HK1018399A - Immediate release ph-independent solid dosage form of cisapride - Google Patents

Description

Immediate release pH-independent solid dosage forms of cisapride

The present invention relates to solid dosage forms of a specific salt of cisapride, in particular cisapride- (L) -tartrate, cisapride- (D) -tartrate, cisapride sulfate or cisapride citrate, which can avoid interaction of drugs with food and can be co-administered with drugs that increase gastric pH. The invention particularly relates to solid oral dosage forms suitable for rapid disintegration and dissolution. The invention also relates to tablets which can be prepared by direct compression.

Introduction to the word

In general, the absorption and bioavailability of any particular therapeutic agent is known to be affected by a variety of factors when administered orally. Such factors include food present in the Gastrointestinal (GI) tract, as in general the time that a drug resides in the GI tract is generally longer in the presence of food than in the fasting state. A drug is said to exhibit a "food effect" or exhibit drug-food interactions if its bioavailability is affected beyond a certain point by the presence of food in the GI tract. The risks associated with the administration of drugs exhibiting a food effect are due to the fact that absorption into the bloodstream may be adversely affected by failure to take the drug at the correct point in time, and thus the patient is at risk of inadequate absorption of the drug to alleviate the condition for which it is suitable.

European patent No. 0076530 discloses the prokinetic (gastrokinetic) drug cisapride and compositions thereof. Cisapride has the following structural formula:the systematic chemical name of cisapride is cis-4-amino-5-chloro-N- [1- [3- (4-fluoro-phenoxy) propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide. Cisapride is a racemic mixture of two enantiomers. Cisapride has excellent gastrointestinal motility stimulating properties and is reported to lack anti-dopaminergic activity. Its use in various gastrointestinal diseases has been widely reported. It has been marketed as a drug for the treatment of gastro-esophageal reflex diseases, in particular esophagitis, negative digestive discomfort and intestinal pseudo-infarction. Cisapride monohydrate is currently commercially available under the following trademark registeredTablets, suspensions and granules: such as PREPULSID^TM、PROPULSID^TM、PROPULSIN^TM、ACENALIN^TM、ALIMIX^TM(this table is not fully included).

The form of cisapride monohydrate has a pH-dependent solubility and dissolution profile. Thus, the bioavailability of cisapride or cisapride monohydrate is pH-dependent. Cisapride monohydrate has low solubility and low solubility when present in a neutral or alkaline environment. Thus, the description of cisapride monohydrate mentions that the drug should be taken 15 to 30 minutes before meals. The principle is that a solid dosage form containing cisapride monohydrate reaches the more or less empty stomach, where the pH is lower and thus cisapride can dissolve. Subsequently, when the patient eats 15 to 30 minutes after taking the drug, the solid dosage form remains in the acidic environment of the stomach for a relatively long period of time. Once cisapride monohydrate enters the near neutral environment of the intestinal tract, the solubility of cisapride monohydrate decreases dramatically.

The results are that cisapride monohydrate shows a food effect, which can be expressed as the ratio of AUC in the fed state to AUC in the fasted state (AUC is the abbreviation for the area under the curve, which is an indicator of the amount of active ingredient present in the blood). The ratio of the AUC for cisapride monohydrate in the fed state to the AUC for the fasted state was about 1.35(p > 0.01). The ratio of the drugs showing no food effect was 1 (ideal state).

Therefore, patients taking cisapride monohydrate must adhere strictly to the above-described treatment regimen to create ideal conditions for high bioavailability of cisapride monohydrate, thereby obtaining maximum benefit from the drug being taken. The patient does not always have to follow taking the medication at the optimal time. Thus, a dosage form whose bioavailability is independent of food (or any other event) would mean a significant improvement over the prior art oral dosage forms of cisapride monohydrate and reduce the extent of variability in absorption between patients.

It would therefore be useful if cisapride could be taken immediately when the patient feels that the pain associated with gastroesophageal reflex is about to occur, without having to take the cisapride 15 to 30 minutes later. With the currently available dosage forms of cisapride, the patient must eat in order to obtain maximum absorption of cisapride monohydrate. From the fact that gastroesophageal reflexes often occur at night and that the esophagus causes pain, it is clear that the patient does not really have a tendency to eat anything. Therefore, it would be advantageous to have a form of cisapride that can be administered food-independently.

There are also problems associated with the pediatric use of cisapride monohydrate. Cisapride monohydrate can be prescribed to young children (one year old). The fact that cisapride monohydrate must be administered 30 minutes prior to a meal suggests that parents often must awaken the child, administer cisapride monohydrate to the child, and then wait half an hour before the child eats. The method is very impractical and it would therefore be very interesting to find a form of cisapride before or even after a meal or preferably not at all dependent on when to eat.

Another problem with oral dosage forms of cisapride monohydrate is as follows. As mentioned above, cisapride may be used to treat a person with gastric or esophageal problems. These patients often co-administer drugs that increase gastric pH. Examples of such combinations are antacids, e.g. aluminium containing antacids like aluminium hydroxide, calcium containing antacids like calcium carbonate or magnesium containing antacids like magnesium hydroxide; h2-antagonists like cimetidine, ranitidine, famotidine, nizatidine, roxatidine (roxatidine), etc.; or proton pump inhibitors like omeprazole, lansoprazole, rabeprazole. The currently preferred co-administration is formulated as a proton pump inhibitor.

Prior Art

WO 94/01112 and WO 94/01111 (published on 20.1.1994, assigned to Sepracor Inc) disclose a very general method of treating gastroesophageal reflex disease and other diseases with (-) -cisapride and (+) -cisapride, respectively, and therapeutically acceptable salts thereof. The use of the salts of the present disclosure and their properties are not specifically mentioned in said application. Nor is it mentioned the problem forming the basis of the present invention. WO 95/34284 (published on 21.12.1995, assigned to Gergely) mentions pharmaceutical formulations, effervescent systems and methods of preparing said formulations with hydrophobic active substances among other cisapride. This application merely mentions effervescent systems that are quite different from the invention of the present disclosure.

EP 670160 (published 6.9.1995, assigned to Gergely) discloses a granulated product or tablet (containing an effervescent system and an active pharmaceutical substance), and a process for its preparation. Cisapride effervescent tablets are described in example 5 of said document. Again, this application merely mentions effervescent systems that are quite different from the invention of the present disclosure.

WO 95/01803 (published 1995 at 19.1) discloses the combination of an H2 antagonist and a gastrointestinal motility agent. The patent publication specifically mentions the use of cisapride in the combination. The disadvantage of the combination of the prior art is that antacids, H2-antagonists and in particular proton pump inhibitors can cause a considerable increase in pH in the stomach. The pH of the stomach (normally between 1 and 1.5) can be raised to 4.5 using antacids, while the pH of the stomach is raised to about 6.5 using proton pump inhibitors. Under such circumstances cisapride monohydrate does not dissolve fast enough to provide rapid and adequate relief.

Our co-pending application PCT/EP95/04198 discloses matrix formulations in which cisapride- (L) -tartrate is embedded in a mixture of viscous polymers. The co-pending application also discloses cisapride- (L) -tartrate formulations. In said application, cisapride- (L) -tartrate has been disclosed as a mixture of diastereomers [ (3R4S) (2R3R) ] and [ (3S4R) (2R3R) ] crystallized as double salts in a ratio of 1: 1 (confirmed by X-ray diffraction). (3R4S) and (3S4R) refer to the enantiomers of cisapride, respectively, (2R3R) to the optically pure L-tartrate salt. It has also been shown that formulations containing cisapride- (L) -tartrate release cisapride in the form of the racemate, i.e. in the form of equal amounts of (+) -cisapride and (-) -cisapride, or in other words the (+) -cisapride- (L) -tartrate and (-) -cisapride- (L) -tartrate in the form of their diastereomeric salts, have unexpectedly the same dissolution rate. Furthermore, it was also found that during the preparation of cisapride- (L) -tartrate, the amount of either of the two diastereomeric salt forms was not high enough to be detected.

However, the matrix formulations of the prior art do not disintegrate and dissolve as rapidly as required for the solid oral dosage forms of the present invention. In contrast, the prior art matrix formulations are designed to slowly release cisapride over a longer period of time.

The invention

The above problems and/or disadvantages associated with prior art formulations are solved by a solid dosage form comprising cisapride in a salt selected from the group consisting of: sulfuric acid, (L) -tartaric acid, (D) -tartaric acid or citric acid, preferably cisapride- (L) -tartrate, suitable for rapid release. Preferably the formulation is adapted for rapid disintegration and dissolution. Preferred formulations are oral solid dosage forms.

The term "adapted for fast dissolution" refers to the fact that the active ingredient may be dissolved from the solid dosage form of the invention by more than 60% within 1 hour at a pH in the range of 1 to 7. The dissolution can be measured in a USP-2 dissolution apparatus according to the standard method described in the european pharmacopoeia or the method proposed by USP test <711 >. The latter test is described in the US pharmacopoeia X XII on page 1578-1579.

We have unexpectedly found that certain salts of cisapride dissolve better in artificial gastric fluid than others: these salts are (L) -tartrate, (D) -tartrate, sulfate and citrate. Furthermore, the described cisapride salts show a pH independent dissolution profile. It should be noted that cisapride hydrochloride and cisapride maleate dissolve more slowly than cisapride monohydrate itself.

The term "solid oral dosage form" generally refers to tablets (swallowable and chewable forms only) and capsules. Thus, the compositions of the present invention in the form of cisapride salts may be formulated as tablets, caplets, gelcaps, capsules.

The present invention includes formulations of cisapride salts according to the present invention and also includes materials that can affect gastric acidity. The substance may be any drug that raises the pH of the stomach (in other words, raises the alkalinity of the stomach). Examples of drugs that raise the gastric pH are mentioned antacids, H2-antagonists or proton pump inhibitors.

The invention also relates to a product containing any of the cisapride salts (preferably cisapride- (L) -tartrate) forms, antacids or H2-antagonists or especially proton pump inhibitors of the invention as a combined preparation for simultaneous, separate or sequential use in the treatment of gastrointestinal disorders, especially disorders related to the gastro-esophageal reflex.

The formulations of the present invention may optionally include antiflatulent agents such as dimethicone, alpha-D-galactosidase, and the like.

Said product containing an antacid, an H2-antagonist or a proton pump inhibitor on the one hand and a cisapride salt form on the other hand is optionally further combined with an antiflatulent agent to provide a dual effect in the treatment of gastrointestinal disorders, as described in WO 95/01803, i.e. cisapride salt as a gastrointestinal motility agent provides enhanced motility while an antacid, H2-antagonist or a proton pump inhibitor provides a systemic effect of reducing acid production.

Accordingly, the present invention further provides a method for the prevention, treatment and alleviation of heartburn, indigestion, gastric acid, binge eating (oveningulence), gastro-esophageal reflex, constipation, dyspepsia and other gastrointestinal disorders, gastrointestinal disorders and including bloating in a mammal (including a human being) in need of such treatment, which method comprises administering to such organism:

a therapeutically effective amount of an antacid, an H2-antagonist, or a proton pump inhibitor;

(ii) a therapeutically effective amount of a salt form of cisapride of the present invention, and optionally

(iii) a therapeutically effective amount of an antiflatulent agent, in particular dimethicone, alpha-D-galactosidase (ADG).

Antacids for use in the above combinations are commercially available. H2-antagonists such as famotidine, ranitidine and cimetidine are also commercially available under different trademarks. Proton pump inhibitors such as omeprazole, lansoprazole, rabeprazole, and the like are either commercially available or known in the art. Dimethicone is a well known and commercially available antiflatulent agent. alpha-D-galactosidase (ADG) is a commercially available enzyme preparation for the hydrolysis of indigestible sugars found in soy or soy products. Active ingredients other than the salt of cisapride are therefore readily commercially available.

The amount of each active ingredient used may vary depending on the severity of the disease and the particular biochemical criteria and the needs of the patient. The amount of each active ingredient used may also vary depending on whether the active ingredient is in tablet or liquid form or by other suitable methods of administration. Physicians and clinicians can readily determine the appropriate amount.

Tablets or capsules according to the present invention comprise the salt form of cisapride, preferably cisapride- (L) -tartrate, preferably applied in finely divided or micronized form. Micronized forms of the salts of cisapride, particularly cisapride- (L) -tartrate, may be prepared by micronization techniques known in the art, for example by grinding in a suitable mill and sieving through a suitable sieve.

The micronized material has a surface area of at least about 10 x 10³cm²/g(1×10³m²/kg), preferably a surface area of more than 12X 10³cm²/g(1.2×10³m²/kg), more preferably a surface area of more than 14X 10³cm²/g(1.4×10³m²/kg)。

The characteristics of the salt of cisapride, particularly the micronized salt form of cisapride- (L) -tartrate according to the present invention are shown in the following different ways. At most 50% of the particles have a diameter greater than 24 μm (i.e. 24X 10)^-6m) and therefore dl₅₀Maximum 24 μm (dl stands for stimulated emission)Diameter of light diffraction measurement).

In some cases, it may be useful to use a coarse substance (rather than a micronized or fine substance) of the salt of cisapride. For example, in the case of direct compression on an industrial scale of a salt containing the invention. When the active ingredient is too fine, problems can arise in the production of tablets by direct compression on industrial (high speed) machines. When the substance is too fine, the tablets show low measured values, possibly for example due to the fact that the micronized substance adheres to the walls of the container.

On the other hand, when the substance is too coarse, a problem of content uniformity (a critical parameter) arises. Particularly in the production of pharmaceutical compositions which are strictly regulated by GMP (manufacturing practice).

In dl₅₀The important particle size range expressed is from about 10 μm to about 150 μm. A more important range is about 20 μm to 100 μm. For formulations using micronized substances, dl is preferred₅₀About 24 μm, while for the formulations using coarser material, dl₅₀Is about 50 μm.

The solid oral dosage form, when in unit dosage form, contains cisapride in base form equivalent to about 0.1mg to 100mg, particularly an engineered (envisaged) dosage form containing cisapride in base form equivalent to about 5mg, about 10mg and about 20 mg. This means, for example, that cisapride- (L) -tartrate is about 0.13mg to about 130mg cisapride- (L) -tartrate. More particularly, a dosage form is contemplated containing about 6.5mg, about 13mg and about 26mg of cisapride- (L) -tartrate.

From the point of view of the fact that the oral dosage form of the present invention is designed to obtain a rapid dissolution of the active ingredient, the excipients of the oral dosage form of the present invention should be selected to provide a rapid dissolution of the active ingredient.

Two oral dosage forms, tablets and capsules, are preferred.

Tablet formulation

In particular the choice of excipients in the tablet is important. The excipients should allow rapid dissolution and, on the other hand, should facilitate the industrial production of tablets with a suitable appearance, a suitable friability and a sufficient hardness.

Tablets should have suitable hardness and friability mainly because the tablets must be produced on an industrial scale at high speed pressure and the tablets must be packed or filled into various containers. If the tablet is not of sufficient hardness or is brittle, the tablet taken by the patient may be broken or a portion of the tablet may have been broken into a powder. This lack of rigidity or fragility prevents the patient from being able to determine whether he has taken the correct amount.

The minimum required hardness of the tablet is about 1.5daN (10 newtons) as determined according to the test described in the european pharmacopoeia (3 rd edition, 1997) page 135 "resistance to breakage of tablets".

It should be noted that the hardness of the tablet depends on the shape of the tablet, among other properties.

Different shapes of tablets may be used according to the invention. The tablets may be round or oblate or oblong or any other shape known in the art. The tablets may be scored. It should be noted that the shape of the tablet may for example have an effect on the disintegration rate.

The disintegration of the tablets was determined according to the pharmaceutical technical method described in the european pharmacopoeia (3 rd edition, 1997) on page 127. The disintegration time of the tablets of the invention should be less than about 30 minutes, importantly less than 20 minutes, and more importantly less than about 15 minutes. Preferred tablets even disintegrate in less than about 3 minutes, and even less than about 1.5 minutes.

The tablets of the invention contain tablet disintegrants such as starch, pregelatinized starch, sodium starch glycolate (Expotab)^) Crospovidone, croscarmellose sodium, clay, microcrystalline cellulose (in Avicel)^Available under the registered trademark), alginates, gums, and other disintegrants known in the art.

The tablets of the invention preferably contain croscarmellose sodium as disintegrant (Carmellose sodium is the british approved name for sodium carboxymethylcellulose, i.e. the sodium salt of a cellulose ether, see Martindale, the Extra Pharmacopeia, 29 th edition, page 1433). The crosslinked Carmellose sodium refers to croscarmellose sodium (USP NF,1995 edition, page 2238).

The disintegrant may be present in an amount from about 3% (w/w) to about 15% (w/w). Importantly, the disintegrant is from about 3% (w/w) to about 10% (w/w). When percentages are used, these percentages are weight to weight (w/w) and represent the ratio (percentage) of the component or excipient to the total weight of the tablet (or the weight of the core in the case of coated tablets). The "core" is an uncoated tablet. When a process with a granulation step is employed, it is advantageous to include a disintegrant in the "internal phase" and the "external phase". The term "internal phase" refers to the composition of the particles and the term "external phase" refers to the composition of the tableting mixture. It was observed that tablets containing a disintegrant in the inner and outer phase showed better disintegration and better dissolution profile.

The tablets may further be formulated with various conventional excipients such as binding agents, flavoring agents, buffering agents, diluents, coloring agents, lubricants, sweeteners, and glidants, depending on the formulation at hand. Some excipients may serve a variety of purposes.

Flavoring agents are optionally incorporated into the compositions and may be selected from synthetic flavored oils and flavored fragrances and/or natural oils, extracts obtained from plant leaves, flowers, fruits and the like, and combinations thereof. These may include cassia oil, wintergreen oil, peppermint oil, cinnamon oil, anise oil, eucalyptus oil, and thyme oil. Also useful are vanilla, citrus oils including lemon, orange, grape, lime, and grapefruit, and fruit extracts including apple, banana, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, and the like. The amount of flavoring agent depends on a variety of factors including the desired organoleptic effect. Generally, when a flavoring agent is used, the flavoring agent is present in an amount of about 0.5% (w/w) to about 3.0% (w/w).

Various materials may be used as fillers or diluents. Examples are spray-dried or anhydrous lactose, sucrose, glucose, mannitol, sorbitol, starch, cellulose (e.g. microcrystalline cellulose; Avicel), dibasic or anhydrous calcium phosphate and others known in the art. Tablets may contain a single filler or diluent or a mixture of fillers or diluents. For example, a mixture of lactose and microcrystalline cellulose may be used. Lactose is used purely as a diluent, whereas microcrystalline cellulose is a filler which has the property of giving the tablet the right hardness and of disintegrating agent since the fibres swell when in contact with water.

A preferred form of lactose is lactose monohydrate DC, which is spray dried lactose monohydrate, corresponding to Pharmtose DCL11 and commercially available from DMV International (Netherlands).

The filler or diluent is present in an amount ranging from about 50% (w/w) to about 95% (w/w) based on the total weight of the tablet or core. The amount of filler or diluent of interest ranges from about 65% (w/w) to about 90% (w/w). Preferably, the amount of filler or diluent ranges from about 66% (w/w) to about 86% (w/w).

Importantly, the ratio of lactose monohydrate to microcrystalline cellulose spray dried mixture used was about 75% by weight lactose monohydrate and about 25% by weight microcrystalline cellulose. The mixture is in MICROCELAC^Commercially available under the registered trademark. The spray-dried lactose monohydrate and microcrystalline cellulose have the advantage that they facilitate an orderly mixing and increase the homogeneity of the tablet content. The solid oral dosage form does contain a relatively small amount of the active ingredient in a large amount of filler. Under such conditions, content uniformity may be a problem in that tablets prepared in the same batch may not all have the same content of active ingredient due to segregation phenomena during the production process. From the fact that regulatory agencies often impose strict standards for solid oral dosage forms, batches of tablets that do not have good content uniformity must be discarded. Spray-dried lactose monohydrate and microcrystalline celluloseThe vitamin has a porous structure and the active component cisapride- (L) -tartrate can enter, resulting in orderly mixing and thus good content uniformity.

The MICROCELAC^May be present in an amount of about 80% (w/w) to 95% (w/w) of the weight of the core, depending on the total amount of the tablet or in the case of a film coating. Preferably, MICROCELAC^Present at about 87% (w/w).

Lubricants may also be used in the manufacture of certain dosage forms and are often used in the manufacture of tablets. Examples of lubricants are magnesium stearate, stearic acid, sodium stearyl fumarate, magnesium lauryl sulfate, hydrogenated vegetable oils, and other materials known in the art. Preferred lubricants are magnesium stearate and sodium stearyl fumarate.

The lubricant is generally present in an amount which may vary from about 0.2% (w/w) to 7.0% (w/w) depending on the total amount of the tablet or the weight of the core in the case of a film coating. Importantly, the lubricant is present in an amount ranging from about 0.5% (w/w) to about 3.0% (w/w). Preferably, the lubricant is present in an amount ranging from about 0.9% (w/w) to about 1.25% (w/w).

Glidants are normally used in the production of tablets, but also in capsules. Important glidants are calcium silicate, magnesium silicate, colloidal anhydrous silicon dioxide or talc. Mixtures of glidants may also be used. A preferred glidant for the tablet core or capsule of the present invention is colloidal anhydrous silicon dioxide. Of the type commonly used in Aerosil^Commercially available under the trademark bazaar (r). Glidants are normally present in an amount of about 0.05% (w/w) to about 1% (w/w) based on the total amount of core content. The preferred amount of glidant is about 0.3%.

The binder may be acacia, alginic acid, carboxymethylcellulose (sodium), cellulose (microcrystalline cellulose), dextrin, ethylcellulose, gelatin, glucose (liquid), guar gum, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene oxide, polyvinylpyrrolidone, starch (pregelatinized), or syrup. An important binder is hydroxypropyl methylcellulose, especially low viscosity hydroxypropyl methylcellulose. A preferred binder is hydroxypropylmethylcellulose 2910, and a 2% aqueous solution thereof has a viscosity of 15mpa.s at 20 ℃.

Other excipients, such as colorants and pigments, may also be added to the tablets of the present invention. Colorants and pigments include titanium dioxide and/or approved dyes for food and pharmaceuticals. The colorant is optionally a component of the tablets of the invention, but when used, the colorant is present at 3.5% (w/w) based on the total amount of the tablet or, in the case of film-coated tablets, the weight of the core.

Preferably, the colorant is present in the coating of the tablet, again the colorant is present in an amount of from about 0.01% (w/w) to about 10% (w/w) based on the total amount of coating, with an important range being from about 0.20% (w/w) to about 7.5% (w/w) based on the total amount of coating.

Tablet blends may be dry-granulated or wet-granulated prior to tableting, as is known in the art. It has been unexpectedly found that tablets can be prepared using direct compression techniques when cisapride- (L) -tartrate is used. When cisapride monohydrate is used as an active ingredient, the formulation requires a surfactant to obtain the necessary wettability of cisapride monohydrate. However, to add surfactant to a tablet formulation, a wet granulation step is required. Thus, a further embodiment of the invention should be mentioned the fact that the tablets according to the invention can be prepared by direct compression, that is to say the "usual" wet granulation step can be omitted. This results in a significant reduction in the production costs of these tablets.

It was also found that tablets prepared by direct compression had a better dissolution profile than similar tablets prepared by a wet granulation step.

The tablets of the invention may be film coated tablets for ease of swallowing, taste masking and better appearance. Many polymeric film coating materials are known in the art. Known film coating agents are sodium carboxymethylcellulose, cellulose acetate phthalate, ethylcellulose, gelatin, pharmaceutical glazes, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, copolymers of methacrylic acid, methylcellulose, polyethylene glycol, polyacetate phthalate, shellac, sucrose, titanium dioxide, waxes, zein. A preferred film coating material is Hydroxypropylmethylcellulose (HPMC). HPMC is commercially available.

The coating agent is normally present in an amount of about 50% (w/w) to about 95% based on the total amount of film coating. An important range is from about 50% (w/w) to about 65% (w/w).

Anti-adherent agents are normally used during film coating to avoid adhesive effects during film formation and drying. A preferred adhesive for this purpose is talc. The antiadherent, especially talc, is present in the film coating in an amount of about 5% (w/w) to 15% (w/w) based on the total amount of coating.

Other components in the film coating may be plasticizers such as castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerol, polyethylene glycol, 1, 2-propylene glycol, triacetin, triethyl citrate. Mixtures of plasticizers may also be used. The type of plasticizer depends on the type of coating agent. A preferred plasticizer according to the present invention is 1, 2-propanediol. The plasticizer is present in about 5% (w/w) to 30% (w/w) based on the total amount of the film coating. An important range is from about 12% (w/w) to about 16% (w/w). The preferred amount of 1, 2-propanediol according to the invention is about 14% (w/w).

Opacifiers like titanium dioxide may also be present in about 10% (w/w) to about 20% (w/w) based on the total amount of coating.

When it is desired to color the tablets, the color is normally used in the coating. Thus, colorants and pigments may be present in the film coating. The preferred colorant is iron oxide, which may be red, yellow, black or a mixture thereof.

The film coating process may be carried out using spray coating equipment well known in the art. Typically the coating is applied in a perforated pan, for example Glatt^(e.g., Glatt Coater 750) AccelaCota^And HiCoater^In perforated pots produced under the trademark.

The tableting process itself is not standard and is readily formed by conventional tableting from the desired mixture or mixture of components into the appropriate shape. The pressure used is in the range of about 0.5 tons per square centimeter (equivalent to about 50MPa) to about 2.0 tons per square centimeter (equivalent to about 200 MPa). Below this lower limit, tablets are formed which exhibit inadequate hardness, while above this upper limit, the tablets may be too hard to dissolve. A preferred range is from about 1.1 tons per square centimeter (equivalent to about 110MPa) to about 1.7 tons per square centimeter (equivalent to about 170 MPa).

Capsule preparation

The capsules according to the invention contain, in addition to the active ingredient, fillers, glidants, lubricants and disintegrants.

The same fillers, glidants, and lubricants described above for tablets may be used in the capsule. The preferred filler is lactose. Preferred glidants are colloidal silicon dioxide and talc. Talc may also provide anti-adherent properties required for handling powders. A preferred lubricant is magnesium stearate. Corn starch may be used as a disintegrant, which is an essential component of the capsule contents in the case of fillers used in the capsule filling equipment. In a capsule filling apparatus using a filling material, the contents of the capsule are compressed together in several consecutive strokes, and the compressed capsule contents are filled into the capsule at the last stroke.

The filler is present in an amount of about 60% (w/w) to about 90% (w/w) based on the total amount of the capsule contents. Preferably, the filler is present in an amount of about 70% (w/w) to about 80% (w/w) based on the total amount of the capsule contents. Preferably, the filler is present in an amount of about 75% (w/w).

The glidant is present in an amount of about 4% (w/w) to 7% (w/w) based on the total amount of capsule contents. Preferably the glidant is present in an amount of about 6% (w/w) based on the total amount of capsule contents.

The lubricant is present in an amount of about 0.5% (w/w) to about 2.0% (w/w) based on the total amount of the capsule contents. Preferably the lubricant is present in an amount of about 1.25% (w/w) based on the total amount of the capsule contents.

Capsules are generally made of gelatin and may be soft or hard gelatin capsules.

The capsules are prepared by conventional methods. Fillers such as lactose are milled with the active ingredient and sieved. The resulting mixture was added to a mixture of the remaining excipients and mixed in a planetary mixer until a homogeneous mixture was obtained. The powder is filled into capsules with capsule filling equipment known in the art (automated).

Applications of

An advantage of the solid oral dosage form according to the invention is that cisapride dissolves rapidly even when the solid oral dosage form according to the invention does not dissolve completely in the acidic environment of the stomach and passes through the intestinal tract (the environment is about neutral, i.e. very weakly acidic), which is not the case for cisapride monohydrate.

The object of the present invention is to use pharmaceutical dosage forms as medicaments for the treatment of gastrointestinal disorders such as idiopathic or diabetic-neuropathy-related gastroparesis, anorexia nervosa after vagotomy or partial gastrectomy (symptoms mainly including early satiety, anorexia, nausea and vomiting); negative upper digestive discomfort by X-ray or endoscopy, characterized by early satiety, postprandial fullness, inability to complete normal volume of food, bloating, excessive eructation, anorexia, nausea, vomiting, or ulcer-like disease (upper abdominal burning or pain), gastroesophageal reflex disease including the treatment or maintenance of esophagitis; in infants: chronic and excessive nausea or nausea when postural and eating approaches fail; intestinal pseudo-obstruction, inadequate propulsive motility resulting from motor dysfunction and retention of gastric and intestinal contents; restoration of colonic propulsive motility as a long-term treatment for chronic constipation. Accordingly, the present invention further provides a method of treating gastrointestinal disorders, particularly gastroesophageal reflex diseases,

due to the nature of the tablets of the present invention, the use of cisapride- (L) -tartrate, cisapride- (D) -tartrate, cisapride sulfate, cisapride citrate for the manufacture of an oral dosage form for the treatment of gastrointestinal disorders without drug-food interaction is disclosed. Sapride- (L) -tartrate, cisapride- (D) -tartrate, cisapride sulfate, cisapride citrate are also used in the manufacture of a medicament for the treatment of gastrointestinal disorders in patients taking general gastric pH increasing drugs, or for the treatment of gastrointestinal disorders in patients taking proton pump inhibitors, H2-inhibitors or antacids (especially as claimed).

The solid oral cisapride dosage forms disclosed or described above can be administered to a mammal, including a human, in need of such treatment, when said mammal is orally administered, regardless of the time of consumption, nature and quantity of the food, without showing the adverse effects of the food. Finally, as a supplement to the present invention, the present invention provides a commercially acceptable therapeutic package comprising a container, an oral dosage form of cisapride (which does not exhibit adverse food effects) contained therein, and written (i.e., printed) non-limiting materials associated with the package, the materials relating to whether the dosage form can be taken with or without food. Such printed matter contains information and/or instructions to a doctor, pharmacist or patient. The print may be "non-limiting as to whether the dosage form is taken with or without food" as it does not include any instructions as to whether the dosage form is taken with or without food, i.e. no mention is made as to the effect of food. Alternatively, the written material indicates to a user (i.e., patient, pharmacist or physician) that the oral dosage form may be taken or administered to a patient by including one or more instructions, without limitation, whether the patient eats or absorbs food (optionally, for example, also instructions like "regardless of type or quantity of food"). The written material must not contain, in terms of food, a limiting language such as "the dosage form cannot be taken with food" or "the dosage form can be taken only when the patient has an empty stomach", etc.

The container may be of any conventional shape or form known in the art, made of pharmaceutically acceptable materials, such as paper or paper cartons, glass or plastic bottles or cans, resealable bags or blister packs with individual doses pressed according to the treatment method. The container used is determined by the exact dosage form contained. Since the cisapride dosage forms of the present invention can be taken or administered to a patient without relying on food intake, the dosage forms can be administered "on-demand". This means that the dosage form is administered on a symptomatic basis. In other words, the patient takes the dosage form of the present invention while feeling that he is suffering from symptoms associated with gastrointestinal disorders. This will greatly improve patient compliance as patients may take medication at the time of symptoms rather than thinking to take medication at the time of eating.

Test section

Example 1: tablet A

The following components were intimately mixed in a planetary mixer: cisapride- (L) -tartrate (13.23mg, 7.35% (w/w)), spray-dried lactose monohydrate (75%) and microcrystalline cellulose (25%) (microcleac)^) (157.23mg, 87.35% (w/w)), croscarmellose sodium (7.2mg, (4.00% (w/w)), colloidal anhydrous silicon dioxide (0.54mg, 0.3% (w/w)), magnesium stearate (1.8mg, 1.00% (w/w), and compressed into 180mg tablets on a tablet press (Korsch or Courtoy RO 2EHS, tablet compression rate of 36000 tablets/hour).

Tablets containing the following ingredients were prepared according to the above examples: cisapride- (L) -tartrate 13.23mg 7.35% (w/w) MICROCELAC^157.23mg 87.35% (w/w) croscarmellose sodium 7.2mg 4.00% (w/w) colloidal anhydrous silicon dioxide 0.54ng 0.3% (w/w) magnesium stearate 1.8mg 1.00% (w/w)

Example 2: tablet B

The following components were intimately mixed in a planetary mixer: cisapride- (L) -tartaric acidSalt (13.23mg, 7.35% (w/w)), lactose DC (116.57mg, 64.76% (w/w)), microcrystalline cellulose (Avicel)^) (38.86mg, 21.59% (w/w)), croscarmellose sodium (7.2mg, (4.00% (w/w)), colloidal anhydrous silicon dioxide (0.54mg, 0.3% (w/w)), sodium stearyl fumarate (3.6mg, 2.00% (w/w), and compressed into 180mg tablets on a tablet press (Korsch or Courtoy RO 2EHS, tablet compression rate 36000 tablets/hr).

Tablets containing the following ingredients were prepared according to the above examples: cisapride- (L) -tartrate 13.23mg 7.35% (w/w) lactose DC 116.57mg 64.76% (w/w) microcrystalline cellulose 38.86mg 21.59% (w/w) croscarmellose sodium 7.2mg 4.00% (w/w) colloidal anhydrous silicon dioxide 0.54mg 0.3% (w/w) sodium stearyl fumarate 3.6mg 2.00% (w/w)

Example 3: tablet C

Tablets having the following composition were prepared in a similar manner as described in examples 1 and 2: cisapride- (L) -tartrate 6.61mg 3.68% (w/w) lactose 123.18mg 68.44% (w/w) microcrystalline cellulose 38.86mg 21.59% (w/w) croscarmellose sodium 7.2mg 4.00% (w/w) colloidal anhydrous silicon dioxide 0.54mg 0.3% (w/w) magnesium stearate 1.8mg 1.00% (w/w)

Example 4: tablet D

Tablets having the following composition were prepared in a similar manner as described in examples 1 and 2: cisapride- (L) -tartrate 26.44mg 14.72% (w/w) lactose 103.34mg 58.39% (w/w) microcrystalline cellulose 38.86mg 21.59% (w/w) croscarmellose sodium 7.2mg 4.00% (w/w) colloidal anhydrous silicon dioxide 0.54mg 0.30% (w/w) magnesium stearate 1.8mg 1.00% (w/w)

Example 5: tablet E

Tablets having the following composition were prepared in a similar manner as described in examples 1 and 2: cisapride- (L) -tartrate 13.23mg 7.35% (w/w) famotidine 10.00mg 5.56% (w/w) MICROCELAC^147.23mg 87.35% (w/w) croscarmellose sodium 7.2mg 4.00% (w/w) colloidal anhydrous silicon dioxide 0.54mg 0.30% (w/w) magnesium stearate 1.8mg 1.00% (w/w)

Simethicone or alpha-D-galactosidase can be added to each of the above formulations in a combined formulation to provide anti-ballooning relief. The amount of simethicone administered to a patient in need of treatment may vary depending on the patient's needs, but may be, for example, in the generally known dose range for treating bloating (20-40 mg per tablet) or may be increased as needed. Generally, ADG may be used in the above formulations in amounts of about 675 to about 2250 GaIU or increased as needed.

Example 6: the preparation of the core film coated tablets was carried out with a wet granulation step: tablet F

6a) Preparation of the binding solution

5.280kg of purified water was transferred to a steam heated jacketed vessel and heated to about 80 ℃. The water was transferred to a stainless steel vessel at 251 and 792g HPMC291015mPa.s were dissolved while stirring with a propeller stirrer (150-500rpm) for 5 minutes. 12.32kg of water was added thereto while stirring for 2 minutes. The solution was then degassed by stirring at 60-150rpm for 10 minutes. The bonding solution thus obtained was allowed to stand for at least 8 hours.

6b) Granulating

23.700kg of lactose monohydrate 200 mesh, 2.911kg of cisapride- (L) -tartrate and 7.920kg of unmodified corn starch were transferred sequentially to the product container of a fluid bed granulator type GPCG 30. The fluidized bed process was carried out and the components were mixed until the outlet air temperature reached about 28 deg.C (process parameters: general air pressure: 5 bar, air flow rate: about 300 to 600m³H, shaking time: 7 seconds, shaking interval 35 seconds, temperature of inlet air: about 45 ℃ to about 55 ℃, temperature of outlet air: about 27 ℃ to about 29 ℃).

The binding solution prepared as described in 6a) was sprayed onto the powder mixture (process parameters: flow rate: about 400 to 1000m³H, shaking time: 7 seconds, shaking interval 35 seconds, diameter of nozzle: 1.8mm, position of nozzle: upper, pressure of spray 3 bar, spray rate: about 200 to 300g/min, temperature of inlet air: about 45 ℃ to about 60 ℃, temperature of outlet air: about 21 ℃ to about 24 ℃).

The drying process starts immediately after the spraying process. The drying process was continued until the outlet air temperature reached about 38 ℃. (Process parameters: air flow Rate: about 400 to 1000 m)³H, shaking time: 7 seconds, shaking interval 35 seconds, temperature of inlet air: about 70 ℃ to about 75 ℃, temperature of outlet air: about 37 ℃ to about 39 ℃).

6c) Preparation of tableting mixtures

The dried granules prepared as described in 6b) were passed through a Frewitt type shaking screen device (mesh size: 1mm, mesh wire thickness: 0.65 mm). The sieved powder was collected in the barrel of a planetary mixer of the Collette MP 90 type (mixing rate: mixer arm: 45rpm, tray (plate): 20rpm) and mixed for 5 minutes to obtain a homogeneous mixture.

6d) Tabletting

The tableting mixture prepared as described in 6c) was compressed into tablets using a Killian rotary tablet press, Biconvex, and white round tablets having a nominal weight of 180mg were prepared by this method. These tablets refer to the core of the tablet described above.

6e) Preparation of the coating suspension

6.307kg of purified water was heated to a temperature in the range of about 70 ℃ to about 75 ℃ in a steam heated jacketed vessel. The water was transferred to a 251 stainless steel container and 880g HPMC 29105 mPa.s and 220g 1, 2-propanediol were added with stirring by a propeller stirrer (stirring rate: about 400 to about 600 rpm). This mixture is referred to as mixture A.

3.153kg of purified water, 176g of talc, 264g of titanium dioxide and 33g of yellow iron oxide were transferred into a 10L stainless steel vessel and homogenized with a Silverson 2LR homogenizer for 10 to 15 minutes. This mixture is referred to as mixture B.

Mixture B was added to mixture A with stirring with a propeller stirrer (stirring rate: about 200 to about 400 rpm). The entire mixture was stirred for 120 minutes during which time the coating suspension was further degassed.

6f) Tablet coating

11.033kg of the coating suspension prepared as described in 6e) was transferred to a 25L stainless steel container. The tablets prepared as described in 6a) to 6d) were transferred to a coating apparatus GC 750 and the tablets were heated. (Process parameters: temperature of inlet air: about 80 ℃ to about 90 ℃, temperature of outlet air after heating: about 47 ℃ to about 49 ℃. spraying the coating suspension onto the tablets was carried out using the parameters: rotation speed of the pan: 8 to 10rpm, temperature of inlet air: about 80 ℃ to about 90 ℃, temperature of outlet air: about 46 ℃ to about 49 ℃, volume of inlet air: about 750m ℃³To about 850m³The pressure in the processing chamber is less than 100mPa, the pressure of the spraying air is as follows: about 2.5 to 3.5 bar, temperature of the coating suspension at room temperature, spray rate: 90 to 100 g/min).

After the spray drying process, the tablets were kept in rotation and cooled until the outlet air temperature reached 30 ℃.

The resulting film coated tablets were round (diameter =8mm), concave and yellow film coated tablets.

The tablets were portioned into polyethylene bottles and Perlen tristar tablets.

The following tablets were prepared according to the above preparation method:

core of tablet F:

the amount of the components (w/w) is 13.23mg of 7.35% (w/w) lactose monohydrate 200 mesh (relative to the tablet core cisapride- (L) -tartrate^*1) 107.73mg 59.85% (w/w) unmodified corn starch 36.00mg 20.00% (w/w) HPMC 291015 mPa.s 3.60mg 2.00% (w/w) microcrystalline cellulose 12.60mg 7.00% (w/w) croscarmellose sodium 5.40mg 3.00% (w/w) colloidal anhydrous silica 0.54mg 0.30% (w/w) magnesium stearate 0.90mg 0.50% (w/w)

Total amount of core: 180.00mg

Tablet F has a film coating component in an amount% (w/w) of 4.00mg 55.95% (w/w)1, 2-propanediol relative to the coating HPMC 29105 mPa.s 4.00mg 13.99% (w/w) titanium dioxide (E171) 1.20mg 16.78% (w/w) talc 0.80mg 11.19% (w/w) yellow iron oxide (E172/C177492) 0.15mg 2.10% (w/w)

Total amount of coating: 7.15mg

(^*1)200 mesh is an indication of the type of lactose monohydrate used.

(2^*) HPMC is hydroxypropyl methylcellulose and the value "2910" refers to the type of hydroxypropyl methylcellulose used. The first two numbers "29" represent the maximum of the methoxy groupAbout the ratio, the third and fourth "10" represent about the ratio of hydroxypropyl groups.

It should also be noted that the viscosity (15mPa.s) of a 2% aqueous solution is measured at 20 ℃. This is an indication of the molecular weight of the HPMC used.

Example 7: tablet G

The following tablets were prepared according to the method described in example 6: cisapride- (L) -tartrate 26.46mg 12.03% lactose monohydrate 200 mesh 111.48mg 50.67% unmodified corn starch 44.00mg 20.00% croscarmellose sodium (x) 4.95mg 2.25% HPMC 29105 mpa.s 2.75mg 1.25% microcrystalline cellulose 11.00mg 5.00% croscarmellose sodium (x) 17.60mg 8.00% colloidal anhydrous silicon dioxide 0.66mg 0.30% magnesium stearate 1.10mg 0.50%

Total amount of tablets: 220.00mg

Two mentions of croscarmellose sodium indicate that croscarmellose sodium is included in both the granulation mixture and the tableting mixture. Thus, croscarmellose sodium is present in both the so-called internal phase (granulate) and the so-called external phase (tableting mixture). Because croscarmellose sodium is present in both the "internal phase" and the "external phase", the tablets so prepared have a better dissolution profile than tablets which are present only in the "external phase".

Tablets were coated as described in example 6.

Example 8: tablet H

The following tablets were prepared according to the method described in example 6: cisapride- (L) -tartrate 26.46mg 12.03% lactose monohydrate 200 mesh 119.18mg 54.17% unmodified corn starch 44.00mg 20.00% croscarmellose sodium (x) 4.40mg 2.00% HPMC 291015 mpa.s 2.20mg 1.00% microcrystalline cellulose 4.40mg 2.00% croscarmellose sodium (x) 17.60mg 8.00% colloidal anhydrous silicon dioxide 0.66mg 0.30% magnesium stearate 1.10mg 0.50%

Total amount of tablets: 220.00mg

See example 7 for an illustration of the external and internal phases of croscarmellose sodium

Tablets were coated as described in example 6.

Example 9: tablet I: tablets containing cisapride base in an amount equivalent to 5mg

The following tablets, cisapride- (L) -tartrate 6.62mg 6.62% lactose monohydrate 200 mesh 60.59mg 60.59% unmodified corn starch 20.00mg 20.00% HPMC 291015 mPa.s 2.00mg 2.00% microcrystalline cellulose 7.00mg 7.00% croscarmellose sodium 3.00mg 3.00% colloidal anhydrous silicon dioxide 0.30mg 0.30% magnesium stearate 0.50mg 0.50%

Total amount of core: 100.00mg

Film coating HPMC 29105 mPa.s 3.00mg 57.03% 1, 2-propanediol 0.75mg 14.26% titanium dioxide 0.90mg 17.11% talc 0.60mg 11.41% yellow iron oxide 0.01mg 0.23% of tablet F

Total amount of coating: 5.26mg

Example 10: tablet J: tablets containing cisapride base equivalent to 10mg

The following tablets, cisapride- (L) -tartrate 13.23mg 7.35% lactose monohydrate 200 mesh 107.73mg 59.85% unmodified corn starch 36.00mg 20.00% HPMC 291015 mPa.s 3.60mg 2.00% microcrystalline cellulose 12.60mg 7.00% croscarmellose sodium 5.40mg 3.00% colloidal anhydrous silicon dioxide 0.54mg 0.30% magnesium stearate 0.90mg 0.50%

Total amount of core: 180.00mg HPMC 29105 mPa.s 4.00mg 55.94% 1, 2-propanediol 1.00mg 13.99% titanium dioxide 1.20mg 16.78% talc 0.80mg 11.19% yellow iron oxide 0.15mg 2.10%

Total amount of coating: 7.15mg

Example 11: tablet K: tablets containing cisapride base equivalent to 20mg

The following tablets, cisapride- (L) -tartrate 26.46mg 12.03% lactose monohydrate 200 mesh 121.38mg 55.17% unmodified corn starch 44.00mg 20.00% HPMC 291015 mPa.s 4.40mg 2.00% microcrystalline cellulose 15.40mg 7.00% croscarmellose sodium 6.60mg 3.00% colloidal anhydrous silicon dioxide 0.66mg 0.30% magnesium stearate 1.10mg 0.50% are prepared according to the method described in example 6

Total amount of core: 220.00mg HPMC 29105 mPa.s 6.00mg 52.86% 1, 2-propanediol 1.50mg 13.21% titanium dioxide 1.80mg 15.86% talc 1.20mg 10.57% yellow iron oxide 0.85mg 7.49%

Total amount of coating: 11.35mg

Example 12: capsule A

The content of the components is based on the total weight of the content

(w/w) cisapride- (L) -tartrate 6.62mg 4.14% lactose 125 mesh 61.00mg 38.13% lactose 200 mesh 60.98mg 38.11% corn starch 20.00mg 12.50% talc 9.00mg 5.60% magnesium stearate 2.00mg 1.25% colloidal anhydrous silica 0.40mg 0.25% (Aerosil)^)

Total amount of capsule contents: 160.00mg

Filling the powder into No. 4 capsules

Example 13: capsule B

The content of the components is based on the total weight of the content

(w/w) cisapride- (L) -tartrate 13.23mg 6.01% lactose 125 mesh 82.00mg 37.27% lactose 200 mesh 81.57mg 37.08% corn starch 27.50mg 12.50% talc 12.40mg 5.64% magnesium stearate 2.75mg 1.25% colloidal anhydrous silicon dioxide 0.55mg 0.25% (Aerosil)^)

Total amount of capsule contents: 220.00mg

Filling the powder into No. 2 capsules

The capsules are prepared by mixing in a planetary mixer and filling the powder in suitable capsules.

Example 14: dissolution test

Tablets containing cisapride- (L) -tartrate having the formulation and prepared as described in example 1 and tablets using cisapride monohydrate in place of cisapride- (L) -tartrate (other components of the composition are the same as those of the formulation) were compared for dissolution at different pH values.

The test method comprises the following steps:

the test strip reagents were placed in glass containers containing 900ml of a particular buffer at 37 ℃. Stirring was carried out with paddles at a rotation rate of 50rpm (revolutions per minute). The test was conducted in a USP test <711> set forth in a USP-2 solution apparatus. This latter test is described in the United states pharmacopoeia XII, page 1578-1579.

a)pH=±1.5(HCl:0.1N)

Time (minutes)	Cisapride- (L) -tartrate solubilized%	Cisapride monohydrate solubilized%
			0515304560	0.0082.7989.3391.3592.1291.95	0.0080.3694.0694.9194.5994.27

And (4) conclusion: the dissolution of cisapride tartrate and cisapride monohydrate in 0.1N HCl (pH = ± 1.5) was comparable.

b) pH =4.5 (USP-buffer)

Time (minutes)	Cisapride- (L) -tartrate solubilized%	Cisapride monohydrate solubilized%
			0515304560	0.0084.5697.3197.5497.1596.89	0.0054.0388.7897.8898.2497.94

And (4) conclusion: cisapride tartrate is more soluble than cisapride monohydrate at pH = 4.5.

c) pH =6.5 (USP-buffer)

Time (minutes)	Cisapride- (L) -tartrate solubilized%	Cisapride monohydrate solubilized%
			05	0.0063.10	0.004.93

15304560

72.2473.1674.2373.79

7.7310.3112.0013.33

And (4) conclusion: cisapride- (L) -tartrate is significantly superior to cisapride monohydrate solubility at pH = 6.5.

Example 15: pharmacokinetic examples

In an open, four-way cross-phase-I test, a total of 12 subjects, 8 men and 4 women, were randomized to receive a single dose of 10mg of cisapride tartrate and hydrate, with and without a standard breakfast.

All subjects were given the following four treatments:

treatment A: cisapride- (L) -tartrate tablets were taken alone two hours prior to the standard breakfast, i.e. on an empty stomach.

Treatment B: cisapride- (L) -tartrate tablets were taken alone immediately after a standard breakfast.

Treatment C: cisapride monohydrate tablets (conventional Prepulsid tablets) were taken alone two hours prior to a standard breakfast, i.e., on an empty stomach.

Treatment D: cisapride monohydrate tablets (conventional Prepulsid tablets) were taken alone immediately after a standard breakfast.

A standard breakfast contains four slices of bread, one slice of ham, one slice of cheese, cream, juice and two cups of coffee or tea (with milk and/or sugar added if required). During treatment B and treatment D, the subjects consumed breakfast first and were given the test drug immediately after eating. Thereafter, the subject returned to normal diet.

The test drug is administered with 100ml of water.

Blood samples were collected 48 hours after dosing. The plasma concentration of cisapride was determined with a validated HPLC method (limit of quantitation =2 ng/ml).

Pharmacokinetic analysis

The following pharmacokinetic parameters of cisapride were determined after each of the four treatments with actual sampling times based on individual plasma concentration-time data:

C_maxpeak plasma concentrations were determined by visual inspection of the data

t_maxTime to peak plasma concentration, determined by visual inspection of the data

Area under the plasma concentration-time curve from time 0 to the last time point of AUClast (last quantifiable concentration, calculated from the sum of linear gradients).

AUC ∞ plasma concentration-time extension to area under infinity

Eliminating t_1/2(t_1/2term) elimination half-life (term half-life), defined according to 0.693/Sz

Calculating the relative bioavailability of cisapride based on the ratio of Cmax to AUC in each treatment

Results

No serious side effects were reported, and no treatment was terminated due to side effects.

The pharmacokinetic results are summarized in the following table:

watch (A)

Parameter(s)	Treatment A	Treatment B	Treatment C	Treatment D
					tmax,h	1.4+0.4	2.1+0.7	1.7+0.5	2.3+0.6
Cmax,ng/ml	61.7+16.7	65.6±17.7	50.6±18.4	65.4±16.9
					Metabolism t1/2,h	8.8±2.9	8.3±2.1	9.1±2.8	7.3±1.2
AUClast,ng.h/ml	533+188	619±221	454±139	599±152
					AUC∞,ng.h/ml	578±203	662±243	497±143	638+163

Discussion of the related Art

In the overnight fasted state, the mean tmax for the test drug cisapride was reached at 1.4. + -. 0.4h (A: cisapride tartrate-fasted) and 1.7+0.5h (cisapride monohydrate-fasted). The effect of food on it delayed tmax to 2.1+0.7h (B: after cisapride tartrate-breakfast) and 2.3 + -0.6 h (D: after cisapride monohydrate-breakfast).

The mean plasma concentrations of cisapride tartrate averaged 61.7 ± 16.7ng/ml (after fasting) and 65.6 ± 17.7ng/ml (after breakfast), with cisapride monohydrate on the market at 50.6 ± 18.4ng/ml (after fasting) and 65.4 ± 16.9ng/ml (after breakfast).

The geometric mean values for Cmax were 107% (B vs a), 80% (C vs a), 133% (D vs C) and 100% (B vs D), with associated 90% confidence limits of 98% -116%, 74% -87%, 122% -145% and 92% -109%. The geometric mean of AUC ∞ was 114% (B vs. A), 98% (C vs. A), 129% (D vs. C) and 101% (B vs. D), with associated 90% confidence limits of 106-.

Bioequivalence of tartrate was demonstrated comparing standard postprandial and fasting state (B vs. a) dosing with respect to total exposure (AUC ∞). The relative bioavailability of the typical commercial tablet (C) to the newly developed tartrate (a) tablet when fasted is also within established criteria of bioequivalence. Administration of cisapride monohydrate (D) after breakfast resulted in greater than 29% exposure and 33% peak levels of cisapride compared to the fasted state (D vs C). When taken after a meal, the two cisapride formulations were bioequivalent.

From the results of this test, comparing the bioavailability of newly developed cisapride tartrate and the typical commercial monohydrate, by the effect of the drug alone and food, the following conclusions can be drawn:

the fed or fasted state had little effect on the absorption, peak levels and total exposure of the newly developed cisapride tartrate.

The bioavailability of cisapride monohydrate in the general market in the fed state is increased by 30%.

Cisapride tartrate and monohydrate are bioequivalent when fed with standard breakfast.

Claims (28)

1. A solid dosage form comprising a pharmaceutically acceptable carrier and, as active ingredient, cisapride in a salt form selected from the group consisting of: cisapride- (L) -tartrate, cisapride- (D) -tartrate, cisapride sulfate, cisapride citrate, characterized by a dissolution of the active ingredient of greater than 60% in 1 hour, when measured in a USP-2 dissolution apparatus using the method set forth in USP test <711>, at a pH in the range of 1 to 7.5.

2. The solid dosage form of claim 1, wherein the solid dosage form is an oral solid dosage form.

3. The solid dosage form according to any of the preceding claims, which active ingredient dissolves more than 70% from the solid dosage form after 60 minutes when measured in a USP-2 dissolution apparatus at pH 6.5 (USP-buffer) using the method set forth in the weekly USP test <711 >.

4. The solid dosage form according to any of the preceding claims, wherein the salt form is cisapride- (L) -tartrate.

5. The solid dosage form according to any of the preceding claims, wherein dl is₅₀The pulverized particle size of the active component expressed is in the range of about 10 μm to about 150 μm.

6. The solid dosage form according to any of the preceding claims, wherein the powdered active ingredient used has a particle size of more than 14 x 10³cm²/g(1.4×10³m²/kg) of a specific surface area.

7. The solid dosage form according to any of the preceding claims, wherein the oral dosage form is a capsule.

8. The solid dosage form according to any of the preceding claims in the form of a tablet.

9. A tablet according to claim 8 containing lactose monohydrate and microcrystalline cellulose as a filler.

10. The tablet according to claim 9, wherein the amount of filler is from about 50% (w/w) to about 95% (w/w) based on the total amount of the tablet or core.

11. The tablet according to claim 10, wherein the amount of filler is from about 66% (w/w) to about 86% (w/w) based on the total amount of the tablet or core.

12. The tablet according to claim 11, wherein the disintegrant is croscarmellose sodium (sodium croscarmellose).

13. The tablet according to claims 8-12, wherein the tablet is a film coated tablet.

14. The tablet of claim 13, wherein the tablet has a core of: cisapride- (L) -tartrate 13.23mg 7.35% lactose monohydrate 200 mesh 107.73mg 59.85% unmodified corn starch 36.00mg 20.00% HPMC 291015 mpa.s 3.60mg 2.00% microcrystalline cellulose 12.60mg 7.00% croscarmellose sodium 5.40mg 3.00% colloidal anhydrous silica 0.54mg 0.30% magnesium stearate 0.90mg 0.50% and having selected amounts of coating ingredients (w/w) relative to the coated HPMC 29105 mpa.s 4.00mg 55.94% 1, 2-propanediol 1.00mg 13.99% titanium dioxide 1.20mg 16.78% talc 0.80mg 11.19% yellow iron oxide 0.15mg 2.10%

Wherein the percentage of the core components is% (w/w) based on the total amount of the core and the percentage of the tablet coating is% (w/w) based on the total amount of the tablet coating.

15. A tablet according to claims 8-14 wherein the hardness of the tablet is at least 1.5daN determined according to the test described on page 135 of the european pharmacopoeia test (1997).

16. Front sideThe solid oral dosage form of any of the preceding claims further comprising an antacid, H₂-antagonists or proton pump inhibitors.

17. A process for preparing a solid oral dosage form according to any of the preceding claims, wherein the active ingredient is intimately mixed with a carrier and either filled into capsules or further tableted.

18. The process of claim 17, wherein the active ingredient and excipients are mixed, compressed into a tablet and optionally film coated.

19. Solid dosage form comprising a compound according to any of claims 1 to 15 and an antacid, H₂-the product of an antagonist or a proton pump inhibitor as a combined preparation for simultaneous, separate or sequential use in the treatment of gastrointestinal disorders, in particular gastro-esophageal reflex related disorders.

20. Use of cisapride- (L) -tartrate, cisapride- (D) -tartrate, cisapride-sulfate, cisapride citrate for the manufacture of an oral dosage form without drug-food interaction for the treatment of gastrointestinal disorders.

21. Use of cisapride- (L) -tartrate, cisapride- (D) -tartrate, cisapride sulfate, cisapride citrate in the manufacture of a medicament for treating gastrointestinal disorders in a patient receiving a medicament for increasing gastric pH.

22. Use of cisapride- (L) -tartrate, cisapride- (D) -tartrate, cisapride sulfate, cisapride citrate for the manufacture of a medicament for the therapeutic administration of proton pump inhibitor, H₂-use in the treatment of gastrointestinal disorders in patients with inhibitors or antacids.

23. Use of cisapride- (L) -tartrate, cisapride- (D) -tartrate, cisapride sulfate, cisapride citrate for the manufacture of an oral dosage form for the treatment of gastrointestinal disorders, which oral dosage form can be administered food-independently.

24. Use of cisapride- (L) -tartrate, cisapride- (D) -tartrate, cisapride sulfate, cisapride citrate for the manufacture of an oral dosage form for the treatment of gastrointestinal disorders, which oral dosage form can be administered at the time of consumption.

25. Use of cisapride- (L) -tartrate, cisapride- (D) -tartrate, cisapride sulfate, cisapride citrate for the manufacture of an oral solid dosage form useful in the treatment of gastrointestinal disorders, said oral solid dosage form being capable of being combined with a proton pump inhibitor, H₂The antagonist or antacid is administered together.

26. A pharmaceutical package suitable for commercial sale comprising a container, an oral dosage form of cisapride which does not exhibit adverse food effects, and written non-limiting material associated with said package as to whether said dosage form may or may not be taken with food.

27. An oral dosage form of cisapride- (L) -tartrate, cisapride- (D) -tartrate, cisapride sulfate, cisapride citrate, which dosage form exhibits a (AUC fed) (AUC fasted) value of less than 1.25.

28. Use of cisapride- (L) -tartrate, cisapride- (D) -tartrate, cisapride sulfate, cisapride citrate for the manufacture of an oral dosage form for the treatment of gastrointestinal disorders, which oral dosage form can be taken when needed.