 8 000 to 1 000 000, e.g., 10 000 to 400 000, e.g., 30 000 to 50 000 (e.g., Kciliricn * Plasdone*®),
- potato starch, wheat starch, corn starch, e.g., having a molecular weight cf from 30 CCO to 120 000,
or a mixture thereof.
The composition of the invention may comprise one or more diluents such as lactose, mannitol, sucrose, calcium sulphate, calcium phosphate, microcristalline cellulose (Avicef®) in an amount within the range of from, e.g., 10 to 70%, e.g., 20 to 50%, e.g., 30% by weight of the composition. Preferably, the diluent is lactose, e.g., lactose 200 mesh (e.g., from DMV® or Alpavit ®), e.g., the monohydrated form.

Other conventional excipients which may optionally be present in the composition'of the invention include preservatives, stabilisers, anti-adherents or silica flew conditioners or giidants, e.g., silicon dioxide (e.g., Sylcid'3, Aeros.T3) as well as FD&C colours such as ferric oxides.
Other excipients disclcsed in the literature, as for instance in Fiedlers "Lexicon e'er Hiifstoffe", 4th Edition, ECV Aulendcrf 19S6 and "Handbook of Pharmaceutical Excipients3 Wade and Weller Ed.(1994), the contents of which are incorporated herein by reference, may be used in the pharmaceutical compositions according to the invention.
The invention is particularly useful fcr pharmaceutical compositions containing an active agent, e.g., an 5H74 receptor agonist, partial agonist or antagonist, e.g., compound A, e.g., the hydrogen maleate salt, which is present in an amount within the range of from about 0.2% to about 20%,'e.g. 0.5 to 15%, and preferably from about 1% to about 10% by weight of the composition.
A preferred composition cf the invention may comprise from about 0.5 to about 15% by weight of active agent, e.g.. a 5H7* receptor agonist, e.g., compound A, e.g., the hydrogen maieate salt, from 20 tc 60% by weight of disintegrant, e.g., crcspovidone, from 1 to about 20% by weight of a lubricant, e.g., mcncgiycerylstearate, from 0.1 to about 10% by weight of a surfactant, e.g., pclcxalkcl, from about 10 to 50% by weight of a diluent, e.g., lactose, and from 1 to 10% by weight cf a binder, e.g., hydroxypropylmethyl cellulose (e.g. HPMC-3). From 1 to 10% by weight cf PEG may also be added.
The weight ratio cf the active agent tc the disintegrant may be from 1:1 to 1:400, e.g., 1:5 to 1:100,1:8 to 1:50, e.g., 1:16 to 1:20.
In a further aspect the present invention provides a pharmaceutical oral, e.g., tablet, composition comprising one of the active agents cited above, e.g., a 5-HT4 agonist, partial agonist or antagonist, e.g., Tegaserod, said composition having dissolution characteristics in water or in USP buffers pH 6.8 and 7.5 of:

For example a ccmpcsiticn according to the invention, e.g., comprising Tegssercd as the active agent, may have dissolution characteristics in water or in US? buffers pH 6.3 and 7.5 cf:
In a further aspect the present invention provides a pharmaceutical crai, e.g., tablet; composition comprising one cf the active agents cited above, e.g., a 5-HT.i agonist, partial agonist or antagonist, e.g., Tegasercd, wherein in use 80% cf said active agent is released in water or in USF buffers pH 6.3 and 7.5 within 5 minutes.
in a further aspect, the present invention provides the use of at least 15% by weight of a cisintegrant in the manufacturing of pharmaceutical composition for the administration cf an acid sensitive and/cr poorly soluble, e.g., in aqueous media, active agent, e.g., a 5-HT4 receptor agonist, e.g., compound A, e.g. the hydrogen maleate salt.
The pharmaceutical compositions of the present invention are useful in the known indications of the particular active agent incorporated therein.
Tne exact amounts of active agent and of the formulation to be administered depend en a number of factors, e.g. the condition to be treated, the desired duration of treatment and the rate of release of active agent.
For example, the amount of the active agent required and the release rate thereof may be determined on the basis of conventional in vitro or in vivo techniques, determining how long a particular active agent concentration in the blood plasma remains at an acceptable level for a therapeutic effect

The pharmaceutical composition of the invention comprising a 5-ri74 receptcr agonist, partial agonist or antagonist is particularly useful for improving sensor/ perception cf rectal distension, e.g. for the treatment of anal incontinence, or for preventing, modulating or treating visceral pain cr discomfort.
5-HT4 receptor agonists, partial agonists cr antagonists, e.g. as disclosed in EP-A1-5C5.322, en the basis cf observed activity, e.g. stimulatory effect en the peristaltic reflex in the isolated guinea-cic :ieum, e.g. as described in EP-A1-505.222. have been found to be useful fcr the treatment of gastrc-intestinal motility disorders, for example to normalise cr to improve the gastric emptying and intestinal transit in subjects having a oisturbec motility, e.g. in irritabie bev/ei syndrome.
in accordanca with the present invention, it has now surprisingly been found that 5-HT4 receptor agonists, partial agonists or antagonists have a beneficial effect, e.g. they exert modulating effects, on the sensor/ perception of rectal distension and en visceral sensitivity cr perception.
It is admitted that receptor properties are net uniform throughout the cut and that thg type of afferent innervation reflects the quality of sensations originating from a particular organ. Fcr example, the rectum belongs to those parts of the gastro-intestinai tract from which also non-painful sensations arise, in contrast to the colon from which only painful sensations emanate.
Anal incontinence may be due to functional disturbances of the main anal continence mechanisms. Anal continence appears to be based on a co-ordinated functioning of the

1.3. A method fcr stimulating 5-HT4 receptors present en afferent r.er/e terminals,
particularly en extrinsic neurones cf the cut, in a subject in need thereof, which
method comprises administering to said subject an effective amount of a 5-KT4
receptor agonist or partial agonist or a pharmaceutical^ acceptable salt thereof.
1.4. A method fcr modulating visceral sensitivity, discomfort or pain via stimulation of 5-
HT4 receptors present on afferent nerve terminals, particularly on extrinsic neurones
of the gut, in a subject in need thereof, which method comprises administering to said
subject an effective amount of a 5-HT4 receptor agonist or partial agonist or a
pharmaceutical^ acceptable salt thereof.

3. A 5-HT4 receptor agonist, paniai agonist or antagonist cr a pharmaceutical^
acceptable salt thereof for use in the manufacture cf a pharmaceutical composition for
use in a method as defined under 1.1 to 1.7 above; cr
4. A pharmaceutical composition for use in a method as defined under 1.1 to 1.7 above
comprising a 5-HT4 receptor agonist, partial agonist or antagonist cr a
pharmaceutical acceptable salt thereof, together with one cr mere pharmaceutical/
acceptable diiuents or carriers therefor, e.g. a composition such as disclosed
hereinabove.
Preferred compounds for use in accordance with the invention include e.g. those listed hereinabove, particularly 5-HT4 receptor full agonists or partial agonists, e.g. (S)-zacopride, cisapride, prucaiopride, SB 205149, SC 53116, RS 67333, RS 67506, BIMU1, BIMU8, (S)-RS 56532, especially Compound A and particularly its hydrogen maleate salt, more

After obtaining 2 distension profiles (5 rnin each) and/cr 10 rnin cf peristalsis under centre! conditions, a 5-HTi receptor agonist, partial agonist cr antagonist, e.g., Compound A, cr vehicle is applied i.v. and the protocol is repeated. Subsequently, the activity of additional units is recorded in the presence of a 5-HT4 receptor agonist, partial agonist or antagonist, e.g., Compound A, or vehicle according to the distensicn/peristaisis protocol. In this assay, the firing rate cf the rectal afferents is reduced after administration cf a 5-HT4 receptor agonist or partial agonist at a dose range of from 0.1 to 3 mg/kg i.v., at distension pressures above 20 mmHg. With Compound A, administered i.v. in incremental doses from 0.15 to 1.2

severity of the condition to be treated. An indicated daily dose is in the range of from about 0.05 to about 30 .no, e.g., from about 0.05 to about 5 mg for parenteral use, and of from about 0.1 to about 20 mg for oral use, conveniently aoministered once or in civided dosages 2 to -x/cay, or In sustained release form. Unit dosage forms for crai administration accordingly comprise from about 0.5 to about 30 mg of 5-HT4 receptcr agcnist, partial agonist cr antagonist, e.g., Compound A, or a pharmaceuticaily acceptable sait thereof, admixed with an appropriate sciid or iicuid, pharmaceuticaily acceptable diiuent cr carrier therefor.
Furthermore, it has also been found that a 5-HT4 receptcr agonist or partial agcnist-e.g., Compound A, have a beneficial effect in the prevention cr treatment of gastrc-intestinal mctiiity disorders, e.g. a stimulatory effect on gastrointestinal motility, in horses and cattle.
Accordingly, there is also provided:
5.1. A method for preventing cr treating gastrointestinal motility disorders, e.g. by stimulating the mctiiity of the gastro-lntestinai tract in horses cr cattle in need thereof, which method comprises administering to the horses cr cattie an effective amount of a 5-HT4 receptcr agonist or partial agonist, e.g.. Compound A, cr a pharmaceuticaily acceptable salt thereof.
5.2. A methcd for preventing or treating gastrc-intestinal mctiiity disorders, e.g. after colic surgery, e.g. post-operative Ileus, in horses or cattle in need thereof, which method comprises administering to the horses or cattle an effective amount of a 5-HT4 receptcr agonist or partial agcnist, e.g., Compound A, cr a pharmaceuticaily acceptable salt thereof.
6. A 5-HT4 receptcr agcnist or partial agcnjst, e.g., Compound A, cr a pharmaceuticaily acceptable salt thereof, for use as a veterinary pharmaceutical e.g. for horses or cattle, e.g. in any of the method 5.1 or 5.1 indicated above cr for use in the manufacture of a veterinary pharmaceutical e.g. for use in a methcd as defined under 5.1 or 5.2.

7. A pharmaceutical composition for veterinary use, e.g. in horses cr cattle, e.g. in any of the method 5.1. or 5.2. as indicated above, comprising a 5-HT4 receptor agonist or partial agonist, e.g., Compound A, or a pharmaceutical/ acceptacie sait thereof, tcgether with a pharmaceutical^ acceptable diluent cr carrier therefor, e.g. a composition as discicsec hereinabove.
Preferred 5-H74 receptor agonists or partial agonists for use in horses or cattle in accordance with the invention include e.g. these listed hereinabove, e.g. (S)-zacopride, prucalcpride, SE2Q514S, SC 53116, RS 67333, RS 57506, 5IMU 1, EIMU 8, (S)-RS 56532, especially Compound A and particularly its hydrogen maleate salt, mere preferably a selective 5-H74 receptor agonist or partial agonist.
Utility of a 5-HT4 receptor agonist or partial agonist, e.g., Compound A, in the treatment of pest-operative Ileus as well as utility in treating conditions as hereinabove specified in hcrses or cattle, mav be demonstrated in accordance with the method hereinafter
described.
20 hcrses having colic syndrome are submitted to abdominal surgery. During surgery s-ccccrdve therapy is applied to thenr. At the end of surgery, a specific 5-HT4 receptor agonist cr partial agonist, e.g., Compound A, is administered Lv. or i.m., e.g. at a dose of from 0.01 to 10 mg/kg. This dose is repeated ever/ 8 to 24 h until spontaneous defecation is observed. Gastro-intestinai motility is evaluated based e.g. on the presence cr absence of gastric reflux as determined by nasogastric intubation, occurrence of borborygmi and timing of defecation after the first injection of the test compound. In this test, the compounds tested, e.g. Compound A, are effective in restoring normal motility function of the equine intestine.
Daily dosages required in practising the veterinary method of the present invention will vary depending upon, for example, the particular compound employed, the mode of administration and the severity of the condition to be treated. An indicated daily dose is in the range of from about 0.01 to about 10 mg/kg, e.g., from about 0.05 to about 5 mg/kg for parenteral use, conveniently administered once or in divided dosages 2 to 4x/day, or in sustained release form.

In a further aspect the invention provides a method for preventing or treating gastrointestinal motility disorders in a subject, e.g., a human or an animal, in need of such a therapy comprising administering to this subject an effective amount of a composition according to the present invention.
in a further aspect the invention a process is provided for improving dissolution properties in aqueous media of a pharmaceutical composition containing an acid sensitive and/cr poorly soluble in aqueous media active agent, e.g., a 5-HT4 receptor agonist, more particularly compound A, e.g. the hydrogen maleate salt.
The pharmaceutical composition of the invention may be prepared by any conventional method known in the art, e.g., by mixing an appropriate amount of the active agent, e.g., a 5-HT4 receptor agonist, with at least 15%, e.g., from 20 to 60%, e.g., from 30 to 50%, e.g., 40%, by weight of a disintegrant based on the total weight of the composition.
It is preferred to formulate in solid form, e.g., unit dosage form. Typical form include capsules and preferably compressed forms such as tablets.
Tne pharmaceutical composition according to the invention may be prepared by e.g., a wet, e.g., water based, granulation manufacturing process (the process equipment, as glass material, may be pre-treated with a siliconizing agent) comprising the successive steps of:
i) pre-mrxing the acid sensitive and/or poorly soluble in water active agent, e.g., a 5-HT4 receptor agonist, e.g., compound A, e.g. the hydrogen maleate salt with 60 to 98% of the diluent, and then sieving the resulting mixture,
ii) mixing purified water with the binder in a weight ratio of from 1:20 to 3:20, and stirring • until dissolution,
iii) adding the surfactant to the solution of ii) and stirring until dissolution,
iv) adding the disintegrant, the remaining diluent and 50 to 70% of the first lubricant to the pre mixture of i) and mixing
v) wetting the mixture of step iv) with the granulating solution from step iii) while mixing

Examples
The fcllcwina examoles illustrate the manufacturina, en an industrial scale. :f ccmcositicns
comprising comccund A hml using a wet aranuiaticn process as discicsed accve.
Example 1
A 2 mc tablet formulation mav be prepared as described hereinafter.
a) Preparation of the Granulated material
Premixinc step
1. 4.432 kg cf compound A hml and 23.583 kg of lactose menchycrate are mixed with an intensive mixer (Colette Gral^ 300 I or Fielder3) ; mixer speed setting : 1; chopper speed setting : 1) for approximately 1.5 minutes, or with a free fall mixer (Turbuia3, Scneco^ or Rchnracf^)
2. The pre-mixture from step 1 is then sieved (oscillating granuiatcr, e.g., Frewitt3 cr Er.veka*; mesh size: 0.8 millimetres).
2. "The pre-mixture is divided into two peniens ci 16.560 kg.
Preparation of the cranulatinc solution -. Approximately 40 kg of purified water are weighed out.
5. 3.500 kg cf methyihycroxyprcpylceiiulose 3 maps are added to the purified water frcm step 4 and this is stirred until dissolution.
6. 1.440 kg of poloxamer 188 are added to the solution frcm step 5 whiie stirring until dissolution.
Granulating steo
7. 23.800 kg of crespovidene, 10.080 kg of lactose menchycrate and ^.320 kg cf Glyceryl menpstearate are weighed cut.
8. One portion of the premixture from step 3 is added to the excipients from step 7 and this is mixed with the intensive mixer, e.g., Colette Graf 300 I or Fielder3 (mixer speed setting : 1; chopper speed setting : 1) for approximately 2 minutes.
9. The mixture from step 8 is wetted with the granulating solution frcm step 6 while mixing with the intensive mixer, e.g., Colette Gral® 300 I or Fielder^ (mixer speed

setting : 1; chopper speed setting : 0; pumping rate approximately : 4 kg/minute) for approximately 12 minutes.
10. Approximated 2 kg of cunfied water are weighed out.
11. The vessel from step 6 is rinsed with the purified water from step 10 and this is added to the mixture from step 3 whiie mixing.
12. The mass is granuiatec by mixing with the intensive' mixer, Colette Graf5 300 I or Fielder3 (mixer speed setting : 1: chopper speed setting : 1) for approximately 2.5 minutes.
Drying step
12. The granulate from step 12 is dried in a fluidised air bed drier (e.g., Glatt3 or
Aeromatic3) for approximately 65 minutes (inlet air temperature approximately 70°C)
to reach the required less on crying (LCD) for the tabletting mixture, i.e., until LCD
14. The granulate sized by sieving (0.3 miilimetres) with an oscillating sieve granulatcr,
e.g., Frewitt3 or Er«veka3.
15. Steps 4 to 14 are repeated with the ether portion of step 2. ■
b) Preparation of the tabletting mixture
16. 8.640 kg of polyethylene glycoi 40C0 and 5.760 kg of glyceryl monostearate are sieved (oscillating granulatcr, e.g., Frewitt® or Erweka®; mesh size: 0.8 miilimetres)
17. The ingredients from step 16 are added to the total mass of granulated material and this is mixed with a free fail mixer, e.g., Soneco® or Rchnracf®, for approximately 20 minutes (10 rpm) to obtain the desired final tabletting mixture.
c^ Compression steo
13. The tabletting mixture from step 17 is pressed into tablets using compression
pressures of 11, 14 or 17 KN on a rotary tabletting machine, e.g., Fette®, Korsh®,
Kelian® or Coarty® (temperature Example 2 : Composition of a 2 ma tablet (1 ma of base corresponds to 1.385 ma of the hvdroaen maleate salt of compound A)

Compound A hml 2.77 (2mg base)
Fciyplasdone XL USP/NF 36.00
Glyceryl mcncstearate USP/NF 9.00
Lactose 200 mesh 30.52
HrMCScFs 4.50
Fclvethvlenecivcoi 40C0 SAG
Water adsorbed 2.C0
Total 92 mc
Example 3
A 6 mg tablet formulation may be prepared by the manufacturing process described
hereinafter.
a) Preparation of the oranuiatec material
Preparation of the granulating solution
1. Approximately 40 kg of purified water are weighed out.
2. 3.600 kg of methylhydrcxyprcpyiceilulose 3 maps are added to the purified water from step 1 while stirring untii dissolution.
3. 1.440 kg of poloxamer 188 are added to the solution from step 2 while stirring untii dissolution (mixing tank under stirring).
Granulating step
4. 4.787 kg of compound A hml and 23.800 kg of crospoviccne, 21.853 kg of lactose monohydrate and 4.320 kg of glyceryl monostearate are weighed out.
5. The ingredients from step 4 are mixed with the intensive mixer, e.g., Colette Graf® 300 I or Fielder® (mixer speed setting: 1; chopper speed setting : 1) for approximately 2 minutes.
6. The mixture from step 5 is wetted with the granulating solution from step 3 while mixing with the intensive mixer, e.g., Colette Gral® 300 I or Fielder® (mixer speed

setting: 1; chopper speed setting : 0; pumping rate approximately 4 kg/minute) for approximately 12 minutes.
7. Approximately 2 kg of purified water are weighed out.
8. The vessel from step 3 is rinsed with the purified water from step 7 and this is added to the mixture from step 6 while mixing.
S. The mass is granulated by mixing with the intensive mixer, e.g., Colette Graf3 300 i or Fielder® (mixer speed setting: 1; chopper speed setting : 1) for approximately 2.5 minutes.
Drying step
10. The granulate from step 9 is dried in a fluidised air bed drier, e.g., Glatt® or Aeromatic®) for approximately 65 minutes (Inlet air temperature approximately 70°C) to reach the desired loss en drying (LOD) for the tabletting mixture, i.e., until LOD 11. The granulate sized by sieving (0.3 millimetres) with an csciilating sieve granulator (Frewitt® or Erweka®)
12. Steps 1 to 11 are repeated.
b) Preparation of the tabletting mixture
13. 8.640 kg of polyethylene glycol 4000 and 5.760 kg of glyceryl mencstearate are sieved with an oscillating sieve granulator, e.g., Frewitt® or Erweka® (0.8 millimetres)
14. The ingredients from step 13 are added to the total mass of granulated material and this is mixed with a free fail mixer, e.g., Soneco® or Rohnrad®, for approximately 20 minutes (10 rpm) in the desired final tabletting mixture.
c^ Compression step
»
15. The tabietting mixture from step 14 is pressed into tablets using compression
pressures of 13, 16 or 1S KN on a rotary tabletting machine, e.g., Fette®, Keren5,
Kelian® or Coarty®(temperature Example 4 : Composition of a 6 mq tablet (1 mq of base corresponds to 1.385 mo of hydrogen maleate of compound A):

Compound A hml 8.31 (6mg base)
Polyplasdone XL USP/NF 50.00
Glyceryl monostearate USP/NF 12.50
Poioxalkol 2.50
Lactose 200 mesh 37.94
HPMC 3cPs 5.25
Poiyethyleneglycol ^000 7.50
Water adsorbed 3.00
Total 128 mg
Example 5
A 0.5 mg tablet formulation may be prepared by the manufacturing process described
hereinafter.
a) Preparation of the cranulaied material
Premixing step
1. 1.994 kg of compound A hml and 31.126 kg of lactose monohydrate are mixed with an intensive mixer (Colette Graf® 300 I or Fielder®) ; mixer speed setting : 1; chopper speed setting : 1) for approximately 1.5 minutes, or with a free fall mixer (Turbula®, Soneco® or Rohnrad®)
2. The premixture from step 1 is then sieved (csciilating granulatcr, e.g., Frewitt® cr Erweka®; mesh size: 0.8 millimetres).
3. The premixture is divided into two portions of 16.560 kg.
Preparation of the granulating solution
4. Approximately 43 kg of purified water are weighed cut.
5. 3.600 kg of methyihydroxyprcpylcellulose 3 maps are added to the purified water from step 4 and this is stirred until dissolution.
6. 1.440 kg of poloxamer 188 are added to the solution from step 5 while stirring until dissolution.

Granulating step
7. 28.800 kg of crospovidcne, 10,080 kg of lactose monohydrate and 4.320 kg of glyceryl moncstearate are weighed out.
8. One portion of the premixture from step 3 is added to the excipients from step 7 and this is mixed with the intensive mixer, e.g., Colette Gral® 300 I or Fielder® (mixer speed setting : 1; chopper speed setting : 1) for approximately 2 minutes.
9. Tne mixture from step 8 is wetted with the granulating solution from step 6 while mixing with the intensive mixer, e.g., Colette Gral® 300 I or Fielder^ (mixer speed setting : 1; chopper speed setting : 0; pumping rate approximately : 4 kg/minute) for approximately 12 minutes.
10. Approximately 2 kg of purified water are weighed out
11. The vessel from step 6 is rinsed with the purified water from step 10 and this is added to the mixture from step 9 while mixing.
12. Tne mass is granulated by mixing with the intensive mixer, Colette Grai3 300 I or Fieider'2 (mixer speed setting : 1; chopper speed setting : 1) for approximately 2.5 minutes.
Drying step
13. The granulate frcm step 12 is dried in a fluidised air bed drier (e.gM Giatf5 or Aeromatic®) for approximately 60 minutes (inlet air temperature approximately 70°C) to reach the required loss on drying (LOD) for the tabletting mixture, i.e. until LOD 14. The granulate sized by sieving (0.8 millimetres) with an oscillating sieve granuiator, e.g., Frewitt® or Erweka*.
15. Steps 4 to 14 are repeated with the other portion of step 3.
b^ Preparation of the tabletting mixture
16. 8.640 kg of polyethylene glycol 4000 and 5.760 kg of glyceryl mcnostearate are sieved (oscillating granuiator, e.g., Frewitt® or Erweka®; mesh size: 0.8 millimetres)
17. The ingredients from step 16 are added to the total mass of granulated material and this is mixed with a free fall mixer, e.g., Soneco® or Rohnrad®, for approximately 20 minutes (10 rpm) to obtain the desired final tabletting mixture.

c) Compression step
18. The tabletting mixture from step 17 is pressed into tablets on a rotary tabietting machine, e.g., Fette®, Korsh®, Kelian® or Coarty9 {temperature Example 6 : Composition of a 0.5 mq tablet (1 ma of base corresponds to 1.385 mo of the hydrogen maleate salt of compound A)
Compound A hml 0.6925 (0.5mg base)
Polyplasdone XL USP/NF 20.00
Glyceryl monostearate USP/NF 5.00
Poloxalkol 1.00
Lactose 200 mesh 17.8075
HPMCScPs 2.50
Polyethyleneglycoi 4000 3.00
Water adsorbed 1.00
Total 51 mg
Example 7 : Composition of a 12 mo tablet (1 ma of base corresponds to 1,385 mg of the
hvdroaen maleate salt of compound A)
The manufacturing process is similar to the process used for the Smg tablets.
Compound A hml 16.62 (12mg base)
Polyplasdone XL USP/NF 72.00
Glyceryl monostearate USP/NF 13.00
Poloxalkol . 3.60
Lactose 200 mesh 49.98
HPMC 3cPs 9.0
Polyethyleneglycoi 4000 10.8
Water adsorbed 4.00
Total 184 mg

WE Claims
1. A method of preparing a solid oral pharmaceutical con: josilion comprising
a) 0.2 to 20% by weight of Compound A

or its salts; and
b) a disintegrant which is present in an amount of at least 15% by weight based on
the total weight of the composition.
2. The method of preparing a composition of claim 1 cornj:rising a disintegrant which is
present in an amount of at least 15% by weight based en the total weight of the
con' position, wherein the disintegrant is a member selected from the group
consisting of crospovidene, sodium starch glycolate, caibcxyniethylceiluiose sodium.
sodium alignate, and a mixture thereof.
3. The method of preparing a composition accotding to claims 1 or 2 in which
Compound A is in the form of its hydrogen maleate (hm»; salt.
4. The method of preparing a composition according to any preceding claims
characterized in that the disintegrant is present in an arrount of 20 to 60% by weight
based on tne total weight of the composition.
5 The method of preparing "a composition according to csims 1 to 3 characterized in that the disintegrant is present in an amount of 40% Uy weight based on the total weight of the composition.

3. The method of preparing a composition according to any proceeding claims characterized in that the disintegrant is crospovidone.
7. The method of preparing a composition accurd-inc; to aity proceeding claims comprising from 1 to 20% by weight of a lubricant.
i3. The method of preparing a composition according to t.xtn 7 characterised ,n that the lubricant comprises a glyceryl mono fatty acid.
9. The: metnod of preparing a composition according lc ci Him 8 characterized in that the lubricant comprises a mixture of glyceryl monosiearate and polyethylene glycol.
"0. The method of preparing a composition according to a;sy proceeding claims comprising from 0.1% to 10% by weight of a surfactant.
11. The method of preparing a composition according to ;iaim SO characterized in that the surfactant comprises poloxamer.
12. The method of preparing a composition according to claim 11, having dissolution characteristics in water of:

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Patent Number

207236

Indian Patent Application Number

812/CHENP/2003

PG Journal Number

26/2007

Publication Date

29-Jun-2007

Grant Date

01-Jun-2007

Date of Filing

23-May-2003

Name of Patentee

M/S. NOVARTIS AG

Applicant Address

Schwarzwaldallee 215, CH-4058 Basel

Inventors:

#	Inventor's Name	Inventor's Address
1	VITZLING, Christian	39, rue de Pommard, F-75012 Paris
2	ENGEL, Günter	Im Hasengarten 11, D-79576 Weil
3	DE BRUIJN, Karel	13, rue du Muhlberg, F-68730 Blotzheim
4	PFANNKUCHE, Hans-Jürgen	Vierthauen 17, D-79576 Weil
5	THEWISSEN, Michael	Apollinarisstrasse 26, D-40227 Düsseldorf
6	ZÜGER, Othmar	Heuwinkelstrasse 13, CH-4123 Allschwil

PCT International Classification Number

A61K 9/20

PCT International Application Number

PCT/EP1999/006083

PCT International Filing date

1999-08-19

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	9910320.2	1999-05-05	Germany
2	9911059.5	1999-05-12	Germany
3	9818340.3	1998-08-21	Germany
4	9823477.6	1998-10-27	Germany