FR2830446A1 - Composition for selective drug release in the colon, comprising capsule containing carboxylated polysaccharide-coated active agent and polyvalent cations - Google Patents

Abstract

A pharmaceutical composition (A) comprises a capsule having an anhydrous interior and an outer shell which is chemically or enzymatically degradable in the colon, and contains (in physically separate form): (a) active agent(s) (I) and optionally excipient(s), coated with polysaccharide(s) having carboxy functions; and (b) polyvalent cation(s) (II) and optionally excipient(s).

Description

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 The present invention relates to a pharmaceutical composition, more particularly intended for the oral route, for specifically releasing at least one pharmaceutical active at the level of the colon.

 The digestive tract of a human or monogastric animal includes the stomach, small intestine (duodenum, ileum, jejunum), and the large intestine (the cecum, colon, rectum). These different parts of the digestive tract are characterized by the presence of enzymes and their own pH.

entre autres des Clostridium, des bactéroides fecalis, des lactobacilles anaérobies, des biphidobactéries. La flore bactérienne fermente une large variété de disaccharides non absorbables, d'oligosaccharides et de polysaccharides. De plus, ! es poiymères non-a-giucans, d'origine naturelle, tels que la cellulose, l'hémicellulose et les substances pectiques sont susceptibles de fermenter dans le gros intestin. Dans le processus de digestion, le côlon absorbe l'eau de la lumière intestinale. Il régule les volumes et concentrations d'électrolytes dans les matières fécales (Na+ et CI- sont résorbés ; K+ et HC03- sont sécrétés par la muqueuse) et abrite une population de micro-organismes qui évolue dans un milieu anaérobie et réducteur. The colon is characterized by an anaerobic environment where grow

Clostridium, bacteroid fecalis, anaerobic lactobacilli, biphidobacteria. The bacterial flora ferments a wide variety of non-absorbable disaccharides, oligosaccharides and polysaccharides. Furthermore, ! Non-α-glucans, of natural origin, such as cellulose, hemicellulose and pectic substances are likely to ferment in the large intestine. In the process of digestion, the colon absorbs water from the intestinal lumen. It regulates the volumes and concentrations of electrolytes in feces (Na + and CI- are resorbed, K + and HC03- are secreted by the mucosa) and hosts a population of microorganisms that evolves in an anaerobic and reducing environment.

 The colon is the seat of many diseases such as constipation, irritations, Crohn's disease, ulcerative colitis, carcinomas and infections. The treatment recommended in the case of these diseases generally consists in administering anti-inflammatory agents, chemotherapeutic agents and / or antibiotics which must be released specifically in the colon. It may also be of interest to specifically release, at this level of the digestive tract, for example, peptides, proteins, dewormers and diagnostic agents.

 For colonic administration to be satisfactory and therefore effective, it is necessary to bring the substances intact and in sufficient concentrations into the ascending colon. Formulation studies have been underway for more than 20 years to administer oral drugs and to be able to release them specifically in

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 colon. Unfortunately, the active ingredients administered orally are generally degraded and / or absorbed before reaching the colon.

 Rectal administration of active ingredients using suppositories or enemas generally do not allow to reach the general sites of colic and colonic absorption diseases. This is the reason why the oral route for the administration of drugs intended to be released and absorbed at the colon level is privileged and constitutes a research axis in the field of galenic pharmacy.

 The galenic formulation must take into account the obstacles of the gastrointestinal system to allow an intact release of the active ingredients at this level and to allow these assets to be then absorbed. To do this, the developed dosage forms must take into account the pH of the gastrointestinal tract, the intestinal flora, the reducing medium present in the colon and the gastrointestinal transit time.

 In addition to the fact that the specific release of active ingredients necessary to treat colon pathologies may be of significant interest, the colon and in particular the ascending colon is also an interesting site of absorption for certain active principles for systemic purposes.

Absorption is relatively lower than in the small intestine, but is offset by a slower transit. In addition, the colon is a more selective absorption site that tends to promote the absorption of hydrophobic molecules by the transcellular route.

 The techniques developed to release a selectively active ingredient in the colon are essentially based on (i) gastrointestinal transit time, (ii) the presence of azoreductases in the colon, (iii) the pH of the colon and (iv) the selective degradation of certain polysaccharides in the colon.

 Some polysaccharides are indeed known to be specifically degraded by the bacteria present in the colon. These polysaccharides (pectins, pectic acid, amylose, alginic acid, etc.) are therefore ideal substances for selectively bringing an active ingredient into the colon. Nevertheless, these polysaccharides have the disadvantage of being water-soluble in most of the digestive tract and consequently freeing

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 prematurely the active principle (s) associated with them. In order to reduce the solubility of the polysaccharides, US Pat. No. 5,525,634 solves this problem by covalently attaching oligosaccharides (cellobiose, lactulose, raffinose, stachyose) to acrylic polymers or by chemically modifying polymers such as chondroitin sulfate and pectin.

de cations po) yva ! ents (Ca, tvtg, S,...) en solution aqueuse dans laquelle un principe actif peut également être présent. Le polymère réticulé précipite, est séché, tamisé, puis est comprimé sous forme de comprimés. In the latter case, the pectin is initially crosslinked in the presence

of cations po) yva! ents (Ca, tvtg, S, ...) in aqueous solution in which an active ingredient can also be present. The crosslinked polymer precipitates, is dried, sieved and compressed into tablets.

réticulation par du formaldéhyde ou des ions Ca2+, Sr, Mg, At, Fe ou Fe conduit à une opération qui peut être préjudiciable à la forme pharmaceutique et risquer de la dégrader (trempage dans des solutions contenant du formaldéhyde, dans des solutions contenant des ions multivalents,...). La réticulation des polysaccharides, avant de réaliser les formes pharmaceutiques, conduit à la difficulté ultérieure d'y incorporer le ou les principes actifs à l'intérieur des polysaccharides réticulés devenus insolubles. De plus, les substances réticulés sont connues pour être difficilement comprimables et servent principalement, dans le domaine de la formulation de comprimés, d'agents désintégrants, ce qui n'est pas toujours souhaitable. The coating of solid pharmaceutical forms such as particles, granules, tablets with polysaccharides followed by a step of

cross-linking with formaldehyde or Ca2 +, Sr, Mg, At, Fe or Fe ions leads to an operation that may be detrimental to the pharmaceutical form and risk degrading it (soaking in solutions containing formaldehyde, in solutions containing ions multivalent, ...). The crosslinking of the polysaccharides, before carrying out the pharmaceutical forms, leads to the subsequent difficulty of incorporating the active ingredient (s) within the crosslinked polysaccharides which have become insoluble. In addition, the crosslinked substances are known to be difficult to compress and serve mainly in the field of tablet formulation, disintegrating agents, which is not always desirable.

 In order to ensure a specific release in the colon, Edman P. and ColI. (WO 92/00732) produced coacervates using polysaccharides specifically degraded by the enzymes present in the colon. These coacervates make it possible to encapsulate active principles and to release them consequently at the level of the colon. In order to avoid premature release of the active principle, the constituent polymers of these coacervates are crosslinked using polyvalent cations such as Ca 2+, Mg 2+, Fe 2+ and Fe 3+. Coacervation with the aid of polysaccharides which are subsequently crosslinked leads to the production of solid pharmaceutical forms containing, because of the technique used, low concentrations of active principles. The weakly carboxylated or highly methoxylated polysaccharides such as pectins give rise to the formation of crosslinking agents in the presence of a polysaccharide agent.

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 crosslinking (Ca2 +, Su2 +, Mg2 +, At, Fe2 + or Fe3 +), which will be insoluble in water and will easily diffuse molecules of active principles.

 Watanabe et al. (WO 95/28963) have described a specific drug delivery system in the colon consisting of an active ingredient coated with a macromolecular substance soluble in organic acidic solvents and a saccharide which rapidly generates organic acids under the action of enteric bacteria present in the lower part of the gastrointestinal tract. The disclosed dosage forms can also be coated with enteric-resistant macromolecules to increase the specificity of the release in the colon. However, the simultaneous or consecutive coating of active ingredients included in granules or tablets with highly carboxylated polysaccharides and multivalent ions leads to the formation of non-reproducible agglomerates, because of the crosslinking during the coating operation. .

 Kinget et al. (WO 92/07553) have prepared solid forms for specific drug release by coating them with copolymers of methacrylic acid and alkyl or hydroxyalkyl (meth) acrylate which have the property of to be resistant in gastric fluids and which dissolve or only disintegrate in the colon if the ratio of free acid groups to esterified carboxylic groups in the copolymer is between 1: 4.5 and 1: 3, the limiting values being excluded. The copolymers described can be prepared either directly by copolymerization of the monomers in proportions such that a copolymer having the specified ratio can be obtained, or starting from a copolymer having a ratio of the different monomers between 1: 1 and 1: 3 and whose free carboxylic functions will be partially esterified so as to obtain the desired ratio.

 The general methods for providing a specific release of active principles in the colon have been described in the patent application WO 95/35100 which claims the coating of starch capsules with the aid of polymers which degrade or dissolve in the cells. physiological conditions encountered in different parts of the digestive tract. The prior art cited in this document describes a system consisting of a starch capsule coated with

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 using a mixture of polymers of the methacrylate type. These polymers dissolve only at values above pH 4.5, thus allowing a formulation comprising them to remain intact in the stomach. As soon as it enters the small intestine, the coating of the capsule begins to dissolve. By adjusting the coating thickness of such formulations, it is possible for one capsule to reach the terminal ileum or ascending colon before releasing its contents.

 EP 0 513 035 describes how a similar result can be achieved by using polymers that specifically degrade in the colonic environment, this being due to the presence of specific reducing conditions there.

 Other methods have also been described to provide specific colonic release. These methods are, but not limited to, the Time Clock Release System (Pozzi et al., APV on Pulsatile Drug Delivery, Koningswinter, May 20, 1992) which is a tablet whose core is coated with a thickness of pharmaceutical excipients. After a determined period of hydration necessary for this coating, the tablet core can be released.

 Puisincap System is an oral pharmaceutical form intended to release its contents at a predetermined time in the gastrointestinal tract. This system consists essentially of a waterproof capsule that contains the active ingredient and sealed at one end by a plug made of a hydrogel. The device is introduced into an ordinary capsule. After ingestion, the gelatin shell dissolves and the hydrogel plug begins to hydrate. At a predetermined and controlled time, the inflated cap is ejected from the body of the device and thus releases the contents of the capsule (Wilding et al., Pharma Res 9,654, 1992 and Binns et al., 3rd Eur Symp.

 Control. Drug Del., Abstract Book, 1994, page 124).

Another system that can be used is that of the controlled explosion of a pharmaceutical form, such as that described in the patent
US 4,871,549.

 The patent application WO 97/25980 discloses the use of hollow polymer beads consisting of styrene-divinylbenzene and methyl

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 methacrylateethylene glycol dimethacrylate within which an active ingredient can be occluded. These beads can be coated with pectin so as to ensure specific release in the colon.

 A polymeric hydrogel system that allows peptide and protein-based drugs to be administered specifically in a site and, more particularly, in the colon has been described in patent application WO 98/01421. The disclosed hydrogel will protect the drug against the acidic environment of the stomach, and then swell at a chemically controlled rate in the environment of the small intestine which has a higher pH. The hydrogel is then degraded in the colon by enzymes and, more specifically, by azoreductases. These pH-sensitive hydrogels are obtained from N-substituted (meth) acrylamide monomers, acrylic or methacrylic acid, a crosslinker containing an aromatic azo bond, and an N, O-diacylhydroxylamine. The chemical regulation of the swelling can be performed by initially introducing N, Odiacylhydroxylamine fragments into the hydrogel. These fragments remain stable in the acidic environment of the stomach, but are subject to hydrolysis when subjected to the pH of the intestine, ie at a pH greater than about 6.5. During hydrolysis, the ionized COOH groups attached to the polymer network are generated. The swelling is maximal when the hydrogel reaches the colon where degradation occurs by cleavage of the azoreductases of the azoaromatic crosslinking agent.

 Azo and / or disulfide polymers for use as drug delivery systems specifically in the colon have been described in patent application 91/11175.

 Mixtures of gelatin and polysaccharides which are degradable in the presence of colonic enzymes and optionally crosslinked with an aldehyde or polyvalent metal ion but which are not degraded or disintegrated in the upper gastrointestinal tract have also described in EP 0 888 778 A1.

 Delayed release dosage forms for specific release in the colon have been described in WO 91/07949. These pharmaceutical forms consist of an active ingredient mixed with

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 amorphous amylose, constituting the core of the coated tablet with amorphous amylose and a cellulose coating film or an acrylic polymer or a mixed mixture. Allwood et al. (WO 89/11269) also suggested using the same concept with vitreous amylose as a matrix agent and as a coating agent.

 In order to selectively bring into the colon probiotic microorganisms such as bifidobacteria, Brown et al. (WO 96/08261 A1) have suggested using modified starches (hydroxypropyl, acetyl, cotenyl succinate, carboxymethyl or succinate).

 Bronsted and Hovgaard (WO 94/01136) claimed drug-specific delivery systems in which the drug is included in or deposited on a matrix system. The matrix element consists of a crosslinked dextran polymer degradable by dextranases.

 D. Friend and D. Wrong (WO 96/40078) prepared tablets containing a mixture of active ingredients such as corticosteroids, 5-amino salicylic acid, peptides or a laxative stimulant and hydrocolloid gums obtained from from plants such as locust bean gum, tragacanth gum or karaya gum. The compositions of the claimed tablets make it possible, after oral administration, to ensure an effective therapeutic release of the active principle in the colon without premature release in the upper part of the digestive tract.

 In order to ensure specific colonic release of corticosteroids, Friend and Fedorak (WO 93/22334) describe the synthesis of prodrugs in which the sugar moiety is bound to the corticosteroid by an ether or thioether linkage at the 21-position of the corticosteroid and which is specifically degraded by colonic bacteria, thus releasing the corticosteroid.

 Newton and Siew (WO 99/21536) describe a method for achieving controlled release forms in the colon. This is ensured by coating solid forms with a film consisting of a mixture of a polymer having film-forming properties and amylose.

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 Thus, the object of the present invention is to provide a solid pharmaceutical form allowing a release at the colon specifically active ingredients it contains.

 It also aims to obviate the aforementioned drawbacks. More particularly, the process for preparing the pharmaceutical form according to the invention is easy and inexpensive.

 These and other objects are achieved by the present invention which relates to a pharmaceutical composition comprising at least one capsule whose interior is essentially anhydrous and whose outer shell is susceptible to be degraded chemically or enzymatically in the colon, said capsule containing: - on the one hand (i) at least one active substance and optionally one or more pharmaceutically acceptable excipients, coated with at least one polysaccharide having carboxylic functions; and - on the other hand (ii) at least one polyvalent cation and optionally one or more pharmaceutically acceptable excipients, these two parts (i) and (ii) being physically separated.

 The composition according to the invention is thus intended to release specifically at least one active substance in the colon.

 Figure 1 corresponds to a diagram of a capsule (1) according to the invention, particles, granules or tablets (2) containing the active ingredient (s) (3) coated with polysaccharides having carboxylic functions (4). The multivalent cations are in the form of particles, granules or tablets (5) introduced as such into the capsule, which also contains the particles, granules or tablets of active ingredients coated with the polysaccharide (s). In order to avoid premature release of particles, granules or tablets after dissolution of the capsules in the stomach or small intestine, these are preferably coated with gastroresistant polymers (6) and which dissolve or degrade at pH t 6.5, the pH observed in the latter part of the small intestine.

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 During the dissolution or degradation of the coating of the capsule, it dissolves, allows the entry of water of biological origin in the capsule. This water dissolves the particles, granules or tablets containing the crosslinking agents (Ca2 +, On ", Mg2 +, Al3 +, Fe2 + or Fe3 +) which react with the carboxylated polysaccharide coating of the particles, granules, tablets containing the active principle (s) This reaction leads to the formation of a hydrogel on the surface of particles, granules or tablets.The hydrogels being insoluble and highly crosslinked, do not allow the molecules of active principles to diffuse. active in the colon is ensured by selective enzymatic degradation of crosslinked polysaccharide macromolecules.

 By active substance or active principle is meant according to the invention any pharmaceutical or physiological agent or a mixture of pharmaceutical or physiological agents. It may be intended for systemic or local pharmacological action in the colon. Among these agents, there may be mentioned anti-inflammatory agents, chemotherapeutic agents, antibiotics, peptides, proteins, dewormers and diagnostic agents.

 Of course, the amount of the active substance in the capsule is an effective amount. This amount to be established is within the reach of the skilled person and depends essentially on the active substance and the desired effect.

 The active substance is generally in the form of powder, minigranules, granules, tablets or capsules.

 In the present case, the specific release of the active substance into the colon is in particular ensured by using polysaccharide macromolecules which can be specifically degraded in the colon.

 The hydrosolubility of the polysaccharides is reduced, after opening the capsules, by crosslinking them with polyvalent ions. This crosslinking can not take place before opening of the capsules, the interior of these being essentially anhydrous.

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 By essentially anhydrous is meant according to the invention a medium whose amount of water is insufficient to allow a crosslinking reaction between the cations and polysaccharides present in the composition. According to the present invention, the water to allow crosslinking must be provided mainly by the biological fluids of the gastrointestinal tract of the human or animal body. More specifically, the maximum percentage by weight of water is 1% relative to the total weight of the capsule contents.

! vtg, At, Fe, Fe ou leur mélange. Des exemples de sels sont notamment choisis parmi les chlorures, iodures, fluorures, sulfites, sulfates, phosphates, nitrites et nitrates. Les exemples de bases sont notamment les hydroxydes ou les carbonates. The polyvalent cations, in the form of salts or of base, are preferably divalent or trivalent cations, such as Ca 2+, Sur 2 ',

! vtg, At, Fe, Fe or their mixture. Examples of salts are chosen from chlorides, iodides, fluorides, sulphites, sulphates, phosphates, nitrites and nitrates. Examples of bases include hydroxides or carbonates.

 The cations are present in the present invention in an amount generally of between 0.0001 and 50% by weight, preferably between 0.0001 and 20% by weight relative to the total weight of the composition according to the invention.

 The polyvalent cations are present in the capsule in the form of powder, minigranules, granules, tablets or capsules.

 Polysaccharides having carboxylic functions are polymers whose osidic units have carboxylic functions.

Preferably, at least 25% of the units of the polysaccharide have a carboxylic function. Advantageously, at least 50% of the units of the polysaccharide have a carboxylic function.

 Among the polysaccharides having carboxylic functions, mention may be made more particularly of pectic acid, alginic acid, polygalacturonic acid and pectinic acid.

 The amount of polysaccharide present in the composition according to the invention is between 0.01 and 99.99% by weight, preferably between 1 and 99% by weight relative to the total weight of the composition.

 The polysaccharides thus coat the active ingredient which is in the form of powder, minigranules, granules, tablets or capsules.

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This coating may be carried out by spraying, in particular in a coating turbine or by coating, in particular in a fluidized air bed.

 Advantageously, this coating is carried out so that the amount of polysaccharide having carboxylic functions represents at least 5% by weight relative to the coated mass expressed by weight. More advantageously, this amount represents at least 8%, even more advantageously 9% by weight relative to the coated mass expressed by weight. Advantageously, the amount of polysaccharide having carboxylic functions represents at most 20%, preferably at most 15%, by weight relative to the coated mass expressed by weight, knowing that beyond the effect provided by the polysaccharides is more improved.

 The capsules of the present invention are generally based on gelatin, a cellulose derivative, starch or a gum.

 The outer shell of the capsule is preferably resistant to chemical and enzymatic degradation in the stomach, preferably also resistant to chemical and enzymatic degradation in the jejunum and duodenum. More particularly, the capsule has a coating which provides it with a resistance as described above. Thus, this coating may correspond to a coating sensitive to pH, sensitive to reduction or sensitive to particular enzymes or to bacteria, so that the coating dissolves or dissolves only in the colon.

Thus, the capsules only release the active ingredient when they have reached the colon.

The thickness of the coating is generally between 80 μm and 300 μm. The thickness of the coating will be chosen according to the mechanism by which it is dissolved.

 Preferred coating materials are those that dissolve or degrade at a pH greater than or equal to 5, preferably at a pH greater than or equal to 6.5. Thus, the coatings only begin to dissolve or degrade when they leave the stomach and enter the small intestine. A substantial thickness of the coating dissolves in a period of about 3-4 hours, which allows the capsule under the coating to open or dissolve only when it has reached the ileum or colon.

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 Such a coating can be prepared from many polymers, such as cellulose acetate trimellitate (CAT), hydroxypropylmethyl cellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), phthalate Cellulose acetate (CAP) and shellac (described in Healy's Enteric Coatings and Dealyed Release, Chapter 7, in Drug Delivery to the Gastrointestinal Tract, editors Hardy et al., Ellis Horwood, Chichester, 1989). For cellulose ester coatings, a thickness of 200 to 250 μm is advantageously employed.

 Preferred compounds are methyl methacrylates or copolymers of methacrylic acid. Such compounds are available as Eudragit polymers (Rohm Pharma). Eudragit polymers are copolymers of methacrylic acid and methyl methacrylate. The preferred compounds are based on Eudragit S100 and / or Eudragit L100.

 This coating of the capsule is generally obtained by spraying, laminating or dipping a solution comprising the polymers, followed by drying.

 The pharmaceutically acceptable excipients possibly present in the composition are generally additives conventionally used. In particular, mention may be made of binders, diluents, flow agents, lubricating agents, pigments or sugars, such as starch, lactose, sucrose, cellulose derivatives or chitosan.

 The methods for preparing powder, minigranules, granules, tablets or capsules are those conventionally used in this field and are therefore within the abilities of those skilled in the art.

 The examples illustrate the invention without limiting its scope.

Examples
Through the various examples described, caffeine was used as a tracer in the various examples. Other active ingredients can be used, with no difference in the studies of release or delivery in the colon.

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 As a crosslinking agent, calcium was taken up in the examples above. No difference in crosslinking of the polysaccharides was observed by choosing other multivalent ions.

Example 1: formulation of granules of active principle
In a planetary mixer are introduced (for a mixture of 500 grams) 100 grams of caffeine, 400 grams of Avicel @ PH 101 sold by the company FMCS) international and are homogenized for 1 minute. 420 grams of deionized water are added and the mixture is homogenized for 15 minutes. A homogeneous wet mass is obtained.

At each extrusion operation, about 1.5 kg of wet mass is used. The extrusion is carried out using an E-140 Niro Aeromatic Fielder extruder marketed by Aeromatic Fielder and a S-140 Niro Aeromatic Fielder spheronizer marketed by Aeromatic Fielder. The grid used is perforated with holes having a diameter of 1 mm. The rotation speeds are for '' impeller '' of 72 revolutions per minute and for the 'Feeder' of 82 revolutions per minute. The spheronization operation is at 500 rpm for 10 minutes. The minigranules obtained are then dried during
10 minutes in the fluidized air bed of an Aeromatic Fielder MP1 type marketed by Aeromatic Fielder. The drying parameters used are: - Lift air flow: 150 m3 / hour - Drying air temperature: 66 C - Product temperature at the end of drying: about 45 C.

 At the end of this drying operation, dry minigranules of homogeneous size are obtained.

Example 2: Formulation of multivalent ion granules
In a planetary mixer are introduced 100 grams of calcium chloride and 400 grams of Avicel @ PH 101. All the powders are mixed for 1 minute. 500 grams of deionized water are added to the powder mixture and homogenized for 15 minutes. A homogeneous wet mass is obtained. With each extrusion operation, approximately 1.5 kg

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 wet mass is used. The extrusion is carried out using an E-140 Niro Aeromatic Fielder extruder and an S-140 Aeromatic Fielder spheronizer. The grid used is perforated with holes having a diameter of 1 mm. The rotational speeds are to "impeller" 70 rpm and for the "Feeder" 80 rpm. The spheronization operation is at 500 rpm for 10 minutes. The minigranules obtained are then dried for 10 minutes in the fluidized air bed of an Aeromatic Fielder MP1 type.

grammes de lactose, 2, 5 grammes d'Aérosil@200 commercialisé par la société Degussa Ag, Frankfurt, et 287, 5 grammes d'Avicei@PH101. L'ensemble des poudres est homogénéisé à 50 tours par minute pendant 15 minutes. 10 grammes de stéarate de magnésium sont ajoutés et l'ensemble est homogénéisé à 50 tours par minute pendant 3 minutes. Le mélangeur de poudres obtenu est introduit dans la trémie d'une machine à comprimer alternative de type Korsch EKO DMS commercialisé par la société Korsch Maschinefabrik, Berlin. Des comprimés de masses homogènes ayant un diamètre de 5 mm de diamètre sont obtenus. The drying parameters used are: - Lift air flow: 460 m3 / hour - Drying air temperature: 70 ° C - Product temperature at the end of drying: about 50 ° C
Example 3: formulation of tablets of active principle
In the container of a mixer Turbula @ marketed by the company WAB, System Schatz, Willy A. Bachofen, Maschinefabrik, Basel, are introduced (for a mixture of 500 grams) 100 grams of caffeine, 100

grams of lactose, 2.5 grams of Aerosil @ 200 marketed by Degussa Ag, Frankfurt, and 287, 5 grams of Avicei @ PH101. All the powders are homogenized at 50 rpm for 15 minutes. 10 grams of magnesium stearate are added and the mixture is homogenized at 50 rpm for 3 minutes. The powder mixer obtained is introduced into the hopper of an alternative Korsch EKO DMS type compression machine marketed by Korsch Maschinefabrik, Berlin. Tablets of homogeneous masses having a diameter of 5 mm in diameter are obtained.

Example 4: Formulation of Multivalent Ion Tablets
In the container of a mixer Turbula @, are introduced (for a mixture of 500 grams) 100 grams of calcium chloride, 100 grams of lactose, 2.5 g of Aerosil @ 200 and 287.5 grams of Avicel @ PH101. The whole of the powders is homogenized at 50 rpm for 15 minutes, 10 grams of magnesium stearate are added and the mixture is homogenized at 50 rpm for 3 minutes. The mixture of powders

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 obtained is introduced into the hopper of an alternative Korsch EKO DMS compression machine. Tablets of homogeneous masses 5 mm in diameter were obtained.

 Example 5: Coating solid forms containing the active ingredient using carboxylated polysaccharides.

 The coating of the minigranules and tablets are carried out in a similar manner. The preparation of the coating solutions of various highly carboxylated polysaccharides (pectic acid, alginic acid) are similar.

 150 g of pectic acid and / or alginic acid are introduced into a beaker. 1350 g of deionized water are added with stirring. The mixture is heated at 50 ° C. with stirring for 1 hour. All the prepared solutions continue to be agitated and heated during their spraying on the minigranules or tablets to be coated.

 Before starting the coating, the minigranules or tablets are dusted by sieving. The coating of minigranules and tablets is carried out in an Aeromatic Fielder MP1 type. The coating parameters are as follows: - Lift air flow: 80 m3 / hour - Drying air temperature at the entrance of the coating chamber: 80 C.

- Coating liquid spray pressure: 2 bars - Coating liquid spray rate: 18 g / min - Quantity of minigranules or tablets: 1.5 kg - Quantity of coating liquid: 1.5 kg
In order to reduce the viscosity of the coating liquid, it is heated to 75 C.

Example 6 Coating Capsules
As examples, 100 grams of powdered Eudragit® S100 are dissolved in 1000 ml of an acetone / isopropyl alcohol mixture in a

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 ratio 4: 6.10 grams of triethyl citrate are added and are dissolved in the previous solution.

 The coating of the capsules is carried out either manually by dipping and drying or automatically by introducing them into a stretall marketed by the company Aeromatic Fielder. In the latter case, for example, 300 capsules n 2 are introduced into a Stréa @ II and are coated with 1000 ml of a solution containing 10% w / v of Eudragit S100 by the technique of "Top Spray "(Industrial Pharmacotechny (p41, IMT Editions, 1998, Chapter 5.4, pages 328-329, Edited by Yves Rosetto et al.) The coating operation is carried out at 60 C and the spraying speed is 20 grams per hour. minute.

Example 7 Release Study and Kinetics of the Active Principle
The caffeine release studies are performed in a dissolutest (Prolabo) using a UV-2101 PC spectrophotometer, Schimadzu.

 Release assays were performed in pH 1.5 release media (pH of the stomach); 6 (pH of the beginning of the small intestine); 6.5 without pectinase and 6.5 with pectinases.

 Buffer medium pH 1, 5: European Pharmacopoeia 2001.

 Buffer medium pH 6: European Pharmacopoeia 2001.

 Buffer medium pH 6.5, without pectinase: 6.8 g of potassium dihydrogen phosphate and 1.4 gram of sodium hydroxide are dissolved in 1000 ml of deionized water. The pH is adjusted if necessary.

 PH 6.5 buffer medium with pectinases: 6.8 g of potassium dihydrogen phosphate and 1.4 gram of sodium hydroxide are dissolved in 997 ml of deionized water. 3 ml of pectinase solution are added.

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 Galenic preparations (1) coated capsules containing 100 mg minigranules coated with pectic acid.

 (2) coated capsules containing 100 mg minigranules coated with alginic acid.

 (3) coated capsules containing 100 mg minigranules coated with pectic acid + 88 mg minigranules containing CaCl2.

 (4) coated capsules containing 100 mg minigranules coated with alginic acid + 88 mg minigranules containing CaCl 2.

 (5) coated capsules containing 200 mg tablets coated with pectic acid + 176 mg tablets containing CaCl2.

 (6) coated capsules containing 200 mg of tablets coated with alginic acid + 176 mg tablets containing CaCl2.

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<tb> 2 <SEP> 0 <SEP> 0 <SEP> 82 <SEP>% <SEP> after <SEP> 20 '
<tb> 100 <SEP>% <SEP> after <SEP> 40 '
<tb> 2 <SEP> 0 <SEP> 0 <SEP> 79 <SEP>% <SEP> after <SEP> 20 '
<tb> 100 <SEP>% <SEP> after <SEP> 41 '
<tb> 3 <SEP> 0 <SEP> 0 <SEP> 0 <SEP>% <SEP> after <SEP> 50 '
<tb> 5 <SEP>% <SEP> after <SEP> 100 '
<tb> 10% <SEP> after <SEP> 200 '
<tb> 3 <SEP> 0 <SEP> 0 <SEP> 0 <SEP>% <SEP> after <SEP> 50 '
<tb> 37 <SEP>% <SEP> after <SEP> 100 '
<tb> 100% <SEP> after <SEP> 180 '
<tb> 4 <SEP> 0 <SEP> 0 <SEP> 0 <SEP>% <SEP> after <SEP> 50 '
<tb> 5 <SEP>% <SEP> after <SEP> 100 '
<tb> 10% <SEP> after <SEP> 180 '
<tb> 5 <SEP> 0 <SEP> 0 <SEP> 0 <SEP>% <SEP> after <SEP> 50 '
<tb> 5 <SEP>% <SEP> after <SEP> 100 '
<tb> 10 <SEP>% <SEP> after <SEP> 200 '
<tb> 5 <SEP> 0 <SEP> 0 <SEP> 0 <SEP>% <SEP> after <SEP> 50 '
<tb> 41 <SEP>% <SEP> after <SEP> 100 '
<tb> 100 <SEP>% <SEP> after <SEP> 180 '
<tb> 6 <SEP> 0 <SEP> 0 <SEP> 0 <SEP>% <SEP> after <SEP> 50 '
<tb> 5 <SEP>% <SEP> after <SEP> 100 '
<tb> 10 <SEP>% <SEP> after <SEP> 180 '
<tb> 6 <SEP> 0 <SEP> 0 <SEP> 0% <SEP> after <SEP> 50 '
<tb> 44 <SEP>% <SEP> after <SEP> 100 '
<tb> 100 <SEP>% <SEP> after <SEP> 150 '
<Tb>
% by weight of release of the active ingredient.

Claims (12)

A pharmaceutical composition comprising at least one capsule, the interior of which is essentially anhydrous and the outer envelope of which is capable of being chemically or enzymatically degraded in the colon, said capsule containing: on the one hand (i) at least one active substance and optionally one or more pharmaceutically acceptable excipients, coated with at least one polysaccharide having carboxylic functions; and - on the other hand (ii) at least one polyvalent cation and optionally one or more pharmaceutically acceptable excipients, these two parts (i) and (ii) being physically separated.  The pharmaceutical composition according to claim 1, wherein the active ingredient is formulated as a coated powder, coated minigranules, coated granules, coated tablets or coated capsules.  The pharmaceutical composition according to claim 1 or 2, wherein the divalent or trivalent ions are formulated as powder, minigranules, granules, tablets or capsules.  4. Pharmaceutical composition according to one of claims 1 to 3, wherein the capsule is coated with a material which dissolves or degrades to a pH greater than or equal to 5.  5. Pharmaceutical composition according to one of claims 1 to 4, wherein the capsule is coated with a material which dissolves or degrades at a pH greater than or equal to 6.5. <Desc / Clms Page number 20>  6. Pharmaceutical composition according to claim 1, wherein the active ingredient is intended for a systemic or local pharmacological action in the colon.  The pharmaceutical composition according to claim 1, wherein the polysaccharide for coating the active ingredient is pectic acid or alginic acid.  8. Pharmaceutical composition according to claim 7 wherein the coating polysaccharide of the active ingredient is pectic acid.  9. Pharmaceutical composition according to claim 1 wherein the inducing ions of the crosslinking are provided by salts or bases of divalent or trivalent ions selected from calcium, magnesium, zinc, iron (II), strontium, aluminum and iron (III).  The pharmaceutical composition of claim 1 wherein the capsule shell is gelatin, a cellulosic derivative, starch or gum.  11. The pharmaceutical composition according to claim 1, in which the active principle (s) can be formulated in the presence of binders, diluents, flow agents, lubricating agents, pigments or sugars, such as sucrose, lactose, cellulose or chitosan.  The pharmaceutical composition of claim 1 wherein the one or more multivalent cation salts or bases may be formulated in the presence of binders, diluents, flow agents, lubricating agents, pigments or sugars such as sucrose, lactose, cellulose or chitosan.