MXPA01001854A - New oral formulation for 5-ht4 - Google Patents

Abstract

The present invention relates to a pharmaceutical composition, in particular to a composition for administering active agents which are poorly soluble in aqueous media, and/or which are acid sensitive.

Description

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 media, and / or which are sensitive to acid. More particularly, the present invention relates to a pharmaceutical composition for administering active agents that act on the gastrointestinal system. The present invention also relates to a process for making these compositions. The term "pharmacist" also covers veterinary use. Pharmaceutical compositions containing active agents that are poorly soluble in aqueous media and / or sensitive to acid are difficult to manufacture. Some of the problems that may arise relate to the adsorption of the active agent on the process equipment during the manufacturing process. Due to the poor solubility of these active agents, it is also difficult to obtain pharmaceutical compositions which, after their administration, have a good speed of dissolution. As a further problem, the active agents can be degraded, for example chemically, during a manufacturing process using acidic conditions, or during the storage of the composition. The present invention provides compositions and processes that eliminate or minimize one or more of the above problems.

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Surprisingly, we have now found that it is possible to produce a pharmaceutical composition for administering active agents that are poorly soluble in aqueous media, eg pure water and / or acid-sensitive, and that, after administration, have good properties of dissolution, a good bioavailability, and that is surprisingly effective. The present invention provides, in one aspect, a solid oral pharmaceutical composition, for example a tablet, comprising an active agent that is poorly soluble in aqueous and / or acid sensitive media, and a disintegrant, for example a super-disintegrant, which is present in an amount of at least 15 weight percent, based on the total weight of the composition. "Poorly soluble" means an active agent having a solubility in aqueous media greater than 0.001 percent and less than 10 percent, for example less than 1 percent, for example less than 0.1 percent, for example less than 0.05 percent , for example less than 0.02 percent, at room temperature, for example at 25 ° C. "Acid sensitive" means an active agent which, under even slightly acidic conditions, for example at a pH of 6, can be transformed to a significant degree into a degradation product, for example by chemical degradation, which may not have no activity, or you can have a .. & -;, thus activity changed, for example within 2 hours. Examples of the compounds are known in the art, and can be asserted by routine experimentation. "Disintegrant" means a substance or mixture of substances added to a solid pharmaceutical composition, for example a tablet, to facilitate its breaking or disintegration after being administered, so that the active ingredient is released from the composition as efficiently as possible. , to allow its rapid dissolution (see, for example, "Remington's Pharmaceutical Science" 18th edition (1990), "The Theory and Practice of Industrial Pharmacy" Lachman et al., Lea and Febiger (1970)). We have also encountered difficulties in the production of commercially acceptable stable formulations, e.g., tablets, of compounds such as those disclosed in European Patent Number 505,322 (incorporated herein by reference), and which are useful as agonists or partial agonists of the 5-HT4 receptor. A preferred 5-HT4 partial agonist disclosed in European Patent Number EP 505,322 is Tegaserod (3- (5-methoxy-l-indol-3-yl-methylene) -N-pentylcarbazimidamide) (Example 13) of the formula : which is hereinafter referred to as Compound A, or a pharmaceutically acceptable salt form thereof, for example, the hydrogen maleate salt (hereinafter "hml"). Compound A has a solubility of about 0.02 percent at 25 ° C in water, and is sensitive to acid. We have found that compositions that give a good absorption, even in the stomach, can be produced. We have also found that Compound A can be adsorbed by certain excipients, such that its dissolution can be substantially reduced after its administration. It has been published in little detail on the biopharmaceutical properties of agonists, partial agonists, or 5-HT4 receptor antagonists, for example, its site of action is not known. The present invention provides, in a further aspect, pharmaceutical compositions that allow a complete dissolution of agonists, partial agonists, or 5-HT4 receptor antagonists, for example Compound A, when administered to humans, for example, to the patients who need it. These compositions allow good availability, and are surprisingly effective. Moreover, they are stable and well reproducible. A process for its preparation is also provided. The active agents that can be used in the compositions according to the present invention, are more generally those that act on the gastrointestinal system, for example, the active serotonergic agents, for example complete agonists, partial agonists, and antagonists of the 5-HT4 receptors, to the extent that they are poorly soluble and / or sensitive to acid. Preferably they are in the salt form, for example hydrogen maleate or hydrochloride, and may be in free form. The 5-HT receptor is a cloned species of the serotonin receptor family, which comprises at least 14 different receptors coupled with G protein (the receptor ionophore of the 5-HT3 subtype is excluded). Four splice variants of the human receptor, 5-HT4A, 5-HT4B, 5-HT4C, and 5-HT4D have been identified, which differ in the length and sequence of the C-terminus of the protein (Blondel et al., FEBS Letters (1997 ) 412: 465-474; Blondel et al., J. Neurochem. (1998) 70: 2252-2261). The biochemical characterization of 5-HT4 receptors revealed a positive coupling with adenylyl cyclase. In man, the expression of the 5-HT4 receptor has been found in the brain, intestine, atrium, urinary bladder, and kidneys. The compounds capable of acting on the serotonin receptor are substituted benzamides, for example cisapride, renzapride, zacopride, cleboppda, cmitapride, mosapride, lintoppda, etoclopramide, or benzoic esters, for example RS 23597-190, M # «SB 204070, SB 207710, or aminoguanidines, zacopride, prucalopride, SB 205149; SC 53116, RS 67333, RS 67506, BIMU 1, BIMU 8, (S) -RS 56532, Tropisetron, Alosetron, GR 113808, GR 125487, SB 207266, RS 23597, RS 39604, RS 100235, DAU 6285, SC 53606, 3 - (5-hydroxy-7-methyl-lH-indol-3-yl-methylene) -N-pentyl-N-methyl-carbazimidamide, indazole-3-carboxamides, 2-oxobenzami-dazol-3-carboxamides (as disclose in European Patent Number EP 908,459, which is incorporated herein by reference), et cetera. 5-HT4 receptor agonists are considered as compounds that can activate 5-HT4 receptors under passive / resting conditions (full or partial activation). As the full agonists or partial agonists of the 5-HT4 receptor, there may be mentioned (S) -zacopride, cisapride, prucalopride, SB 205149, SC 53116, RS 67333, RS 67506, BIMU 1, BIMU 8, (S) -RS 56532 and Compound A, particularly its hydrogen maleate salt. The 5-HT4 receptor antagonists are considered as compounds that do not activate the 5-HT4 receptors, but act as inhibitors of the agonists at the 5-HT4 receptors. As the 5-HT4 receptor antagonists, mention may be made of GR 113808, GR 125487, SB 203186, SB 204070, SB 207266, RS 23597, RS 39604, RS 100235, DAU 6285, SC 53606, 3- (5-hydroxy-7- methyl-lH-indol-3-l-methylene) -N-pentyl-N-methyl-carbazimidamide. The 5-HT4 receptor agonists are useful for the prevention and treatment of disorders of gastro-testicular mobility, for example, Irritable Bowel Syndrome (IBS), .jtÍ-J £!) M¿-ÍaÍ. & hsA, Gastroesophageal Reflux Disease (GERD), Functional Dyspepsia (FD), and Post-Operative ileus (POI). In a preferred embodiment, the composition of the invention comprises from 20 to 60 percent, for example from 30 to 50 percent, for example 40 percent by weight of a disintegrant, based on the total weight of the composition. We have observed that use of this high percentage of disintegrant further improves the rate of dissolution in aqueous media, but also prevents the active agent from being adsorbed on the excipients. As disintegrants, the composition of the invention may comprise: crospovidone (molecular weight> 106), for example, Po-lyplasdone XL®, Kollidon CL®, Polyplasdone XL-10®, pregelatinized starch (Molecular Weight: 30,000 -120,000), for example starch 1500®, STA-Rx 1500®, sodium starch glycolate (Molecular Weight: 500,000-1,000,000), for example Primojel®, calcium carboxymethylcellulose (CMC-Ca), sodium carboxymethylcellulose (CMC-Na) (Weight Molecular, 90,000-700,000), for example Ac-Di-Sol®, sodium alginate, or a mixture thereof. Preferably, the disintegrant is crospovidone, which is preferably insoluble in water. Preferably, it exhibits rapid high capillarity or pronounced hydration capacity with little tendency to gel formation. Preferably, the particle size is from about 1 to 500 microns. The preferred particle size distribution is less than 400 microns, for example for Polyplasdone XL®, less than 80 microns, for example less than 74 microns, for example, for Polyplasdone XL-10®, approximately 50 percent more than 50 microns , and a maximum of 1 percent more than 250 microns in size, for, for example, Kollidon CL®. A preferred crospovidone is Polyplasdone XL®, for example with a density of approximately 0.213 grams / cubic centimeter (in bulk) or 0.273 grams / cubic centimeter (tamped). The pharmaceutical composition of the invention may further comprise one or more excipients. The composition may further comprise one or more lubricants, for example in an amount within the range of, for example, 1 to 20 percent, for example 5 to 15 percent, for example 10 percent by weight of the composition. Examples of the lubricants include: glyceryl fatty monoacid, for example having a molecular weight of 200 to 800, for example glyceryl monostearate (for example Myvaplex®, USP grade), polyethylene glycol (PEG), having a molecular weight of 100 to 10,000, for example from 1,000 to 8,000, for example from 2,000 to 6,000, for example from 2,500 to 5,000, for example Macro-gol 4000 (Pulver) BP, hydrogenated castor oil (for example, Cutina®), and the like , or a mixture thereof. In a preferred composition, the lubricant is glyceryl monostearate. The lubricant properties of this preferred composition can be improved by the addition of polyethylene glycol (PEG), for example Macrogol 4000 (Pulver) BP.

The composition of the invention may comprise one or more surfactants, for example in an amount in the range of 0.1 to 10 percent, for example 1 to 5 percent, for example 2 percent by weight of the total composition. The pharmaceutically suitable surfactants may be nonionic or anionic. As the non-ionic surfactants, the following can be used: polyoxyethylene sorbitan fatty acid esters (polysorbates: molecular weight: 500 to 2,000), for example, mono- and tri-lauryl-, palmityl-, stearyl-, and oleyl-esters , for example Tween®, for example Tween 80®; polyoxyethylene fatty acid esters (molecular weight: 500 to 5,000), for example Myrj® or Cetiol®; polyoxyethylene-polyoxypropylene copolymers, for example having a molecular weight of from 1,000 to 20,000, for example from 6,000 to 15,000, for example from 7,000 to 10,000, for example Pluronic® or Emkalyx®; polyoxyethylene-polyoxypropylene block copolymers, for example having a molecular weight of from 1,000 to 20,000, for example from 6,000 to 15,000, for example from 7,000 to 10,000, for example Poloxamer 188®; the reaction products of a natural or hydrogenated castor oil and ethylene oxide, for example Cremophor®; dioctyl succinate or di- [2-ethylhexyl] succinate; mono- and di-fatty acid esters of propylene glycol (for example, from 6 to 8 carbon atoms), for example Mi-glyol®. or mixtures thereof. As suitable anionic surfactants, for example, sodium lauryl sulfate or sodium docusate can be used. Unless otherwise reported, the chain containing fatty acid or carbon is from about 8 to 22 carbon atoms, for example from 18 carbon atoms. The composition of the invention may comprise one or more binders, for example in an amount in the range of 1 to 10 percent, for example 2 to 8 percent, for example 5 percent by weight. In particular, hydroxypropylmethylcellulose, for example having a molecular weight of 10,000 to 1,500,000, for example HPMC-3 (3mPa-s) (for example Pharmacoat®, Methocel®), polyvinylpyrrolidone, for example having a molecular weight of 2,500 to 3,000,000 for example from 8,000 to 1,000,000, for example from 10,000 to 400,000, for example from 30,000 to 50,000 (for example, Kollidon®, Plasdone®), potato starch, wheat starch, corn starch, for example, which have a molecular weight of 30,000 to 120,000, 5 or a mixture thereof. The composition of the invention may comprise one or more diluents, such as lactose, mannitol, sucrose, calcium sulfate, calcium phosphate, microcrystalline cellulose (Avicel®), in an amount within the range of, for example, 10 to 70. percent, for example 20 to 50 percent, for example 30 percent by weight of the composition. Preferably, the diluent is lactose, for example 200-mesh lactose (for example from DMV® or Alpavit®), for example, the monohydrated form. Other conventional excipients which may be optionally present in the composition of the invention include preservatives, stabilizers, antiadhesives, or silica flow conditioners, or brighteners, for example silicon dioxide (eg, Syloid®, Aerosil®), as well as colors FD &C such as ferric oxides. Other excipients disclosed in the literature, such as in Fiedler's "Lexicon der Hilfstoffe", 4th edition, ECV Aulendorf 1996, and "Handbook of Pharmaceutical Excipients" Wade and Weller Editors (1994), whose content is incorporated into the present as a reference, can be used in the compositions pharmaceutical preparations according to the invention. The invention is particularly useful for pharmaceutical compositions containing an active agent, for example an agonist, partial agonist, or 5-HT4 receptor antagonist, for example Compound A, for example the salt of hydrogen maleate, which is present in a amount within the range of about 0.2 percent to about 20 percent, for example 0.5 to 15 percent, and preferably from about 1 percent to about 10 percent by weight of the composition. A preferred composition of the invention may comprise from about 0.5 to about 15 weight percent of the active agent, for example a 5HT4 receptor agonist, for example Compound A, for example the hydrogen maleate salt, from 20 to 30% by weight. 60 weight percent of a disintegrant, for example crospovidone, from 1 to about 20 weight percent of a lubricant, for example glyceryl monostearate, from 0.1 to about 10 weight percent of a surfactant, for example poloxalkol , from about 10 to 50 weight percent of a diluent, for example lactose, and from 1 to 10 weight percent of a binder, for example hydroxypropylmethylcellulose (for example HPMC-3).

One may also add from 1 to 10 weight percent of PEG.

The weight ratio of the active agent to the disintegrant can be from 1: 1 to 1: 400, for example from 1: 5 to 1: 100, from 1: 8 to 1:50, for example from 1:16 to 1:20 . In a further aspect, the present invention provides an oral pharmaceutical composition, for example a tablet, comprising one of the active agents mentioned above, for example an agonist, partial agonist or 5-HT4 antagonist, for example Tegaserod, having this composition dissolution characteristics in water or in USP regulators of a pH of 6.8 and 7.5 of: time (minutes) amount (percentage) 5 30 - 90 15 ¡0 - 100 30 95 - 100 60 100 For example, a composition according to the invention, for example comprising Tegaserod as the active agent, may have dissolution characteristics in water or in USP regulators of a pH of 6.8 and 7.5, of: time (minutes) amount (percentage) 5 48.9 15 95.5 30 99.7 60 100 In In a further aspect, the present invention provides an oral pharmaceutical composition, for example a tablet, comprising one of the active agents mentioned above, ÉSi¿ &¿¿iiBitetfef -. a ^? Sf ^ m ^ M ^ example a agonist, partial agonist, or 5-HT4 antagonist, for example Tegaserod, where, in use, 80 percent of the active agent is released in water or in USP regulators of a pH of 6.8 and 7.5, within 5 minutes. In a further aspect the present invention provides the use of at least 15 weight percent of a disintegrant in the manufacture of a pharmaceutical composition for the administration of an acid sensitive and / or poorly soluble active agent, for example in aqueous media , for example a 5-HT4 receptor agonist, for example Compound A, for example the hydrogen maleate salt. The pharmaceutical compositions of the present invention are useful in the known indications of the particular active agent incorporated therein. The exact amounts of the active agent and the formulation to be administered depend on a number of factors, for example the condition to be treated, the desired duration of treatment, and the rate of release of the active agent. . For example, the amount of active agent required, and its rate of release, can be determined based on conventional techniques in vi tro or in vivo, by determining how long a particular concentration of the active agent in the blood plasma remains at an acceptable level for a therapeutic effect.

Examples of the doses provided in a solid formulation, for example a tablet, are, for Irritable Bowel Syndrome (IBS), from 1 milligram to 12 milligrams of active agent, for functional dyspepsia (FD) and gastroesophageal reflux disease (GERD). ), from 0.2 to 2 milligrams of active agent, in particular Compound A, for example the hydrogen maleate salt, per day, for a 70 kilogram mammal, for example humans, and in standard animal models. The greater tolerability of the active agent, in particular of Compound A, for example the salt of hydrogen maleate, provided by the compositions, can be observed in conventional animal tests and in clinical trials. The pharmaceutical composition of the invention, comprising an agonist, partial agonist, or 5HT receptor antagonist, is particularly useful for improving the sensory perception of rectal distention, for example for the treatment of anal incontinence, or for preventing, modulating, or Treat pain or visceral discomfort. We have found that agonists, partial agonists, or 5-HT receptor antagonists for example as disclosed in European Patent Number EP-A1-505, 322, based on the observed activity, for example, the stimulating effect on the peristaltic reflex in guinea pig ileus isolated, for example as described in European Patent Number EP-Al-505,322, are useful for the treatment of disorders of gastrointestinal mobility, for example to normalize or improve gastric emptying and intestinal transit in subjects who have altered mobility, for example in irritable bowel syndrome. In accordance with the present invention, it has now been found in a surprising manner, that agonists, partial agonists, or 5-HT4 receptor antagonists, have a beneficial effect, for example exert modulating effects, on the sensory perception of rectal distention. , or on sensibility or visceral perception. It is admitted that the receptor properties are not uniform throughout the intestine, and that the type of afferent innervation reflects the quality of sensations that originate from a particular organ. For example, the rectum belongs to the parts of the gastrointestinal tract where non-painful sensations also occur, in contrast to the colon, where only painful sensations emanate. Anal incontinence can be due to functional alterations of the main mechanisms of anal continence. The anal conti-ence seems to be based on a coordinated functioning of the neuromuscular machinery that manages sensation and rectal compliance, the rectum-anal inhibitory reflex, the reflex contractions of the external anal sphincter and the pu-borectalis muscle. Although the contractions of skeletal muscle (external sphincter and puborectalis) are of great importance in the maintenance of continence, it is probably the triggering effect of rectal sensation and perception that has a crucial role, and in fact, is often abnormal in the incontinent patients. Anal incontinence is a dysfunction 5 that occurs particularly in the diabetic and elderly population. There is a medical need to modulate the sensitivity, discomfort, or visceral pain in patients suffering from gastrointestinal disorders, and from a treatment of the dysfunctions 10 of anal continence. In accordance with the particular findings of the present invention, there is provided: 1.1 A method for preventing, modulating, or treating visceral pain or discomfort, for example abdominal, in a subject who need, which method comprises administering to this subject an effective amount of an agonist, partial agonist, or 5-HT4 receptor antagonist, or a pharmaceutically acceptable salt thereof. 1.2 A method for modulating visceral sensitivity or perception in a subject in need thereof, which method comprises administering to this subject an effective amount of an agonist, partial agonist, or 5-HT4 receptor antagonist, or a pharmaceutically acceptable salt thereof . 1.3. A method for stimulating the present 5-HT receptors in the afferent nerve terminals, particularly in the extrinsic neurons of the intestine, in a subject in need thereof, which method comprises administering to this subject an effective amount of an agonist or partial agonist of the 5-HT4 receptor, or a pharmaceutically acceptable salt thereof. 1.4 A method to modulate the sensitivity, discomfort, or visceral pain, by stimulating the 5-HT4 receptors present in the afferent nerve terminals, particularly in the extrinsic neurons of the intestine, in a subject in need, whose method comprises administering to this subject an effective amount of an agonist or partial agonist of the 5-HT4 receptor, or a pharmaceutically acceptable salt thereof. 1.5 A method for regulating or stabilizing the myeloid afferent fibers of the plexus in a subject in need thereof, which method comprises administering to this subject an effective amount of an agonist or partial agonist of the 5-HT4 receptor, or a salt pharmaceutically acceptable thereof. 1.6 A method for improving the sensory perception of rectal distension in a subject in need, whose method comprises administering to this subject an effective amount of a Agonist, partial agonist, or 5-HT receptor antagonist, or a pharmaceutically acceptable salt thereof. 1.7 A method for the treatment of dysfunctions of anal continence in a subject in need thereof, whose method comprises administering to this subject an effective amount of a Agonist, partial agonist, or 5-HT4 receptor antagonist, or a pharmaceutically acceptable salt thereof. As an alternative to the above, the present invention also provides: 2. An agonist, partial agonist, or antagonist of the 5-HT receptor, or a pharmaceutically acceptable salt thereof, for use in a method as defined in 1.1 to 1.7. previous; or 3. An agonist, partial agonist, or 5-HT4 receptor antagonist, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a pharmaceutical composition for use in a method as defined in 1.1 to 1.7 above; or 4. A pharmaceutical composition for use in a method as defined in 1.1 to 1.7 above, which comprises an agonist, partial agonist, or 5-HT4 receptor antagonist, or a pharmaceutically acceptable salt thereof, together with a or more pharmaceutically acceptable diluents or vehicles therefor, for example a composition as disclosed hereinbefore. Preferred compounds for use in accordance with the invention include, for example, those listed hereinabove, particularly the agonists or partial agonists of the 5-HT4 receptor, for example (S) -zacopride, cisa-ppda, prucalopride, SB 205149 , SC 53116, RS 67333, RS 67506, BIMU 1, BIMU 8, (S) -RS 56532, especially Compound A, and particularly its hydrogen maleate salt, more preferably selective 5-HT receptor agonists or partial agonists, and antagonists of the 5-HT4 receptor, for example Tropisetron, GR 113808, GR 125487, SB 204070, SB 207266, RS 23597, RS 39604, RS 100235, DAU 6285, SC 53606, 3- (5-hydroxy-7-methyl- lH-indol-3-yl-methylene) -N-penti1-N-methyl-carbazimidamide, and the like. "Selective" means a compound that does not substantially bind to, or stimulate, the 5HT3 serotonin receptor. A group of compounds excludes Tropisetron. The utility of an agonist, partial agonist, or antagonist of the 5-HT4 receptor in the prevention, modulation, or treatment of visceral pain or discomfort, for example abdominal, or modulation of visceral sensitivity or perception, or regulation or stabilization of the fibers Myenteric afferents of the plexus is demonstrated in convenient tests, for example according to the method described hereinafter. Decerebrate cats, without anesthesia, under continuous monitoring of blood pressure, are paralyzed with alcuronium chloride dissolved in intravenous rheomacrodex (200 microgrammes / kilogram initially, and complementary doses of 100 mi-crograms / kilogram, if necessary), and artificially ventilated. The individual unit activity of the afferent fibers is recorded in a monopolar form from the peripheral ends of centrally cut filaments of sacred dor-salts roots. Tension receptors are identified by sounding their receptive fields in the wall of the mobilized rectum. Then, the response of the units to the distension in rectal ramp controlled by barostat is determined. The quantitative response characteristics of the units are evaluated with respect to the distension pressure, and the resulting rectal diameter. In an alternative way, the response of the units to pressure induced peristalsis is measured. After obtaining 2 distension profiles (5 minutes each), and / or 10 minutes of peristalsis under control conditions, an agonist, partial agonist or 5-HT4 receptor antagonist, for example compound A, is applied intravenously. or a vehicle, and the protocol is repeated. Subsequently, the activity of additional units is recorded in the presence of an agonist, partial agonist, or 5-HT4 receptor antagonist, for example Compound A, or vehicle, according to the distention / peristalsis protocol. In this assay, the firing rate of rectal afferents is reduced after the administration of an agonist or partial 5-HT4 receptor agonist in a dose range of 0.1 to 3 milligrams / kilogram intravenously, at distension pressures above. of 20 mmHg. With Compound A, administered intravenously in increasing doses from 0.15 to 1.2 milligrams / kilogram, the most prominent inhibition occurs at 50 mmHg, and a mean-maximum reduction is obtained in approximately 0.7 milligrams / kilogram. ? ^^ < ^ Sa ^^ Íagal ^ l &! ^ A ^^ > < e3, -: ^ ta &M¿¿affei ^ l .- ^, / The utility of an agonist, partial agonist, or antagonist of the 5-HT receptor, for example Compound A, can be demonstrated in the treatment of incontinence anal, as well as its utility in the treatment of conditions as specified hereinabove, according to the method described hereinafter. The intraluminal pressures and reflexes are measured in the last 60 centimeters of the colon of 10 healthy volunteers fasting, by means of perfusion manometry. Three latex balloons placed at 50, 30, and 10 centimeters allow volume stimulation. The basal values of colonic intraluminal pressures and reflexes are established. Subsequently, inhibitory relaxations of the internal anal sphincter reflex are triggered, inflating the balloons by increments of 10 milliliters to a maximum volume of 150 milliliters. During the inflation phase, two parameters are evaluated: a) the reflux threshold (volume capable of inducing a substantial reduction in pressure of the internal anal sphincter), and b) the threshold of sensation (volume capable of inducing a reflex of conscious defecation) . After the baseline registers, each subject is given an agonist, partial agonist, or 5-HT receptor antagonist, for example Compound A, orally, and 30 to 90 minutes later, the intravenous pressure and reflexes are evaluated. - Colonic lummales again by the same method. In this test, the agonist, partial agonist, or antagonist of the -HT4 receptor, for example Compound A, significantly reduced the sensation threshold, when administered in a dose of 2 to 12 milligrams orally. The agonists, partial agonists, or antagonists of the 5-HT4 receptor, for example Compound A, can be administered by any conventional route, in particular enterally, preferably orally, for example in the form of tablets or capsules, or parenterally , for example in the form of injectable solutions or suspensions, or in a suppository form. Agonists, partial agonists, or 5-HT4 receptor antagonists, for example Compound A, can be administered in free form or in pharmaceutically acceptable salt form. These salts exhibit the same order of activity as agonists, partial agonists, or antagonists of the 5-HT4 receptor in free form. The daily dosages required in the practice of the method of the present invention will vary depending on, 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 0.05 to about 30 milligrams, for example from about 0.05 to about 5 milligrams for parenteral use, and from about 0.1 to about 30 milligrams for oral use, conveniently administered once or in dosages divided 2 to 4 times a day, or in a sustained release form. The unit dosage forms for oral administration, according to the above, comprise from about 0.5 to about 30 milligrams of agonist, partial agonist, or 5-HT4 receptor antagonist, for example Compound A, or a pharmaceutically acceptable salt. thereof, mixed with a suitable solid or liquid pharmaceutically acceptable diluent or carrier, therefor. In addition, it has also been found that a partial agonist or agonist of the 5-HT4 receptor, for example Compound A, has a beneficial effect in the prevention or treatment of gastrointestinal motility disorders, for example a stimulatory effect on the gastrointestinal mobility, in horses and in cattle. In accordance with the above, it is also provided: 5.1. A method for preventing or treating disorders of gastrointestinal mobility, for example by stimulating the mobility of the gastrointestinal tract in horses or in cattle that need it, which method comprises administering to cattle or cattle an effective amount of an agonist or partial agonist of the 5-HT4 receptor, for example Compound A, or a pharmaceutically acceptable salt thereof. 5.2 A method for preventing or treating disorders of gastrointestinal mobility, for example after cholecal surgery, for example post-operative ileus, in horses or cattle in need thereof, which method comprises administering to horses or cattle an effective amount of an agonist or partial agonist of the 5-HT4 receptor, for example Compound A, or a pharmaceutically acceptable salt thereof. 6. An agonist or partial agonist of the 5-HT4 receptor, for example Compound A, or a pharmaceutically acceptable salt thereof, for use as a veterinary pharmaceutical product, for example for horses or cattle, for example in any of the methods 5.1 or 5.2 indicated above, or for use in the manufacture of a veterinary pharmaceutical product, for example for use in a method as defined in 5.1 or 5.2. 7. A pharmaceutical composition for veterinary use, for example in horses or livestock, for example in any of the methods 5.1 or 5.2, as indicated above, which comprises an agonist or partial agonist of the 5-HT4 receptor, for example the Compound A, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier therefor, for example a composition as disclosed hereinbefore. Preferred 5-HT4 receptor partial agonists or agonists for use in horses or cattle according to the invention include, for example, those mentioned hereinabove, for example (S) -zacopride, prucalo-pride, SB 205149, SC 53116, RS 67333, RS 67506, BIMU 1, BIMU 8, (S) -RS 56532, especially Compound A, and particularly its hydrogen maleate salt, more preferably an agonist or partial agonist of the selective 5-HT4 receptor. The utility of the agonist or partial agonist of the 5-HT4 receptor, for example Compound A, in the treatment of post-operative ileus, as well as the utility in the treatment of conditions as specified hereinabove, in horses or cattle, it can be demonstrated according to the method described hereinafter. 20 horses that have colic syndrome undergo abdominal surgery. During the surgery, supportive therapy is applied. At the end of the surgery, an agonist or partial agonist of the 5-HT4 receptor, for example Compound A, is administered intravenously or intramuscularly, for example, in a dose of 0.1 to 10 milligrams / kilogram. This dose is repeated every 8 to 24 hours, until spontaneous defecation is observed. Gastrointestinal motility is evaluated based, for example, on the presence or absence of gastric reflux, determined by nasogastric intubation, borborigm presentation, and defecation time after the first injection of the test compound. In this test, the compounds tested, for example Compound A, are effective in restoring the normal mobility function of the equine intestine. The daily dosages required to practice the veterinary method of the present invention will vary depending on ? att? ^^? And * ¿& of, for example, the particular compound used, the mode of administration, and the severity of the condition to be treated. An indicated daily dose is in the range of about 0.01 to about 10 milligrams / kilogram, for example of about 0.05 to about 5 milligrams / kilogram for parenteral use, conveniently administered once or in dosages divided 2 to 4 times a day, or in a sustained release form. In a further aspect, the invention provides a method for preventing or treating disorders of gastrointestinal mobility in a subject, for example a human or animal, in need of this therapy, which comprises administering to this subject an effective amount. of a composition according to the present invention. In a further aspect of the invention, there is provided a process for improving the dissolving properties in aqueous media of a pharmaceutical composition containing an active agent sensitive to acid and / or poorly soluble in aqueous media, for example a receptor agonist. -HT4, more particularly Compound A, for example the salt of hydrogen maleate. The pharmaceutical composition of the invention can be prepared by any conventional method known in the art, for example by mixing an appropriate amount of the agent active, for example a 5-HT4 receptor agonist, with when 8%, at least 15 percent, for example 20 to 60 percent, for example 30 to 50 percent, for example 40 percent by weight of a disintegrant, based on the total weight of the composition . It is preferred to formulate in solid form, for example in a unit dosage form. The typical form includes capsules, and preferably compressed forms, such as tablets. The pharmaceutical composition according to the invention can be prepared, for example, by a wet granulation manufacturing process, for example based on water (the processing equipment, like the glass material, can be pretreated with a siliconizing agent) , which comprises the successive steps of: i) pre-mixing the active agent sensitive to the acid and / or poorly soluble in water, for example a 5-HT4 receptor agonist, for example Compound A, for example the maleate salt of hydrogen, with 60 to 98 percent of the diluent, and then sieving the resulting mixture, ii) mixing purified water with the binder in a weight ratio of 1:20 to 3:20, and stir until dissolution, iii) add the surfactant to the solution of i) and stir until dissolution, iv) add the disintegrant, the remaining diluent, and ~ ^ lí uftHw. TO. 50 to 70 percent of the first lubricant to the mixture p * £ é-via i), and mix, v) moisten the mixture from step iv) with the granulation solution from step iii) while mixing, vi) granulate the mixture of step v) by mixing, vii) drying the granulate to reach a required dose when drying, for example, for the tabletting mixture, viii) sizing the granulate by sifting. For the manufacture of tablets, the granulate of viii) is mixed, for example, in a free-fall mixer, with the remainder of the first lubricant and the second, to obtain the final desired mixture for the formation of tablets, which can be compress in tablets. This can be done with conventional tablet-forming machines, for example, in a rotating machine, at compression pressure of, for example, 2 to 30 KN for example 5 to 27 KN, for example 10 to 20 KN ( KN = Kilo Newtons). The composition according to the invention can also be prepared by an alternative wet granulation manufacturing process, where the pre-mixing and sifting of step i) is not performed. In this case, the active agent, the disintegrant, the diluent, and about 60 percent of the first lubricant are pre-mixed with each other, and then moistened with the wetting solution of step iv).

Compositions comprising any of the aforementioned active agents can be prepared by a process as disclosed above. If desired, the pharmaceutical compositions of the invention are stored under conditions of low relative humidity, for example an RH (relative humidity) of less than 50 percent, for example less than, for example, 30 to 50 percent, and at room temperature, preferably less than 20 ° C. The compositions provide systems stable to storage. Minor degradation is detected after storage for up to 1 year at room temperature, for example at 25 ° C. The compositions of the invention can be packaged in a conventional manner to keep moisture out, for example in a blister pack, optionally with a desiccant. The compositions of the invention may have a water content of 0 to 3 percent, based on the total weight of the composition. The present invention relates, in a further aspect, to a composition, comprising in particular Compound A, as obtained by one of the above processes, to provide a stable, small form.

EXAMPLES The following examples illustrate the manufacture, on an industrial scale, of compositions comprising Compound A hml using a wet granulation process as disclosed above.

Example 1 A 2 milligram tablet formulation can be prepared as described hereinafter. a) Preparation of the granulated material Pre-mixing step 1. 4.432 kilograms of Compound A hml, and 28,688 kilograms of lactose monohydrate, are mixed with an intensive mixer (Colette Gral® 300 liters, or Fielder®), position of the speed of the mixer: 1; position of the speed of the chopper: 1; for approximately 1.5 minutes, or with a free fall mixer (Turbula®, Soneco® or Róhnrad®). 2. The preliminary mixture from step 1 is then sieved (oscillating granulator, for example Frewitt® or Erweka®, mesh size: 0.8 mm). 3. The premix is divided into two portions of 16,560 kilograms. Preparation of the granulation solution 4. Approximately 40 kilograms of purified water are weighed. 5. 3,600 kilograms of methylhydroxypropylcellulose 3 maps are added to the purified water from step 4, and this is stirred until dissolved. 6. 1440 kilograms of poloxamer 188 are added to the solution of step 5, while stirring until dissolved. Granulation step 7. Weigh 28,800 kilograms of crospovidone, 10,080 kilograms of lactose monohydrate, and 4,320 kilograms of glyceryl monostearate. 8. A portion of the premix from step 3 is added to the excipients from step 7, and this is mixed with the intensive mixer, for example Colette Gral®, 300 liters, or Fielder® (position of the speed of the mixer: 1; position of the speed of the chopper: 1) for about 2 minutes. 9. The mixture from step 8 is moistened with the granulation solution from step 6 while mixing with the in-tensile mixer, for example Colette Gral®, 300 liters, or Fielder® (position of mixer speed: 1; the speed of the chopper: 0, approximate pumping speed: 4 kilograms / minute) for approximately 12 minutes. 10. Approximately 2 kilograms of purified water are weighed. 11. The container from step 6 is rinsed with purified water from step 10, and this is added to the mixture from step 9 while mixing. 12. The dough is granulated by mixing with the intensive mixer, Colette Gral®, 300 liters, or Fielder® (position of the «Mixer speed: 1; position of the chopper speed: 1) for about 2.5 minutes. Drying step 13. The granulate of step 12 is dried in a fluidized air bed dryer (e.g., Glatt® or Aeromatic®), for about 65 minutes (inlet air temperature of about 70 ° C) to reach the Loss on drying (LOD) required for the tabletting mix, ie, up to a loss when drying <4.4 percent. 14. The granulate is dimensioned by sifting (0.8 mm) with an oscillating screen granulator, for example Frewitt® or Erweka®. 15. Steps 4 to 14 are repeated with the other portion of step 3. b) Preparation of the tablet-forming mixture 16. 8.640 kilograms of polyethylene glycol 4000, and 5.760 kilograms of glyceryl monostearate (oscillating granulator, eg Frewitt) are screened. ® or Erweka®, mesh size: 0.8 mm). 17. The ingredients of step 16 are added to the total mass of the granulated material, and this is mixed with a free-fall mixer, for example Soneco® or Rohnrad® for approximately 20 minutes (10 rpm), to obtain the forming mixture. desired final tablets. c) Compression Step 18. The tablet-forming mixture of step 17 is compressed into tablets using compression pressures of 11, 14, or 17 KN, in a rotary tablet-making machine, for example Fette®, Korsh®, Kelian® or Coarty® (temperature <20 ° C; RH (relative humidity) <40 percent).

Example 2; Composition of a 2 milligram tablet (1 milligram of base corresponds to 1385 milligrams of the hydrogen maleate salt of Compound A) Compound A hml 2.77 (2 mg base) Poliplasdone XL USP / NF 36.00 Glyceryl monostearate USP / NF 9.00 Poloxalkol 1.80 Lactose 200 mesh 30.53 HPMC 3cPs 4.50 Polyethylene glycol 4000 5.40 Water adsorbed 2.00 Total 92 mg.

Example 3 A 6 milligram tablet formulation can be prepared by the manufacturing process described hereinafter. a) Preparation of the granulated material Preparation of the granulation solution 1. Approximately 40 kilograms of purified water are weighed. 2. Add 3,600 kilograms of methylhydroxypropyl cellulose 3 maps to the purified water from step 1, while agitating until dissolved. 3. 1440 kilograms of poloxamer 188 are added to the solution of step 2, while stirring until dissolved (mixing vessel with stirring). Granulation step 4. 4.787 kilograms of Compound A hml and 28,800 kilograms of crospovidone, 21,853 kilograms of lactose monohydrate, and 4,320 kilograms of glyceryl monostearate are weighed. 5. The ingredients of step 4 are mixed with the intensive mixer, for example Colette Gral®, 300 liters, or Fielder® (mixer speed position: 1, chopper speed setting: 1) for about 2 minutes 6. The mixture from step 5 is moistened with the granulation solution from step 3, while it is mixed with the intensive mixer, for example Colette Gral®, 300 liters, or Fielder® (position of the mixer speed: 1; position of the speed of the chopper: 0; pumping speed of approximately 4 kilograms / minute) for approximately 12 minutes. 7. Approximately 2 kilograms of purified water are weighed ^^ ß ^^^ ü ^ aJ ^ M ^ each. 8. The container from step 3 is rinsed with the purified water from step 7, and this is added to the mixture from step 6 while mixing. 9. The dough is granulated by mixing with the intensive mixer, for example Colette Gral®, 300 liters, or Fielder® (position of the mixer speed: 1; position of the speed of the chopper: 1) for about 2.5 minutes. Drying step 10. The granulate of step 9 is dried in a fluidized air bed dryer, for example Glatt® or Aeromatic®, for about 65 minutes (air inlet temperature of about 70 ° C), to achieve the loss when dried (LOD) desired for the tablet-forming mixture, i.e., up to a loss when drying < 4.4 percent. 11. The granulate is dimensioned by sifting (0.8 mm), with an oscillating screen granulator (Frewitt® or Erweka®). 12. Steps 1 to 11 are repeated. B) Preparation of the tablet-forming mixer 13. 8,640 kilograms of polyethylene glycol 4000, and 5,760 kilograms of glyceryl monostearate are screened with an oscillating screen granulator, for example Frewitt® or Erweka® (0.8 mm). 14. The ingredients of step 13 are added to the total mass of the granulated material, and this is mixed with a free-fall mixer, for example Soneco® or Rohnrad®, for about 20 minutes (10 rpm), into the mixture. Ultimate desired tablet former. 5 c) Compression step 15. The tablet-forming mixer of step 14 is compressed into tablets using compression pressures of 13, 16, or 19 KN, in a rotary tablet-forming machine, for example Fette®, Korsh®, Relian® or Coarty® (temperature < 20 ° C, RH (relative humidity) < 40 percent.

Example 4: Composition of a 6 milligram tablet (1 milligram base corresponds to 1385 milligrams of hydrogen maleate of Compound A); 15 Compound A hml 8.31 (6 mg base) Poliplasdone XL USP / NF 50.00 Glyceryl monostearate USP / NF 12.50 Poloxalkol 2.50 200 mesh lactose 37. 94 20 HPMC 3cPs 6. 25 Polyethylene glycol 4000 7.50 Water adsorbed 3.00 Total 128 mg.

Example 5 A tablet formulation of 0.5 milligrams can be prepared by the manufacturing process described hereinafter. a) Preparation of the granulated material Pre-mixing step 1. 1.994 kilograms of Compound A hml, and 31,126 kilograms of lactose monohydrate, are mixed with an inten- sive mixer (Colette Gral®, 300 liters or Fielder®); position of the speed of the mixer: 1; position of the speed of the chopper: 1; for approximately 1.5 minutes, or with a free fall mixer (Turbula®, Soneco® or Róhnrad®). 2. The preliminary mixture from step 1 is then sieved (oscillating gravure, for example Frewitt® or Erweka®, mesh size: 0.8 mm). 3. The premix is divided into 2 portions of 16,560 kilograms. Preparation of the granulation solution 4. Weigh approximately 43 kilograms of purified water. 5. 3,600 kilograms of methylhydroxypropylcellulose 3 maps are added to the purified water from step 4, and this is stirred until dissolved. 6. 1440 kilograms of poloxamer 188 are added to the solution of step 5, while stirring until dissolved. Granulation step 7. We weigh 28,800 kilograms of crospovidone, 10,080 kilograms of lactose monohydrate, and 4,320 kilograms of glyceryl monostearate. 8. Add a portion of the premix from step 3 to the excipients from step 7, and this is mixed with the intensive mixer, for example Colette Gral®, 300 liters, or Fielder® (position of the mixer speed: 1, position of the chopper speed: 1) for about 2 minutes. 9. The mixture from step 8 is moistened with the granulation solution from step 6 while mixing with the intensive mixer, for example Colette Gral®, 300 liters, or Fielder® (position of mixer speed: 1; -the speed of the chopper: 0, approximate pumping speed: 4 kilograms / minute) for approximately 12 minutes. 10. Weigh approximately 2 kilograms of purified water. 11. The container 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. The dough is granulated by mixing with the intensive mixer, Colette Gral®, 300 liters, or Fielder® (position of the mixer speed: 1; position of the speed of the mixer: 1) for approximately 2.5 minutes.

Drying step 13. The granulate from step 12 is dried in a fluidized air bed dryer (eg, Glatt® or Aeromatic®) for approximately 60 minutes (inlet air temperature of approximately 70 ° C) to reach the loss on drying (LOD) required for the tablet-forming mixture, that is, up to a loss on drying = 4.5 percent. 14. The granulate is dimensioned by sifting (0.8 mm) with an oscillating screen granulator, for example Frewitt® or Erweka®. 15. Steps 4 to 14 are repeated with the other portion of step 3. b) Preparation of the tablet-forming mixture 16. 8.640 kilograms of polyethylene glycol 4000, and 5.760 kilograms of glyceryl monostearate (oscillating granulator, eg Frewitt) are screened. ® or Erweka®, mesh size: 0.8 mm). 17. The ingredients of step 16 are added to the total mass of the granulated material, and this is mixed with a free-fall mixer, for example Soneco® or Rohnrad®, for approximately 20 minutes (10 rpm), to obtain the desired final tablet forming mix. c) Compression step 18. The tablet-forming mixture of step 17 is compressed into tablets in a rotary tablet-forming machine, for example Fette®, Korsh®, Kelian® or Coarty® (temperature <20 °). C; RH (relative humidity) < 40 percent).

Example 6; Composition of a 0.5 milligram tablet (1 milligrams of base corresponds to 1385 milligrams of the hydrogen maleate salt of Compound A) Compound A hml 0.6925 (0.5 mg base) Poliplasdone XL USP / NF 20.00 Glyceryl monostearate USP / NF 5.00 10 Poloxalkol 1.00 Lactose 200 mesh 17.8075 HPMC 3cPs 2.50 Polyethylene glycol 4000 3.00 Water adsorbed 1.00 15 Total 51 mg.

Example 7; Composition of a 12 milligram tablet (1 milligram of base corresponds to 1385 milligrams of the hydrogen maleate salt of Compound A) 20 The manufacturing process is similar to the process used for the 6 milligram tablets. Compound A hml 16.62 (12 mg base) Poliplasdone XL USP / NF 72.00 Glyceryl monostearate USP / NF 18.00 25 Poloxalkol 3.60 -. ^^^^? J ^^ XS ^^^^ S ^ Á? Attjiis jt ^^? ^ f Lactose 200 mesh 49.98 HPMC 3cPs 9.0 Polyethylene glycol 4000 10.8 Water adsorbed 4.00 Total 184 mg. t 37% ¿JSJ,

Claims (26)

1. A solid oral pharmaceutical composition comprising an effective amount of an acid sensitive active agent, 5 and a disintegrant that is present in an amount of at least 15 weight percent, based on the total weight of the composition.

2. A solid oral pharmaceutical composition comprising an effective amount of an active agent that is poorly 10 soluble in aqueous media, and a disintegrant that is present in an amount of at least 15 weight percent, based on the total weight of the composition.

3. A pharmaceutical composition according to claim 1 or 2, wherein the active agent has a solubility in aqueous media of less than 1 percent.

4. A pharmaceutical composition according to any of claims 1 to 3, wherein the active agent is a serotonergic compound.

5. A pharmaceutical composition as claimed in any one of the preceding claims, wherein the active agent is an antagonist of the 5-HT4 receptor.

6. A pharmaceutical composition as claimed in any of claims 1 to 4, wherein the active agent is a 5-HT4 receptor agonist. 25

7. A pharmaceutical composition according to the ^^^^^^^^ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Vindication 6, wherein the 5-HT4 receptor agonist is Tegaserod, preferably its hydrogen maleate salt (hml).

8. A pharmaceutical composition as claimed in any of the preceding claims, wherein the disintegrant is crospovidone.

9. A pharmaceutical composition as claimed in any of the preceding claims, comprises a lubricant.

10. A pharmaceutical composition according to claim 10, wherein the lubricant comprises a fatty mono-acid glyceryl.

11. A pharmaceutical composition according to claim 9, wherein the lubricant comprises a mixture of glyceryl monostearate and polyethylene glycol.

12. A pharmaceutical composition as claimed in any of the preceding claims, which comprises a surfactant.

13. A pharmaceutical composition according to claim 12, wherein the surfactant comprises a poloxamide.

14. The use of at least 15 weight percent of a disintegrant, in the manufacture of a solid pharmaceutical composition for the administration of an acid sensitive active agent. 5

15. The use of at least 15 percent by weight of a ßSiai,% *. psg »sg¿3¡fc, -» fe¿-a & fc ^. disintegrating, in the manufacture of a solid pharmaceutical composition, for the administration of an active agent that is acid-sensitive and / or has poor solubility in water.

16. The use according to claim 14 or 15, wherein the active agent is a 5-HT4 receptor agonist.

17. The use according to claim 16, wherein the 5-HT4 receptor agonist is Tegaserod, preferably its hydrogen maleate salt.

18. The use of a pharmaceutical composition according to any of claims 1 to 13, for the manufacture of a composition for the prevention and treatment of disorders of gastrointestinal mobility in humans or animals.

19. A process for improving the dissolution properties of a pharmaceutical composition as claimed in any of claims 1 to 13.

20. A method for preventing, modulating, or treating visceral pain or discomfort, to modulate visceral sensitivity or perception, to improve the sensory perception of rectal distension, or to treat dysfunctions of anal continence in a subject in need thereof, which method comprises administering to this subject an effective amount of an agonist, partial agonist, or 5-HT4 receptor antagonist, or a pharmaceutically acceptable salt thereof.

21. An agonist, partial agonist, or antagonist of the TeuS.-ceptor 5-HT4, or a pharmaceutically acceptable salt thereof, for use in the manufacture of a pharmaceutical composition to be used to prevent, modulate, or treat visceral pain or discomfort, modulate visceral sensitivity or perception, improve the sensory perception of rectal distension, or treat dysfunctions of anal continence.

22. A pharmaceutical composition for use to prevent, modulate, or treat visceral pain or discomfort, modulate visceral sensitivity or perception, improve sensory perception of rectal distention, or treat dysfunctions of anal continence, which composition comprises an agonist, agonist partial, or antagonist of the 5-HT4 receptor, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable diluents or carriers therefor.

23. A method for preventing or treating gastrointestinal motility disorders in horses or cattle that need it, which method comprises administering to horses or cattle an effective amount of an agonist or partial agonist of the 5-HT receptor, or a pharmaceutically salt acceptable of it.

24. An agonist or partial agonist of the 5-HT receptor, or a pharmaceutically acceptable salt thereof, for use as a veterinary pharmaceutical product, or for use in the manufacture of a veterinary pharmaceutical product.

25. A pharmaceutical composition for veterinary use, which comprises a partial agonist or agonist of the 5HT4 receptor, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier therefor.

26. A pharmaceutical composition comprising Tegaserod, having dissolution characteristics in water or in USP regulators of a pH of 6.8 and 7.5, of: time (minutes) amount (percentage) 5 30-90 15 80 - 100 30 95 - 100 60 100