MXPA98008710A - Dosage form solid independent of the ph, of immediate release - Google Patents

Abstract

The present invention relates to oral dosage forms of some particular salts of cisapride, more in particular, cisapride- (L) -tartrate, cisapride- (D) -tartrate, cisapride-sulfate, or cisapride citrate, which prevents the interaction of food, and what allows the comedication of agents that increase the pH of the stomach. The invention relates in particular to oral, solid dosage forms suitable for rapid dissolution. The present invention also relates to tablets that can be prepared by direct compression.

Description

DOSAGE FORM SOLID INDEPENDENT OF THE PH. OF IMMEDIATE RELEASE The present invention relates to solid dosage forms of particular saltse of cisapride, more in particular cisapride- (L) -tartrate, cisapride- (D) ~ tartrate, cisapride-sulfate, or cisapride citrate, which prevent the interaction of food drug and that allow the co-medication of agents that increase the pH of the stomach. The invention relates particularly to solid oral dosage forms suitable for rapid disintegration and dissolution. The present invention also relates to tablets that can be prepared by direct compression.

BACKGROUND OF THE INVENTION In general, it is known that the absorption and bioavailability of any particular therapeutic agent can be affected by numerous factors when dosed orally. These factors include the presence of food in the gastrointestinal tract (Gl) because, in general, the gastric residence time of a drug is usually significantly longer in the presence of food than in the fasting state. If the bioavailability of a drug is affected beyond a certain point due to the presence of foods in the Gl tract, it is said that the drug exhibits a "food effect", or shows a drug-food interaction. The risk of taking drugs that exhibit a food effect derives from the fact that absorption into the bloodstream can be adversely affected when the drug is not taken at the correct time, so that the patient risks insufficient absorption as to correct the condition by which the drug is administered. European Patent No. 0,076,530 discloses the gastroprokinetic agent cisapride, and compositions thereof. Cisaprida has the following structural formula.

The systematic chemical name of cisapride is cis-4-amino-5-chloro-N- [l- [3- (4-fluorophenoxy) propyl] -3-methoxy-4-piperidinyl] -2-methoxybenzamide. Cisapride is a racemic mixture of two enantiomers. Cisapride has excellent gastrointestinal motility stimulating properties, and it is reported that it is free of antidopaminergic activity. Its usefulness in a variety of gastrointestinal disorders has already been reported extensively. It is currently being marketed as a medicine for the treatment of esophageal reflux disorders, inter alia, esophagitis, gast clothes resis, negative upper digestive complaints, and intestinal pseudo-obstruction. Cisapride monohydrate is currently commercially available as tablets, suspension and granules under registered trade names, such as PREPULSID ™, PROPULSID ™, PROPULSION, ACENALIN ™, ALIMIX ™ (this list is not complete). Cisapride in its monohydrate form has a dissolution profile and a pH-dependent solubility. Consequently, the bioavailability of cisapride or cisapride monohydrate depends on the pH. Cisapride monohydrate has a low solubility and low dissolution when present in a neutral or basic ENVIRONMENT. Therefore, the information brochure of cisapride monohydrate mentions that the drug should be taken 15 to 30 minutes before meals. The fundamental reason is that the solid dosage form comprising cisapride monohydrate reaches a more or less empty stomach, where the pH is reasonably low, and consequently cisapride can be dissolved. Subsequently, when the patient eats 15 to 30 minutes after the solid oral dosage form was administered, the solid dosage form remains a little longer in the stomach acid environment. Once cisapride monohydrate enters the more or less neutral ENVIRONMENT of the intestine, the solubility of cisapride MONOHYDRATE decreases rapidly. Consequently, cisapride monohydrate shows a good effect, which can be expressed as the ratio of AUC in the fed state to the AUC in the fasted state. (AUC is the abbreviation of area under the Curve, which is an indication of the amount of active ingredient that is present in the blood). The ratio for cisapride monohydrate, from AUC in the fed state to AUC in the fasted state, is approximately 1.35 (p >; 0.01). A drug that shows no effect of food would have a ratio of 1 (in an ideal case). Therefore, a patient taking cisapride monohydrate must follow the previously described regimen in a very strict manner, to create optimal conditions for the high bioavailability of cisapride monohydrate, and consequently to maximize the benefit of the drug taken . Patients do not always have the discipline to take their medication at the optimal time. Therefore, a dosage form that makes the bioavailability independent of food (or any other event for that matter), would mean a serious improvement over the oral dosage forms of cisapride monohydrate of the preceding art, and would reduce the range of variability in absorption between patients. Therefore, it would be useful if cisapride could be administered immediately to patients who feel proximal pain associated with gastro esophageal reflux, without having to eat 15 to 30 minutes after the administration of cisapride. With the currently available cisapride dosage forms, the patient would have to eat something to obtain maximum absorption of the cisapride monohydrate. In view of the fact that gastro esophageal reflux often occurs during the night, and in view of the fact that the esophagus is causing the pain, it is obvious that the patient is not really inclined to eat anything. Consequently, it would be advantageous to have a form of cisapride that can be administered or taken independently of food. There is also a problem associated with the pediatric use of cisapride monohydrate. Cisapride monohydrate is prescribed for children (up to 1 year). The fact that cisapride monohydrate has to be administered up to 30 minutes before the meal, implies that parents often have to wake up these children, administer cisapride monohydrate, and then wait half an hour to feed those children. This procedure is very impractical, and it would be very interesting to find a form of cisapride that is suitable for administration to children just before the meal, or even after the meal, or even better, completely independent of when the food is given. Yet another issue of the oral dosage forms present of cisapride is as follows. As mentioned earlier, cisapride is used to treat people who have stomach or esophagus problems. Often, these patients receive co-edication to increase the pH of the stomach.

Examples of such co-medication are antacids, such as aluminum-containing antacids, for example, A1 (0H) 3 calcium-containing antacids, for example, CaCO3, or magnesium-containing antacids, for example Mg (0H) 2; H2 -antagonists, for example cimetidine, ranitidine, famotidine, nizatidine, roxatidine, and the like, or proton pump inhibitors, for example omeprazole, lansoprazole, rabep razol. Currently the preferred comedication recipe proton pump inhibitors.

PREVIOUS TECHNIQUE WO 94/01112 and WO 94/01111, published on January 20, 1994, assigned to Sepracor Inc., disclose very general methods for the use of (-) - cisapride respectively (+) - cisapride, as well as salts Therapeutically acceptable thereof, for the treatment of gastro-esophageal reflux diseases and other disorders. In said applications there is no specific mention of the use of the salts currently disclosed and the properties thereof. There is also no mention of the problem that forms the basis of the present invention. W0 95/34284, published on December 21, 1995, assigned to Gergely, mentions pharmaceutical preparations with a hydrophobic active substance, among other cisapride, and an effervescent system, and a process for the preparation of said preparations. This application only mentions effervescent systems that are totally different from the invention that is discovered in the present. EP 670160, published on September 6, 1995, assigned to Gergely, discloses a tablet or granular product containing an effervescent system and an active pharmaceutical substance, as well as a method for its preparation. In Example 5 of said document, effevescent tablets of cisapride are described. Again, in this application only effervescent systems are discovered that are totally different from the invention disclosed herein. WO 95/01803, published on January 19, 1995, discloses combinations of H2 antagonists and gastrointestinal motility agents. Said patent application specifically mentions the use of cisapride in said combination. The disadvantage of said combination of the prior art is that antacids, H2 antagonists, and especially proton pump inhibitors can cause a considerable increase in the pH of the stomach. With antacids the pH of the stomach, which is usually between 1 and 1.5, can rise to about 4.5, and with proton pump inhibitors the pH of the stomach can rise to about 6.5. In such environment the cisapride monohydrate does not dissolve fast enough to give a quick relief. Our co-pending application PCT / EP95 / 04198 corresponding to the patent application Argentina Minutes No. 334. 075 discovers a matrix formulation in which cisapride- (L) -tartrate is fixed in a mixture of viscous polymers. Said co-pending application also describes the preparation of cisapride- (L) -tartrate. In said application it was already discovered that the cisapride- (L) -tartrate salt is a mixture of the diastereomers C (3R4S) (2R3R)] and [(3S4R) (2R3R)], which crystallize as a double salt in a ratio 1: 1 (This is confirmed by X-rays). The (3R4S) and (3S4R) refer to the respective enantiomers of cisapride, and the (2R3R) refers to the optically pure L-tartrate. It was also shown that formulations containing cisapride- (L) -tartrate released cisapride in a racemic form, ie, equal amounts of (+) - cisapride and (-) - cisapride, or in other words, the diastereomeric salt forms (+) - cisapride- (L) -tartrate and (-) - cisapride- (L) -tartrate unexpectedly have equal dissolution ratios. Furthermore, it was also found that during the preparation of cisapride- (L) -tartrate, no enrichment of one of the two forms of diastereomeric salts could be detected. Such matrix formulations of the prior art, however, do not disintegrate and dissolve as rapidly as is required for the solid oral dosage forms of the present invention. In contrast, the matrix formulations of the preceding art are designed to give a sustained release of cisapride over a much longer period of time.

DESCRIPTION OF THE INVENTION The aforementioned problems and / or disadvantages associated with the formulations of the prior art are solved by the solid dosage forms comprising a cisapride salt with an acid selected from sulfuric acid, (L) -tartaric acid, (D) -acid tartaric, or citric acid, preferably cisapride- (L) -tartrate suitable for rapid dissolution. The formulations are preferably suitable for rapid disintegration as well as dissolution. Preferred formulations are oral solid dosage forms. The words "suitable for rapid dissolution" refer to the fact that of the solid dosage forms of the present invention, the active ingredient can be dissolved by more than 60% within 1 hour at a pH ranging from 1 to 7. Said solution can be measured according to standard methods described in the "European Pharmacoeipea", or as set forth in the USP < 711 > in a USP-2 dissolution apparatus. This last test is described in the US Pharmacopeia XXII, pages 1578-1579. Unexpectedly, we have found that certain salts of cisapride have a better dissolution in artificial gastric juice than others: those salts are (L) -tartrate, (D) -tartrate, sulfate and citrate. Still further, said cisapride salts show a dissolution profile which is substantially independent of pH. It should be noted that the salt form of cisapride with hydrochloric acid, as well as with maleic acid, dissolves more slowly than the same cisapride monohydrate. The term "solid oral dosage forms" generally refers to tablets (both chewable and swallowed forms) and capsules. Accordingly, the present cisapride salt form composition can be formulated into tablets, capsules, or gel capsules. This invention encompasses formulators comprising the cisapride salts according to the present invention, and further comprising a substance that can influence the acidity of the stomach. Said substance can be any medication that increases the pH of the stomach (in other words: it makes the stomach more basic). As examples of just medication that increases the pH of the stomach, there should be mentioned antacids, H2 antagonists, or proton pump inhibitors. The invention furthermore relates to products containing any of the cisapride salt forms of the present invention, preferably cisapride- (L) -tartrate, and an antacid or an H2 antagonist, or especially a proton pump inhibitor. , as a combined preparation for simultaneous, separate or sequential use in the treatment of gastrointestinal disorders, especially conditions related to gastroesophageal reflux. The formulations of the present invention may optionally include an antiflatulent, such as simethicone, alpha-D-galactodidase, and the like. Said products comprising combinations of antacids, H2 antagonists, or proton pump inhibitors on the one hand, and the forms of cisapride salts on the other hand, optionally further combined with an antiflatulent, provide the dual action approach to the treatment of gastrointestinal disorders, as described in WO 95/01803, that is, the salt of cisapride as a gastrointestinal motility agent offers enhanced motility while the antacid, the H2 antagonist, or the proton pump inhibitor offer a systemic effect of reduced acid production. The present invention therefore provides a method for preventing, treating, and alleviating acidity, indigestion, sour stomach, hyperindulgence, gastro esophageal reflux, constipation, dissectomy, and other gastrointestinal disorders, and gastrointestinal disorders, and optionally flatulence, in mammals, including humans, who need treatment thereof comprising administration to said organism of: (i) a therapeutically effective amount of an antacid, an H2 antagonist or a proton pump inhibitor, and (ii) a therapeutically effective amount of a cisapride salt form of the present invention, and optionally (iii) a therapeutically effective amount of an antiflatulent, in particular simethicone or alpha-D-galactosidase (ADG). The antacids to be used in the combination described above are commercially available. H2 antagonists such as famotidine, ranitidine, and cimetidine are also commercially available under different trade names. Proton pump inhibitors, such as omeprazole, lansoprazole, rabeprazole, and the like, are either commercially available or known in the art. Simethicone is a well known and commercially available antiflatulent. Alpha-D-galactosidase ADG is a commercially available enzyme preparation used to hydrolyse indigestible sugars found in beans or bean products. The active ingredients that are not cisapride salts, therefore, are commercially available. The dosages of each of the active ingredients may vary according to the severity of the condition and the particular biochemistry and need of the patient. The dosages of the active ingredients may also vary according to whether the active ingredients are administered in tablet or liquid form, or by some other suitable administration method. A doctor or clinician can determine without difficulty the appropriate dosages. The tablets or capsules according to the invention comprise the salt forms of cisapride, preferably cisapride- (L) -tartrate, which are preferably in a microfine or micronized form for some uses. The micronized forms of the cisapride salt forms, especially cisapride- (L) -tartrate, can be prepared by micronization techniques known in the art, for example by grinding in appropriate grinders and screening through appropriate sieves. The specific surface area of said micronized material should reach at least about 10 x 103 cm2 / g (1 x 103 m2 / kg), preferably the specific surface area should reach more than 12 x 103 cm2 / g (1.2 x 103 m2 / kg), more preferably the specific area should reach more than 14 x 103 cm / g (1.4 x 103 m2 / kg). According to this invention, the characteristics of the micronized salt forms of cisapride, especially cisapride- (L) -tartate, expressed in a different form as follows. As a maximum 50% of the particles can have a diameter greater than 24 μm (ie 24 x 10-6 m), consequently the dioxide has a maximum value of 24 μm (di represents diameter measured by laser diffraction). In some cases it may be useful to use thicker material (than the micronized or microfine material) of the cisapride salts described herein. For example in the case of the direct compression of tablets comprising the salts of the present invention on an industrial scale. When the active ingredient is too thin problems can arise when producing tablets by direct compression in industrial machines (high speed). When the material is too thin, the tablets show low test values, which may for example be due to the fact that the micronized material adheres to the walls of the containers. On the other hand, when the material is too thick a problem may arise with the uniformity of content, which is a decisive parameter. Especially for the production of pharmaceutical compositions which is governed by the strict requirements of GMP (Good Manufacturing Practices). An interesting variation of particle size expressed in dies is from about 10 μm to about 150 μm. A more interesting variation is from about 20 μm to 100 μm. For formulations where micronized material is used, the preferred di is approximately 24 μm. For formulations where the thickest material is used, the preferred diameter is approximately 50 μm. The solid oral dosage form when in a unit dosage form comprises the equivalent of about 0.1 mg to 100 mg of cisapride in its base form, more particularly dosage forms containing the equivalent of about 5 mg are contemplated, about 10 mg, and about 20 mg of cisapride in its base form. This means, for example, for cisapride- (L) -tartrate from about 0.13 mg to about 130 mg cisapride- (L) -tartrate. More particularly are dosage forms containing about 6.5 mg, about 13 mg, and about 26 mg of cisapride- (L) -tartrate. In view of the fact that the present oral dosage forms are designed to give a rapid dissolution of the active ingredient, the excipients of the oral dosage forms of the present invention should be chosen to allow rapid dissolution of the active ingredients. Solid oral dosage forms are preferred, ie, tablets and capsules.

TABLETS Especially with tablets, the choice of excipients is important. The excipients should allow rapid dissolution, and on the other hand the excipients should allow convenient industrial production of tablets with an appropriate appearance, appropriate friability, and sufficient hardness. The tablets should have appropriate friability and hardness mainly because said tablets have to be manufactured on an industrial scale in high speed presses, and said tablets have to be packed or filled in all kinds of containers. If the tablet has an insufficient hardness, or is somewhat friable, the tablet that is taken by the patient may be broken, or parts of the tablet may have crumbled to powder. As a consequence of this insufficient hardness or friability, the patient can no longer be sure that he is taking the correct amount. The minimum required hardness of the tablets should be from about 1.5 daN (deca Newton) as measured by the test as described in the "European Pharmacopoeia" (3rd edition, 1997) on page 135, "resistance to rupture of tablets. " It should be noted that the hardness, among other properties, of the tablets depends on the shape of the tablets. Different forms of tablets can be used according to the present invention. The tablets may be circular or oblate or oblong, or any other form that is known in the art. The tablets can be incised. It should be noted that also the shape of the tablets may for example have an influence on the rate of disintegration. The disintegration of the tablets is measured according to the pharmaceutical technical procedure as described in the "European Pharmacopoeia", third edition (1997), page 127. The disintegration time of the present tablets should be less than about 30 minutes, interestingly less than 20 minutes, and more interestingly less than about 15 minutes. Preferred tablets still have a disintegration time of less than about 3 minutes, even less than about 1.5 minutes. The tablets of the present invention comprise tablet disintegrants, such as starch, pregelatinized starch, sodium starch glycolate (Explotab®), cross-linked providone, cross-linked sodium carboxymethylcellulose, clays, icrocrystalline cellulose (of the type available under the trademark Avicel®, alginates, gums and others known in the art The tablets of the present invention preferably comprise as crosslinked Carmellose Sodium disintegrant (Carmellose Sodium is the British Approved Name of sodium carboxymethylcellulose, i.e. the sodium salt of a cellulose ether, see Martindale , "Extra Pharmacopoeia," 293 edition, page 1433.) Such cross-linked Carmellose Sodium is referred to as Sodium Croscarme (USP NF, 1995 edition, page 2238.) The disintegrant may be present in an amount of about 2% (p / p) to approximately 15% (w / w) An interesting variation for the disintegrant is from about 3% ( p / p) at approximately 10% (w / w). When percentages are used, these percentages are weight by weight (w / w), and represent the ratio (in percentage) of the ingredient or excipient based on the total weight of the tablet (or in the case of coated tablets, from the center). the tablet). The "center of the tablet" is the tablet without the coating. When a process is used where there is a granulation step, it may be advantageous to have a disintegrant in the "internal phase" and in the "external phase". The term "internal phase" refers to the composition of the granules, and the term "external phase" refers to the composition of the compression mixture. It was observed that the disintegrating tablets in the internal and external phase showed a better disintegration and a better dissolution profile. The tablet can also be formulated to include a variety of conventional excipients, according to the exact formulation, such as binders, flavorings, buffers, diluents, colors, lubricants, sweetening agents, and glidants. Some excipients can serve multiple purposes. Optionally, flavors can be incorporated into the composition, which can be selected from oils of synthetic flavors, and aromatic and / or natural flavoring oils, extracts from leaves of plants, flowers, fruits and so forth, and combinations thereof. These may include cinnamon oil, pyroclase oil, peppermint oils, bay oil, anise oil, eucalyptus, thyme oil. Also useful as flavors are vanilla, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, banana, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, and others. The amount of flavor may depend on a number of factors, including the desired organoleptic effect. In general, the flavor will be present in an amount from about 0.5% (w / w) to about 3.0% (w / w), when a flavor is used. A variety of materials such as fillers or diluents can be used. Examples are anhydrous or spray dried lactose, sucrose, dextrose, mannitol, sorbitol, starch, cellulose (for example microcrystalline cellulose); Avicel), anhydrous dibasic calcium phosphate, and others known in the art. A tablet may comprise a single filler or diluent, or a mixture of fillers or diluents. For example, a mixture of lactose and microcrystalline cellulose can be used. Lactose is used as a pure diluent, while microcrystalline cellulose is a filler that has the property of producing tablets with an appropriate hardness, and has disintegrating properties because the cellulose fibers dilate on contact with water. A preferred form of lactose is DC lactose monohydrate, which corresponds to Pharatose DCL 11 which is commercially available from DMV International, The Netherlands, said lactose monohydrate DC is spray-dried lactose monohydrate.

The fillers or diluents may be present on a scale from about 50% (w / w) to about 95% (w / w) based on the total weight of the tablet or tablet center. Interestingly, the amount of fillers or diluents ranges from about 65% (w / w) to about 90% (w / w). Preferably, the amount of fillers or diluents ranges from about 66% (w / w) to about 86% (P / P). Interestingly, a spray-dried mixture of lactose monohydrate and microcrystalline cellulose can be used in a ratio of about 75% by weight of lactose monohydrate, and about 25% by weight of microcrystalline cellulose. The mixture can be obtained commercially under the registered trade name MICR0CELACR. This spray-dried mixture of lactose monohydrate and microcrystalline cellulose has the advantage that it will promote orderly mixing, which improves the uniformity of the contents of the tablets. In fact, solid oral dosage forms contain relatively small amounts of active ingredient in a large amount of filler. In such conditions the uniformity of the content may present problems, that is, the tablets prepared in the same batch may not all have the same content of active ingredient due to the segregation during manufacturing. In view of the fact that Regulatory Authorities often apply very stringent rules for the uniformity of content of solid oral dosage forms, games with tablets that do not have a good uniformity of content should be discarded. The spray-dried mixture of lactose monohydrate and microcrystalline cellulose has a porous structure in which the active ingredient cisapride- (L) -tartrate can be inserted, leading to an ordered mixture and consequently a good uniformity of content. Said MICR0CELACR is present in an amount ranging from about 80% (w / w) to 95% (w / w) based on the total weight of the tablet, or tablet center in the case of film-coated tablets. Preferably, the MICROCELACR is present in an amount of about 87% (w / w). Lubricants may also be used in the manufacture of certain dosage forms, and will generally be employed when producing tablets. Examples of lubricants are magnesium stearate, stearic acid, sodium stearyl fumarate, magnesium lauryl sulfate, hydrogenated vegetable oil, and others known in the art. Preferred lubricants are magnesium stearate and sodium stearyl fumarate. Lubricants in general are present in an amount ranging from about 0.2% (w / w) to 7.0% (w / w) based on the total weight of the tablet or the tablet center in the case of tablets coated with movie. Interestingly, lubricants are present in amounts ranging from about 0.5% (w / w) to about 3.0% (w / w). Preferably, the lubricants are present in amounts ranging from about 0.9% (w / w) to about 1.25% (w / w). Sliders are normally used in the manufacture of tablets and also capsules. Interesting gliders are calcium silicate, magnesium silicate, colloidal anhydrous silica or talc. Sliding mixtures can also be used. The preferred glide for the tablet center or the capsule of this invention is colloidal anhydrous silica. The type normally used can be obtained commercially under the commercial man Aerosil®. Sliders are typically present in an amount ranging from about 0.05% (w / w) to about 1% (w / w) based on the total weight of the tablet center content. The preferred amount of slider is approximately 0.3%. The binders can be acacia, alginic acid, carboxymethylcellulose (sodium), cellulose (microcrystalline), dextrin, ethylcellulose, gelatin, glucose (liquid), guar gum, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, polyethylene oxide, povidone, starch (pregelatinized) ) or syrup. Interesting binders are hydroxypropyl methylcelluloses, especially low viscosity hydroxypropyl methylcelluloses. The preferred binder is hydroxypropyl methylcellulose 2910, of which a 2% aqueous solution at 20 ° C has a viscosity of 15 mPa.s.

Other excipients such as coloring agents and pigments can also be added to the tablets of the present invention. The coloring agents and pigments include titanium dioxide and / or dyes approved for use in food and pharmaceuticals. A coloring agent is an optional ingredient in the tablet of the present invention, but when used, the coloring agent will be present in an amount up to 3.5% (w / w) based on the weight of the total tablet, or the center of the tablet in the case of film coated tablets. Preferably, the coloring agent is present in the tablet coating, where again the coloring agent may be present in an amount ranging from 0.01% (w / w) to approximately 10% (w / w) based on the weight total coating; An interesting variation starts from about 0.20% (w / w) to about 7.5% (w / w) based on the total weight of the coating. As is known in the art, tablet combinations can be either dry granulated or wet granulated before being tableted. Unexpectedly, it was found that when using cisapride- (L) -tartrate it was possible to prepare tablets using direct compression techniques. When cisapride monohydrate would be used as an active ingredient, the formulation requires a surfactant to obtain the necessary wettability of the cisapride monohydrate. However, to add a surfactant to a tablet formulation, a wet granulation step is required. Accordingly, as another embodiment of the present invention, it should be mentioned that the tablets of the present invention can be prepared by direct compression, that is, the usual wet granulation step can be omitted. This causes a considerable cost reduction in the production of these tablets. It was further found that tablets prepared by direct compression gave a better dissolution profile than analogous tablets prepared by a wet granulation step. The tablets of the present invention can be film coated to provide ease in swallowing, flavored cover, and elegant appearance. Many polymeric film coating materials are known in the art. The known film coating agents are sodium carboxymethylcellulose, cellulose acetate, cellulose acetate phthalate, ethylcellulose, gelatin, pharmaceutical glaze, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, methacrylic acid copolymer, methylcellulose, polyethylene glycol, polyvinyl acetate phthalate, gum, sucrose, titanium dioxide, wax, zein. A preferred film coating material is hydroxypropyl methylcellulose (HPMC). HPMC can be obtained commercially. Coating agents are usually present in an amount ranging from about 50% (w / w) to about 95% (w / w) based on the total weight of the film coating. The interesting variation is from about 50% (w / w) to about 65% (w / w). Anti-adhesives are usually used in the film coating process to avoid sticking effects during film formation and drying. The preferred anti-adhesive for this purpose is talcum powder. The anti-adhesive, and especially talc, is present in the film coating in an amount of about 5% (w / w) to 15% (w / w) based on the total weight of the coating. Other ingredients of the coating film can be plasticizers, such as castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, propylene glycol, triacetin, triethyl citrate. In addition, mixtures of plasticizers can be used. The type of plasticizer depends on the type of coating agent. The preferred plasticizer according to the present invention is propylene glycol. Said plasticizer it is usually present in an amount ranging from 5% (w / w) to 30% (w / w) based on the total weight of the film coating. An interesting variation of plasticizer is from about 12% (w / w) to about 16% (w / w) based on the total weight of the film coating. The preferred amount of propylene glycol according to the present invention is about 14% (w / w). An opacifier such as titanium dioxide may also be present in an amount ranging from about 10% (w / w) to about 20% (w / w) based on the total weight of the coating. When colored tablets are desired, then the color is normally applied in the coating. Accordingly, they may be present in the film coating, coloring agents and pigments. Preferred coloring agents are ferric oxides, which may be either red, yellow, black, or combinations thereof. Said film coating process can be carried out using spray coating equipment well known in the art. Typically the coating can be carried out in a perforated pan, such as those manufactured under the trade name of Glatt® (for example Glatt Coater 750) AccelaCota and HiCoater. The process of conversion to tablets is another standard form, and can be easily practiced by forming a tablet from a desired combination or mixture of ingredients, in the appropriate manner using a conventional tablet press. Pressures ranging from about 0.5 ton / cm2 (corresponding to about 50 MPa) to about 2.0 ton / cm2 (corresponding to about 200 MPa) are used. Below the lower limit, the tablets formed will not show an appropriate hardness, and above the upper limit, the tablets may be so hard that they do not dissolve further. The preferred variation is from about 1.1 ton / cm2 (corresponding to about 110 MPa) to about 1.7 ton / cm2 (corresponding to about 170 MPa).

CAPSULES The capsules according to the present invention comprise, apart from the active ingredient, fillers, glidants, lubricants and disintegrants. The same fillers, glidants, and lubricants as described above for the tablets can be used in the capsules. The preferred charge is lactose. Preferred glidants are colloidal silicon dioxide and talc. Talc also provides the anti-adhesion properties needed to handle the powders. The preferred lubricant is magnesium stearate. Corn starch can be used as a disintegrant, which is a necessary ingredient for the contents of the capsule in case the capsule loading equipment uses tamping. In capsule loading equipment that uses tamping, the capsule contents are packed together in several consecutive strokes, and at the last stroke the content of the packed capsule is supplied to the capsule. The fillers are present in an amount ranging from about 60% (w / w) to about 90% (w / w) based on the total weight of the contents of the capsule. Preferably, the fillers are present in an amount ranging from about 70% (w / w) to about 80% (w / w) based on the total weight of the contents of the capsule. Preferably, the fillers are present in an amount of about 75% (w / w). The glidants are present in an amount of about 4% (w / w) to 7% (w / w) based on the total weight of the contents of the capsule. Preferably, the glidants are present in an amount of about 6% (w / w) based on the total weight of the contents of the capsule. The lubricant or lubricants are present in an amount ranging from about 0.5% (w / w) to about 2.0% (w / w). Preferably, the lubricant or lubricants are present in an amount of about 1.25% (w / w) based on the total weight of the contents of the capsule. The capsules are usually prepared from gelatin, they can be soft or hard gelatin capsules. The capsules are prepared in a conventional manner. The filler, for example lactose, is ground together with the active ingredient and sieved. The resulting mixture is added to a mixture of the rest of the excipients and mixed in a planetary mixer until a homogeneous mixture is obtained. This powder is introduced into the capsule using capsule filling equipment known in the art (automatic).

USE An advantage of the present solid oral dosage form is that, even though the solid oral dosage form according to the present invention has not yet been completely dissolved in the acidic environment of the stomach, and passes into the intestine, where the medium environment is approximately neutral, that is, much less acidic, then even cisapride tartrate is able to dissolve rapidly, which is not the case with cisapride monohydrate. The pharmaceutical dosage form, subject of the present invention, is to be used as a medicine for the treatment of gastrointestinal disorders, such as gast aphoeresis, either idiopathic or associated with diabetic neuropathy, anorexia nervosa, after vagotomy or partial gastrectomy ( symptoms mainly consist of early satiety, anorexia, nausea and vomiting); X-ray symptoms or negative endoscopic superior digestive discomfort, characterized by early satiety, postprandial swelling, inability to finish a normal-sized meal, swelling, excessive belching, anorexia, nausea, vomiting, or ulcer-like complaints (epigastric heartburn or pain ), gastro-esophageal reflux disorders, including the curative and maintenance treatment of esophagitis; in babies: chronic and excessive regurgitation or vomiting, when positional and dietary measures have failed; intestinal pseudo-obstruction, associated with motility dysfunctions resulting in insufficient propulsive peristalsis, and in stasis of intestinal and gastric contents; Restoration of colonic propulsive motility as a long-term treatment of chronic constipation. Accordingly, the present invention further provides a method of treating gastrointestinal disorders, especially gastro-esophageal reflux disease. Due to the properties of the present tablets, the use of cisapride- (L) -tartrate, cisapride- (D) -tartrate, cisapride sulfate, cisapride citrate, for the manufacture of an oral dosage form without food drug interaction is discovered. , for the treatment of gastrointestinal disorders. It is also stated in particular, the use of cisapride- (L) -tartrate, cisapride- (D) -tartrate, cisapride sulfate, cisapride citrate, for the manufacture of a drug for the treatment of gastrointestinal disorders in patients taking medication that increases the pH of the stomach in general, or for the manufacture of a medically for the treatment of gastrointestinal patients who are taking proton pump inhibitors, H2 inhibitors, or antacids. The solid oral cisapride dosage forms disclosed and described above, can be administered to a mammal, including man, in need of such treatment, when the mammal has eaten, without taking into consideration how long before or the nature and amount of food, without exhibiting an adverse food effect. For this purpose, and as a further feature of this invention, the invention provides a therapeutic package suitable for commercial sale, comprising a container, an oral dosage form of cisapride, which does not exhibit an adverse food effect, contained in the not limited, and associated with said package, written (ie, printed) material not limited as to whether the dosage form can be taken with or without food. The written material is of the type that contains information and / or instructions for the doctor, pharmacist or patient. The written material may be "not limited as to whether the dosage form can be taken with or without food" by virtue of not including any statement as to whether the dosage form can be taken with or without food, is say, the statement does not say anything about the effects of food. Alternatively, the written material may be non-limited containing one or more statements affirmatively informing the user (i.e., the patient, pharmacist, or physician) that said oral dosage form may be taken or administered to a patient without regard to whether the patient has eaten, or otherwise drunk food (optionally, for example, also stating something like "without regard to type or amount of food"). The written material may not contain limiting language regarding food, for example., "This dosage form can not be taken with food", or "This dosage form can only be administered after the patient has fasted", or Similar. The container can be in any conventional form or form as is known in the art, which is made of a pharmaceutically acceptable material, for example a paper or cardboard box, a plastic or glass bottle or jug, a re-sealable bag , or a blister pack with individual dosages to be removed from the container by pressure according to a therapeutic scheme. The container used may depend on the exact dosage form involved. In view of the fact that the present cisapride dosage form can be taken or administered to a patient independently of a meal, the dosage form can be administered "pro re nata". This means that the administration of the dosage form can be driven by the symptom. In other words, the patient can take the present dosage form when the patient feels one of the symptoms that are associated with the gastrointestinal disorder of the one suffering. This greatly improves patient compliance, because instead of having to think about taking their medication with food, the patient can take the medication when the symptom appears.

EXPERIMENTAL PART EXAMPLE 1 TABLET A The following ingredients were intimately mixed in a planetary mixer: cisapride- (L) -tartrate (13.23 mg, 7.35% (w / w)), spray-dried mixture of lactose monohydrate (75%) and microcrystalline cellulose (25%) ( MICROCELAC) (157.23 mg, 87.35% (w / w)), rmel rmel lose sodium (7.2 mg, (4.00% (w / w)), colloidal anhydrous silica (0.54 mg, 0.3% (w / w)) »magnesium stearate (1.8 mg, 1.00% (w / w)), and were compressed a machine for converting tablets (type Korsch or Courtoy RO 2EHS, with a compression ratio of 36,000 tabl / h), preparing 180 mg tablets The tablet prepared according to the previous example comprises: cisapride- (L) -tartrate 13.23 mg 7.35% (w / w) MICROCELAC 157.23 mg 87.35% (w / w) rmel rmel lose sodium 7.2 mg 4.00% (w / w) anhydrous colloidal silica 0.54 mg 0.3% (p / p) p) magnesium stearate 1.8 mg 1.00% (w / w) EXAMPLE 2 TABLET B The following ingredients were intimately mixed in a planetary mixer: cisapride- (L) -tartrate (13.23 mg, 7.35% (w / w)), lactose DC (116.57 mg, 64.76% (w / w)), microcrystalline cellulose (Avicel®) ) (38.86 mg, 21.56% (w / w)), crsoscamellose sodium (7.2 mg, (4.00% (w / w)), colloidal anhydrous silica (0.54 mg, 0.3% (w / w)), sodium styryl fumarate (3.6 mg, 2.00% (w / w)), and were compressed in a tablet conversion machine (type Korxch or Courtoy RO 2EHS, with a compression ratio of 36,000 tabl / h), preparing tablets of 180 mg. (L) -tartrate 13.23 mg 7.35% (w / w) lactose DC 116.57 mg 64.76% (w / w) microcrystalline cellulose 38.86 mg 21.59% (w / w) rmel rmel lose sodium 7.2 mg 4.00% (w / w) colloidal anhydrous silica 0.54 mg 0.3% (w / w) sodium stearyl fumarate 3.6 mg 2.00% (w / w) EXAMPLE 2 TABLET B In a manner analogous to that described in examples 1 and 2, tablets were prepared with the following composition: cisapride- (L) -tartrate 6.61 mg 3.68% (w / w) lactose 123.18 mg 68.44% (w / w) microcrystalline cellulose 38.86 mg 21.59% (w / w) rmel rmel lose sodium 7.2 mg 4.00% (w / w) colloidal anhydrous silica 0.54 mg 0.3% (w / w) magnesium stearate 1.8 mg 1.00% (w / w) EXAMPLE 4 TABLET D In a manner analogous to that described in Examples 1 and 2, tablets with the following composition were prepared: cisapride- (L) -tartrate 26.44 mg 14.72% (w / w) lactose 103.34 mg 58.39% (w / w) microcrystalline cellulose 38.86 mg 21.59% (w / w) croscarmellose sodium 7.2 mg 4.00% (w / w) anhydrous silica colloidal 0.54 mg 0.30% (w / w) magnesium stearate 1.8 mg 1.00% (w / w) EXAMPLE 5 TABLET E In a manner analogous to that described in Examples 1 and 2, tablets with the following composition were prepared: cisapride- (L) -tartrate 13.23 mg 7.35% (w / w) famotidine 10.00 mg 5.56% (w / w) MICROCELACR 147.23 mg 87.35% (w / w) croscarmellose sodium 7.2 mg 4.00% (w / w) colloidal anhydrous silica 0.54 mg 0.30% (w / w) magnesium stearate 1.8 mg 1.00% (w / w) In the combination formulations Simethicone or alpha-D-galactosidase can be added to each of the above formulations to provide antiflatulent relief. The amount of simethicone administered to a patient in need of treatment thereof may vary according to the need of the patient, but may be, for example, the typical dosage scale known to treat flatulence (20-40 mg per tablet), or It can be increased as necessary. In general, the amount of ADG that can be employed in the above formulations ranges from about 675 to about 2250 GalU, or can be increased as necessary.

EXAMPLE 6 PREPARATION OF TABLETS COATED WITH FILM USING THE WET GRANULATION STEP FOR THE CENTERS OF THE TABLETS TABLET F 6a) Preparation of the binder solution. 5,280 kg of purified water were transferred to a metal covered vessel by steam heating, and were heated to a temperature of approximately 80 ° C. The water was transferred to a 25 1 stainless steel container, and 792 g HPMC 2910 15 mPa.s were dissolved while mixing for 5 minutes with a propeller mixer (150-500 rpm). Again, 12.32 kg of water were added while mixing for 2 minutes. Subsequently, the solution was desalinated by mixing at a speed of 60-150 rpm for 10 minutes. The binder solution thus prepared is allowed to stand still for a minimum of 8 hours. 6b) Granulation. 23,700 kg of lactose monohydrate 200 mesh, 2,911 kg of cisapride- (L) -tartrate, and 7,920 kg of unmodified corn starch were successively transferred to the product container of the fluidized bed granulator type GPCG 30. The fluid bed process was started, and the ingredients were mixed until the temperature of the air outlet reaches approximately 28 ° C (process parameters: general air pressure: 5 bar, air flow rate: from approximately 300 to 600 m3 / h, time shaking: 7 seconds, shaking time interval 35 seconds, inlet air temperature: from about 45 ° C to about 55 ° C, outlet air temperature: from about 27 ° C to about 29 ° C). The binder solution prepared as described in 6a) was sprayed onto the powder mixture (process parameters: air flow rate: from about 400 to about 1000 m3 / h, shaking time: about 7 seconds, time interval of shaken: approximately 35 seconds, nozzle diameter: 1.8 mm, nozzle position: upper, spray pressure 3 bar, spray ratio: from approximately 200 to 300 g / min, inlet air temperature: from approximately 45 ° C at about 60 ° C, outlet air temperature: from about 21 ° C to about 24 ° C). After spraying, homogeneously moist granules were obtained. The drying process started immediately after the spraying process. The drying process was continued until the temperature of the air outlet reached approximately 38 ° C, (process parameters: air flow rate: from approximately 400 to 1000 m3 / h, shaking time: 7 seconds, interval of shaking time 35 seconds, inlet air temperature: from about 70 ° C to about 75 ° C, outlet air temperature: from about 37 ° C to about 39 ° C). 6c) Preparation of the compression mixture. The dried granules prepared as described in 6b) were passed through an oscillating sieving apparatus of the Frewitt type (mesh openings: 1 mm, wire thickness: 0.65 mm) together with 2,772 kg of microcrystalline cellulose, 1,188 kg of croscarmellose sodium, 118 g anhydrous colloidal silica, and 198 g of magnesium stearate. The sieved powder was collected in the planetary mixer container of the Collette MP 90 type (mixing speed: mixing arm: 45 rpm and stabilization: 20 fm) and mixed for 5 minutes until a homogeneous mixture was obtained. 6d) Compression. The compression mixture prepared as described in 6c) was pressed into tablets using a Killian rotary tablet press. In this way, circular, white, and biconvex tablets with a nominal weight of 180 mg were prepared. These tablets were previously referred to as the center of the tablet. 6e) Preparation of the coated suspension. 6,307 kg of purified water were heated in a vessel with a steam-heated metal cover, at a temperature ranging from about 70 ° C to about 75 ° C. The water was transferred to a 25 1 stainless steel vessel, and 880 g of HPMC 2910 mPa.S and 220 g of propylene glycol were added while mixing in a propeller mixer (mixing speed: from about 400 to about 600 rpm) This mixture is referred to as mixture A. 3.153 kg of purified water , 176 g of talc, 264 g of titanium dioxide, and 33 g of yellow ferric oxide were transferred to a stainless steel container of 10 1, and were homogenized for 10 to 15 minutes using a Silverson 2LR homogenizer. referred to as mixture B. Mix B was added to mixture A while it was mixed with a propeller mixer (mixing speed: from about 200 to about 400 rpm). for 120 minutes to further discourage the coating suspension. 6f) Coated with the tablets. 11,033 kg of the coating suspension prepared as described in 6e) were transferred to a 25 1 stainless steel container. The tablets prepared as described in 6a) to 6d) were transferred to the GC 750 coating apparatus, and warmed the tablets. (Process parameters: inlet air temperature: from about 80 ° C to about 90 ° C, exit air temperature after warming: from about 47 ° C to about 49 ° C. The coated suspension was sprayed on the Tablets using the following parameters: rotating pan speed: 8 to 10 rpm, inlet air temperature: from about 80 ° C to 90 ° C, outlet air temperature: from about 46 ° C to about 49 ° C, Inlet air volume: from about 750 3 to about 850 m3, process chamber pressure <100 mPa, spray air pressure: from 2.5 to 3.5 bar-, the temperature of the coating suspension is room temperature, proportion Spray: from 90 to 100 g / min After the spraying process was finished, the tablets were kept rotating and allowed to cool until the air outlet temperature reached 30 ° C.

The resulting film-coated tablets were circular (diameter = 8 mm), concave and coated with a yellow film. The tablets were placed in polyethylene bottles and three-star Perlen ampoules. In accordance with the preparation described above, the following tablet was prepared: Tablet Tablet Center F Ingredient Quantity% (w / w) tablet center cisapride- (L) -tartrate 13.23 mg 7.35% (w / w) lactose monohydrate 200 107.73 mg 59.85% (w / w) mesh (* l) unmodified corn starch 36.00 mg 20.00% (w / w) HPMC 2910 15 mPa. s (* 2) 3.60 mg 2.00% (w / w) cellulose mic roc crystalline 12.60 mg 7.00% (w / w) thread rmellose sodium 5.40 mg 3.00% (w / w) anhydrous silica colloid 0.54 mg 0.30% (p / p) magnesium stearate 0.90 mg 0.50% (w / w) total weight of tablet cent: 180.00 mg Tablet film coating F: Ingredient Quantity% (P / P) / coating HPMC 2910 5mPa.s 4.00 mg 55.95% (w / w) Propylene glycol 1.00 mg 13.99% (w / w) Titanium dioxide (E171) 1.20 mg 16.78% (w / w) Talc 0.80 mg 11.19% (w / w) Ferric Oxide Yellow 0.15 mg 2.10% (w / w) (E172 / C177492) Total coating weight 7.15 mg (* 1) 200 mesh is an indication of the type of lactose monohydrate that is used. (* 2) HPMC means hydroxypropyl methylcellulose, the number "2910" refers to the type of hydroxypropyl methylcellulose that is used. The first two digits, "29", represent the approximate percentage of methoxyl groups, and the third and fourth digits, "10" represent the approximate percentage of hydroxypropyl groups. In addition, the viscosity (15 mPa.s) of a 2% aqueous solution measured at 20 ° C is indicated. This is an indication of the molecular weight of HPMC that is used.

EXAMPLE 7 TABLET G According to the method described in Example 6, the following tablet was prepared: cisapride- (L) -tartrate 26.46 mg 12.03% lactose monohydrate 200 mesh 111.48 mg 50.67% unmodified corn starch 44.00 mg 20.00% croscarmellose sodium (*) 4.95 mg 2.25% HPMC 2910 15 mPa.s 2.75 mg 1.25% microcrystalline cellulose 11.00 mg 5.00% croscarmellose sodium (*) 17.60 mg 8.00% colloidal anhydrous silica 0.66 mg 0.30% magnesium stearate 1.10 mg 0.50% total tablet weight: 220.0 mg (*) The fact that croscarmellose sodium is mentioned twice indicates that croscarmellose sodium is included in the granulation mixture and in the compression mixture. As a result, there is croscarmellose sodium present in the so-called internal phase (the granulate) and in the so-called external phase (the compression mixture). With croscarmellose sodium present in the "internal" and "external" phase, the dissolution profile of the tablet thus prepared is better than with the tablet where croscarmellose sodium is present only in the "external" phase. The tablet was coated as described in Example 6.

EXAMPLE 8 TABLET H According to the method described in Example 6, the following tablet was prepared: cisapride- (L) -ta rt time 26.46 mg 12.03% lactose monohydrate 200 mesh 19.18 mg 54.17% unmodified corn starch 44.00 mg 20.00% croscarmellose sodium (*) 4.40 mg 2.00% HPMC 2910 15 mPa.s 2.20 mg 1.00% cellulose microcrystalline 4.40 mg 2.00% croscarmellose sodium (*) 17.60 mg 8.00% anhydrous colloidal silica 0.66 mg 0.30% magnesium stearate 1.10 mg 0.50% total tablet weight: 220.0 mg (*) see croscarmellose observation in external and internal phase as described in example 7. The tablet was coated as described in example 6.

EXAMPLE 9 TABLET L: TABLET COMPRISING EQUIVALENT OF 5 MG CISAPRIDA BASE.

According to the method in example 6, the following tablet was prepared: cisap rida- (L) -tartrate 6.62 mg 6.62% lactose monohydrate 200 mesh 60.59 mg 60.59% unmodified corn starch 20.00 mg 20.00% HPMC 2910 15 mPa.s 2.00 mg 2.00% microcrystalline cellulose 7.00 mg 7.00% croscarmellose sodium 3.00 mg 3.00 % colloidal anhydrous silica 0.30 mg 0.30% magnesium stearate 0.50 mg 0.50% tablet total weight: 100.0 mg HPMC 2910 5 mPa.s 3.0 mg 57.03% Propylene glycol 0.75 mg 14.26% Titanium dioxide 0.90 mg 17.11% Talc 0.60 mg 11.41% Ferric Oxide Yellow 0.01 mg 0.23% Total coating weight: 5.26 mg EXAMPLE 10 TABLET J: TABLET COMPRISING EQUIVALENT OF 10 MG BASIS CISAPRIDA According to the method described in Example 6, the following tablet was prepared: cisapride- (L) -tartrate 13.23 mg 7.35% lactose monohydrate 200 mesh 107.73 mg 59.85% unmodified corn starch 36.00 mg 20.00% HPMC 2910 15 mPa.s 3.60 mg 2.00% microcrystalline cellulose 12.60 mg 7.00% croscarmellose sodium 5.40 mg 3.00% colloidal anhydrous silica 0.54 mg 0.30% magnesium stearate 0.90 mg 0.50% total tablet weight: 180.0 mg HPMC 2910 5 mPa.s 4.00 mg 55.94% Propylene glycol 1.00 mg 13.99% Titanium dioxide 1.20 mg 16.78% Talc 0.80 mg 11.19% Yellow Ferric Oxide 0.15 mg 2.10% Total coating weight: 7.15 mg EXAMPLE 11 TABLET K: TABLET COMPRISING EQUIVALENT OF 20 MG BASIS CISAPRIDA According to the method described in example 6, the following tablet was prepared: cisap rida- (L) -tartrate 26.46 mg 12.03% lactose monohydrate 200 mesh 121.38 mg 55.17% unmodified corn starch 44.00 mg 20.00% HPMC 2910 15 mPa.s 4.40 mg 2.00% microcrystalline cellulose 15.40 mg 7.00% croscarmellose sodium 6.60 mg 3.00% colloidal anhydrous silica 0.66 mg 0.30% magnesium stearate 1.10 mg total tablet weight: 220.00 mg HPMC 2910 5 mPa.s 6.00 mg 52.86% Propylene glycol 1.50 mg 13.21% Titanium dioxide 1.80 mg 15.86% Talcum 1.20 mg 10.57% Yellow Ferric Oxide 0.85 mg 7.49% Total coating weight: 11.35 mg EXAMPLE 12 CAPSULE A.

Ingredient Quantity% (w / w) based on total weight of content cisapride- (L) -tartrate 6.62 mg 4.14% lactose 125 mesh 61.00 mg 38.13% lactose 200 mesh 60.98 mg 38.11% corn starch 20.00 mg 12.50% talc 9.00 mg 5.60% magnesium stearate 2.00 mg 1.25% anhydrous silica colloid 0.40 mg 0.25% (Ae rosilR) total weight of the contents 160.00 mg of the capsule: The powder is placed in a type of capsule number 4.

EXAMPLE 13 CAPSULA B.

Ingredient Quantity% (w / w) based on total weight of content cisapride- (L) -tartrate 13.23 mg 6.01% lactose 125 mesh 82.00 mg 37.27% lactose 200 mesh 81.57 mg 37.08% corn starch 27.50 mg 12.50% talc 12.40 mg 5.64% magnesium stearate 2.75 mg 1.25% colloidal anhydrous silica 0.55 mg 0.25 % (AerosilR) total weight of the contents 220.00 mg of the capsule: Elk powder is placed in a type of capsule number 2. The capsules as described above are prepared by mixing the ingredients in a planetary mixer and filling with the powder the appropriate capsules.

EXAMPLE 14 EXPERIMENTS OF DISSOLUTION.

The dissolution of the tablets comprising cisida rida- (L) -tartrate, which are prepared and have the same composition as described in example 1, was compared with tablets comprising cisapride monohydrate in place of cisapride- (L) -tartrate (the rest of the composition and the preparation are the same) at different pH values.

Experimental method: The evaluation tablet was taken to a glass container containing 900 ml of the specified buffer at a temperature of 37 ° C. The stirring is carried out by means of a paddle at a rotating speed of 50 rpm (rotations per minute). This test is exposed in USP test < 711 > in a USP-2 dissolution apparatus. This last test is described in "US Pharmacopeia XXII", pages 1578-1579. a) pH = ± 1.5 (HCl: 0.1 N) Conclusion: the dissolution of cisapride tartrate and cisapride monohydrate is comparable in 0.1 N HCl (pH = ± 1.5). ) pH = 4.5 (USP-buffer) c) pH = 6.5 (USP-buffer) Conclusion: the dissolution of cisapride tartrate is clearly superior to that of cisapride monohydrate at pH = 6.5.

EXAMPLE 15 PHARMACOKINETIC EXAMPLE In a phase I crossover trial of four forms, a total of 12 subjects, 8 male and 4 female, were randomly chosen to receive single doses of 10 mg of cisapride as the tartrate salt and as the monohydrate, with and without a standard breakfast. All subjects were given the following 4 treatments: Treatment A: a single intake of a tablet of cisapride- (L) -tartrate, 2 hours before a normal breakfast, ie, fasting conditions. Treatment B: a single intake of a tablet of cisapride- (L) -tartrate immediately after a normal breakfast. Treatment C: a single tablet intake of cisapride monohydrate (regular Prepulsid tablet), 2 hours before a normal breakfast, ie, fasting conditions. Treatment D: a single tablet intake of cisapride monohydrate (regular Prepulsid tablet), after normal breakfast. A normal breakfast consists of four slices of bread, a slice of ham, a slice of cheese, butter, jelly and two cups of coffee or tea, if desired with milk and / or sugar, which was served. During treatments B and D, the subjects first took their breakfast, and took their trial medication immediately after finishing it. Then, the subjects could resume their usual diet. The test medication was taken with 100 ml of water. Blood samples were taken up to 48 hours after the dose. Plasma concentrations of cisapride were determined by means of a validated HPLC method (limit of quantification = 2 ng / ml).

PHARMACOKINETIC ANALYSIS Based on the individual plasma concentration-time information, using the actual sample times, the following pharmacokinetic parameters of cisapride were determined after each of the four treatments. Cmax peak plasma concentration, determined by visual inspection of the information. Tmax time to achieve the peak plasma concentration, determined by visual inspection of the information. AUC last area under the plasma concentration curve - time, from time 0 to the last point of time (last quantifiable concentration, calculated by linear trapezoidal summation).

AUC8 area under the concentration of plasma-time extrapolated to infinity. t ^ term terminal period, defined as 0.693 / Sz. The relative bioavailability of cisapride was calculated as the ratios of Cmax and AUC in the various treatments. RESULTS No serious adverse effects were reported, and no treatment was discontinued due to adverse effects. The pharmacokinetic results are summarized in the following table: TABLE DISCUSSION The mean tmax of cisapride with the ingestion of the trial medication after a one-night fast was reached after 1410.4 h (A: cisapride tartrate-fasting), and 1.7 + 0.5 h (cisapride monohydrate-fasting). The influence of one meal delayed tmax to 2,110.7 h (B: cisapride tartrate-after breakfast) and 2,310.6 h (D: cisapride monohydrate-after breakfast). Mean peak plasma concentrations of cisapride averaged 61.7116.7 ng / ml (fasting) and 65.6117.7 ng / ml (after breakfast) for tartrate salt, and 50.6118.4 ng / ml (fasting) and 65.4116.9 ng / ml (after breakfast) for the regular cisapride monohydrate marketed. The geometric mean Cmax ratios were 107%, (B against A), 80% (C against A), 133% (D against C), and 100% (B against D), with associated classical intervals of 90% confidence, 98% - 116%, 74 - 87%, 122 - 145%, and 92 - 109%. The relationships of AUC 8 geometric means were 114%, (B against A), 88% (C against A), 129% (D against C), and 101% (B against D), with associated classical intervals of 90% of confidence, from 106 - 123%, 81 - 94%, 120 - 139%, and 92 - 107%. With respect to the total exposure (AUC 8) the bioequivalence for the tartrate salt is demonstrated, comparing the administration after a normal breakfast and while fasting (B against A). When fasting, the relative bioavailability of the regular commercialized tablet (C) against the newly developed tartrate salt (A) is also within the established criteria for bioequivalence. Cisapride monohydrate when administered after breakfast (D) resulted in 29% higher exposure and 33% higher peak levels of cisapride compared to fasting conditions (D against C). Both formulations of cisapride are bioequivalent when taken after a meal (D against B). From the results of this trial, comparing the bioavailability of the newly developed cisapride tartrate with the regular monohydrate marketed, after a single intake, and the effects of food on them, we can conclude the following: Feeding or fasting conditions have little influence on absorption, peak levels, and total exposure of newly developed cisapride tartrate. The regular cisapride monohydrate marketed is subject to 30% increased bioavailability under feeding conditions. When taken with a normal meal, cisapride tartrate and monohydrate are bioequivalent.

Claims (28)

NOVELTY OF THE INVENTION CLAIMS

1. - A solid dosage form comprising a pharmaceutically acceptable carrier, and as an active ingredient, a cisapride salt form selected from cisapride (L) -tartrate, cisapride (D) -tartrate, cisapride sulfate, cisapride citrate , characterized in that more than 60% of the active ingredient is dissolved within 1 hour on a pH scale of 1 to 7.5, when evaluated as set forth in the < 711 > of the USP in a USP-2 dissolution apparatus, as described in US Pharmacopeia XXII, pages 1578-1579. 2. A solid dosage form according to claim 1, characterized in that more than 70% of the active ingredient is dissolved after 60 minutes at a pH of

6. 5 (shock absorber USP), when evaluated as set forth in claim 1.

3. A solid dosage form according to claim 1 or 2, wherein the salt form is (L) -tartrate of cisapride.

4. A solid dosage form according to claim 3, wherein the diameter of the active ingredient in powder varies from 10 μm to 150 μm, measured by means of laser beam diffraction.

5. - A solid dosage form according to claim 4, wherein the active ingredient in powder has a specific surface area of more than 14 x 103 cm2 / g (1.4 x 103 m2 / kg).

6. A solid dosage form according to any of the preceding claims, wherein the solid dosage form is an oral solid dosage form.

7. A solid dosage form according to claim 6, wherein the oral dosage form is a capsule.

8. A solid dosage form according to claim 6, in the form of a tablet.

9. A solid dosage form according to claim 6, further comprising an antacid, an H2 antagonist or a proton pump inhibitor.

10. A solid dosage form according to claim 6, which exhibits a value of (AUC with food) / (AUC in fasting) of less than 1.25. 11.- A tablet in accordance with the claim 8, comprising lactose monohydrate and microcrystalline cellulose with fillers. 12.- A tablet in accordance with the claim 11, wherein the amount of filler varies from 66% (w / w) to 86% (w / w), based on the total weight of the tablet or tablet core. 13. A tablet according to claim 12, wherein the amount of filler varies from 66% (w / w) to 86% (w / w), based on the total weight of the tablet or tablet core. 14.- A tablet in accordance with the claim 13, wherein the disintegrant is cross-linked sodium carboxymethylcellulose (Croscarmellose sodium). 15. A tablet according to claims 8 to 14, wherein the tablet is a film-coated tablet. 16. A tablet according to claim 15, wherein the tablet has a tablet core with the following composition: (L) -Tarate of cisapride 13.23 mg 7.35% Lactose monohydrate 200 mesh 107.73 mg 59.85% Unmodified corn starch 36.00 mg 20.00% HPMC 2910 15 mPa.s 3.60 g 2.00% microcrystalline cellulose 12.60 mg 7.00% croscarmellose sodium 5.40 mg 3.00% colloidal anhydrous silica 0.54 mg 0.30% magnesium stearate 0.90 mg 0.50% and one coated has the following composition: HPMC 2910 5 mPa.s 4.00 mg 55.94% Propylene glycol 1.00 mg 13.99% Titanium dioxide 1.20 mg 16.78% Talc 0.80 mg 11.19% Ferric Oxide Yellow 0.15 mg 2.10% where the percentages of the ingredients of the tablet core are% (w / w) based on the total weight of the tablet core, and the percentages of the tablet coating they are% (w / w) based on the total weight of the tablet coating. 17. A tablet according to claims 8 to 16, wherein the tablet has a hardness of at least 1.5 daN, measured in accordance with the test described in the European Pharmacopeia (1997) on page 135. 18.- A process for the preparation of an oral solid dosage form according to any of the preceding claims, wherein the active ingredient is intimately mixed with the vehicle, and inserted into capsules, or else formulated additionally in tablets. 19. A process according to claim 18, characterized in that the active ingredient and the excipients are mixed, compressed into tablets and optionally coated with film. 20. A product containing a solid dosage form according to any of claims 1 to 17, and an antacid, an H2 antagonist or a proton pump inhibitor, as a combined preparation for simultaneous, separate use. or sequential in the treatment of gastrointestinal disorders, especially conditions related to gastroesophageal reflux. 21. A pharmaceutical package suitable for commercial sale, comprising a container, an oral dosage form of cisapride that does not exhibit an adverse effect with the food and, associated with said package, a written material not limited on whether the form of Dosage can be taken with or without food. 22. The use of (L) -tartrate of cisapride, (D) -tartrate of cisapride, cisapride sulfate, citrate of cisapride, for the manufacture of an oral dosage form without drug-food interaction, for the treatment of disorders gastrointestinal 23. Use according to claim 22, characterized in that the oral dosage form can be administered independently of the meals. 24. The use according to claim 22, characterized in that the oral dosage form can be administered during meals. 25. The use according to claim 22, characterized in that the oral dosage form can be administered together with a proton pump inhibitor, an H antagonist or an antacid. 26. The use according to claim 22, characterized in that the oral dosage form can be administered pro re nata. 27.- The use of (L) -tartrate of cisapride, (D) -tartrate of cisapride, sulfate of cisapride, citrate of cisapride, for the manufacture of a medicine to treat gastrointestinal disorders in patients taking medication that increases the pH of the stomach. 28. The use according to claim 27, characterized in that the drug that increases the pH of the stomach is a proton pump inhibitor, an H2 inhibitor or an antacid.