MXPA00003438A - Delayed total release gastrointestinal drug delivery system - Google Patents

Abstract

A gastrointestinal delivery system is provided. The system comprises a drug in combination with a swellable core material, the core being surrounded by a water-insoluble or relatively water-insoluble coating material in which particulate water-insoluble material is embedded. When the delivery device enters the gastrointestinal tract, the particulate matter takes up liquid, thus forming channels interconnecting the drug-containing core with the outside of the delivery device. Through these channels liquid enters the core which then swells to the point at which the coating is broken. When the integrity of the coating is destroyed, the core then disintegrates immediately releasing all or most of the drug at a specific site. By controlling parameters in the device, such as the core material, carrier material in the coating, and particulate matter, the location of release of the drug can be carefully controlled. Thus, the invention is also directed to a method of using the device for the treatment of disease by the release of drugs in the gastrointestinal tract in a location- and time-dependent manner.

Description

SYSTEM OF RELEASE OF GASTROINTESTINAL DRUG DELAY TOTAL DELAYED Field of the Invention The invention is directed to a drug delivery system for the delivery of pharmaceutical compounds administered enterally to specific sites throughout the gastrointestinal tract by the immediate (non-sustained) release of all or most of the drug in place specific. The drug delivery system has the ability to completely lose integrity in a very short period of time allowing the release of virtually all the drug contained therein at the disintegration site. The characteristics that allow this capacity are a coating that forms channels that allows the controlled entry of liquid to a core and a core capable of absorbing liquid and swelling enough to cause the breakdown of a coating that surrounds the nucleus, the nucleus disintegrates quickly after the integrity of the coating is broken.

Background of the Invention The specific delivery of drugs to a selected target in the gastrointestinal tract is desirable for REF: 33150 the treatment of a wide variety of diseases and conditions. It is especially desirable to be able to release drugs, so that they are directed to, and absorbed in, specific regions of the gastrointestinal tract. The targeting of drugs to specific regions along the gastrointestinal tract provides the ability to locally treat gastrointestinal diseases, thereby avoiding the systemic side effects of drugs or the inconvenient and painful direct release of the drugs. Such specific release also potentially increases the efficacy of the drug and allows a reduction in the minimum effective dose of the drug. Coat-based release systems exist in the art. It has been reported that some systems target particular parts of the body. For example, U.S. Patent No. 5,593,697 discloses a pharmaceutical implant containing a biologically active material, an excipient comprised of at least one water-soluble material and at least one water-insoluble material, and a polymer film coating adapted to rupture a predetermined period of time after implantation. In one form, a two-layer film coating forms a barrier impermeable to the drug. An insoluble external film controls the degree of access of the physiological fluid to an internal film that is soluble at physiological pH. By varying the thickness of the outer film, the access of the physiological fluid to the inner film occurs, and in this way the time before the failure of the inner film must be controlled. The failure of the inner film then allows an inflatable excipient (disintegrant) to exert a force on the outer film which then breaks freeing the contents of the core. In another embodiment, a single layer film is used. A film coating comprising a mixture of ethylcellulose and a copolymer of glycol and lactic acid is used. Ethylcellulose is an insoluble polymer and thus when the PLGA polymer is hydrolyzed in the film, the film becomes porous and allows the release of the drug. The rate of hydrolysis of PLGA depends on the ratio of lactic to glycolic acid in the polymer. U.S. Patent No. 4,252,786 a controlled release tablet for the administration of medicinal agents for a prolonged period of time. This involves the application of a film comprising a combination of hydrophobic and hydrophilic polymers to a delayed release matrix of the inflatable, insoluble type, to modify the rate of drug release. Initially when the film is intact, the release of the drug contained in the matrix is controlled primarily by the diffusion of the solvent and the solute molecules through the film. When water or gastric fluid permeates through the film, the gummy complex is formed in the nucleus and the slight swelling of the complex causes the film to break or erode. The rate of release is then controlled by the gummy complex. The application of a water-permeable film, relatively insoluble in water, mainly controls the rate of release of the drug while the gel is being generated from the matrix and it has been reported that this generates a smooth, gradual, more uniform release rate over a period of time. approximately 8-12 hours, approaching a zero-order release pattern. U.S. Patent Nos. 5,260,069 and 5,472,708 describe a dosage form for releasing drugs, and in particular drugs that can not be released by diffusion through a porous coating, such as water insoluble drugs. Granules are provided in a unit dosage form such as a capsule or tablet. The granules are composed of a core containing a drug and an inflatable agent which expands its volume when exposed to water. The core is enclosed within a membrane or coating that is permeable to water. The membrane is composed of a polymer that forms a permeable but insoluble film in water, a polymer that forms a water soluble film and a permeability reducing agent. Water diffuses through the coating and into the core.

As the water is released by the hinged agent, the core expands, exerting force on the coating until it explodes, releasing the drug. The agent that reduces permeability reduces the rate at which water reaches the inflatable agent, thereby delaying the release time. The water soluble polymer dissolves, weakening the coating, so that it explodes soon. By varying the proportions of the three coating ingredients and / or thickness of the coating, it is reported that the release time can be controlled effectively. U.S. Patent No. 4,897,270 describes a pharmaceutical tablet comprising a tablet core and a film coating for masking the taste of the core. The core disintegrates immediately upon rupture of the film coating. The film coating allows the permeation of moisture towards the core, which breaks very quickly after contact with the gastrointestinal fluid. In this way, the core disintegrates immediately, allowing the dispersion and dissolution of the drug. U.S. Patent No. 5,204,121 describes a drug delivery system in the form of granules wherein the granules consist of a core containing the active compound. The core is surrounded by a jacket containing polymer and a nondigestible lacquer layer that is permeable to water. The outer layer of lacquer does not dissolve but carries the water to the jacket layer controlling the migration which then brings the liquid into contact with the core containing the drug. U.S. Patent No. 4,891,223 discloses compositions for the sustained release of a pharmaceutical comparison, comprising a core containing a drug, a first coating containing a swellable polymer upon penetration of the surrounding media, and a second coating, enveloping the first coating, which comprises a polymer that is soluble in water and that forms a semipermeable barrier. The external coating allows the diffusion of the media to the first coating and then the diffusion of the dissolved drug to the surrounding media. The second coating may have extensibility required to prevent rupture of the second coating due to swelling of the first coating up to a specific time in the release pattern. U.S. Patent No. 4,327,725 describes a variation of a basic osmotic device for drug delivery. The structure of the device is an active agent enclosed in a hydrogel layer that is enclosed in a semipermeable membrane. The semipermeable membrane allows diffusion of the external fluid but does not allow the diffusion of the active agent solution into the surrounding environment. The hydrogel swells with the absorption of external fluid and exerts pressure on the solution of active agent in the external fluid. The solution of the active agent in the external fluid is then released to the surrounding media through a single passage specially constructed through the hydrogel layer and the membrane.

Drug Release in the Food Channel Addressing drugs to desired places in the food channel can be complicated. Several factors must be taken into consideration for the release to desirable areas of the alimentary canal. Each segment of the alimentary canal has different characteristics, which can prevent or favor the permeation of drugs through the membrane. The following characteristics must be taken into account. 1. Anatomical - Surface area, epithelium, presence of mucous cells, venous drainage, lymphatic drainage; 2. Physiological characteristics - absorption pathways, pH, motility and transit time, enzymes; 3. Biochemical characteristics - endogenous secretion, pH, intestinal flora, enzymes; 4. Mechanical characteristics - mucous and aqueous coating layers and their exchange rate. 5. Immunological characteristics - antigenic stimulation on the epithelial surface. In controlled release systems currently known in the art, the drugs are released by diffusion and erosion through the gastrointestinal tract. Upon arrival at a target site a large portion of the drug may have already been released, leaving only a small portion of the drug for local release, or may pass through the site without being released to a significant degree.

Stomach Release Current techniques for targeting drugs to the stomach are based on the understanding that sustained release and peroral controlled release may be of limited duration due to gastrointestinal transit time, which is closely related to the rate of gastric emptying. Methods for the prolongation of gastric retention time include the incorporation of fatty acids to reduce physiological gastric emptying (Groning R., et al., Drug Dev. Ind. Pharm, ID: 527-39 (1984)) and the use of bioadhesive polymers. Such systems have been developed using polymers such as polycarbophil, sodium carboxymethyl cellulose, tragacanth gum, acrylates and methacrylates, modified celluloses and polysaccharide gums (Smart, JD et al., J. Pharm Pharmacol 36: 295 (1984)) . Another system for directing drugs to the stomach and avoiding gastric emptying is known as a hydrodynamically balanced system. This system is based on capsules or tablets with a lower apparent density than gastric fluid. In this way, the dosage form remains floating in the stomach. These dosage forms are comprised of 20-75% of one or more hydrocolloids (eg, hydroxyethylcellulose and hydroxypropyhylcellulose (Sheth, PR, Drug, Dev. Ind. Pharm.10: 313-39 (1983); Chien, YWy Drug Dev. Ind. Pharm 9: 1291-330 (1983), Desai, S. and Bolton, S., Pharm. Res. 10: 1321-5 (1993)), Banakar (Amer. Pharm. 21: 39-48 (1987). )) describes gastroinfillable release devices The device contains one or more inflatable chambers which are filled with a gas at body temperature (for example, a gasification liquid or a gas-forming solid, such as bicarbonate or carbonate). The chambers are incorporated into a plastic matrix and encapsulated in gelatin.

The dissolution of the gelatinous coating inflates the device and diffusion of the drug occurs. Certain of these devices include osmotic pressure compartments containing osmotically active salts. The dissolution of these salts by the gastric fluid pumps the drug. Others are based on a floating, two-layer compressed matrix. (Ugani, H.M., et al., Int. J. Pharmaceut, 35: 157-64 (1987)). One of the layers is comprised of a hydrophilic polymer and a composition that generates carbon dioxide. The carbon dioxide maintains the buoyancy and the other hydrophilic layer releases the drug from the matrix. A further method for targeting gastric drug involves a form of intragastric retention, made of polyethylene or a polyethylene mixture (Cargill, R., et al., Pharm. Res. : 533-536 (1988); Cargill, R., et al. , Pharm. Res. 5: 506-509 (1989)).

Delivering to the Small Intestine Release of drugs to sites beyond the stomach is especially desirable for drugs that are destroyed by acidic conditions or enzymes in the stomach, or for drugs that cause local irritation in the stomach. The mechanisms to direct drugs to the stomach are applicable to the release of drugs to the upper small intestine. However, the direction to other areas of the small intestine involves several additional systems. The low pH of the stomach and the presence of gastric enzymes has led to forms in which the drug is provided with an enteric coating. This coating protects the gastric mucosa from the irritation of the drug. The coating is effected with a selectively insoluble substance, and protects the drug from inactivation by gastric enzymes and / or low pH. The most common enteric coatings are copolymers of methacrylic acid (Eudragits ™), cellulose acetate phthalate, cellulose acetate succinate and styrene-maleic acid copolymers (Ritschel, WA, Angewan te Biopharmazie, Stuttgart (1973), pp. 396-402).; Agyilirah, GA, et al., "Polymers for Enteric Coating Applications" in Polymers for Controlled Drug Delivery, Tarcha, P.J. ed., CRC Press, (1991) Boca Ratón, pp. 39-66). The most significant disadvantage of enteric coatings is the variability in time of gastric emptying. This results in a large variation in blood drug levels. Another method to direct drugs to the small intestine is the absorption of the drug via the lymphatic system. Capillary and lymphatic vessels are permeable to lipid soluble compounds and low molecular weight portions (Magersohn, M., Modern Pharmaceutics, Marcel Dekker, New York (1979), pp. 23-85) (Ritchel, W.A., Meth Find Ex. Clin.

Pharmacol 13 (5): 313-336 (1991)). Macromolecules, such as peptides, are absorbed into the lymphatic vessels through Peyer's patches, which occurs equally throughout all segments of the small intestine. Peyer patches are more prevalent in young individuals and are characterized by disappearing in relation to age (Comes, J., Gut 6: 230 (1965)). In Peyer's patches, the antigens are processed to be presented to regulatory T cells.

Activated T cells migrate to the inflamed tissue, where the suppressor cytokines neutralize T cells and any other inflammatory cells. This method is currently under investigation (Ermak, T.H., et al., "Strategies for Oral Immunization and Induction of Gastric Immunity "in Proceed.

Intern. Symp. Control . I laughed Bioact. Ma ter. 22: 334 (1995)). The main disadvantage of directing drugs / peptides to Peyer patches in their reduced availability beyond the average age (Andraesen, Acta Pa trol Microbiol. 49 (Suppl): 81 (1943)). Therefore, they provide a target site for absorption up to a moderate age. Targetting Peyer's patches in a particular segment of the small intestine may be useful in limiting destructive side reactions. The lymphatic drainage of the small intestine provides an absorption window and has the promoted design of the delivery systems directed to this window (Norimoto et al., Internet, J. Pharm.14: 149-157 (1983)). Another method of targeting drugs to the small intestine involves the use of intestinal sorption promoters. Studies have been carried out using long chain fatty acids, including linoleic acid, acylcarnitines, and palmitocarnitine (Morimoto, K., et al., Internet, J. Pharmaceutic 14: 49-57 (1983); et al., Aires J. Physiol. 14: G-332-40 (1986)). Bioadhesives have also been used to prolong intestinal transit, as in oral delivery systems. Adhesion to the intestinal mucosa takes place either by mechanical entanglement or other mechanisms (Longer, M.A. et al., Pharm., In. 7: 114-7 (1986)). The excipients for the extension of the transit time Gl are also under development. Triethanolamine myristate has been shown to increase gastrointestinal transit time and improve absorption of riboflavin (Gronig, R. and Heun, G., Drug Dev. Ind. Pharm., 10: 521-539 (1984); Palin, KJ, et al., Int. J. Pharm. 19: 101-121 (1984)) . Most of the specific delivery systems for the small intestine are still in the experimental phase except for enteric coated tablets. However, as discussed above, the enteric coating can not provide reproducible blood drug levels. Thus, there is a need for a system that directs the delivery of a desired agent to the small intestine.

Colon Release Due to its location in the distal portion of the alimentary canal, the colon is a particularly difficult access. The enteric coating has been used to divert absorption in the stomach and release the drug to the small intestine. The release is based on the pH differences between these two parts of the food channel (Ritchel, WA Angewndte Biopharmazio, Syuttgart Wissensec, Verlag (1973), pp 396-02; Agyilirah, GA and Banker, GS, "Polymers for Enteric Coating Applications "in Polymers for Con trolled Drug Delivery, Tarcha, PJ, ed., CRC Press, (1991) Boca Raton, pp. 39-66). However, it has been shown that blood levels of enteric dosage forms are variable and erratic due to differences in the rate of gastrointestinal emptying. Also, enteric coatings do not all allow the directing of the drug to a particular part of the small intestine in a reproducible manner (Kenyon, C. J. et al., Int.J. Pharm., 112: 201-213 (1994).; Ashford, M. Et al. , Pharm. 91: 241-245 (1993)). In current techniques for targeting drugs to the colon, the solid formulations of the desired drug molecules are coated with a pH-resistant polymer coating. Such formulations are similar to enteric coated formulations which can be used to deliver drugs to the distal ilium. Enteric coatings include biodegradable polymers such as shellac and cellulose acetate phthalate (Levine et al. Gastroenology 92: 1031-1044 (1987)). In contrast to enteric coated formulations, however, colonic release formulations are designed to withstand low and slightly basic pH values (of around seven) for several hours. During this time, it is assumed that the stomach and small intestine pass and reach the large intestine, where the coating disintegrates and initiates the process of drug release. In this way, drugs such as 5-amino salicylic acid (5-ASA), and some steroids have been released into the colon. The polymers used for this purpose are commonly derived from acrylic acid or cellulose derivatives such as cellulose acetate phthalate, or ethyl cellulose (Rasmussen, SN, et al., Gastroen terology 83: 1062 (1982); Levine, DS, et al., Gastroenterology 92: 1031 (1987); Mardini H., et al., Gut 25: 1084-1089 (1987)). However, an important limitation of this technique is the uncertainty of the location and environment in which the coating begins to degrade. Depending on the pattern of gastrointestinal mobility, which can vary widely in individual patients and in different disease states, the degradation of the coating can occur deep in the "colon, or within the small intestine." The presence of chain fatty acids short, carbon dioxide and other fermentation products, and bile acid residues, often reduces the pH of the colon to approximately six (Stevens, CE., Amer. J. Clin. Nutr. 31.-S161 (1978); McNeil , NI, et al., Gut 28: 101 (1987).) This change in pH draws attention to the question of reliability about the colonic pH greater as a shot.

The ability of colonic flora to degrade substrates that are resistant to small bowel digestion has been studied as an alternative method for colonic drug release. This principle was used to release laxative products, mainly sennosides and related compounds (Fairbairn, JW, J. Pharm, Pharmacol 1: 683 (1949), Hardcastle, JD, et al., Gut 11: 1038 (1970); Cummings, JH, Gut 15: 758 (1974)). A drug traditionally used in the treatment of inflammatory bowel disease is sulfasalazine. Sulfasalazine is composed of antibacterial sulfapyridine linked to the anti-inflammatory 5-ASA with an azo bond. 5-ASA is responsible for the clinical effect (Khna, A.K., et al., Lancet 2: 892 (1977)). Sulfasalazine is a prodrug which carries the active 5-ASA to the colon, where the bacterial reduction of the azo group liberates the molecule with the desired therapeutic properties (Klotz, U., Clin.Pharma cokin, 10: 285 (1985)). With the prodrugs 5-ASA (sulfasalazine, azodisalicylate and salicylazobenzoic acid), the release of the original drug is mediated by bacterial enzymes located in the target organ, rather than by the enzymes of the target tissues. However, the azo compound is potentially toxic.

In U.S. Patent No. 5,525,634, a delivery device containing a drug in combination with a matrix is described. The matrix contains a polymer that contains saccharide. The matrix-drug combination can be coated or uncoated. The polymer can be resistant to chemical or enzymatic degradation in the stomach and susceptible to enzymatic degradation in the colon by colonic bacteria. Whether the matrix is resistant or not to chemical and enzymatic degradation in the stomach, the mechanism of drug release in the colon is due to the degradation of the matrix by colonic bacteria and the release of the drug included in the matrix as a result of the degradation of the matrix by bacterial colonic enzymes. European Patent 485840 (from Rohm GmbH), the application of which was published on May 20, 1992, discloses a gastrointestinal delivery device containing, as a coating, a mixture of a polysaccharide and Eudragit ™. However, this formulation does not allow control of the rate of liquid entry into the formulation. Therefore, control of the drug release site can not be achieved. In addition, the polysaccharide is not provided in particulate form. W097 / 25979 describes a drug delivery device that allows targeting in various parts of the gastrointestinal tract. A core containing a drug coated with a hydrophobic polymer which contains water-insoluble, hydrophilic particles included therein. These particles serve as channels for the aqueous medium to enter the nucleus and for the release of drugs by diffusion through these channels. This release system can target several parts of the gastrointestinal tract and slowly release surface drug loading. U.S. Patent No. 4,627,850 (Deter al.) Discloses an osmotic capsule for the controlled rate release of a drug comprising external and internal walls each formed of different polymeric material, the inner wall defining a space containing the drug, with a passage through the walls connecting the outside of the outer wall with the inside of the inner wall. US Patent No. 4,904,474 (Theeuwes et al.) Discloses a colonic drug delivery device comprising means for delaying release in the drug and in the small intestine and means for releasing the drug in the colon. This device comprises osmotic means for forcing the active pharmaceutical agent out of the compartment in which it is contained through an outlet provided in such compartment, towards the colon.

The means for delaying release in the stomach or small intestine are pH-resistant coatings. The delay in drug release is based on time. The structure is calculated so that the content of the internal space filled by the drug is not forced out before the device reaches the preselected target region of the gastrointestinal tract. Although there is evidence that certain proteins and peptides such as interleukin II, interferon, colony stimulating factor, tumor necrosis factor, and melanocyte stimulating hormone can create new and effective therapies for diseases that are poorly controlled until now, The acceptance of these proteins as drugs is currently limited by the methods of release. Colonic release may be a preferred route of administration for these and other novel protein and peptide drugs. In addition, colonic release is also important to direct. drugs for the treatment of inflammatory bowel disease and ulcerative colitis. Treatment methods for other colon disease states could benefit from the immediate release of a drug in the colon. Severe constipation either idiopathic or caused by drugs (eg, morphine, dopamine) or by disease states (eg, Parkinson's disease, spinal cord damage, multiple sclerosis, diabetes mellitus) is frequently caused by dysfunction of Colonic mobility (Sarna, SK, Digest, Dis. &Sci. 36: 821-882 (1991); Sarna, SK, Digest Dis. &Sci. 36 998-1018 (1991)). These conditions are not treated satisfactorily by the available laxative drugs. The dysfunction of colon mobility can be characterized by (i) inability of the colonic motor activity to push the fecal content towards the caudal direction (colonic inertia or gastroparesis); and (ii) inability of the colonic motor activity to provide the propulsive force at the time of defecation (colonic pseudo-obstruction). In most cases, the dysfunction in colonic mobility originates in neurological disorders. The therapy in these cases should therefore be directed towards improving the transit of the intraluminal content, modulating the neural control systems. Prokinetic agents are agents that increase the transit of material through the Gl tract. They affect Gl mobility through action on specific drug-receptor cell interactions, they can interfere with the release of one or more mediators that affect Gl mobility, such as acetylcholine or dopamine, can act directly on smooth muscle. As a result, mobility Gl can be stimulated by dopamine antagonists, such as metoclopramide and domperidone, or by substances which increase the release of acetylcholine, such as metoclopramide and cisapride, or by substances that open directly to receptors. muscarinics on smooth muscle, such as betanecol. However, it has been found that these agents cause neuroendocrine side effects or accelerate colonic transit without a consistent increase in the frequency of evacuations. Reversible acetylcholinesterase inhibitors, such as neogstiamine and its salts, physostigmine and its salts and pyridostigmine bromide, have been shown to increase colonic mobility and cause defecation and even diarrhea when administered intravenously or orally (Kreis, ME et al. Gastroen terology 114: S0128 (1998), Ponevc RJ, et al., Gastroenology 114: G0140 (1998), Turegano-Fuentes, F., et al., Dis. Colon Rectum 40: 1353-1351 (1977), Stephenson, BM , et al., The Lancet 342: 1181-1182 (1993); Keeler, JR, et al., J. Am. Med. Assoc. 266: 693-695 (1991); Sadjapour, K., J. Am. Med. Assoc. 249: 1148 (1983); Anderson, NE, et al., Neurology 41: 985-981 (nineteen ninety six); Battle, W.M., et al. , Gastroenterology 19: 1211-1221 (1980)). However, it is not advantageous to administer these drugs systemically since they affect the smooth muscles of the whole body giving unacceptable side effects. Oral administration is also problematic due to erratic bioavailability and the possibility that the drugs cause buffer side effects in the gastrointestinal tract. (Breyer-Pfaff, U., et al., Clin.Pharmacol.Ther.P. 37: 495-501 (1985); Aquilonius, SM, et al., Eur. J. Clin. Pharmacol. 18: 423-428 (1980 )). There is also a need to release to the colon drugs that are reported to be absorbable in the colon, such as, inter alia, steroids and xanthines. This could increase the efficiency and allow the reduction of the effective dose required (Godbillon, J. et al., British Journal of Clinical Pharmacology 19: 113S (1985); Antonin, K. et al., British Journal of Clinical Pharmacology 19: 131S (1985); Fara, JW, Third International Conference on Drug Absortion, Edinburgh (1988)). It is known that propranolol, oxyprenolol, metropolol, timolol, and benazepril are preferably absorbed into the jejunum while it is known that cimetidine, furosemide, hydroclothiazide, and amoxicillin are preferably absorbed in the duodenum. For a review, see Rubinstein, A., Biopahrm. Drug. Dispos 11: 465-415 (1990). Currently available enterally administered preparations of drugs designed for colonic release are not feasible for long-term use in humans, in part due to the potential toxicity of the azo compounds. There is a need for an improved colonic release system that can be used with a wide variety of drugs and bioactive compounds. Especially, there is a need for the release of drugs such as the aforementioned drugs and other prokinetic drugs to the colon and for surface release immediately to treat constipation. Such release would be advantageous since it would allow the release of the drug to the site of action, thus allowing the use of low doses and avoiding problems of bioavailability of the systemic side effects and local side effects in the upper gastrointestinal tract. Thus, there is a need for an immediate release version of a targeted delivery system. Immediate release would provide an advantage where a high concentration of drug is necessary for a relatively short period of time, either for clinical reasons or to affect a concentration directed gradient to increase absorption.

Brief Description of the Invention The invention is directed to a delivery system or device for delivery directed to one or more specific places in the alimentary canal. The system or device contains a core and a coating. The core contains a drug in combination with a carrier material. This carrier material has the property of swelling upon contact with an aqueous medium such as that found in the alimentary canal. In this way, the core has the essential characteristics of the ability to absorb a large amount of aqueous medium and to swell considerably. However, the core has the additional essential feature of rapidly disintegrating after it breaks. covering. In this way, the coating used by the invention prevents the release of the drug until the predetermined time when the particles in the coating have swollen enough to allow the entry of an aqueous medium into the core. The core swells and pops the coating. The discovered nucleus then disintegrates, releasing surface charge of drug. Accordingly, in a first embodiment, the core provides the following components: a water-insoluble polymer that swells considerably but does not form a strong gel (i.e., a hydrogel), a disintegrant and a hardness enhancer. Useful water insoluble polymers include, but are not limited to, an insoluble metal salt of a polysaccharide such as calcium pectinate or calcium alginate, or a strongly crosslinked polysaccharide such as guar gum cross-linked with glutaraldehyde, pectin, acid Alginic or other vegetable gums. In preferred embodiments, calcium pectinate is the water insoluble polymer. Useful disintegrants include, but are not limited to, Crispovidona. Other disintegrants are also known in the art. Useful hardness enhancers include, but are not limited to, microcrystalline cellulose. In a preferred embodiment, the core shape includes tablets and granules, especially compressed tablets and tablets in matrix form. The coating comprises a material that is not soluble or minimally soluble, in aqueous solution, within which is included a hydrophilic material, not soluble in water, particulate. The essential characteristics of the coating are a relatively rigid hydrophobic polymer, included with particles of an insoluble hydrophilic polymer that allow water to enter in a controlled manner. The particles preferably have the ability to swell. The coating serves to control the speed of liquid entry to the tablet. The factors that influence the rate of absorption of the liquid are the weight percent of the hydrophilic particles, the size of the particles, the characteristics of the swelling of the particles, and the degree of hydrophilicity. The core also has an influence on the rate of water absorption for a given coating thickness. A relatively high concentration of water-soluble salts in the core (relative to the outside of the tablet) produces a high osmotic gradient across the coating membrane, increasing the absorption of the liquid. This design allows the controlled introduction of water or aqueous medium, such as in the gastrointestinal tract to the device. When the aqueous medium contains the particulate material, the particulate matter swells. The particles eventually form channels from the outside of the device to the core containing the drug. The core is flooded with fluid and then swells, breaks the coating, disintegrates, and all or most of the drug is released with an explosive effect.

The core can be designed with variable swelling speeds, for example, swelling fast, moderately fast, slow, etc. Accordingly, the location of the release of the drug is controlled by specific variable parameters such as the thickness of the external coating, the amount of particles included in the coating, the type of particles included in the coating, the particle size distribution of the the particles included in the coating, the core carrier, the swelling speed of the core, the swelling ability of the particulate matter in the coating, the hydrophilicity of the particulate matter in the coating, the swelling speed of the core, and the concentration of salt in the nucleus. Thus, the drug delivery system of the invention further provides a method for enterally administering a drug or other bioactive compound to a patient in need of such a drug whenever it is necessary or desired that such a drug be provided, specifically , locally in the gastrointestinal tract. In the invention, the drug is not released only through the channels created in the coating, but is released by a burst or explosion for a predetermined time at which the coating will break and disintegration of the tablet with simultaneous release will occur. of all or most of the drug. The invention in this way is useful for the local or targeted release of a drug where slow release is undesirable or otherwise a high peak concentration is necessary. It is also advantageous to improve the absorption of poorly absorbed drugs by providing a strong concentration gradient through light at a point considered suitable, either in the small intestine or in the colon, although in preferred embodiments the drug delivery site is the colon. Preferred treatment areas include, but are not limited to, the ilium and the colon. The drug delivery system further provides a method for releasing effective levels of one or more drugs designed for the local treatment of diseases of particular areas of the alimentary tract. Those diseases include, but are not limited to, Crohn's disease, colitis, irritable bowel syndrome (IBS), local spasmolytic action, mucosal ulceration, diarrhea, constipation, colic, carcinomas, cysts, infectious disorders and disorders by parasites. The drug delivery system also provides a method for oral immunization through Peyer's patches and through the colon.

The drug delivery system also offers the opportunity to direct the local release of agents for photodynamic therapy. The drug delivery system also provides a method for the systemic release of effective levels of drug through a target area of the alimentary canal. Drugs that are better absorbed and / or show less side effects, in the distal parts of the alimentary canal can be directed to these sites. The release system allows the release of the duodenum, jejunum, ilium, ascending colon, transverse colon and descending colon as the site for the systemic release of the drug. The invention further provides methods for the preparation of the drug delivery system. The preferred preparation method is by preparing a suspension of the water-insoluble, hydrophilic particles in an alcoholic solution of a hydrophobic polymer. This suspension is spray coated on the core tablet or capsule using conventional tray coating technology.

Brief Description of the Figures Figure 1. Release of diclofenac from tablets 29-76 / A (10% CPV), coated with ethylcellulose / CaP (ratio 1: 1).

Figure 2. Diclofenac release of tablets 229-99 / A (5% CPV), coated with ethyl cellulose / CaP (ratio 1: 1). Figure 3. Diclofenac release of tablets 229-93 / B (hardness 11-13), coated with ethylcellulose / CaP (ratio 1: 1). Figure 4. Diclofenac release of tablets 229-93 / A (hardness 5-6), coated with ethylcellulose / CaP (1: 1 ratio). Figure 5. Release of sodium salicylate from tablets 229-113, coated with ethylcellulose / CaP (ratio 1: 1). Figure 6. Diclofenac release of tablets 263-129 (CaP + CPV + granulated EC, diclofenac + CPV + granulated EC, 50% of Emcocel, D = 7mm), coated with etocel 20 / CaP (ratio 1: 1). Figure 7. Diclofenac release of tablets 263-123 (CaP + CPV + granulated EC, diclofenac + CPV + granulated EC, 50% of Emcocel, D = 7mm), coated with etocel 20 / CaP (40% CaP). Figure 8. Diclofenac release of tablets 263-123 (CaP + CPV + granulated EC, diclofenac + CPV + granulated EC, 50% of Emcocel, D = 7mm), coated with etocel 20 / CaP (45% CaP).

Figure 9. Diclofenac release of tablets 263-123 (CaP + CPV + granulated EC, diclofenac + CPV + granulated EC, 50% of Emcocel, D = 7mm), coated with etocel 20 / CaP (55% CaP). Figure 10. Diclofenac release of tablets 229-76 / A, coated with ethylcellulose / CaP (ratio 3: 7). Figure 11. Release of Pyridostigmine Bromide from Tablets 350-80 (10 mg of drug / tablet) coated with ethyl cellulose / CaP (ratio 1: 1).

DETAILED DESCRIPTION OF THE PREFERRED MODALITIES DEFINITIONS In the following description, a number of the terms used in pharmacology are used extensively to provide a clear and consistent understanding of the specification and the claims, and the scope given to such terms, were provided. following definitions. Where specifically indicated, the terms used herein were used according to their normal meaning and / or recognized in the art. For example, the terms "colon", "large intestine", "small intestine", "stomach", "rectum", "ileus" are all used according to their recognized meaning in the art.

The term "release device" or "delivery system" is intended to refer to a preparation that is designed to deliver a desired agent, such as a drug. The preparation can be a combination of simple or complex formulations of chemical compounds, with or without excipients. The release can be controlled so that the site, time, rate of release and / or actual release and release of a desired agent can be pre-established by the formulation or preparation composition. Such control can occur by physical and / or chemical means. In the context of the invention, "release device" and "release system" are interchangeable. But the term "drug" is intended to describe any pharmaceutical or physiological agent, bioactive compound or combination thereof, useful in the diagnosis, cure, mitigation, treatment or prevention of a disease, or for any other medical purpose. The term "drug" is intended to be broadly interpreted and is not limited in terms of chemical composition or biological activity. The term "core" is intended to describe the central part of anything. With respect to the present invention, the term "core" refers in particular to that part of the drug delivery system that is surrounded by the particle-containing coating and that contains the drug to be released from the delivery system. The term "particulate" is intended to describe a composition composed of separate particles. In the context of the present invention, those separate particles are included in the coating material surrounding the core. It is the absorption of the liquid by these particles that creates channels, pores, or networks that allow the swelling of the nucleus. When the insoluble polymer swells, the individual particles of that polymer swell but remain as individual particles. They do not coalesce into a simple gel (ie, coherent gel) which would prevent the tablet from disintegrating (ie, behaving like a hydrogel). In the context of the invention, "coating", "Coating", "film", "layer", "cover" and the like are interchangeable. The term "insoluble in water" is intended to mean that it is not capable of being dissolved. Within the context of the present invention, the property of insolubility in water is important as follows. Both the hydrophobic film and the hydrophilic particulate matter are insoluble in water and insoluble in the fluids of the gastrointestinal tract. This property is important for hydrophobic coatings to prevent premature coating dissolution and the uncontrolled release of the subsequent drug. The property is also important for the hydrophilic particulate matter so that the formed channels remain intact and continue to allow liquid flow to control the controlled release of the drug. The dissolution of the particulate matter would result in empty channels that would cause undesirable accelerated water absorption and / or premature release of the drug. On the contrary, with the term "soluble in water" it is meant that it is susceptible to being dissolved. The term "hydrophobic" when applied to film media, in addition to its normal definition, refers to compounds that are relatively non-water permeable and water soluble. The term "hydrophilic", when applied to a film, means, in addition to its normal definition, relatively water-permeable and water-soluble compounds. The term "included" or "embedded" is intended to describe the firm fixation of a material in a medium. Within the context of the present invention, this term refers to fixed particulate matter in the coating medium. The term "microcapsule", "microparticle", and "Microsphere" is used in the sense recognized in the art as spheroidal or partially spheroidal particles in the submicron range up to about 1000 microns. Preferred ranges are from 1 to 200 microns, and especially from 2 to 100 microns. The term "channel" is intended to describe a passage through which something flows. In the context of the present invention, it is the connection formed by the absorption of water and the swelling of the particulate matter in the coating so that there is a continuous contact between the swollen particulate matter to form ducts through which the aqueous medium The external system or release device is finally brought into contact with the core material in the device. The term "administrator" is intended to describe the introduction of the delivery system or device of the present invention into a subject. When the administration is for treatment purposes, the administration may be for prophylactic or therapeutic purposes. When provided prophylactically, the substance is provided before any symptoms. The prophylactic administration of the substance serves to prevent or attenuate any subsequent symptoms. When provided therapeutically, the substance is provided at (or immediately after) the onset of a symptom. The therapeutic administration of this substance serves to attenuate any current symptom.

The term "animal" is intended to describe any living creature that contains cells in which the devices of the present invention can be effective. Also among such animals are humans; however, the invention is not intended to be limited thereto, but it is within the contemplation of the present invention to apply the compositions of the invention to any or all animals that may experience the benefits of the invention. Thus, the system and methods of the invention are not limited to administration to humans and are especially useful for the veterinary administration of drugs to any animal, including (but not limited to) pets such as dogs, cats, horses, fish and birds, zoo animals, control and treatment of wild animals, and animals of agricultural importance for the food and dairy industry such as cattle, dairy cows, pigs and poultry. The invention is directed to a delivery system or release device containing a water-insoluble or relatively water-soluble coating around a drug containing an inflatable core. The coating consists of a hydrophobic polymer that resists water ingress to the tablet with non-soluble hydrophilic particles, which are capable of swelling (but not necessarily) through which the aqueous solution enters the tablet in a controlled manner. The coating serves to control the speed of liquid entry to the tablet. The design is such that the coating determines the rate of water absorption while the core swells, which depends on the speed of water absorption and the swelling properties and the core itself determines the time of coating breakage. The properties of the core also give the characteristic that it disintegrates after the coating breaks, giving an explosive release of drug at a predetermined site in a gastrointestinal tract. The drug can be included in the core material or otherwise associated with the core material eg dry blended, or wet granulation. The core may be in the form of a tablet in the form of a matrix or a capsule containing the drug. The core may be in the form of pure drug granules. Alternatively, the core may contain drug granules coated on a separate core material. Alternatively, the core may contain microcapsules containing the drug material. They can be present in more than one of those forms and more than one drug can be released in the same delivery system. In all these forms, the release of the drug from the nucleus is effective. The core has the essential characteristics of being able to absorb enough liquid so that it swells considerably, and disintegrates rapidly after the coating is broken. By "swelling considerably" it is intended to describe that sufficient swelling occurs to obtain and result in a pressure that initiates and / or otherwise facilitates disintegration. By "rapid disintegration" it is intended to describe that the disintegration occurs essentially explosively, but the explosion or burst is sufficient to release effective amounts of the drug from the delivery device or system. The essential components of the core are (1) an insoluble polymer that is capable of swelling considerably but does not form a strong gel, (2) a disintegrant, and (3) a hardness enhancer. An example of a water-insoluble polymer useful includes, but is not limited to, a water-insoluble metal salt of a polysaccharide. In a preferred embodiment, the polymer is calcium pectinate or calcium alginate. In a highly preferred embodiment, calcium pectinate is the most preferred. When calcium pectinate is used, it is preferably present in the core in a range of about 20-70% (w / w); more preferably, 30-60%.

Another example of a water insoluble polymer useful is a highly crosslinked polysaccharide. Preferred embodiments of such polysaccharides include guar gum cross-linked with glutaraldehyde, pectin and alginic acid. Other useful polymers include other cross-linked vegetable gums. If a polymer is crosslinked, the crosslinking should be such that the polymer swells considerably but does not form a coherent gel. The degree of crosslinking appropriate (ie, "strong" within the context of the invention) means that a large percentage of the monomer units are crosslinked, or alternatively, that many crosslinks exist per polymer chain. The absolute degree of cross-linking is flexible, and is based on the desired results as explained above. In this way, the crosslinking can be correlated with the formation of the hydrogel by assays known in the art. Disintegrants include, but are not limited to, Crospovidone and microcrystalline starch, although any suitable disintegrant is relevant. Those would be known to those skilled in the art. A reference listing disintegrants and other types of dosage components can be found, for example, in Pharmaceuti cal Dosage Forms: Tablets, Vol. 1, Herbert A. Lieberman, et al. , eds., Second Edition, Marcell Dekker Inc., New York, NY (1984). In a highly preferred embodiment, Crospovidone is the preferred agent. Crospovidone is preferably present in the core in a range of about 5-12% (w / w) and more preferably around 10%. The core also includes a hardness enhancer. Useful hardness enhancers, include, but are not limited to, microcrystalline cellulose (Emcocel ™), starch, polyvinylpyrrolidone, low molecular weight hydroxypropylcellulose, and low molecular weight hydroxypropylmethylcellulose. In a preferred embodiment, microcrystalline cellulose (MCC) is the hardness enhancer. The MCC is preferably present in the core in a range of about 20-50% (w / w), and more preferably 30-40%. The core optionally contains lubricants, such as magnesium stearate or talc, lubricants, such as fuming silica, granule binders, such as ethylcellulose, polyvinylpyrrolidone, pectin, with ethylcellulose (NF-7) as a binder. However, other binders are known in the art (Pharmaceutical Dosage Forms: Tablets, Vol. 1, Herbert A. Lieberman, et al., Eds., Second Edition, Marcell Dekker Inc., New York, NY (1984)). In this way, the core material may include normal pharmaceutical additives and excipients. (See Handbook of Pharmaceutical Excipients, 2nd ed., Wade, A. and Wellwem P.J., eds., American Pharmaceutical Association (1994)). Combinations of materials for the core are also useful. For example, additional useful core materials include, but are not limited to, combinations of calcium pectinate, microcrystalline starch, starch, polyvinylpyrrolidone, microcrystalline cellulose, calcium phosphate, and cross-linked guar gum. In preferred embodiments, the core material includes a combination of calcium pectinate, microcrystalline starch, starch, microcrystalline cellulose and calcium phosphate. In a preferred embodiment, the core material includes calcium pectinate, Crospovidone, microcrystalline cellulose, microcrystalline starch or starch or any combination thereof. Alternative core materials include, but are not limited to, carboxymethyl cellulose, calcium alginate, cross-linked guar gum, cross-linked polysaccharide, cross-linked vegetable gum, cross-linked hydrophilic polymer, alginic acid, sodium alginate, carrageenan, or any other standard tablet excipient. known to those skilled in the art (See Handbook of Pharmaceuti cal Excipients, 2nd ed., Wade, A. and Weller PJ, eds., American Pharmaceutical Association (1994)).

The coating is a mixture of a water-insoluble hydrophilic particulate material included and dispersed in a water-insoluble material. The coating does not need to be completely insoluble in water. The important parameter is that it allows the slow introduction of water or other liquid fluid, such as that found in the intestinal tract. When the liquid reaches the included hydrophilic particles, the particles include liquid. The particles eventually form channels from the outside of the device to the core containing the drug. In this way, water enters through the channels in a controlled manner, causing the core to swell. The coating breaks at a predetermined time, and the core disintegrates then. The core swells to the point at which the integrity of the coating breaks down and all or most of the drug is released in the explosion (a short period) at the breaking site. The coating is designed to break at a predetermined time, so that the core disintegrates and all or most of the drug is released at the desired breakthrough site. The essential characteristics of the coating are that it contains (1) a relatively rigid hydrophobic polymer, and (2) insoluble hydrophilic polymer particles, which preferably swell in liquid, and which allow the liquid to enter the core in a controlled way by means of channels formed by this. The polymer should be sufficiently rigid, so that when it is molded as a film, which includes the non-soluble hydrophilic particle, the parameter "robustness" - which is the area under the stress-strain curve in which the polymer is not tear (the units are energy / area) - will give values of 0.009-0.21 Mpa. The relatively rigid, hydrophobic polymer useful includes, but is not limited to, ethylcellulose, Eudragit RLMR, Eudragit RSMR, shellac and zein. Ethylcellulose is the preferred polymer. NE-20 ethyl cellulose is a highly preferred polymer. Eudragit RLMR is a copolymer of dimethylamine acrylate / ethyl methacrylate, a copolymer based on acrylic esters and methacrylic acid with a low content of quaternary ammonium groups. The molar ratio of the ammonium groups to the remaining (meth) acrylic and neutral acid esters is about 1:20. This polymer corresponds to the "Type A Ammonium Methacrylate Copolymer" USP / NF. The Eudragit RSMR is a copolymer of ethyl methacrylate / chlorotrimethyl ammonium methyl methacrylate, a copolymer based on acrylic esters and methacrylic acid with a low content of quaternary ammonium groups. The molar ratio of ammonium groups to the remaining neutral (meth) acrylic acid esters is 1:40. The polymer corresponds to the "Ammonium methacrylate copolymer of type B" USP / NF. The Eudragit RSMR is a copolymer of methacrylic acid / methyl methacrylate or ethyl acrylate, an anionic copolymer based on methacrylic acid and methyl methacrylate or a methacrylic acid and ethyl acrylate. The ratio of free carboxyl groups to ester groups of about 1: 1. This polymer corresponds to "Type A and Type C Methacrylic Acid Copolymer" USP / NF. The hydrophilic particles insoluble in the coating are preferably particles that will swell. Examples of substances useful for particles include, but are not limited to, polysaccharides. Such polysaccharides include but are not limited to particles of calcium pectinate, calcium alginate, calcium xanthate, any metal salts of a polysaccharide containing an acid group where the salt renders the water insoluble polysaccharide, microcrystalline starch, insoluble starch, any water insoluble polysaccharide, (eg, cellulose or microcrystalline cellulose), any polysaccharide that becomes insoluble by interaction with a polycation or polyanion, and any covalently crosslinked polysaccharide where the crosslinker renders the water insoluble polysaccharide. Such crosslinking agents include but are not limited to glutaraldehyde, formaldehyde, and epichlorohydrin, diacid chlorides, diisocyanates, diacid anhydrides, and diamines. In a highly preferred embodiment, the particulate matter is, or contains, calcium pectinate. The coating material may optionally contain a plasticizer to improve its properties as is known in the art. The coating that is near the core and surrounds the core can optionally be coated with itself, an outer coating, especially an enteric coating, as is known in the art. This is especially useful if the material covering the core or the particles included in it are adversely affected by the acid conditions of the stomach. Additional external coatings include, but are not limited to coatings to facilitate swelling or mask the taste. In the preferred embodiments, the coating material that is near the core and in which the particles are included contains calcium pectinate (as the non-soluble hydrophilic particles) and Eudragit RLMR or Eudragit RSMR (as the hydrophobic film),. Cospovidona and Eudragit RLMR or Eudragit RSMR or calcium pectinate and ethylcellulose. In the most preferred embodiment, the coating material comprises calcium pectinate and ethylcellulose, most preferably ethylcellulose NE-20. The insoluble carrier may or may not include a plasticizer according to the normal properties of a film as is known to those skilled in the art. The technique. In alternative embodiments, the coating includes, but is not limited to, any combination of a water-insoluble polysaccharide, water-insoluble cross-linked polysaccharide, a water-insoluble polysaccharide metal salt, a water-insoluble protein or crosslinked peptide, a crosslinked water insoluble hydrophilic polymer in a dry powdered form as particulate matter and any hydrophobic polymeric coating known in the art as a water insoluble carrier. Specific examples of useful particulate material include, but are not limited to, insoluble starch, microcrystalline starch, microcrystalline cellulose, chitosan, calcium or zinc alginate, calcium xanthate, borax complex and guar gum, guar gum cross-linked with glutaraldehyde or formaldehyde, dextran cross-linked with glutaraldehyde or formaldehyde, dextran cross-linked with epichlorohydrin, soluble starch cross-linked with glutaraldehyde or formaldehyde, hydrolyzed gelatin cross-linked with glutaraldehyde or formaldehyde, gelatin cross-linked with glutaraldehyde or formaldehyde, collagen cross-linked with glutaraldehyde or formaldehyde, any insoluble complex of a polysaccharide and a protein or peptide, hydroxypropylcellulose cross-linked with glutaraldehyde or formaldehyde, hydroxyethylcellulose cross-linked with glutaraldehyde or formaldehyde, hydroxypropylmethylcellulose cross-linked with gutaraldehyde or formaldehyde, or any of the carbomers (acrylic acid polymers) ico reticulated). Specific examples of the water-insoluble carrier include, but are not limited to, Eudragit RLMR, Eudragit RSMR, ethylcellulose, shellac and zein. In a preferred embodiment of the invention, the delivery system or device is a tablet containing a core material, which is a disintegrable tablet. The tablet is made with standard pelletizing and pelletizing techniques and coated using tray coating technology. Instead of a solution, a suspension of particulate material is sprayed into a solution or fine suspension of the spillover coating material on the tablets. The suspension is stirred to keep it relatively homogeneous. Hot or cold air is flowed over the tablets to allow a film to form and the tablets to dry. Suitable solvents for such polymer solutions or suspensions are typical solvents known to those skilled in the art for spray coating tablets., and include, but are not limited to, water, ethanol, acetone and isopropanol. Ethanol is the preferred solvent.

It should be recognized, however, that any inflatable material is potentially useful as the core material. The functional requirements are simply contact with watery matter and in the gastrointestinal tract and after contact with the channels formed by the particulate material that has absorbed water, the core swells enough to break the coating and disintegrates enough to allow All or most of the drug present in the nucleus is released in an explosion or burst. Any material that is determined empirically causing the necessary amount of swelling can be used. It should also be recognized that any material can form the included particles. The functional requirement is that the material absorbs watery matter from the gastrointestinal tract after forming channels or networks by What water can flow into the core and allow it to swell. The release of the drug is controlled by several of the following parameters: (1) size of the particulate matter; (2) coating thickness; (3) type of material that forms the particulate matter; (4) ratio of particulate matter; (5) material that forms insoluble film in. Water; (6) swelling of the particulate matter; (7) intrinsic hydrophilicity of the particulate material; (8) speed of swelling of the core; and (9) concentration of salt in the core. The diameter of the core can range from 1 mm to 15 mm, and is preferably 6-9 mm. The level of coating can range from 2 to 50 mg / cm2, and is preferably from 4 to 20 mg / cm2. The percent of particulate matter in the coating can range from 1 to 95%, and is preferably 50-70%. The particle size of the particulate matter can range from 0.1 microns to 500 microns, and is preferably from 1 to 150 microns. In particularly preferred embodiments, the delivery system or device is a 9-mm tablet of a drug (e.g., sodium salicylate or diclofenac sodium), a swelling polymer (e.g., calcium pectinate), an agent that causes the disintegration of the tablet (for example, Crospovidone) and a hardness enhancer (for example, microcrystalline cellulose) coated with a suspension of one part of calcium pectinate and one part of ethylcellulose in 20-30 parts of ethanol. The best results are obtained with calcium pectinate with a particle size of < 149μ and a film coating of 13 mg / cm2. This modality allows the release of a drug soluble in the colon since it gives a delay of approximately 4 hours in the release of the drug under conditions of intestinal TS USP (U. S. Pharmacopoeia XXII, National Formulary XVII, page 1789 (1990)) when two dissolution apparatuses are used (U. S. Pharmacopeia XXII, National Formulary XVII, page 1579 (1990)). The preferred embodiment is coated with Eudragit LMR as an enteric coating to protect calcium pectinate from the effects of acidic stomach pH. The enteric coating dissolves in the upper part of the small intestine. The calcium pectinate particles begin to swell slowly when intestinal fluid enters the coating. After about 4 hours, channels have been formed, the core has been swollen and the drug has been released explosively after the disintegration of the tablet. A thinner coating will reduce the delay in drug release and allow the release of the drug to the distal portion of the small intestine. Thus, the drug delivery system serves as a means to direct drugs administered enterally to various regions of the gastrointestinal tract. Accordingly, a subject in need of treatment with the desired agent can conveniently obtain such treatment by orally ingesting the composition of the invention.

Examples of agents that are useful for colonic release include non-steroidal anti-inflammatory drugs (NSAIDs) such as sulindac, diclofenac, flubiprofen, indomethacin, and aspirin.; steroid drugs such as dexamethasone, budesonide, beclomethasone, fluticasone, thioxocortal, and hydrocortisone; contraceptives and steroid hormones such as estrogens, estradiol and testosterone; immunosuppressants such as cyclosporin; bronchodilators such as thiofilin and salbutamol; antianginal and antihypertensive agents such as isosorbide dinitrate, isosorbide mononitrate, nitroglycerin, nifedipine, oxyprenolol, dilitiazem, captopril, atenolol, benacepril, metoprolol, and vasopril; antispasmodic agents such as cymethropium bromide; anticolitis agents such as 5-aminosalicylic acid; antiarrhythmia agents such as quinidine, verapamil, procainamide, and lidocaine; neoplastic agents such as methotrexate, tamoxifen, cyclophosphamide, mercaptopurine, and etoposide; protein or peptide drugs such as insulin, human growth hormone, interleukin II, interferon, calcitonin, leuprolide, tumor necrosis factor, bone growth factor, melanocyte stimulating hormone, captopril, somatostatin, octapeptide analogue of somatostatin , cyclosporine, renin inhibitor, superoxide dismutase, other hormones and vaccines; proteins or peptides containing tissue antigens under autoimmune attack for absorption via Peyer's patches (Cárdenas, L., and Clements, JD, Clin. Mi crobi ol. Rev. 5/3; 328-342 (1992), anticoagulants such such as heparin or short-chain heparin, antimigraine drugs such as ergotomine, glibenclamide, 5-hydroxytryptamine receptor agonist type gepiron, 5HT antagonist, methephamid, menthol, antibiotics such as neomycin, beta-lactams such as ampicillin and amoxicillin, cephalosporins such as cephalexin and cloxacillin, and macrolides such as erythromycin; PGEi analogues to protect the gastroduodenal mucosa from damage by NSAIDs, such as misoprostol; prokinetic drugs such as metoclopramide and cisapride; cholinergic agonists such as betanecol, carbacol, methacholine and pilocarpine, dopamine antagonists such as metoclopramide and domperidone, and reversible acetylcholine inhibitors lcholinesterase, such as neostigmine and its salts, physostigmine and its salts and pyridostigmine bromide. Protein drugs, such as LH-RH and insulin, can survive longer and be better absorbed from the colon than from the small intestine. Other drugs have been shown to possess colonic absorption, such as diclofenac, quinidine, thiofylline, isosorbide dinitrate, nifedipine, oxprenolol, metoprolol, glibenclamide, 5-hydroxytryptamine receptor agonist type A gepiron; 5HT3 antagonist wavesteron; metcephamid; menthol; benacepril (ACE inhibitor). Examples of drugs that are useful for treating various other regions of the alimentary canal are as follows: Gastroesophageal Reflux Disease co-H2 receptor antagonists (e.g., Tagamet, Zantac), proton pump inhibitors (e.g., Omeprazole) ); Esophagitis by candidanistatin or clotrimazole; Duodenal ulcer H2 receptor agonists, prostaglandins (eg, Cytotec, Prostin), proton pump inhibitors - (eg, Prilosec, Omeprazole, Sucralfate); Pathological Hypersecretory Conditions, Syndrome-Zollinger-Ellison-H2 receptor agonists; Gastri tis - H2 receptor agonists, PGEi analogs to protect the gastroduodenal mucosa from damage by NSAIDs such as misoprostol, GHR-IH drugs to treat pancreatitis such as somatostatin, and antispasmodic drugs to treat local spasmolytic action such as the cymethropium bromide. The therapeutic benefits of the delivery system depend on its ability to effectively release levels of drug to a specific site in the gastrointestinal tract. It allows the treatment of diseases, including but not limited to, ulcerative colitis, Chron's disease, colon carcinoma, esophagitis, esophagitis via Candida, duodenal ulcers, gastric ulcers, Zollinger-Ellison syndrome (gastrinoma), gastritis, chronic constipation , diarrhea, pancreatitis, local spasms, local infections, parasites and other changes within the gastrointestinal tract due to effects of systemic disorders (eg, vascular, infectious and neoplastic inflammatory conditions). The direct release of drugs to these regions increases the amount of drug absorbed in this region and the amount of drug to which the cells are exposed directly in that region. The direct release or directing of drugs also decreases the systemic distribution of drugs and therefore reduces the potentially dangerous and undesirable side effects. High concentrations of a drug obtained by an immediate release of the drug in a predetermined section of the gastrointestinal tract may increase the absorption of poorly absorbable drugs by means of a gradient of higher concentration. The delivery system or delivery device is also useful for diagnostic purposes, such as site-specific delivery of x-ray contrast agents (e.g., barium sulfate, sodium diatrizoate, other iodine-containing contrast agents) ultrasound contrast agents (eg, microspheres containing air), contrast agents or amplifiers for magnetic resonance imaging, tomography or emission agents of positrons. The delivery system and the delivery device are also useful for the release of monoclonal antibody markers for tumors. Specific embodiments of the formulations prepared from the composition of the invention include, for example, drug tablets in the form of a matrix, especially tablets prepared by compression, drug granules in the form of a matrix, either free or packaged in capsules of gelatin, or any other means that allow oral administration; drug nanoparticles in matrix form, either free or packaged in gelatin capsules or any other means that allow oral administration; and multilayer tablets, coated capsules, coated microcapsules, coated granules or microgranules, granules or microgranules coated in a capsule, granules or microgranules coated in a coated capsule, coated granules, microgranules or microcapsules pressed into a tablet and coated granules, microgranules or microcapsules pressed into a tablet and additionally coated. All techniques for the preparation of those formulations are well known in the art. The amount of drug can vary as desired for the effective release of the desired drug and in consideration of the patient's age, sex, physiological condition, disease and other medical criteria. In addition, the amount of drug released by the system of the invention will depend on the relative efficacy of the drug. The amount of specific drug necessary for effective results in the delivery system and the methods of the invention can be determined according to techniques known in the prior art. For example, recommended doses such as those known in the art (for example, see the Physicians' Desk Reference, (ER Barnhart, publisher), The Merck Index, Merck &Co., New Jersey, and The Pharmacologi cal Basis of Therapeutics, AG Goodman et al., Ed. Pergamon Press, New York), provide a basis for estimating the amount of a drug that has previously been required to provide an effective level of activity. Examples of drugs whose effective amounts for use in the delivery system of the invention can be determined in this manner including anti-inflammatory agents, including non-steroidal and steroidal anti-inflammatory agents, such as sulindac, indomethacin, diclofenac, flurbiprofen, aspirin, dexamethasone , budesonide, beclomethasone, fluticasone, thioxocortal, and hydrocortisone; immunosuppressants such as cyclosporin; bronchodilators, such as salbutamol and thiofylline; anti-anginal and antihypertensive agents such as diltiazem, captopril, nifedipine, isosorbide dinitrate, oxyprenolol; antispasmodic agents such as cymetropine bromide; antineoplastic agents, including methotrexate, tamoxifen, cyclophosphamide, mercaptopurine eostoside; anti-colitis drugs, such as 5-aminosalicylic acid; and anti-arrhythmia agents, such as quinidine, verapamil, procainamide, and lidocaine; protein or peptide drugs, such as insulin, human growth hormone, interleukin II, interferon, calcitonin, leuprolide, tumor necrosis factor, bone growth factor, melanocyte stimulating hormone, captopril, somatostatin, octapeptide analogue of the somatostatin, cyclosporine, renin inhibitor, superoxide dismutase; other hormones; vaccines; anticoagulants, such as heparin or short-chain heparin; antimigraine drugs, such as ergotomine; prokinetic drugs such as metoclopramide and cisapride; cholinergic antagonists such as betanecol, carbachol, methacholine and pilocarpine; dopamine antagonists such as metoclopramide and domperidone; reversible acetylcholinesterase inhibitors, such as neogstimine and its salts, physostigmine and its salts and pyridostigmine bromide. The tablets and capsules can be prepared and tested by techniques well known in the art, for example, as described in Remington's Pharmaceutical Sciences, Mack Publishing Company, and especially in Chapter 89, the pharmaceutical preparation and manufacture of "Tablets, Capsules and Pills ". In all modalities, if desired, more than one drug can be delivered to the patient in the same matrix. In tablet embodiments, for example, the compositions of the invention can provide a wide range of drug amounts, for example, the amount of drug can vary from about 0.01-95% by weight. In another embodiment, a compressed tablet is formulated containing effective levels of the desired drugs or pharmaceutical compounds as in the tablet form, and an amount of the components of the invention that would allow the disintegration of the tablet and the release of the drugs. after exposure of the tablet to one or more microorganisms present in the colon. Other suitable embodiments will be known to those skilled in the art.

The examples best describe the materials and methods used to carry out the invention. The examples are not intended to limit the invention in any way.

Examples 1-7 Materials and Methods The calcium pectinate powder containing 4% calcium (food grade) was distributed by Genu Copenhagen Pectin (Denmark). For the preparation of the coating suspension, the calcium pectinate was subjected to fractionation using a shaking sieve (Levy Laboratory Equipment, LTD) and a sieve of 149μ (ASTM) 100, diameter 8"(20.32 cm)) to obtain the fraction with a particle size of <149μ, Emcocel 90M (microcrystalline cellulose) (BP grade), Eudragit E 100 (Eud.E), ethylcellulose EC-N100 NF 0100 (EC), magnesium stearate (USP grade), crosslinked polyvinylpyrrolidone (UPS grade) (CPVP or Crospovidone), diclofenac sodium (BP grade) and sodium salicylate (USP grade) were obtained from Mendel, Rohm Pharma (Germany) , Aqualon (Holland), Merck (Germany), Basf, Amoli Organics (India) and Merck (Germany), respectively Pyridostigmine bromide was obtained from Orgasynth Industries (France) Ethyl alcohol was USP grade.

The granulation or dry blending method was used to prepare the blends to compress a tablet by pressing. For dry blending, all components of a formulation except magnesium stearate were manually mixed for 20 to 30 minutes in a polyethylene bag. Magnesium stearate was added and the mixture was further mixed for about 2 to 3 minutes. The granulation will be described for each individual experiment. 8-mm diameter biconvex cores were compressed automatically using a Korsh EK 0 single-punch tablet press operated by an Erweka drive unit (AR 400). The weights of the nuclei fluctuated between 220 to 300 mg depending on the formulation of the nucleus. The hardness of the core was tested using a Schleninger-2E hardness tester. The 9 mm diameter biconvex cores were also automatically compressed using a Kilian RLS-15 15-pin tablet press equipped with a ROF-M type control unit. The hardness of the final cores was measured using a Vankel VK200RC hardness tester. The coating suspension was prepared by dissolving ethyl cellulose (4% w / w) (8 g of EC / 200 g of solution), in ethanol and then powdered calcium pectinate was added to the desired weight ratio. The coating suspension was then maintained by vigorously stirring through the coating process to prevent deposition of the calcium pectinate. The coating system consisted of a polyethylene tray coater (~ 12 cm in diameter), a Heidolph drive motor (RZR 2051, electronic), a peristaltic pump (Masterflex, Digital Consolé Drive, Cole-Palmer Instrument Comany) and a nozzle composed of a "Y" connector tube fixed to one end of the air supply system and over the other to the coating suspension through the peristaltic pump and a 1.2 mm stainless steel tip attached to the head of the tube "Y" connector. The coating conditions are such that the temperature, dew velocity (suspension flow rate), air pressure (for suspension spray), and fan airflow, and fan rotation speed were maintained. constant through the coating process. Dissolution studies were carried out in intestinal fluid TS (phosphate buffer, pH 7.5 without enzymes) using a Vankel 7000 solution tester. Once the tablet was placed in 900 ml of intestinal fluid TS, it was stirred with a paddle at 50 RPM. The solutions were maintained at 37 ° C with a Vankel VK650A heater / circulator. Samples of 3 ml were taken using a Vankel VK8000 automatic sampling device, at intervals of 30 minutes up to 4 hours, followed by intervals of 1 hour up to 12 hours and finally intervals of 2 hours up to 20 hours. Actual determinations of drug release (dissolution results) for coated and uncoated tablets were carried out using an HP 8452A Diode Array Spectrophotometer. The drugs released from coated and uncoated tablets were quantified using a calibration curve obtained from the standard solution, in the intestinal solution TS, in the concentration range of 0-50ppm.

Example 1 Control of Bursting Time by Weight (Thickness) of Coating Tablets were produced using dry blending of the components. The formulation of the core is given in Table I (229-76A). The nuclei were 8 mm in diameter and had a hardness of 11-12 Kp. The uncoated core underwent disintegration in intestinal TS within several seconds releasing all diclofenac. The cores were spray coated with different amounts of ethylcellulose: calcium pectinate (1: 1 w / w). The results are shown in Figure 1. An 8 mg receptor per tablet gave a delay of 2 hours; 11 mg gave a delay of 4 hours; 17 mg a delay of 9 hours; 20 mg gave a delay of 12 hours. In each case the tablets disintegrated completely after the delay time. The reduction in the amount of Crospovidone to 5% (formulation 229-99A) gave essentially identical results. In Figure 2, 7 mg per tablet coating resulted in a delay of 2 hours; 12 mg resulted in a delay of 4 hours; and 17 mg resulted in an 8-hour delay, before the drug was released in a burst or burst. Formulations without Crospovidone did not provide a burst or burst at all.

Table 1: Formulations of the Core of the Tablet 15 twenty Table 1: Formulations of the Tablet Core (continued) EXAMPLE 2 Effect of tablet hardness Tablet cores were made using the dry mixing method and compressing to different compression forces to create tablets with different hardness. The formulation was identical to that of 229-76A (Table 1). The nuclei of the 229-93B tablet gave a hardness of 11-13 kp while the nuclei of the 229-93A tablet gave a hardness of 5-8 kp. The cores were spray-coated with ethylcellulose: calcium pectinate at a weight / weight ratio of 1: 1 as in Example 1. The dissolution studies of coated tablets 229-93B, shown in Figure 3 showed that a coating of 12 mg per tablet gave a delay of 5 hours before the drug was released as a burst or burst. The coated 229-93A tablets did not show an explosion or burst of drug release. After a delay of 7-8 hours for a coating level of approximately 10 mg per tablet, the drug was released slowly (Figure 4).

EXAMPLE 3 Effect of the Hardness Analyzer (Emcocel) and Inflatable Component (Calcium Pectinate) The tablet cores were formulated without Emcocel (formulation 229-99B, see Table 2), or without the inflatable polymer of calcium pectinate (formulation 229-99C, see Table 2). The tablets were produced under compression conditions that gave them almost identical hardness Table 2: Formulations of the Tablet Core Table 2: Tablet Core Formulations (continued) The tablets were spray coated as in Example 1. In both cases, the tablets did not show a release of the drug in the form of a burst or burst. After a delay in the release of the drug depending on the weight of the coating, the drug was released in a burst or burst and part of the remaining drug content was released slowly.

Example 4 Effect of Drug Solubility on the System Tablets were formulated using the highly soluble sodium salicylate drug in place of partially soluble diclofenac sodium. The formulation used is described in Table 3. The tablets were spray coated with varying thicknesses of ethylcellulose: calcium pectinate (1: 1) as in Example 1. Figure 5 shows the results of the dissolution of those tablets in TS intestinal. Sodium salicylate, being more soluble, produces a more rapid entry of water into the tablet, causing a decrease in the delay times for a given coating thickness (compare FIGS. 1 and 5). A 15 mg coating gave only a 1 hour delay time, a coating of 19 mg per tablet gave a delay of 2 hours to the burst or burst of drug, lj- while a coating of 24 mg gave a delay of 2.5- 3 hours. The osmotic action for the inlet water is high if the drug (a salt) is present in higher concentrations in the tablet. To test this explanation we obtained similar results by formulating diclofenac-5 sodium tablets with the addition of calcium chloride (Table 3). Those tablets were also spray coated as in Example 1. A 19 mg coating gave a delay until the burst or burst of one hour when compared to a delay of 9 hours for a 17 mg coating observed? in Example 1.

Table 3: Tablet Core Formulations Table 3: Tablet Core Formulations (continued) EXAMPLE 5 Cores Made with Granulation Tablet cores were produced using a wet granulation method. The advantage of wet granulation over dry mixing is that of improved content uniformity for potent, low concentration drugs, and greater batch-to-batch reproducibility of the process. The granulation also improves the flowability of the powder and the hardness of the obtained tablets. The granulation was carried out as follows: 5.4 g of low viscosity ethylcellulose (for example nf-7) were dissolved in 90 ml of ethanol, 265 g of calcium pectinate were mixed with 15.75 g of Crospovidone. The ethylcellulose solution was slowly added. The mixture was mixed well in a pestle mortar and then dried at 60-65 degrees for 1.5 hours and at 40 degrees overnight. The low viscosity ethylcellulose (0.9 g) was dissolved in 15 ml of ethanol. Diclofenac (45 g) was mixed with 2.7 g of Crospovidone and the ethyl cellulose solution was added. The mixture was mixed with a mortar and pestle and dried overnight at 40 degrees. The -. granules were then mixed with the rest of the components and the tablets weighed.

Table 4: Tablet Core Formulations Table 4: Tablet Core Formulations (continued) The granulated calcium pectinate swells more efficiently than the powdered calcium pectinate allowing a decrease in the percentage of calcium pectinate in the formulation. The tablets of formulation 263-129 (Table 4) were compressed and coated with ethylcellulose; calcium pectinate (1: 1). The solution was studied in intestinal TS. The results are shown in Figure 6. The tablets coated with 8 mg per tablet gave a delay of 1 hour until the burst or burst. The tablets coated with 11 mg gave a delay of 2.5-3 hours. The tablets coated with 17 mg gave a delay of 4-4.5 hours. 25 mg gave a delay of 7.5 to 8 hours.

Example 6 Control of Burst Time Changing EC Ratio: CaP An alternative method to control coating thickness to control the delay time to release in the form of a burst or burst of the drug, is to control the amount of calcium pectinate in the coating. The tablet cores of formulation 263-129 (Table 4) were coated with ethyl cellulose: calcium pectinate, with a variable calcium pectinate content of 40% to 55%. Figure 7 shows the results obtained for a coating with a content of 40% calcium pectinate, Figure 8 for 45%, Figure 29 for 50% and Figure 9 for 55%. The results show that for each type of coating, the duration of the delay until the release in the form of bursting of the drug can be controlled by the thickness of the coating. The results show that for a given coating thickness, there is a shorter delay when there is a higher percentage of calcium pectinate in the coating. Table 5 is a collection of data for the delay time as a function of% calcium pectinate.

Table 5: Delayed Drug Release as a CaP% Function in Coating In addition, the tablets of Formulation 229-76A (Table 1) were coated with calcium pectinate films with a content of 50% and 70% . The results of the delay in drug release for 50% calcium pectinate in the coating are shown in Figure 1, and for 70% in Figure 10. With 70% of the calcium pectinate in the coating is needed a thick coating that is able to obtain a delay of 4 hours.

Example 7 Pills of Total Delayed Release Pyridostigmine Bromide (Lot 350-80) 1.6 grams of Eudragit S100 were dissolved in 10 ml of ethanol. 2.5 gm of pyridostigmine bromide was added to the ethanol solution, which was stirred until complete dilution. 40 gm of calcium pectinate were mixed with 2.4 gm of Crospovidone in a mortar with pistil while the ethanolic solution of Eudragit S100 and pyridostigmine bromide was added slowly. After the mixture was well mixed, it was dried at 40 ° C for 16 hours and then at 80 ° C for 8 hours. The granules were sieved and the fraction of <was used; 420 μ. The granules consisted of pyridostigmine with 1.4 gm of silicon dioxide, Aerosil R972, for 5 minutes to improve its flow properties. The mixture was transferred to a polyethylene bag to which 14 gm of crosspovidone and 68.6 gm of microcrystalline cellulose, Emcocel 90 M, were added. The mixture was mixed for 20-30 minutes. Magnesium stearate, 1-24 gm, was added and the mixture was mixed for another 2-3 minutes. 8 mm biconvex cores were pressed automatically into a Wick Ges.mbh single punch press. The nuclei weighed 250 mg and had a hardness of 10 Kp. The nuclei were coated with ethylcellulose: calcium pectinate 1: 1 as described in the previous examples and tested for their dissolution in intestinal TS solution. The results of the dissolution test are shown in Figure 11. The tablets coated with 21.5 g of coating gave a delay of 4 hours until the immediate release of the drug content. The tablets coated with 31 mg gave a delay of 6.5 hours until the release of the drug in the form of burst or burst, while those coated with 44.2 mg gave 13 hours until the release of the drug in the form of burst or burst.

Discussion of Exemplary Material The calcium pectinate particles in an ethylcellulose film are capable of dramatically altering the properties of the barrier film and giving a new dimension to the control of release of soluble drugs from a matrix. A disintegrable tablet is incapable of directing the release of a drug without an appropriate coating. This coating should prevent the diffusion of the drug from the tablet and control the absorption of the liquid towards the core to control the time and placement of the disintegration of the tablet. The core must be able to break the coating at a predetermined time and then disintegrate. To allow targeted release of a soluble drug a diffusion barrier is necessary. This barrier should allow control over drug release at a synchronized point, so that little or no drug is released sooner than desired. The combination of water-insoluble, but hydrophilic, particles in a hydrophobic coating allows control of the entry of water into the tablet and therefore the controlled disintegration time. It has been shown that by controlling various parameters (percent of particles, particle size, film thickness, polymer identity, particulate material identity and core composition), the release time can be controlled of the drug of an immediate release disintegrable tablet. The general trend is as follows. 1. Core composition: The more soluble the components, either the drug or the salt, in the core, the greater the osmotic pressure of the liquid through the membrane, and the faster the liquid crosses through the channels in the membrane towards the core. 2. Percent of particles: The greater the percent of non-soluble, hydrophilic particles, included in the hydrophobic polymer, the faster the release of the drug. It is thought that this is because they form more channels through which the liquid can enter the nucleus. 3. Particle particle size: The smaller the particle size, the faster the release of the drug for a given percent of particles. Smaller particles means that they are more numerous particles for a given percentage of weight. The particles also have a large total surface area, so that a greater interaction between the particles included in the film is possible, possibly leading to more channels for the liquid to enter the nucleus. 4. Thickness of the film: The thicker the film, the slower the release of the soluble drug. Thicker films require a longer swelling time of the hydrophilic insoluble particles throughout the entire cross section of the hydrophobic barrier film. 5. Identity of the polymer and particles: A more hydrophobic polymer, the longer the release time when all parameters remain the same. The formation of hydrophilic channels will take longer when the polymer is more hydrophobic. The more hydrophilic and inflatable the particles, the faster the release when all the other parameters remain the same, since the liquid enters the nucleus through the swollen hydrophilic channels causing the nucleus to swell and break the coating. The more swollen the larger particles the channels. The more hydrophilic the particles, the faster the channels are formed and provide more efficiency to the diffusion of the liquid through them. It is important to have many parameters that allow the control of the immediate total release of a drug since each drug - matrix combination is unique and the characteristics of the different sites in the gastrointestinal tract are also unique. The present invention will allow the designer to develop the film coating that fits the needs of any system. Having now fully described the invention, it will be understood by those skilled in the art that the invention may be effected with a wide range of equivalent conditions, parameters and the like, without affecting the spirit or scope of the invention or any modality thereof. All references cited here are fully incorporated by reference for their relevant teachings.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (37)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A delivery device for the immediate localized release of a desired agent in the gastrointestinal tract of an animal, the device is characterized in that it comprises: a. a core comprising the agent and a core material that swells when exposed to an aqueous liquid; and b. a coating surrounding the core, the coating has an external surface, the coating comprises hydrophilic particulate matter, insoluble in water, included in a water-insoluble carrier, where the particulate matter forms channels in the coating in the presence of liquid on the external surface of the coating towards the core, to absorb the liquid through the core, where the particulate matter in the channels controls the speed of entry of the aqueous liquid to the core; where upon exposure to the aqueous liquid, the core material swells, breaks the coating and disintegrates rapidly; where the disintegration of the nucleus is sufficient to immediately release effective amounts of the agent of the device in a localized area of the gastrointestinal tract.

The device according to claim 1, characterized in that the core is selected from the group consisting of a tablet, capsule and granule.

The device according to claim 1, characterized in that the water-insoluble carrier is selected from the group consisting of: a copolymer of dimethylaminoethyl acrylate / ethyl methacrylate, a copolymer based on acrylic esters and methacrylic acid with a low content of quaternary ammonium groups, where the molar ratio of ammonium groups to remaining neutral (meth) acrylic acid esters is approximately 1:20; and ethyl methacrylate / chlorotrimethylammonioethyl methacrylate copolymer, a copolymer based on acrylic esters and methacrylic acid with a low content of quaternary ammonium groups where the molar ratio of the ammonium groups to the remaining neutral (meth) acrylic acid esters is 1 : 40, ethylcellulose; shellac; and zeina.

4. The device according to claim 1, characterized in that the outer surface of the coating (b) is further coated with an enteric coating.

The device according to claim 1, characterized in that the material of the inflatable core is selected from the group consisting of polysaccharide, crosslinked polyacrylic acid, and modified cellulose.

The device according to claim 5, characterized in that the polysaccharide • is selected from the group consisting of insoluble metal salts or cross-linked derivatives of alginate, pectin, xanthamate gum, guar gum, tragacanth gum and bean gum, carrageenan, starch, microcrystalline starch, microcrystalline cellulose, metal salts thereof, and covalently crosslinked derivatives thereof.

The device according to claim 5, characterized in that the modified cellulose is selected from the group consisting of crosslinked derivatives of hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose and carboxymethylcellulose and metal salts of carboxymethylcellulose.

The device according to claim 1, characterized in that the particulate material comprises a polymer selected from the group consisting of a water-insoluble polysaccharide, a cross-linked polysaccharide insoluble in water, a water-insoluble polysaccharide metal salt, a protein water insoluble crosslinked, a water insoluble crosslinked peptide, water insoluble protein: polysaccharide complex, a water insoluble peptide: polysaccharide complex, a polysaccharide or a protein or peptide made insoluble by interaction with a polycation or a polyanion and a crosslinked hydrophilic polymer insoluble in water in the form of dry powder.

The device according to claim 8, characterized in that the polysaccharide is selected from the group consisting of an insoluble metal salt of pectin, xanthamate gum. carrageenan, tragacanth gum, bean gum, and alginic acid; an insoluble crosslinked derivative of xantham gum, guar gum, dextran, carrageenan, tragacanth gum, bean gum, pectin, starch, hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose and alginic acid, cellulose, microcrystalline cellulose, insoluble starch and microcrystalline starch.

The device according to claim 9, characterized in that the insoluble metal salt of alginic acid is selected from the group consisting of calcium alginate, zinc alginate, aluminum alginate, ferric alginate and ferrous alginate.

The device according to claim 9, characterized in that the insoluble metal salt of pectin is selected from the group consisting of calcium pectinate, zinc pectinate, aluminum pectinate, ferric pectinate and ferrous pectinate.

The device according to claim 8, characterized in that the crosslinking is by means of a crosslinking agent selected from the group consisting of formaldehyde, glutaraldehyde, epichlorohydrin, diacid chloride, diacid anhydride, diisocyanates, diamines and borax.

The device according to claim 8, characterized in that the water insoluble crosslinked protein is selected from the group consisting of hydrolyzed gelatin crosslinked with glutaraldehyde, hydrolyzed gelatin crosslinked with formaldehyde, gelatin crosslinked with glutaraldehyde, hydrolyzed gelatin crosslinked with formaldehyde, collagen cross-linked with glutaraldehyde and collagen cross-linked with formaldehyde.

The device according to claim 8, characterized in that the crosslinked hydrophilic polymer insoluble in water is a carbomer.

15. The device according to claim 8, characterized in that the crosslinked water insoluble hydrophilic polymer is Crospovidone.

16. The device according to claim 4, wherein the water-insoluble carrier is ethylcellulose, the insoluble hydrophilic particles in water are calcium pectinate, and the enteric coating is a methacrylic acid copolymer / acrylate or acrylate anionic ethyl based on i) methacrylic acid and methyl methacrylate or ii) methacrylic acid and ethyl acrylate, where the ratio of free carboxyl groups to ester groups is about 1: 1.

17. The device according to claim 1, characterized in that the desired agent is a diagnostic or therapeutic agent.

18. The device according to claim 17, wherein the therapeutic agent is selected from the group consisting of nonsteroidal (NSAID), a steroid, a contraceptive, a steroidal hormone, an immunosuppressant, a bronchodilator, an antianginal antiinflammatory agents, an antihypertensive, an antispasmodic agent, an anticolitis agent, an antiarrhythmic agent, a neoplastic agent, a protein, a peptide, a hormone, a vaccine, an anticoagulant, an antimigraine agent, glibenclamide, a receptor agonist 5-4? ú ± XD? trip_p? na type .., one aitagcnis to reaeptrr a apfcagcrásta 5H., metcepiamida, menthol, an antibiotic, a prostaglandin Ei analogue, a prokinetic drug, a cholinergic agent, a dopamine antagonist and a reversible inhibitor of acetylcholinesterase.

19. The device according to claim 18, characterized in that the therapeutic agent is selected from a group consisting of a prokinetic drug, a cholinergic agonist, a reversible inhibitor of acetylcholinesterase.

20. The device according to claim 19, characterized in that the therapeutic agent is the reversible inhibitor of acetylcholinesterase.

21. The device according to claim 20, characterized in that the reversible cholinesterase inhibitor is selected from the group consisting of pyridostigmine bromide, neostigmine brcsnuro neostigmine, neostigmine methylsulfate, fisosistigmina, physostigmine salicylate and physostigmine sulphate.

22. The device according to claim 18, characterized in that the therapeutic agent is a non-steroidal antiinfamatory agent.

23. The device according to claim 22, characterized in that the non-steroidal anti-inflammatory agent is selected from the group consisting of diclofenac, flurbiprofen and sulindac.

The device according to claim 17, characterized in that the therapeutic active agent is useful for the treatment of colitis, Crohn's disease, irritable bowel syndrome, gastritis, pancreatitis, hypertension, angina, arthritis, rheumatoid arthritis, asthma, arrhythmia, local spasmolytic action, mucosal ulceration, diarrhea, constipation, polyps, carcinoma, cysts, and infectious disorders or a parasitic disorder.

25. A method for delivering a desired agent to the gastrointestinal tract of an animal, characterized in that the method comprises oral administration of the drug delivery device according to any of claims 1-16.

26. The method according to claim 25, characterized in that the agent is a diagnostic agent or a therapeutic agent.

27. The method of compliance with the claim 25, characterized in that the agent is the diagnostic agent.

28. The method according to claim 25, characterized in that the agent is the therapeutic agent.

29. The method according to claim 25, characterized in that the portion of the gastrointestinal tract where the agent is released is selected from the group consisting of the stomach, the small intestine, the colon and the rectum.

30. The method according to claim 25, characterized in that the animal has been diagnosed as having a condition selected from the group consisting of colitis, Crohn's disease, irritable bowel syndrome, gastritis, pancreatitis, hypertension, angina, arthritis, rheumatoid arthritis, asthma, arrhythmia, local spasmolytic action, mucous ulceration, diarrhea, constipation, polyps, carcinoma, cysts, infectious disorders and parasitic disorders ...

31. The method of compliance with the claim 29, characterized in that the condition is constipation.

32. A method for delivering a desired agent to the gastrointestinal tract of an animal, wherein the method is characterized in that it comprises oral administration of the delivery device according to claim 17.

33. The method according to claim 32, characterized in that the agent is selected from the group consisting of a prokinetic drug, a cholinergic agonist, and a reversible acetylcholinesterase inhibitor.

34. The method of compliance with the claim 32, characterized in that the agent is a reversible inhibitor of acetylcholinesterase.

35. The method of compliance with the claim 33, characterized in that the reversible acetylcholinesterase inhibitor is selected from the group consisting of pyridostigmine bromide, neostigmine, neostigmine bromide, neostigmine methylsulfate, physostigmine, physostigmine salicylate or physostigmine sulfate.

36. The method according to claim 32, characterized in that the agent is a non-steroidal anti-inflammatory agent.

37. The method according to the claim 35, characterized in that the non-steroidal anti-inflammatory agent is selected from the group consisting of diclofenac, flurbiprofen and sulindac. GASTROINTESTINAL RELEASE SYSTEM DELAYED TOTAL DELAYED SUMMARY A gastrointestinal delivery system is provided. The system comprises a drug in combination with an inflatable core material, the core is surrounded by a water-insoluble or relatively water-insoluble coating material in which the insoluble particulate water material is included. When the delivery device enters the gastrointestinal tract, the particular matter absorbs the liquid, thereby forming channels that interconnect the core containing the drug with the outside of the delivery device. Through these channels liquid enters the nucleus which then swells to the point where the coating breaks. When the integrity of the coating is destroyed, the core then disintegrates immediately releasing all or most of the drug at a specific site. By controlling the parameters in the device, such as the core material, the carrier material in the coating, and the particulate matter, the location of the release of the drug can be carefully controlled. Thus, the invention is also directed to a method of using the device for the treatment of diseases by releasing the drug in the gastrointestinal tract in a place- and in a time-dependent manner.