Coatable core for modified release drug formulation

Abstract

A method for producing a coatable core for a sustained release drug formulation for oral administration to deliver the drug to the colon. The method includes forming a core comprising a drug. An outer layer coating composition is formed by combining a first aqueous composition of an enzymatically degradable polymer that is degradable by colonic bacterial enzymes; a second aqueous composition of an enteric coating polymer with a pH threshold of about pH 6 or higher; and an organic anti-adhesion agent. The core is then coated with the outer layer coating composition to create a core coated with an outer layer.

Description

Method for producing delayed-release drug formulations The present invention relates to a method for producing a sustained-release drug formulation with a core comprising a drug and a sustained-release coating. In particular, the invention relates to a sustained-release drug formulation for delivering the drug to the intestine. Drugs that target the gut have been well-known for over a hundred years. The target of drugs is usually the small intestine, although the colon can be used as a route to achieve local or systemic therapy. The need for drug coating varies depending on the target site. To reach the colon, drugs need to pass through the small intestine, so a sustained-release coating designed to release the drug in the colon needs to not release the drug in the small intestine. Coated products for release in the small intestine typically use polymer coatings that dissolve or degrade in a pH-dependent manner. In the low pH environment of the stomach, the polymer coating is insoluble. However, upon reaching the small intestine, the pH rises to 5 and above and the polymer coating dissolves or degrades. The conventional coating used is one that contains ionizable carboxyl groups. At higher pH levels, the carboxyl groups ionize and thus the polymer coating degrades or dissolves. Conventional polymers of this type include Eudragit® L and Eudragit® S. Various methods of improving release in the small intestine are known to ensure earlier release of the drug. US2008 / 0200482 is one such reference that partially neutralizes the carboxylic groups to reduce the pH that causes disintegration. WO2008 / 135090 discloses a tablet with an inner coating of partially neutralized material and an outer coating with less or no neutralization. The material is said to disintegrate earlier than it has passed through the stomach. Drug delivery to the colon usually requires an alternative route. The colon is susceptible to several diseases, including inflammatory bowel disease, irritable bowel syndrome, constipation, diarrhea, infection, and cancer. In such conditions, targeting the colon can maximize therapeutic efficacy. The colon can also be used as a portal for drugs to enter the systemic circulation. Various formulations have been developed for drug delivery to the colon, including prodrugs as well as formulated dosage forms, and the concept is gaining popularity as it can be applied to other drugs. Larger bacterial populations in the colon have also been used in the development of enteral drug delivery dosage forms, such as digestible carrier materials made from naturally occurring polysaccharides that form substrates for many enzymes produced by resident bacteria in the colon. These materials can normally pass through the intact upper gastrointestinal tract but are digested upon entering the colon. Examples include starch, amylose, amylopectin, pectin, chitosan, galactomannan, and guar gum. One of the main attractions of using polysaccharides in this bacterial enzyme approach to enteric drug delivery is that the materials used are food grade and therefore safe for human use. These materials are typically used as coatings or as matrix carriers in the bulk material and their digestion by colonic bacterial enzymes upon entry into the large intestine results in the release of the drug load. An example of such a formulation, which uses an amylose coating, is disclosed in EP0343993A (BTG International Limited). However, the main limitation of these naturally occurring materials is that they swell excessively in aqueous environments, leading to clearance of the drug load in the upper gastrointestinal tract. To circumvent this problem, natural materials have been used in combination with various impermeable materials. EP0502032A (British Technology Group Ltd) teaches the use of an outer coating comprising a forming layer of cellulose or acrylate polymer material and amorphous amylose for a tablet containing an active compound. The polymer material used is a pH independent free polymer material. An article in the journal Controlled Release (Milojevic et al; 38; (1996); 75-84) reports the results of research on the incorporation of a wide range of insoluble polymers into an amylose coating in order to control the swelling of the amylose. A range of cellulose and acrylate-based copolymers are evaluated and a commercially available ethyl cellulose (Ethocel®) is found to effectively control swelling. A pH-dependent soluble coating of Eudragit® L 100 is used but only in a multi-layer system consisting of a bioactive coating with an inner amylose coating followed by an outer Eudragit® L 100 coating. An amylose-based coating composition is disclosed in WO99 / 21536A (BTG International Limited). The coating composition comprises a mixture of amylose and a pH independent water-soluble polymer forming layer which is comprised of a water-soluble acrylate or cellulose polymer material. WO99 / 25325A (BTG International Limited) also discloses a sustained release coating comprising amylose and (preferably) ethyl cellulose or alternatively an insoluble acrylate polymer. The coating composition also comprises a plasticizer and this method finds particular application in the preparation of dosage forms comprising active ingredients which are unstable at temperatures above 60°C, as the composition is formed at temperatures below this. WO03 / 068196A (Alizyme Therapeutics Ltd) discloses a specific sustained release coating for the bioactive prednisolone sodium metasulphobenzoate comprising glassy amylose, ethyl cellulose and dibutyl sebacate. The use of polysaccharides other than amorphous amylose in a sustained release coating is disclosed in GB2367002 (British Sugar PLC). Examples include guar gum, karaya gum, tragacanth gum and xanthan gum. Microparticles of these polysaccharides are dispersed in a water-soluble polymer film-forming matrix consisting of, for example, a cellulose derivative, an acrylic polymer or a lignin. WO01 / 76562A (Tampereen Patenttitoimisto Oy) discloses an oral pharmaceutical formulation containing a drug and chitosan (a polysaccharide derived from chitin) for controlled release. The drug and chitosan are mixed into a homogeneous mechanical powder composition which is granulated and then tableted. The granulation may be carried out with an enteric polymer (such as a methacrylic acid copolymer) or the granules may be prepared with a porous enteric coating. WO2004 / 052339A (Salvona LLC) discloses a pH-dependent drug release system which is a free-flowing powder of hydrophobic solid nanospheres and comprises a drug encapsulated in a pH-sensitive microsphere. The nanospheres are composed of drug substance in combination with a waxy material and the pH-sensitive microsphere is composed of a pH-sensitive polymer (such as Eudragit® polymer) in combination with a water-sensitive material such as a polysaccharide. An article in the European Journal of Pharmaceutical Sciences (Akhgari et al; 28; March 2006; 307-314) reports the results of research on the use of some polymethacrylate polymers, including inulin, for controlling swelling. The polymethacrylate polymers tested were Eudragit® RS; Eudragit® RL; a 1:1 mixture of Eudragit® RS and Eudragit® RL; Eudragit® FS; and a 1:1 mixture of Eudragit® RS and Eudragit® S. US5422121 (Röhm GmbH) discloses an oral dosage form comprising a core containing at least one active ingredient contained within a shell material comprising a polysaccharide which, in combination with a polymer-forming layer, is degraded in the large intestine. The weight ratio of polysaccharide to polymer-forming layer is from 1:2 to 5:1, preferably from 1:1 to 4:1. Premature release of the active ingredient from the core can be suppressed by the use of a gastro-resistant release layer. This reference discloses tablets comprising an inner release layer of Eudragit® L30D with an outer layer comprising Eudragit® L30D and guar gum (Example 2). WO96 / 36321A discloses an oral dosage form comprising a core containing bisacodyl and an enteric polymer coating for the core, the coating comprising at least one inner coating layer and one outer coating layer. Each of the inner coating layers is an enteric polymer that begins to dissolve in an aqueous medium with a pH of about 5 to about 6.3, and the outer coating layer is an enteric polymer that begins to dissolve in an aqueous medium with a pH of about 6.8 to about 7.2. The enteric polymer coating material for the inner layer(s) is selected from the group consisting of cellulose acetate phthalate; cellulose acetate trimellitate; hydroxypropyl methylcellulose phthalate; hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalate; poly(methacrylic acid, methyl methacrylate) 1:1; poly(methacrylic acid, ethyl acrylate) 1:1; and compatible mixtures thereof. WO2013 / 164315A discloses a colonic drug delivery formulation comprising a core containing a drug and a coating comprising an inner layer and an outer layer. A mixture of a pH-dependent layer-forming polymeric material and a polysaccharide such as starch is used as the outer layer, and the inner layer is soluble in intestinal fluid or gastrointestinal fluid. This reference is among the formulations in which the outer layer uses a “semi-organic” coating composition. The “semi-organic” coating composition is prepared from an aqueous dispersion of a polysaccharide and an organic (typically, ethanolic) solution of the pH-dependent layer-forming polymeric material. The preparation of pharmaceutical formulations requires the use of various excipients such as fillers, extenders, plasticizers and regulators. A special group of excipients used in the preparation of coating formulations are anti-adherents. To prevent the tendency of the powder or granules to stick and agglomerate during processing and storage, anti-adherents are typically added to coating formulations. This helps prevent a tablet or capsule from sticking to the surface, to the walls and from being hit by the processing machine. The most commonly used anti-adherents are inorganic materials such as talc and colloidal silica. For example, WO2013 / 164315A describes the use of talc in combination with an aqueous coating composition. WO2013 / 164315A also describes the use of the organic anti-adherent, glyceryl monostearate (GMS), in coating formulations prepared using a “semi-organic” coating composition. It is desirable to provide an improved method for producing a sustained-release drug formulation for drug delivery to the colon. According to a first aspect of the present invention, there is provided a method of producing a sustained release pharmaceutical formulation for oral administration for delivering a drug to the colon of a subject, said method comprising: providing a core comprising a drug; a first aqueous composition of an enzymatically degradable polymer that is degradable by intestinal bacterial enzymes (first polymeric material); a second aqueous composition of an enteric layer-forming polymer having a pH threshold of about pH 6 or higher (second polymeric material); and an organic anti-adhesion agent; to form an outer layer coating composition to form an outer layer coated core. The inventors have discovered that the use of an organic anti-adhesion agent applied to an aqueous outer layer results in coatings that are more digestible in vitro by α-amylase and produces a sustained-release drug formulation that improves gastric resistance and exhibits a faster drug release profile in Krebs buffer (pH 7.4). The first aqueous composition, the second aqueous composition and the organic anti-blocking agent can be combined in any order. Preferably, the second aqueous composition is added dropwise to the first aqueous composition, followed by the addition of the organic anti-blocking agent. The outer layer coating composition is preferably a completely homogeneous dispersion or suspension. In embodiments where the enzymatically degradable polymer is starch, it is preferred that the first aqueous composition is prepared by dispersing the starch in at least one alcohol, preferably a C1 to C6 alcohol, namely methanol; ethanol; propan-1-ol; propan-2-ol; butan-1-ol; butan-2-ol; and mixtures thereof. It is particularly preferred to use butan-1-ol alone. Water is then usually added thereto with stirring. The resulting dispersion is usually heated to the point of overflow (i.e., cooking) and then cooled with stirring overnight to obtain an aqueous dispersion. The purpose of the alcohol(s) is to dissolve the starch ready to form an aqueous dispersion. Alternatively, the polysaccharides can be dispersed directly in water. In addition, in cases where starch is used as a polysaccharide, alcohol helps to stabilize the washed amylose during the cooking process. In particular, it is believed that amylose forms complex V with butan-1-ol, which slows down the rate of crystallization upon cooling. The reassociation of amylose into double helices is known as re-dissociation and is thought to reduce the digestibility of the starch. It is preferred that the second aqueous composition is formed by suspending the enteric polymer in water by stirring to form a suspension and partially neutralizing the suspension with a base. Preferably, a base is added to the suspension in an amount sufficient to neutralize the carboxylic acid groups present in the enteric polymer, from about 10% to about 30%, preferably from 15% to 20%. In principle, any pharmaceutically acceptable base may be used. Preferred bases include potassium hydroxide and aqueous ammonia. A more preferred base is aqueous ammonia. Preferably, the aqueous ammonia has a concentration of about 0.5 N to about 2 N, for example from about 0.5 N to 1.5 N, preferably about 1 N. In the embodiments, the organic anti-adhesion agent is in the form of an aqueous dispersion. Preferably, the aqueous dispersion includes a surfactant. The surfactant is added to facilitate the dispersion of the organic anti-adhesion agent. In principle, any pharmaceutically acceptable surfactant is suitable. The surfactant is usually non-ionic or hydrophilic. A particularly preferred surfactant is polysorbate 80 (Tween®). In principle, any pharmaceutically acceptable organic anti-adherent may be used. Preferred organic anti-adherents include glyceryl monostearate (GMS) and stearic acid. The organic anti-adherent is typically present in the coating composition in an amount of between about 2 wt% and 20 wt%, for example from about 5 wt% to about 15 wt%, preferably about 7 wt% to about 12.5 wt%, preferably about 10 wt%, based on the dry weight of the enteric polymer. In preferred embodiments, the outer layer coating composition comprises no more than 5% v / v organic solvent, preferably no more than 4% v / v, preferably no more than 3% v / v, preferably no more than 2% v / v, preferably no more than 1% v / v. In some embodiments, the core is pre-coated with a separate layer comprising a non-ionic polymer forming a layer that is soluble in gastrointestinal fluid; or an inner layer comprising a polymeric material that is soluble in intestinal or gastrointestinal fluid (third polymeric material); or both the separate layer and the inner layer. The third polymeric material is selected from the group consisting of a polycarboxylic acid polymer that is at least partially neutralized and a non-ionic polymer, provided that the third polymeric material is a non-ionic polymer, the inner layer comprising at least one additive selected from a buffering agent and a base. Enzymatically degradable polymer (the first polymer material) An enzymatically degradable polymer is broken down or digested by one or more bacterial enzymes present in a person's large intestine (colonic bacterial enzymes). Such enzymes are produced by colonic bacteria and include amylases such as alpha-amylases, beta-amylases and iso-amylases, amylopolonase, glucoamylase, alpha-glucosidase, maltogenic amylase, glycosyltransferases and amylomaltase. One skilled in the art is able to determine whether a substance is susceptible to attack by colonic bacterial enzymes using techniques that are within the general knowledge. For example, a predetermined amount of a given substance can be exposed to an assay containing an enzyme from a colonic bacteria and the change in weight of the substance over time can be measured. Alternatively, the amount of degradation product produced as a result of the action of colonic bacterial enzymes can be measured. The enzymatically degradable polymer is preferably a polysaccharide. Suitable polysaccharides are selected from the group consisting of starch, amylose, amylopectin, chitosan, chondroitin sulfate; cyclodextrin, dextran, pullulan, carrageenan, scleroglucan, chitin, cordylane, levan and hemicelluloses such as xylan, glucuronoxylan, arabinoxylan, glucomannan, xylo-glucan. The polysaccharide is preferably starch. Starch is typically obtained from natural sources such as cereals, legumes and seed tubers. Suitable starches for use in the present invention are typically food grade starches and include rice starch, wheat starch; corn (or corn) starch; pea starch; potato starch; sweet potato starch; tapioca starch; sorghum starch; Sago starch and arrowroot starch. Below is the use of corn starch with an example. Starch is usually a mixture of two different polysaccharides, amylose and amylopectin. Different starches may contain different proportions of these two polysaccharides. Most natural (unmodified) corn starches contain from about 20 wt% to about 30 wt% amylose, with the remainder being at least amylopectin. Suitable starches include “high amylose” and “low amylose” starches. High amylose starches are particularly preferred. "High amylose" starches are starches that contain at least 50 wt% amylose. Particularly suitable starches contain from about 50 wt% to about 75 wt% amylose, preferably from about 50 wt% to about 70 wt%, preferably from about 50 wt% to about 65 wt%, most preferably from about 50 wt% to about 60 wt%, for example about 55 wt%. "Low amylose" starches are starches that have less than 50 wt% amylose and at least 50 wt% amylopectin, for example up to 75 wt% amylopectin and even up to 99 wt% amylopectin. Starches suitable for use in the present invention typically contain at least 0.1 wt%, for example at least 10 wt% or 15 wt%, preferably at least 35 wt% amylose. Such starches contain no more than 99.9 wt% amylose, i.e. no more than 90 wt% or 85 wt%, preferably no more than 65 wt% amylopectin. Such starches may contain up to about 99 wt% amylose and less than 1 wt% amylopectin. Starches suitable for use in the present invention may contain up to 100% amylopectin, typically from about 0.1 wt% to about .99.9 wt% amylopectin. The starch may be, for example, unmodified waxy maize starch. This starch typically contains 100% amylopectin. The desired starches do not contain more than 50 wt% amylopectin. Suitable starches contain about 25 wt% to 35 wt% amylopectin, i.e. about 30 wt% amylopectin. The person skilled in the art is able to determine the relative amounts of amylose and amylopectin in any given starch. For example, near infrared spectroscopy (NIR) can be used to determine the amount of amylose and amylopectin in a starch using calibration curves obtained by NIR using laboratory-produced mixtures of known amounts of these two components. In addition, the starch can be hydrolyzed to glucose using amyloglucosidase. A series of phosphorylation and oxidation reactions catalyzed by enzymes leads to the formation of nicotinamide adenine dinucleotide phosphate (NADPH). The amount of NADPH formed is stoichiometric with the original glucose content. Suitable test kits for this method are available (e.g. from R-Biopharm GmbH in Germany). Another method that can be used involves exposing the coating to digestion by bacterial enzymes, e.g.α-amylase, for the production of short-chain fatty acids (SCFA) which can be quantified using gas-liquid chromatography using a capillary column. The starches of interest are "ready-to-use" starches, i.e. starches that do not require any processing prior to use in the context of the present invention. Examples of "high amylose" starches include Eurylon® 6 (or IV) and Amylo N-400 (Roquette, Lestrem, France) or Amylogel 03003 (Cargill, Minneapolis, USA), all of which are examples of corn starches containing 50-70 wt% amylose. Enteric polymer forming the layer (second polymeric material) The enteric polymer forms a pH-sensitive layer and has a pH threshold of about pH 6 or higher. The "threshold pH" is the pH below which the solution is insoluble and at or above which it is soluble. The pH of the surrounding environment therefore causes the dissolution of the polymeric material. Thus, none (or essentially none) of the enteric polymer dissolves below the pH threshold. When the pH of the surrounding environment reaches (or exceeds) the pH threshold, the latter material dissolves. By "insoluble" we mean that 1 gram of the second substance requires more than 10,000 ml of solvent (surrounding medium) to dissolve at a given pH. By "solution" we mean that 1 gram of the second substance requires less than 10,000 ml, preferably less than 5,000 ml, preferably less than 1,000 ml, even more preferably less than 100 ml or 10 ml of solvent to dissolve at a given pH. "Ambient environment" preferably means the environment found in the gastrointestinal tract, such as gastric juice or intestinal juice. Alternatively, the ambient environment may be the laboratory equivalent of the environment in the gastrointestinal tract. The normal pH of gastric juice is usually in the range of 1 to 3. Enteric polymer is insoluble at pH 6 and soluble at pH 6 or higher and is therefore insoluble in gastric juice. The pH of the intestinal fluid gradually increases from about 6 in the duodenum to about 7 to 8 in the distal small intestine. The enteric polymer is preferably insoluble below pH 6.5 (and soluble at about pH 6.5 or higher) and preferably insoluble below pH 7 (and soluble at about pH 7 or higher). The pH threshold at which substances are soluble may be determined by a simple titration technique, which is part of the general knowledge of the person skilled in the art. Examples of suitable enteric coating polymers include an acrylate polymer, a cellulose polymer, or a polyvinyl-based polymer. Examples of suitable cellulose polymers having a pH threshold of pH 10 or higher include cellulose acetate phthalate (CAP) and hydroxypropyl methylcellulose acetate succinate. The enteric polymer forming the layer is preferably a co-polymer of acrylic acid (meth) and C1-4alkyl acrylic acid (meth), for example, a copolymer of methacrylic acid and methacrylic acid methyl ester. Such a polymer is known as a poly(methacrylic acid / methyl methacrylate) copolymer. Suitable examples of such polymers are typically anionic and are not of the sustained release polymethacrylate type. The ratio of carboxylic acid groups to methyl ester groups ("acid:ester ratio") in these copolymers determines the pH at which the copolymer dissolves. The acid to ester ratio may be from about 2:1 to about 1:3, for example about 1:1 or preferably about 1:2. The molecular weight (MW) of the desired anionic copolymers is typically from about 120,000 to 150,000, preferably about 135,000. The desired polyanion (methacrylic acid / methyl methacrylate) copolymers include Eudragit® L (acid:ester ratio about 1:1; MW about 135,000; pH threshold about 6), Eudragit® S 100 (acid:ester ratio about 1:2; MW about 135,000; pH threshold about 7) and Eudragit® FS (poly(methyl acrylate / methyl methacrylate / methacrylic acid); acid:ester ratio about 1:10; MW about 220,000; pH threshold about 7). The enteric polymer forming the layer may be a copolymer of methacrylic acid and ethyl acrylate. Eudragit® L 100-55 poly(methacrylic acid / ethyl acrylate); acid:ester ratio about 1:1; MW about 250,000; pH threshold about 6. Eudragit® copolymers are manufactured or distributed by Evonik, Darmstadt, Germany. Since enteric polymers are suitable layer-forming polymers, they may be used. An example of a suitable composition would be a mixture, for example a 1:1 mixture, of Eudragit® L and Eudragit® S 100. However, the use of a specific layer-forming polymeric material, for example a poly(methacrylic acid / methyl methacrylate) copolymer, alone is preferred. The use of Eudragit® S 100 alone as the enteric coating polymer is particularly preferred. Preferably, the exemplary polymers are used as the enteric layer-forming polymer in at least semi-neutralized form, i.e. at least a portion, for example at least 10%, preferably between 15% and 20% (on a mole basis), preferably at least 50% and preferably at least 90% of the carboxylic acid groups are in the form of carboxylate anions. Outer layer The ratio of enzymatically degradable polymer to enteric polymer forming the layer is typically at least 1:99, i.e. at least 10:90 and preferably at least 25:75. This ratio is typically not more than 99:1, e.g. not more than 75:25 and preferably not more than 60:40. In some embodiments, this ratio may not be more than 35:65. In some embodiments, the ratio is from 10:90 to 75:25, e.g. from 10:90 to 60:40 and preferably from 25:75 to 60:40. In some particular embodiments, the ratio is from 15:85 to 35:65, e.g. from 25:75 to 35:65 and preferably about 30:70. In other particularly preferred embodiments, the ratio is from 40:60 to about 60:40, for example about 50:50. The thickness of the outer core coating typically ranges from about 10 μm to about 300 μm. The thickness of the specific coating depends on the composition of the coating and the size of the core. For example, the thickness of the coating is directly proportional to the amount of polysaccharide present in the coating. Thus, in a design where the outer layer coating comprises high amylose starch and Eudragit® S in a ratio of about 30:70, the coating thickness may be from about 70 μm to about 300 μm, and preferably from about 150 μm to about 250 μm. The thickness (in μm) for a coated composition depends on the size of the core. The amount of enteric polymer in the outer layer is not related to the size of the core. The outer coating typically has an enteric polymer coating amount of from about 2 mg / cm2 to about 10 mg / cm2, for example from about 2 mg / cm2 to about 8 mg / cm2, or from about 3 mg / cm2 to about 8 mg / cm2, or from about 4 mg / cm2 to about 5 mg / cm2 to about 8 mg / cm2, or from about 6 mg / cm2 to about 8 mg / cm2, or from about 7 mg / cm2 to about 8 mg / cm2, for example about 7.5 mg / cm2. This applies when the outer coating only comprises the film-forming enteric polymer and when the outer layer comprises a mixture of the film-forming enteric polymer and an enzymatically degradable polymer. The core diameter is typically from about 5x4-10 m to about 25 mm. In addition to the organic anti-adhesion agent, the outer layer coating composition may optionally include one or more conventional auxiliaries for polymeric layers, such as a film-forming plasticizer (e.g. triethyl citrate), surfactants (e.g. polysorbate 80) and pigments (e.g. red iron oxide or yellow iron oxide). Third polymer material The core may be coated directly with the aforementioned outer layer coating composition, or may optionally be pre-coated with an inner layer coating composition to form an inner layer coated core. The inner layer comprises a layer-forming polymer (third polymeric material) that is soluble in intestinal fluid or gastrointestinal fluid (both gastric and intestinal fluid). The third polymeric material is selected from the group consisting of a polycarboxylic acid polymer that is at least partially neutralized and a nonionic polymer, provided that, if the polymeric material is a nonionic polymer, the inner layer comprises at least one additive selected from a buffering agent and a base. By "gastric fluid" the inventors mean the aqueous fluid in the stomach of a mammal, particularly a human. This fluid contains about 0.1 N hydrochloric acid and significant amounts of potassium chloride and sodium chloride, and plays a major role in the digestion of food by activating digestive enzymes and denaturing ingested protein. Gastric acid is produced by cells lining the stomach, and other cells produce bicarbonate, which acts as a buffer to prevent the gastric fluid from becoming acidic. By "intestinal fluid" the inventors mean the fluid in the lumen of the intestine of a mammal, particularly a human. Intestinal fluid is a pale yellow-blue fluid secreted by glands lining the intestinal wall. Intestinal fluid includes fluids in the small intestine, i.e., fluids in the duodenum (or "duodenal fluid"), fluids in the jejunum (or "jejunal fluid"), and fluids in the ileum (or "ileal fluid"), and fluids in the large intestine, i.e., "colonic fluid". A skilled person can readily determine whether a polymer is soluble in gastric fluid or intestinal fluid. If a polymer is soluble in water (or an aqueous solution), e.g. a buffer solution at a pH of 1 to 3, then that polymer is typically soluble in gastric fluid. Similarly, if a polymer is soluble in water (or an aqueous solution, e.g. a buffer solution) at a pH of 5 to 8, that polymer is typically soluble in intestinal fluid. Alternatively, the compositions of gastric fluid and intestinal fluid are known and may be reproduced in vitro. If a polymer is soluble in artificial gastric fluid or intestinal fluid in vitro, it is typically soluble in gastric fluid or intestinal fluid. Any water-soluble, pharmaceutically acceptable carboxylic acid polymer and pharmaceutically acceptable nonionic polymers are in principle suitable for use as the third polymeric material. The solubility of water-soluble polymers may be pH dependent, for example the polymeric material may be a pH-sensitive polymer having a pH threshold. The polymeric material may be soluble in at least one fluid selected from gastric fluid, duodenal fluid, jejunal fluid, and ileal fluid. However, in preferred embodiments, the solubility of the third polymeric material in water is not dependent on pH, at least not within the pH range found in the urine. In preferred embodiments, the layer of the third polymeric material is soluble at any point in the stomach and intestines, e.g., in the gastrointestinal fluid. Polycarboxylic acid polymers ("anionic" polymers) are polymers or copolymers containing a multitude of carboxylic acid functional groups that ionize in aqueous environments such as intestinal fluid to form carboxylate anions. In embodiments where the third polymeric material is a polycarboxylic acid polymer, the third polymeric material is at least partially neutralized, i.e. at least a portion, e.g. at least 10%, preferably at least 25%, preferably at least 50%, and preferably at least 90%, of the carboxylic acid groups are in the form of carboxylate anions. In certain preferred embodiments, all of the carboxylic acid groups in the third polymeric material are in the form of carboxylate anions. Such polymers are referred to herein as "fully neutralized." In preferred embodiments, the second and third polymeric materials are based on the same polycarboxylic acid polymer with the third polymeric material having a higher degree of neutralization than the second polymeric material. For example, for a particular polycarboxylic acid polymer, the second polymeric material may be in an unneutralized form with the third polymeric material partially or completely neutralized. Alternatively, the second polymeric material may be in a neutralized form, with the third polymeric material also partially neutralized (although to a somewhat greater extent neutralized) or completely neutralized. Examples of suitable polycarboxylic acid polymers include cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), cellulose acetate trimethylate (CAT), xanthan gum, alginates and shellac. However, the polycarboxylic acid polymer is preferably selected from acrylic acid (meth) and alkyl acrylic acid (meth) polymers, for example, C1-4 alkyl, ester and a copolymer of methacrylic acid and methyl ester of methacrylic acid are suitable. Such a polymer is known as a poly(methacrylic acid / methyl methacrylate) copolymer or "polymethacrylate". The ratio of carboxylic acid groups to methyl ester groups ("acid:ester ratio") in these polymers determines the pH at which the copolymer is soluble. The acid to ester ratio may be from about 2:1 to about 1:3, for example about 1:1 or preferably about 1:2. The molecular weight (MW) of preferred anionic copolymers is typically from about 120,000 to 150,000, preferably about 125,000 or about 135,000. Preferred copolymers for the third polymeric material are discussed in detail in the section above for the second polymeric material and include Eudragit® L, Eudragit® S; Eudragit® FS 30 D; Eudragit® L30D-55; and Eudragit® L100-55. Preferably, exemplary polymers are used because the third polymeric material is at least partially, preferably completely, neutralized. Semi-neutralized polymers suitable for use as the third polymeric material and methods for their production are known in the art, for example US2008 / 0200482A and WO2008 / 135090A. These polymers may be fully neutralized by adding further base to the coating solutions. In preferred embodiments, the third polymeric material is an at least partially, preferably fully neutralized polymer of (meth) acrylic acid and a C1-4 alkyl (meth) acrylic acid. In preferred embodiments, the third polymeric material is a fully neutralized polymer of (methyl) acrylic acid and a methyl ester of acrylic acid (particularly Eudragit® S). The inventors have observed that fully neutralized Eudragit® S is capable of forming a layer and is easily and completely soluble independently of the minimum pH range found in the intestine, for example from about pH 5 to about pH 8. Fully neutralized Eudragit® S is particularly preferred for use as the third polymeric material in the present invention. Other polymers suitable for use as the third polymeric material include pharmaceutically acceptable non-ionic polymers, e.g. pharmaceutically acceptable polymers that do not ionize in aqueous media. In these embodiments, the inner layer further comprises at least one additive selected from a buffering agent and a base. In particular, the inner layer of this embodiment preferably comprises a base and optionally a buffering agent. In preferred embodiments, the inner layer comprises both a buffering agent and a base. Suitable examples of buffering agents and bases are discussed below. It is preferred that the nonionic polymer of the inner layer is a nonionic cellulose-based polymer. Examples of suitable nonionic cellulose-based polymers include methylcellulose (MC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC). A particularly preferred nonionic cellulose-based polymer is HPMC. Non-cellulosic polymers such as poly(ethylene oxide)-graft-polyvinyl alcohol, polyvinyl pyrrolidinone (PVP), polyethylene glycol (PEG), PVP-grafted PEG, and polyvinyl alcohol (PVA) are also preferred. Mixtures of layer-forming polymeric materials may be used if appropriate. The polymer components in such mixtures may be polycarboxylic acid polymers, nonionic polymers or mixtures of polycarboxylic acid polymers and nonionic polymers. An example of a suitable mixture would be a mixture, such as a 1:1 mixture, of Eudragit® L and Eudragit® S, and a mixture, such as a 1:1 mixture of Eudragit® S and HPMC. However, the use of a specific layer-forming polymeric material alone, such as a poly(methacrylic acid / methyl methacrylate) copolymer and especially Eudragit® S is preferred. Open In preferred embodiments, the inner layer comprises at least one base. The purpose of this base is to provide an alkaline environment beneath the outer layer when intestinal fluid begins to penetrate the outer layer. The inventors, without being limited to any particular theory, believe that the alkaline environment facilitates dissolution and subsequent degradation of the outer layer because the pH of the alkaline environment is above the pH threshold of the second polymeric material, thereby accelerating the release of the drug from the formulation after the outer coating has dissolved or degraded. In principle, any pharmaceutically acceptable base may be used. The base is typically a non-polymeric compound. Suitable bases include inorganic bases such as sodium hydroxide, potassium hydroxide and ammonium hydroxide and organic bases such as triethanolamine, sodium bicarbonate, potassium carbonate, trisodium phosphate, trisodium citrate or physiologically tolerable amines such as triethylamine. The base is preferably selected from the group consisting of hydroxide bases, alkali metal bicarbonates, alkali metal carbonates, alkali metal phosphates, alkali metal citrates or physiologically tolerable amines. Preferably, the base is a hydroxide base and is particularly preferably sodium hydroxide. In a design where the third polymeric material is a fully neutralized polycarboxylic acid polymer, the base encapsulated in the inner layer is typically a base that is used to neutralize the polymer and adjust the pH of the inner coating composition to a pH of from about pH 7.5 to about pH 10 (see below). In a design where the third polymeric material is a nonionic polymer, the inner layer typically comprises a base, or more typically a combination of a base and a buffering agent. The amount of base present in the inner layer depends at least in part on the final pH of the inner coating composition prior to coating a given batch of cores, including the number of coated cores in the batch and the amount of inner layer coating preparation used in the batch coating process. Buffering agent The inner layer includes at least one buffering agent. The purpose of the buffering agent is to provide or increase the buffering capacity beneath the outer layer as intestinal fluid begins to permeate the outer layer. Without wishing to be bound by any particular theory, the inventors believe that the buffering agent increases the buffering capacity of the soluble inner layer and aids in ionization and dissolution of the polymer in the outer layer. For a given pH, the higher the buffering capacity, the faster the polymer dissolves. In designs where there is a base in the inner layer, the buffering agent helps to maintain an alkaline environment beneath the outer layer as intestinal fluid begins to permeate the outer layer. The buffering agent may be any suitable buffering agent known to the skilled person. The buffering agent may be an organic acid such as a pharmaceutically acceptable non-polymeric carboxylic acid, for example, a carboxylic acid having 1 to 16, preferably 1 to 3, carbon atoms. Suitable carboxylic acids are disclosed in WO2008 / 135090A. Citric acid is an example of such carboxylic acids. The carboxylic acids may be used in the form of carboxylate salts and mixtures of carboxylic acids, carboxylate salts or both. The buffering agent may be an inorganic salt such as an alkali metal salt, an alkaline earth metal salt, an ammonium salt, and a soluble metal salt. For soluble metal salts, manganese, iron, copper, zinc, and molybdenum can be mentioned as metals. Preferably, the inorganic salt is selected from chloride, fluoride, bromide, iodide, phosphate, nitrate, nitrite, sulfate, and borate. Phosphates such as potassium dihydrogen phosphate are preferred over other inorganic buffer salts and organic acid buffers due to their higher buffering capacity at the pH of the coating solution, e.g., pH 8. The buffer(s) are present in the inner layer in an amount of from about 1 wt % to about 60 wt %. For example, from about 1 wt % to about 50 wt %, preferably from about 1 wt % to about 40 wt %, preferably from about 1 wt % to about 20 wt %, more preferably from about 1 wt % to about 4 wt %, more preferably from about 1 wt % to about 3 wt %, and more preferably from about 1 wt % based on the dry weight of the third polymer in the inner layer. Inner layer The thickness of the inner core coating layer typically ranges from about 10 μm to about 150 μm. As with the outer coating layer, the thickness of a particular coating will depend on the coating composition and the core size. As with the outer layer, the amount of polymer in the inner layer is not related to the size of the core. The inner layer typically has a coating amount of nonionic polymer from about 2 mg / cm2 to about 5 mg / cm2, for example about 3 mg / cm2, based on the dry weight of the third polymeric material. In addition to the buffering or base agent, the inner layer may contain one or more materials conventional for polymeric layers, including materials selected from plasticizers (e.g. triethyl citrate), anti-adhesion agents (e.g. GMS) and surfactants (e.g. polysorbate 80). Additional layers The core may be coated directly using the aforementioned inner layer coating composition or the aforementioned outer layer coating composition. Alternatively, the core may be pre-coated using the aforementioned separate layer coating composition to form a separate layer coated core and then coated using the aforementioned inner layer coating composition or the aforementioned outer layer coating composition. When the composition of the core is incompatible with the sustained release coating, a separate layer may be desirable. For example, the present invention includes designs in which the inner layer provides an alkaline environment which is believed to aid in the dissolution and degradation of the outer layer. However, if the core contains a drug that has acidic groups, the inner layer may be incompatible with the core. An example of a drug with an acidic group would be 5-ASA. In such cases, the inclusion of a separate layer is appropriate. Any suitable discrete layer known to the skilled person can be used. In the present embodiment, the discrete layer comprises a non-ionic polymer forming the layer. Suitable non-ionic polymers include methyl cellulose (MC); hydroxypropyl cellulose (HPC); hydroxypropyl methyl cellulose (HPMC); poly(ethylene oxide)-graft-polyvinyl alcohol; polyvinyl pyrrolidone (PVP); polyethylene glycol (PEG) and polyvinyl alcohol (PVA). Non-ionic cellulose-based polymers (such as HPMC) as well as PVA are preferred. Mixtures of non-ionic polymers can also be used. A particularly preferred mixture is HPMC and PEG. The discrete layer can additionally comprise a softening agent. Suitable softeners include, but are not limited to, polyethylene glycol, triethyl citrate, triacetin and acetyl triethyl citrate. There may also be an intermediate layer between the outer and inner layers, provided that the intermediate layer does not adversely affect the release properties of the formulation. However, the outer layer is usually provided in contact with the inner layer, i.e. the outer layer is usually applied directly to the inner layer, i.e. there is usually no intermediate layer separating the inner and outer layers. Core The "core" is a solid body to which the coating is applied. The core may be in any suitable dosage form, for example, a tablet, a pellet, a granule, a microparticle, a hard or soft capsule, or a microcapsule. In preferred embodiments, the core is a tablet or a capsule. The core contains the drug(s). The drug(s) may be present in the body of the core, for example in the matrix of a tablet or pellet, or in the contents enclosed in a capsule. Alternatively, the drug may be in a coating applied to the core, for example where the core is a granule of edible material such as sugar, for example where the core is in the form of a non-prilled granule or dragee. The core may consist of the drug(s) alone, or more usually it may consist of the drug(s) and at least one pharmaceutically acceptable carrier. In this connection, the core is typically a tablet or pellet and in the case of a tablet will typically comprise a mixture of the drug(s) with another useful ingredient selected from a filler or diluent, for example lactose or cellulosic materials such as microcrystalline cellulose; a binder, such as polyvinylpyrrolidone (PVP) or hydroxypropyl methylcellulose (HPMC); a disintegrant, such as croscarmellose sodium (e.g. Ac-Di-Sol®) and sodium starch glycolate (e.g. Explotab®); and / or a lubricant, such as magnesium stearate and talc. The core may be a compressed granule comprising at least some of these ingredients. The core may be uncoated, or the core may be pre-coated with a separate layer or an inner layer to which the outer layer coating is applied directly. The separate layer and inner layer are discussed in more detail above. The minimum diameter of each core is typically at least about 10-4m, typically at least about 5 x 10-4m, and preferably at least about 10-3m. The maximum diameter is typically no more than 30 mm, typically no more than 25 mm, and preferably no more than 20 mm. In preferred embodiments, the core diameter is from about 0.2 mm to about 25 mm, and preferably from about 0.2 mm to about 4 mm (e.g., for pellets or small tablets) or from about 5 mm to about 25 mm (e.g., for certain tablet or capsule embodiments). The term "diameter" refers to the largest linear dimension through the core. Different aspects According to a second aspect of the invention, there is provided a sustained release pharmaceutical formulation for oral administration to deliver the drug to the colon. The formulation comprises: The core consists of a drug and An outer coating layer for the core, the outer coating layer comprising a mixture of an enzymatically degradable polysaccharide that is degraded by colonic bacterial enzymes, an enteric polymer forming the layer having a pH threshold of about pH 6 or higher, and an organic anti-adhesion agent; wherein the outer coating layer comprises no more than 5000 ppm of free residual organic solvent. or wherein the outer coating layer comprises at least 10% by weight of at least one softening agent based on the total weight of the enteric polymer constituting the layer. In an embodiment according to the second aspect of the invention, the core may be directly coated with the outer coating layer. Alternatively, an optional separate layer or inner layer may be located between the core and the outer coating layer. The optional inner layer is as defined above and comprises a polymeric material that is soluble in intestinal or gastrointestinal fluid. The optional separate layer is as defined above and comprises a non-ionic polymer forming the layer that is soluble in gastrointestinal fluid. The outer coating layer typically does not contain more than 5000 ppm of free residual organic solvent, for example, not more than 4000 ppm or more than 3000 ppm or more than 2000 ppm or more than 1000 ppm or more than about 750 ppm, or more than 500 ppm, or more than 250 ppm, or more than 100 ppm, or more than 75 ppm, or more than 50 ppm, or more than 25 ppm or more than 10 ppm. The outer coating layer typically comprises at least about 10% by weight of at least one softening agent (e.g., TEC), for example, at least about 15%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50% of the outer coating. The outer coating typically comprises at least no more than 70% by weight of at least one softening agent, i.e., about 60% by weight of the softening agent. The formulation may include multiple coated cores to provide a single dose of drug(s), particularly in designs where the cores are "small", e.g., less than 5 mm in diameter. Multiple unit dosage forms including coated cores with a diameter of less than 3 mm may be preferred. The present invention has application in multiphase drug release formulations comprising at least two coated cores, such as coated pellets, in the same dosage form, e.g. a capsule, wherein the coated cores of one plurality differ from another. The coatings may differ from one plurality to another in terms of coating thickness or composition, e.g. ratio or identity of components. Multiphase drug release formulations will be particularly suitable for patients with Crohn's disease affecting different areas of the intestine. The release in the formulation according to the present invention is delayed until the intestine, and preferably the colon. The release in certain formulations may also be sustained. However, in preferred formulations, the release is pulsatile. The time between initial exposure to conditions suitable for drug release and the onset of drug release is known as the "latency time." The "latency time" depends on various factors, including coating thickness and composition, and may vary from patient to patient. Formulations according to the present invention typically exhibit a lag time of at least 10 minutes under colonic conditions. In most embodiments, the lag time is from about 10 minutes to about 4 hours. Complete drug release may occur over 5 hours, e.g., over 4 hours after exposure to these conditions. A formulation is usually defined as gastroresistant if it has less than 10 wt % drug release in an acidic environment after 2 hours. Formulations according to the present invention typically exhibit less than 10 wt % drug release in acidic environments and may be considered gastroresistant. Formulations typically exhibit less than 1 wt % drug release in acidic environments and are typically non-releasing in acidic environments. When starch is combined with an acrylate layering agent to form a coating for the core, typically less than 5% drug release occurs over 6 hours under conditions simulating the stomach and small intestine. The core comprises at least one drug. This formulation is usually used to administer a single drug as the sole active therapeutic ingredient. However, more than one drug may be administered in a single formulation. The formulations of the present invention are designed to administer a wide range of drugs. Suitable drugs include those known to be administered to the intestine using sustained release oral formulations. The present invention may be used to administer drugs with local or systemic effects. The formulations of the invention are particularly useful in the enteral administration of drugs that contain at least one acidic group, such as a carboxylic acid group. Such drugs may be acidic drugs or zwitterionic drugs. An example of such drugs is 5-aminosalicylic acid (5-ASA, otherwise known as mesalamine or mesalazine). The identity of the drug(s) in the formulation will obviously depend on the therapeutic condition. In this regard, the formulation has particular utility in the treatment of IBD (including Crohn's disease and ulcerative colitis); IBS; constipation; diarrhea; infections; and cancer, particularly colon or large bowel cancer. For the treatment or prevention of IBD, the formulation may comprise at least one drug selected from the group consisting of anti-inflammatory agents (e.g. 5-ASA, 4-ASA, sulfasalazine and balsalazide); non-steroidal anti-inflammatory agents (e.g. ibuprofen and diclofenac); steroids (e.g. prednisolone; budesonide or fluticasone); immunosuppressants (e.g. azathioprine; cyclosporine and methotrexate); antibiotics; and biological agents including peptides, proteins and antibody fragments. Suitable examples of biological agents include alkaline phosphatase antibodies and anti-TNF antibodies such as infliximab, adalimumab, certolizumab pegol, glimimab and ustekinumab. For the treatment or prevention of cancer, the formulation may comprise at least one antineoplastic agent. Suitable antineoplastic agents include fluorouracil; methotrexate; dactinomycin; bleomycin; etoposide; taxol; vincristine; doxorubicin; cisplatin; daunorubicin; VP-16; raltitrexed; oxaliplatin and pharmaceutically acceptable derivatives and salts thereof. For the prevention of colorectal cancer or colon cancer, primarily in patients suffering from colitis, the formulation may comprise the anti-inflammatory agents 5-ASA, sulindac, celecoxib, or eflornithine (DFMO). For the treatment or prevention of IBS, constipation, diarrhea, or infection, the formulation may comprise at least one active agent suitable for the treatment or prevention of these conditions. Pharmaceutically acceptable derivatives or salts may also be used in the formulation. An example of a suitable salt is prednisolone, methylprednisolone sodium succinate. Another example is fluticasone propionate. The present invention has particular utility in the treatment of IBD (especially ulcerative colitis) or the prevention of colorectal or colon cancer (primarily in colitis patients), both using 5-ASA. The drug also serves as a portal of entry of drugs into the systemic circulation via the colon. This is particularly advantageous for peptide and protein drugs that are unstable in the upper gastrointestinal tract. The invention can also be used for chronotherapy. The formulation typically contains an active therapeutic agent of or any drug, which may be from about 0.01 wt % to about 99 wt % based on the total weight of the formulation. The actual dosage will be determined by the skilled person using his or her common general knowledge. However, for example, a "low" dose formulation typically does not contain more than about 20 wt % of the drug and preferably consists of from about 1 wt % to about 10 wt %, e.g. about 5 wt % of the drug. A "high" dose formulation typically contains at least 40 wt % of the drug and preferably from about 45 wt % to about 85 wt %, e.g. about 50 wt % or about 80 wt %. The formulations of the present invention can include any core size. In some embodiments, the drug can be present in the core formulation in an amount of from about 50 mg to about 1650 mg, or from about 100 mg to about 1550 mg, or from about 150 mg to about 1500 mg, or from about 200 mg to about 1450 mg, or from about 250 mg to about 1400 mg, or from about 300 mg to about 1350 mg, or from about 350 mg to about 1300 mg, or from about 400 mg to about 1250 mg, or from about 450 mg to about 1200 mg, or from about 500 mg to about 1150 mg, or from about 550 mg to about 1100 mg, or from about 600 mg to about 1050 mg, or from about 650 mg to about 1000 mg, or from about 700 mg to about 950 mg. mg, from about 800 mg to about 1600 mg, or from about 850 mg to about 1600 mg, or from about 900 mg to about 1500 mg, or from about 950 mg to about 1400 mg, or from about 1000 to about 1300 mg, or from about 1150 to about 1200 mg. Preferably, the drug is present in an original amount of about 400 mg, about 800 mg, about 1200 mg, about 1500 mg, or about 1600 mg. The formulations of the present invention may be prepared using the methods mentioned above. Examples The embodiments of the present invention will now be described with reference to the drawings, in which: Fig. 1 is a comparative graph of drug release as a function of time from coated 5-ASA tablets according to Sample 1, Sample 2, Comparative Samples 1 and 2 when exposed to 0.1M HCl (data not shown) and Krebs buffer (pH 7.4) for 2 hours; Figure 2 is a comparative graph of drug release as a function of time from 5-ASA coated tablets according to Sample 1, Sample 2, Comparative Samples 2 and 1, when exposed to 0.1N HCl for 2 hours (data not shown) and then Sørensen buffer (pH 6.8) for 18 hours; Figure 3 is a comparative graph for drug release as a function of time from 5-ASA coated tablets according to Comparative Sample 2 exposed to 0.1N HCl for 2 hours (data not shown) and then Sørensen buffer (pH 6.8) for 18 hours; Figure 4 is a comparative graph of drug release as a function of time from 1600 mg 5-ASA coated tablets according to samples 3 and 5, when exposed to 0.1M HCl and then Hank's buffer (pH 6.8) for 2 hours. Figure 5 is a comparative graph of drug release as a function of time from 1600 mg 5-ASA coated tablets according to samples 3 and 5, when exposed to 0.1M HCl for 2 hours and then Kreb's buffer (pH 7.4) for 10 hours. Materials Eudragit® S 100 was purchased from Evonik GmbH, Darmstadt, Germany. Corn starch (Eurylon® 6) was purchased from Roquette, Lestrem, France. Polysorbate 80 (Tween® 80), butan-1-ol, triethyl citrate (TEC), 95% ethanol, butanol, potassium phosphate monobasic (KH2PO4), sodium dihydrogen phosphate dihydrate (Na2HPO4•2H2O) and sodium hydroxide were all purchased from Sigma-Aldrich, Buchs, Switzerland. Syloid 244 FP was purchased from Grace, Discovery Science, Belgium and Aerosil 300 from Evonik GmbH, Darmstadt, Germany. HPMC (Pharmacoat 603) was purchased from Shin-Etsu and hydroxypropyl methylcellulose (HPMC, Methocel E3 or Methocel E5) was purchased from Colorcon. Glyceryl monostearate (GMS) was purchased from Cognis. Polyethylene glycol (PEG) was purchased from Aldrich. Red iron oxide and yellow iron oxide (Sicovit) were purchased from BASF. HPMC capsules were purchased from Qualicaps. Gelatin was purchased from Gelita. Ammonia solution (25%) was purchased from VWR International LTD, Poole, UK. Preparation of capsule cores combined with gelatin 5-ASA granules were prepared by mixing 5-ASA with an aqueous solution of HPMC in a high shear granulator at 550 rpm. The granules were passed through a 6.34 mm sieve (Comil) before drying at 45°C. The dried granules were then sieved through a 1.6 mm cone mill. Size 00 capsules were filled with 550 mg to 630 mg of dry 5-ASA granules and the capsules were mixed with 21.8% gelatin solution and dried at room temperature. Preparation of tablet cores The 1600 mg rectangular cores were prepared according to the following procedure. The amount of each component in each tablet core was: 160 mg mesalazine, 32 mg hypromellose, 178 mg microcrystalline cellulose, 54 mg sodium starch glycolate, 2 mg colloidal silicon dioxide, and 1 mg magnesium stearate. Mesalazine (8 kg) and an aqueous solution containing HPMC (160 g, Pharmacoat® 603) were granulated in a high-speed mixer granulator. The wet granules were passed through a 9.4 mm sieve (Comil) before drying in a fluid bed dryer at an inlet air temperature of approximately 80°C until the product temperature reached 42°C. The dry granules were sieved using a 1.6 mm iron sieve. The dry granules were mixed with microcrystalline cellulose (Avicel® pH 102) and sodium starch glycolate (Explotab®) in an 80 L drum for approximately 20 minutes at 28 rpm. Magnesium stearate and colloidal silicon dioxide (Aerosil® 200) were both separately mixed with approximately 500 g of a mixture of mesalazine granules, microcrystalline cellulose and sodium starch glycolate and passed through a 1 mm sieve before being added to the rest of the ingredients. The mixture was mixed for approximately 5 minutes at 28 rpm to form a final compact. The final blend was compressed using a Fette P1200 tablet press with an external lubrication system (PKB). Magnesium stearate was sprayed onto the punches of the tablet press at a rate of 400 g / h. The obtained capsules and tablet cores were coated as discussed below in Examples 1 to 3 and Comparative Examples 1 to 9. Sample 1 (5-ASA capsule cores coated with a 70:30 blend of Eudragit® S 100 and high amylose starch; aqueous coating composition containing 5% GMS and polysorbate 80) This coating was made from a mixture of aqueous starch dispersion (first aqueous composition) and aqueous Eudragit® S 100 dispersion (second aqueous composition). Aqueous starch dispersion was prepared by dispersing corn starch in butan-1-ol followed by water, with magnetic stirring. The ratio of corn starch:butan-1-ol:water was 1:1:12.5. The resulting dispersion was heated to boiling point and then cooled overnight with stirring. The aqueous dispersion of Eudragit® S 100 was prepared by dispersing Eudragit® S 100 in water with high-speed stirring followed by partial neutralization (15–20) with 1N ammonia solution (obtained by dilution of a 25% ammonia solution). The aqueous dispersion of Eudragit® S 100 was added dropwise to the starch dispersion to obtain a ratio of Eudragit® S 100:starch of 70:30. The mixture was stirred for 1 hour and 60% TEC (based on the weight of Eudragit® S 100 polymer) and 5% glyceryl monostearate (GMS, based on the weight of Eudragit® S 100 polymer) were added and mixed for a further 1 hour. The aqueous suspension of 13.18% red iron oxide (based on the weight of Eudragit® S 100 polymer) and 2.27% yellow iron oxide (based on the weight of Eudragit® S 100 polymer) was added and the mixture was mixed for a further 10 minutes to form the outer layer coating composition. GMS was added as an emulsion prepared at a w / w concentration of 5%. Polysorbate 80 (40% by weight of GMS) was dissolved in distilled water followed by the GMS dispersion. The dispersion was then heated to 75°C for 15 min with vigorous magnetic stirring to form an emulsion. The emulsion was cooled to room temperature while stirring. Pigment suspension was created by suspending red and yellow iron oxide pigments in water for 10 min under homogenization. The outer layer coating composition was sprayed onto the 5-ASA capsule core mixed with gelatin using a pan coater coating machine, until a coating amount of 5 mg / cm2 of Eudragit® S 100 was obtained. The spray coating parameters were as follows: spray rate 2.5-3.4 g / min. spray pressure 0.4 bar; pattern pressure 0.4 bar; air flow 40 m3 / h; inlet air temperature 54-60°C; outlet air temperature 41.4-42.5°C; product temperature 29.5-41°C; drum speed 10-14 rpm. Sample 2 (5-ASA capsule cores coated with a 50:50 mixture of Eudragit® S 100 and high amylose starch; aqueous coating composition containing 10% GMS and polysorbate 80) The coating was made from a mixture of aqueous starch dispersion (first aqueous composition) and aqueous Eudragit® S 100 dispersion (second aqueous composition) using the same method described for Example 1 with 10% GMS (based on Eudragit® S 100) (weight of polymer). The aqueous dispersion of Eudragit® S 100 was added dropwise to the starch dispersion to obtain a ratio of Eudragit® S 100:starch of 50:50. The outer layer coating composition was sprayed onto the 5-ASA capsule core mixed with gelatin using a pan coater, until a coating amount of 5 mg / cm2 of Eudragit® S 100 was obtained. The spray coating parameters are as described for sample 1. Sample 3 (1600 mg 5-ASA tablet core coated with a separate HMPC layer and an outer layer of a 70:30 mixture of Eudragit® S 100 and high amylose starch; the aqueous coating composition contains 5% GMS, based on Eudragit S® 100 and polysorbate) Separate layer A separate layer of aqueous mixture of HPMC and 20% PEG 6000 was used. HPMC was dissolved in water under magnetic stirring and then PEG 600 was added to form a layer of the separate layer coating composition. The separate layer coating composition was sprayed onto the 5-ASA tablet cores using a pan coater until the HPMC coating amount reached 3 mg / cm2, to form the separate layer coated tablet cores. Outer layer The outer layer coating was made from a mixture of aqueous starch dispersion (first aqueous composition) and aqueous Eudragit® S 100 dispersion (second aqueous composition) prepared according to Example 1. The outer layer coating composition was sprayed onto the core separated from the spray-coated 5-ASA tablet using a pan coater coating machine, until a coating amount of 5 mg / cm2 of Eudragit® S 100 was obtained. The spray coating parameters were as follows: spray rate 2.0 - 2.8 g / min. spray pressure 0.4 bar; pattern pressure 0.5 bar; air flow 40 m3 / h; inlet air temperature 52-60 °C; outlet air temperature 40.0-45.0 °C; product temperature 32.0 - 36.0 °C; drum speed 10-12 rpm. Comparative Example 1 (5-ASA capsule cores coated with a 70:30 mixture of Eudragit® S 100 and high amylose starch; "semi-organic" coating composition containing 5% GMS, based on Eudragit® S 100 and polysorbate) The coating was applied from a mixture of aqueous starch dispersion and organic solution Eudragit® S 100. Aqueous starch dispersion was prepared by dispersing corn starch in butan-1-ol followed by water, with magnetic stirring. The ratio of corn starch:butan-1-ol:water was 1:2:25. The resulting dispersion was heated to boiling point and then cooled with stirring overnight. The organic solution of Eudragit® S 100 was prepared by dissolving Eudragit® S 100 in 96% ethanol with high-speed stirring. The starch dispersion was added dropwise to the Eudragit® S 100 solution to obtain a ratio of Eudragit® S 100:starch: 70:30. The mixture was stirred for 1 hour and 29% TEC (based on the weight of Eudragit® S 100 polymer) and 5% glyceryl monostearate (GMS, based on the weight of Eudragit® S 100 polymer) were added and mixed for a further 1 hour. A suspension of 13.18% red iron oxide (based on the weight of Eudragit® S polymer) and 2.27% yellow iron oxide (based on the weight of Eudragit® S 100 polymer) was added to the ethanol and the mixture was mixed for a further 10 minutes to form the outer layer coating composition. As prepared in Sample 1, GMS was added in the form of an emulsion. The outer layer coating composition was sprayed onto the 5-ASA capsule core mixed with gelatin using a pan coater coating machine, until a coating amount of 5 mg / cm2 of Eudragit® S 100 was obtained. The spray coating parameters are as described for Example 1. Comparative Example 2 (5-ASA capsule cores were coated with a 70:30 mixture of Eudragit® S 100 and high amylose starch; aqueous coating composition containing 50% talc) This coating was made from a mixture of aqueous starch dispersion and aqueous Eudragit® S 100 dispersion using the same method described for sample 1 with talc (50% based on the total weight of Eudragit® S 100 polymer) as an anti-adhesion agent instead of GMS. Talc was added in the form of a blue suspension with red and yellow iron oxide pigments. The outer layer coating composition was sprayed onto the 5-ASA capsules coated with the separate layer using a pan coater, until a coating amount of 5 mg / cm2 of Eudragit® S 100 was obtained. Spray coating parameters are as described for Example 1. Comparative Example 3 (1600 mg 5-ASA tablet core coated with an HPMC isolation layer and an outer layer of a 70:30 mixture of Eudragit® S 100 and high amylose starch; "semi-organic" coating composition containing 5% GMS and polysorbate) Separate layer A separate layer was prepared and applied to 5-ASA tablet cores according to Sample 3. Outer layer The outer layer coating was made of a mixture of aqueous starch dispersion and organic solution Eudragit® S 100 as described for Comparative Example 1. The outer layer coating composition was sprayed onto the 5-ASA tablet cores coated with the separate layer using a pan coater, until a coating amount of 5 mg / cm2 of Eudragit® S 100 was obtained. The spray coating parameters are as described for Example 3. Comparative Example 4 (1600 mg 5-ASA tablet core coated with HPMC isolation layer and an outer layer of 70:30 mixture of Eudragit 100 S 100 and high amylose starch; "semi-organic" coating composition containing 50% talc) The outer layer coating of the aqueous starch dispersion mixture and the organic solution of Eudragit® S 100 was applied using the same method described for Comparative Sample 1 with talc (50% by weight of the Eudragit® S 100 polymer) as an anti-adhesion agent instead of GMS. Talc was added as an ethanolic suspension along with red and yellow iron oxide pigments. The outer layer coating composition was sprayed onto the 5-ASA tablet cores coated with the separate layer using a pan coater, until a coating amount of 5 mg / cm2 of Eudragit® S 100 was obtained. The spray coating parameters are as described for Example 3. Comparative Example 5 (1600 mg 5-ASA tablet cores coated with a separate HPMC layer and an outer layer of a 70:30 blend of Eudragit® S 100 and high amylose starch; "blue" coating composition containing 50% talc) Separate layer A separate layer was prepared and applied to 5-ASA tablet cores according to Sample 3. Outer layer The outer layer coating was made from a mixture of aqueous starch dispersion and aqueous Eudragit® S 100 dispersion as described for Comparative Example 2. The outer layer coating composition was sprayed onto the 5-ASA tablet cores coated with the separate layer using a pan coater, until a coating amount of 5 mg / cm2 of Eudragit® S 100 was obtained. The spray coating parameters are as described for Example 1. Comparative Example 6 (1600 mg 5-ASA tablet cores coated with a separate HPMC layer and an outer layer of a 70:30 blend of Eudragit® S 100 and high amylose starch; "blue" coating composition containing 5% talc) Separate verse A separate layer was prepared and applied to 5-ASA tablet cores according to Sample 3. Outer layer The outer layer coating was made of a mixture of aqueous starch dispersion and aqueous Eudragit® S 100 dispersion as described for Comparative Example 2 with talc (5% by weight of Eudragit® S 100 polymer) as an anti-adhesion agent. The outer layer coating composition was sprayed onto the 5-ASA tablet core coated with a separate layer using a pan coater, until a coating amount of 5 mg / cm2 of Eudragit® S 100 was obtained. The spray coating parameters are as described for sample 1. Comparative Example 7 (1600 mg 5-ASA tablet cores coated with a separate HPMC layer and an outer layer of a 70:30 mixture of Eudragit® S 100 and high amylose starch; "blue" coating composition containing 5% talc and polysorbate 80) Separate layer A separate layer was prepared and applied to 5-ASA tablet cores according to Sample 3. Outer layer The outer layer coating of the mixture of aqueous starch dispersion and aqueous Eudragit® S 100 dispersion was applied using the same method described for Comparative Sample 2, with talc (5% based on the solid content of Eudragit® S 100) as an anti-adhesion agent. Talc was added in the form of an aqueous dispersion with polysorbate 80 (40% by weight of talc). The outer layer coating composition was sprayed onto the 5-ASA tablet cores coated with the separate layer using a pan coater, until a coating amount of 5 mg / cm2 of Eudragit® S 100 was obtained. The spray coating parameters are as described for sample 1. Comparative Example 8 (1600 mg 5-ASA tablet cores coated with a separate HPMC layer and an outer layer of a 70:30 mixture of Eudragit® S 100 and high amylose starch; "blue" coating composition containing 5% colloidal silicon dioxide) Separate layer A separate layer was prepared and applied to 5-ASA tablet cores according to Sample 3. Outer layer The outer layer coating was a mixture of aqueous starch dispersion and aqueous Eudragit® S 100 dispersion as described for Comparative Example 2 with 5% colloidal silicon dioxide (Aerosil® 300) as anti-adherent. Colloidal silica (Aerosil® 300) was added in the form of a dispersion. Aerosil 300 (5% based on the total weight of Eudragit® S 100 polymer) was homogenized in water for 10 minutes and then added to the mixture of aqueous starch dispersion and aqueous Eudragit® S 100 dispersion. The outer layer coating composition was sprayed onto the core of the 5-ASA tablet with a separate layer using a pan coater, until a coating amount of 5 mg / cm2 of Eudragit® S 100 was obtained. The spray coating parameters are as described for Example 1. Comparative Example 9 (1600 mg 5-ASA tablet core coated with an HPMC separator and an outer layer of a 70:30 blend of Eudragit® S 100 and high amylose starch; "blue" coating composition containing 5% colloidal silicon dioxide) Separate layer A separate layer was prepared and applied to 5-ASA tablet cores according to Sample 3. Outer layer The outer layer coating was made of a mixture of aqueous starch dispersion and aqueous Eudragit® S 100 dispersion as described for Comparative Example 2 with 5% colloidal silicon dioxide (Syloid 244 FP) as an anti-adherent. Colloidal silica (Syloid 244 FP) was added in the form of a dispersion. Syloid 244 FP (5% based on the total weight of Eudragit® S 100 polymer) was homogenized in water for 10 minutes and then added to the mixture of aqueous starch dispersion and aqueous Eudragit® S 100 dispersion. The outer layer coating composition was applied to the 5-ASA tablet core with a separate layer using a pan coater, until a coating amount of 5 mg / cm2 of Eudragit® S 100 was achieved. The spray coating parameters are as described for sample 3. Acid resistance test Acid resistance testing was performed using a disintegration apparatus and basked rack assembly. 6 coated tablets or capsules were tested in 0.1 M HCl for 2 hours at 37°C. If no cracks or deformation of the coating were observed, the tablets and capsules were considered acid resistant. The acid resistance of the coated tablets was also determined after mechanical stress. Six tablets were subjected to 100 rotations (25 rpm / 4 minutes) in a friability test before testing in 0.1 M HCl for 2 hours at 37°C. Drug Release Experiment #1 - Simulated Fasting State and Then Dissolution in Hanks Buffer at pH 6.8 In vitro dissolution studies were performed on a USP Type II apparatus using a pedal speed of 50 rpm and an ambient temperature of 37 ± 0.5°C. To simulate the “fasted” state, capsules or tablets were first tested in 0.1 M HCl for 2 hours and then in Hanks’ buffer (pH 6.8) for 10 hours. The pH of the buffer was stabilized at 6.8 ± 0.05 by continuous sparging with 5% CO2 / 95% O2. Absorbance measurements were performed at 5-min intervals with an absorption wavelength of 301 nm in HCl and 330 nm in Hanks buffer (pH 6.8). Drug Release Experiment #2 - Simulated Fasting State and Then Dissolution in Krebs Buffer at pH 7.4 In vitro dissolution studies were performed on a USP Type II apparatus using a pedal speed of 50 rpm and an ambient temperature of 37 ± 0.5°C. To simulate the “fasted” state, tablets or capsules were first tested in 0.1 M HCl for 2 hours and then in Krebs buffer (pH 7.4) for 10 hours. Drug release experiment #3 - Simulated fasting state followed by dissolution in Sørenson buffer at pH 6.8 In vitro dissolution studies were performed on a USP Type II apparatus using a pedal speed of 50 rpm and an ambient temperature of 37 ± 0.5°C. The coated capsules or tablets were tested in Sørenson buffer at pH 6.8 (35. 35.4 mM KH2PO4 + 35.6 mM NaH2PO4). To simulate the “fasted” state, capsules or tablets were first tested using a disintegration apparatus in 0.1 M HCl for 2 hours, followed by 18 hours in Sørenson buffer (pH 1.6). Drug release experiment #4 - Simulated fasting state followed by dissolution in Sørenson buffer at pH 6.8 with 50 U / mL α-amylase (α-amylase release effect). In vitro dissolution studies were performed on a USP Type II apparatus using a pedal speed of 50 rpm and an ambient temperature of 37 ± 0.5°C. The coated capsules or tablets were tested in Sørenson buffer at pH 6.8 (35.4 mM KH2PO4 + 35.6 mM NaH2PO4) containing 50 U (units) / ml α-amylase derived from B. licheniformis. To simulate the “fasted” state, capsules or tablets were first tested using a disintegration apparatus in 0.1 M HCl for 2 hours, followed by 18 hours in Sørenson buffer (pH 6.8). Results Coated capsules The results presented in Figures 1 to 3 show that the coated capsules prepared according to the method of the present invention have improved dissolution properties compared to the coated capsules of the comparative samples. In simulated gastric fluid, all coated capsules tested were stable for at least 2 hours, independent of the coating composition. Furthermore, in aqueous solution at pH 6.8 (data not shown), no release of 5-ASA was observed from any of the tested capsules during the 10 hours when the capsules were exposed to simulated small intestinal conditions (Drug Release Test #1, Hank's Buffer, pH 6.8). Notably, preparation of the outer coating using the aqueous coating composition resulted in coated capsules that were resistant to simulated small intestinal conditions, independent of the starch ratio (Samples 1 and 2) and independent of the anti-adhesion agent used, namely GMS (Samples 1 and 2) and talc (Comparative Sample 2). However, it should be noted that when the capsules were exposed to pH 7.4 (drug release test No. 2, Figure 1), the initial release of 5-ASA from the coated capsules prepared according to the method of the present invention occurred earlier than that of the capsules of Comparative Example 1 (prepared using a conventional “semi-organic” coating composition). It is noteworthy that increasing the starch content of the coating did not significantly change the dissolution profile under these conditions (Figure 1, Comparative Examples 1 and 2). Replacing GMS with talc as an anti-adherent agent resulted in a delay in the initial release of 5-ASA (Figure 1, Comparative Examples 1 and 2). In aqueous solution at pH 6.8, enzyme-stimulated release was observed for coated capsules of samples 1 and 2 (drug release experiments no. 3 and no. 4, Fig. 2). In particular, initial release of 5-ASA was observed when α-amylase was present in the buffer solution at pH 6.8. This is in accordance with WO2013 / 164315A, which shows that the presence of starch in the outer layer causes a significant release of the active ingredient upon exposure to colonic enzymes even if the pH of the surrounding environment is well below the pH threshold of the second polymeric material. This result also indicates that the presence of colonic enzymes in the surrounding environment is essential to achieve significant release of the active ingredient under these conditions, thereby effectively preventing premature drug release. Increasing the starch coating content does not cause a significant change in the dissolution profile under these conditions. In contrast, while a reduced enzyme release was observed for the capsules of Comparative Example 1 (prepared using a "semi-organic" outer coating composition), the release of the coated capsules of Examples 1 and 2 according to the present invention was delayed. Without being bound by any particular theory, the inventors believe that this can be explained by a stronger layered structure when the coating is prepared from a "semi-organic" coating composition material. The inventors have also observed that replacing GMS with talc as an anti-adherent agent leads to higher variability in coating dissolution and loss of the enzymatically induced release from the capsules, and consequently the drug release mechanism is compromised when the pH is lower than the pH at which the enteric polymer dissolves (Figure 3, Comparative Example 2). Therefore, coatings consisting of GMS as an anti-adherent agent are superior to those containing talc as an anti-adherent agent. Furthermore, since talc is a less effective anti-adherent agent than GMS, it is necessary to use it in higher amounts than GMS (50 wt % talc based on Eudragit® S 100 versus 10 wt % GMS). This means that the amount of excipients in the coating is significantly higher, which could potentially prevent amylase from accessing the starch embedded in the layer matrix. Coated tablets These coatings were applied to 1600 mg 5-ASA tablets coated with a separate HPMC layer without any processing problems. The results presented in Table 1 and Figures 4 and 5 show that the coated tablets prepared according to the method of the present invention improved gastric resistance as well as gastric resistance after mechanical impact (Example 3) and improved dissolution properties compared to the coated tablets of the comparative sample. In simulated gastric fluid (0.1M HCl for 2 hours), coated tablets of both Sample 3 and Comparative Sample 3 (both using GMS as an anti-caking agent) were resistant for at least 2 hours. Therefore, the use of GMS as an anti-caking agent in the outer coating layer produces coated tablets that are gastro-resistant, regardless of whether an aqueous or semi-organic coating layer is used to prepare the outer layer. The coated tablets of Comparative Examples 5 to 9 (all of which use an inorganic anti-adhesion agent) do not have sufficient resistance in simulated gastric fluid, which results in premature release of 5-ASA. Furthermore, the coated tablets of sample 3 showed 100% acid resistance even after mechanical impact. In contrast, the coated tablets of comparative samples 5 to 9 showed very poor acid resistance after mechanical impact. Table 1 Samples Anti-adhesion agent Outer layer coating composition % Acid resistance % Acid resistance after mechanical impact Type Quantity (%) Sample 3 GMS 5 blue 100 100 Comparative sample 3 GMS 5 semi-organic 100 100 Comparative sample 4 Talc 50 semi-organic 83.33 83.33 Comparative sample 5 Talc 50 blue 83.33 33.33 Comparative sample 6 Talc 5 blue 33.33 16.67 Comparative sample 7 Talc 5 blue 33.33 0.00 Comparative sample 8 Aerosil ® 300 5 blue 0 0 Comparative sample 9 Syloid 244 FP 5 blue 0 0 When coated tablets were tested in vitro for drug release in a pH 6.8 buffer to simulate the conditions of the proximal small intestine, after exposure to simulated gastric conditions (Drug Release Test No. 1), higher dissolution resistance was observed for coated tablets of Sample 3 containing 5% GMS in the outer coating than for tablets of Comparative Sample 5 containing talc in the outer coating (Figure 4). Specifically, the release of 5-ASA from tablets of Sample 3 after 10 hours was much less than 5%, while the coated tablets of Comparative Sample 5 showed approximately 30% release of 5-ASA after 10 hours. Furthermore, upon exposure to pH 7.4 Krebs buffer (Drug Release Test No. 2) to simulate the conditions of the ileocolon region, rapid pH release of 5-ASA was observed for the coated tablets of Sample 3 containing GMS (Figure 5). In the outer coating, it is shown that when the pH of the enteric polymer is stimulated (pH above 7), rapid dissolution of the coating and drug release occur. Replacing GMS with talc as an anticoagulant (Comparative Sample 5) results in a delay in the initial release of 5-ASA, slower dissolution of the coating and consequently a slow release of 5-ASA (Figure 5). Therefore, it can be seen that the combination of an organic anti-adhesion agent and an aqueous outer coating composition produces a delayed release formulation that is superior to the comparative formulation. It is to be appreciated that the invention is not limited to the details described above with reference to the preferred embodiments, but that numerous changes and modifications can be made without departing from the scope of the invention as defined in the following claims.

Claims

Claims 1. A method for producing a sustained-release pharmaceutical formulation for oral administration to deliver the drug to the colon, said formulation comprising: forming a core comprising a drug; combining a first aqueous composition of an enzymatically degradable polymer that is degradable by colonic bacterial enzymes; a second aqueous composition of an enteric layer-forming polymer with a pH threshold of about pH 6 or higher; and an organic anti-adhesion agent, to form an outer layer coating composition; coating the core with the outer layer coating composition to form an outer layer-coated core.

2. The method claimed in claim 1, wherein the anti-adhesion agent is in the form of an aqueous dispersion.

3. The method claimed in claim 2, wherein the aqueous dispersion comprises a surfactant.

4. The method claimed in claim 3, wherein the surfactant is non-ionic.

5. The method claimed in claim 3 or 4, wherein the surfactant is hydrophilic.

6. The method as claimed in any one of the preceding claims, wherein the organic anti-adherent is glyceryl monostearate (GMS) or stearic acid.

7. A method as claimed in any one of the preceding claims, wherein the core is pre-coated with a separate layer comprising a non-ionic polymer forming the layer which is soluble in the fluid of the digestive tract; or an inner layer comprising a polymeric material which is soluble in the fluid of the intestine or digestive tract, said polymeric material being selected from the group consisting of an at least partially neutralized polycarboxylic acid polymer and a non-ionic polymer, provided that the polymeric material is a non-ionic polymer, said inner layer comprising at least one additive selected from a buffering agent and a base or both of the separate layer and the inner layer.

8. The method as claimed in claim 7, wherein the inner layer comprises a buffering agent and a base.

9. A sustained release pharmaceutical formulation for oral administration to deliver a drug to the colon, comprising: a core comprising a drug, and an outer coating layer for the core, the outer coating layer comprising a mixture of an enzymatically degradable polysaccharide that is degraded by colonic bacterial enzymes, an enteric polymer forming the layer having a pH threshold of about pH 6 or higher, and an organic anti-adhesion agent; wherein the outer coating layer does not contain more than about 5000 ppm of free organic solvent residue; or wherein the outer coating layer comprises at least 10% by weight of at least one softening agent based on the weight of the enteric polymer forming the layer.

10. The sustained-release pharmaceutical formulation according to claim 9 comprising an inner layer located between said core and said outer coating layer, wherein said inner layer comprises a non-ionic layer-forming polymer that is soluble in digestive fluid, a buffering agent, and a base.

11. A sustained-release pharmaceutical formulation according to claim 9 or 10, comprising a discrete layer located on the surface of the core, said discrete layer comprising a layer-forming ionic polymer that is soluble in gastrointestinal fluid.

Images