JP6626470B2 - Delayed release drug formulation - Google Patents

Description

  The present invention relates to a delayed release formulation having a drug-containing core and a delayed release coating. In particular, it relates to a delayed release formulation for delivering a drug to the colon.

  Targeting drugs to the intestine is well known and has been known for over 100 years. Although the colon can be used as a means to achieve local or systemic treatment, the drug is usually targeted to the small intestine. The requirements for coating the drug depend on its target site. In order to reach the colon, the drug must pass through the small intestine, so it is a requirement that a delayed release coating intended to release the drug in the colon does not release the drug in the small intestine.

  Coating products for release in the small intestine typically use polymer coatings that dissolve or disintegrate 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 above 5 and the polymeric coating dissolves or disintegrates. Commonly used coatings are those containing ionizable carboxyl groups. At higher pH levels, the carboxyl groups ionize, rendering the polymer coating disintegrable or soluble. Common polymers of this type that have been used include Eudragit® L and Eudragit® S.

  Various methods are known for improving release in the small intestine by ensuring earlier release of the drug. U.S. Pat. No. 6,037,064 is one of several references disclosing partially neutralizing carboxyl groups to lower the pH at which disintegration occurs. U.S. Pat. No. 6,064,064 discloses a tablet having an inner coat of partially neutralized material and an outer coat with a lower or no degree of neutralization. This allegedly results in disintegration at an earlier point in time when it is transferred from the stomach.

  Drug release in the colon typically requires another approach. The colon is predisposed to many disease states, including inflammatory bowel disease, irritable bowel syndrome, constipation, diarrhea, infections and carcinomas. In such conditions, a colon-targeting drug will maximize the therapeutic efficacy of the treatment. The colon can also be used as a portal to transfer drugs into the systemic circulation. Various formulations, such as prodrugs and formulation forms, have been developed for the delivery of colonic drugs, and once the proven concept can be applied to other drugs, the latter is more widespread.

  The development of colon drug delivery dosage forms has also exploited the greater bacterial population in the colon through the use of natural polysaccharides as carrier materials that constitute substrates for many enzymes of the resident colonic bacteria. . These materials can pass directly through the upstream gastrointestinal tract, but are digested as they enter the colon. Currently considered include amylose, pectin, chitosan, and galactomannan.

  Amylose is resistant to digestion by enzymes in the upstream gastrointestinal tract. However, it is fermented in the colon by α-amylase enzymes produced by a majority of the 400 bacterial species resident in the colon.

  One great attraction of using polysaccharides in this bacterial enzyme approach to colon drug delivery is that the materials used are food grade and are therefore safe for human use. They are usually applied as a coating or incorporated into the core material as a matrix carrier and enter the colon and be digested by colonic bacterial enzymes, leading to the release of the drug load. An example of such a formulation employing an amylose coating is disclosed in US Pat.

  However, a major limitation with these natural materials is that they swell excessively in aqueous media, resulting in leachable drug loads in the upstream digestive tract region. To avoid this problem, natural materials have been used as a mixture with various impermeable materials.

  U.S. Patent No. 6,038,077 teaches the use of an outer coating comprising a film-forming cellulose or acrylate polymer material and amorphous amylose for tablets containing the active compound. The polymer material used is a pH independent release polymer material.

  Non-Patent Document 1 reports findings on incorporating various insoluble polymers into an amylose coating to control amylose swelling. A range of cellulosic and acrylate-based copolymers have been evaluated and commercial ethyl cellulose (Ethocel®) has been found to control swelling most effectively. Eudragit® L100 pH-dependent soluble coating has been used only for multilayer systems containing bioactives coated with an inner coating of amylose and then with an outer coating of Eudragit® L100.

  Additional amylose-based coating compositions are disclosed in US Pat. The coating composition comprises a mixture of amylose and a water-insoluble, pH-independent film-forming polymer formed from a water-insoluble cellulose or acrylate polymer material.

  U.S. Patent No. 6,064,064 also discloses a delayed release coating comprising amylose and (preferably) ethylcellulose or, alternatively, an insoluble acrylate polymer. The coating composition also includes a plasticizer, and the method finds particular use in the preparation of dosage forms containing active materials that are unstable at temperatures above 60 ° C. Is formed.

  U.S. Patent No. 6,037,064 discloses certain delayed release coatings for bioactive prednisolone sodium metasulfobenzoate, including glassy amylose, ethylcellulose and dibutyl sebacate.

  The use of polysaccharides other than amorphous amylose in delayed release coatings is disclosed in US Pat. Examples include guar gum, karaya gum, tragacanth gum and xanthan gum. The fine particles of these polysaccharides are dispersed in a water-insoluble, film-forming polymer matrix formed, for example, from cellulose derivatives, acrylic polymers or lignin.

  Patent Document 9 discloses an oral pharmaceutical preparation containing a drug and chitosan (a polysaccharide obtained from chitin) for controlling its release. The drug and chitosan are mixed into a homogeneous mechanical powder mixture, which is granulated and then tableted, if desired. Granulation may be performed with an enteric polymer (such as a copolymer of methacrylic acid), or the granules may be provided with a porous enteric coating.

  U.S. Patent No. 6,064,064 discloses a pH-dependent drug release system that is a free-flowing powder of solid hydrophobic nanospheres containing a drug encapsulated in pH-sensitive microspheres. Nanospheres are formed from drugs in combination with wax materials, and pH-sensitive microspheres are formed from pH-sensitive polymers (such as Eudragit® polymers) in combination with water-sensitive materials such as polysaccharides.

  Non-Patent Document 2 reports findings on the use of certain polymethacrylate polymers, among others, to control inulin swelling. The polymethacrylate polymers tested were Eudragit® RS; Eudragit® RL; a 1: 1 mixture of Eudragit® RS and Eudragit® RL; Eudragit® FS; and Eudragit It was a 1: 1 mixture of (R) RS and Eudragit (R) S.

  US Pat. No. 5,077,086 discloses an oral dosage form containing a core containing at least one active ingredient in a shell material containing a polysaccharide that degrades in the colon as a mixture with a film-forming polymer. The weight ratio of polysaccharide to film forming polymer is from 1: 2 to 5: 1, preferably from 1: 1 to 4: 1. A gastric resistant separating layer can be used to prevent premature diffusion of the active ingredient from the core. This reference particularly exemplifies a tablet having an inner separating layer of Eudragit® L30D together with an outer layer comprising Eudragit® L30D and guar gum (Example 2).

  U.S. Patent No. 6,064,087 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 an outer coating layer. The (each) inner coating layer is an enteric polymer that begins to dissolve in the aqueous medium at a pH of about 5 to about 6.3, and the outer coating layer is an aqueous coating medium at a pH of about 6.8 to about 7.2. It is an enteric polymer that begins to dissolve. The enteric polymer coating material for the inner layer is cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyvinyl acetate phthalate, poly (methacrylic acid, methyl methacrylate) 1: 1 , Poly (methacrylic acid, ethyl acrylate) 1: 1 and compatible mixtures thereof.

  U.S. Patent No. 6,047,064 discloses a colon drug delivery formulation using a mixture of a pH dependent film forming polymeric material and a polysaccharide such as starch. While this formulation is known to exhibit a delayed release followed by a relatively rapid release of the drug, it would be preferable if the drug release was more rapid in the colon.

US Patent Application Publication No. 2008/0200482 International Publication No. 2008/135090 pamphlet European Patent Application Publication No. 0339399 (BTG International Limited) European Patent Application Publication No. 0502032 (British Technology Group Ltd) International Patent Publication No. WO 99/21536 (BTG International Limited) pamphlet WO 99/25325 (BTG International Limited) Pamphlet Pamphlet of International Publication No. 03/068196 (Alizyme Therapeutics Ltd) British Patent No. 2367002 (British Sugar PLC) International Patent Publication No. WO 01/76562 (Tamperen Patentitioimisto Oy) Pamphlet International Publication No. 2004/052339 (Salvona LLC) pamphlet U.S. Pat. No. 5,422,121 (Roehm GmbH) WO 96/36321 pamphlet WO 2007/122374 pamphlet

Journal of Controlled Release (Mirojevic et al .; 38; (1996); 75-84). European Journal of Pharmaceutical Sciences (Akhgari et al .; 28; March 2006; 307-314).

  It is an object of the present invention to provide a delayed release preparation having a drug-containing core and a delayed release coating. In particular, it is an object of the present invention to provide a delayed-release preparation for delivering a drug to the colon.

  According to a first aspect of the present invention, there is provided a delayed release drug formulation for oral administration for delivering a drug to the colon of a patient, the formulation comprising a core comprising the drug, an outer layer and an inner layer. Wherein the outer layer comprises a mixture of a first polymeric material susceptible to attack by colonic bacteria and a second polymeric material having a pH threshold above about pH 6; and the inner layer comprises: A third polymeric material that is a nonionic polymer soluble in intestinal fluid or gastrointestinal fluid; and the inner layer includes at least one additive selected from a buffer and a base.

  We have disclosed a polymer soluble in intestinal or gastrointestinal fluid, for example, an inner layer comprising a partially or fully neutralized polycarboxylic acid polymer, and a first polymer susceptible to attack by colonic bacteria. The material, e.g., the polysaccharide, and a second polymeric material having a pH threshold above about pH 6, e.g., partially of the same type as the polymer of the inner layer but not neutralized or less than the third polymeric material. That the coating having an outer layer of a mixture with a polycarboxylic acid polymer that is neutralized exhibits superior colonic release properties over similar coatings designed for site-specific release in the colon Was found. In this context, the drug release from the formulations according to the invention seems to be accelerated in the colon when compared to similar colon release formulations. Without being bound by any particular theory, the present inventors have found that once intestinal or gastrointestinal fluid has penetrated the outer layer, the inner layer begins to dissolve before the outer layer and the It is believed that a flow zone is formed. The flow zone not only facilitates dissolution and / or disintegration of the outer layer from the inside, but also softens and breaks down the core, so that as the outer layer degrades, the drug is released from the core more quickly.

  The first polymeric material comprises at least one polysaccharide selected from the group consisting of starch, amylose, amylopectin, chitosan, chondroitin sulfate, cyclodextrin, dextran, pullulan, carrageenan, scleroglucan, chitin, curdlan and levan. Is preferred. It is particularly preferred that the first polymer material is starch.

  In a preferred embodiment, the second polymeric material is an anionic polymeric material, more preferably an anionic copolymer of (meth) acrylic acid and an alkyl (meth) acrylate.

  In a preferred embodiment, the second polymeric material is a copolymer of (meth) acrylic acid and an alkyl (meth) acrylate.

In a particularly preferred embodiment, the present invention relates to a delayed release drug formulation comprising a core comprising the drug and a coating for the core comprising an outer layer and an inner layer, wherein the outer layer comprises starch and (meth) acrylic acid and (meth) acrylic acid. The mixture comprises a mixture with a copolymer of acrylic acid C _1-4 alkyl esters, and the inner layer comprises a fully neutralized copolymer of (meth) acrylic acid and (meth) acrylic acid C _1-4 alkyl esters.

  Some materials, such as amylose, which are susceptible to attack by colonic bacteria, swell when exposed to aqueous fluids, such as gastrointestinal fluids. Such swelling is undesirable because it typically results in premature release of the drug. Swelling is controlled by including a pH-dependent material with a pH threshold of pH 6 or higher.

  A further technical advantage of the present invention is that the drug can be used for extended periods of time (i.e., while the coating is intact and dissolved / dissolved), for example, as compared to the formulation disclosed in WO 01/76562. Substantially no release (during disintegration), after which the drug is released relatively quickly. This is in contrast to homogeneous tablets, where the drug release profile is gradual rather than beating after a delay.

  Yet another technical advantage of the present invention compared to WO 2007/122374 is that the release of the drug is accelerated once the formulation is exposed to the conditions of the colonic environment.

First polymeric material The first polymeric material typically comprises a polysaccharide, eg, a polyglucoside, preferably containing a plurality of glucose units. In a preferred embodiment, the polysaccharide is at least one polysaccharide selected from the group consisting of starch, amylose, amylopectin, chitosan, chondroitin sulfate, cyclodextrin, dextran, pullulan, carrageenan, scleroglucan, chitin, curdlan and levan. It is. More preferably, the polysaccharide is starch, amylose or amylopectin, most preferably starch.

  One skilled in the art can determine, using techniques that are part of the common general knowledge, whether a polymeric material is susceptible to attack by colonic bacteria. For example, a defined amount of a given material can be subjected to an assay containing enzymes from bacteria found in the colon, and the change in weight of the material over time can be measured.

  The polysaccharide is preferably starch. Starch is usually extracted from natural sources such as cereals, beans, and potatoes. Starches suitable for use in the present invention are typically food grade starches, such as rice starch, wheat starch, corn (or corn) starch, pea starch, potato starch, sweet potato starch, tapioca starch, sorghum starch, Sago starch, and arrowroot starch. The use of corn starch is exemplified below.

  Starch is typically a mixture of two different polysaccharides, amylose and amylopectin. Different starches may have these two polysaccharides in different proportions. Most native (native) corn starch has about 20% to about 30% by weight amylose, with the balance at least substantially composed of amylopectin. Starches suitable for use in the present invention typically have at least 0.1% by weight, for example at least 10% or 15%, preferably at least 35% by weight amylose.

  "High amylose" starch, ie, having at least 50% by weight amylose, is preferred. Particularly suitable starches have about 55% to about 75%, for example about 60% or about 70% by weight amylose. In particular, starches having about 50% to about 60% by weight amylose are also suitable.

  Starches suitable for use in the present invention may have up to 100% amylopectin, more typically from about 0.1% to about 99.9% by weight amylopectin. "Low amylose" starches, ie starches having up to 50% by weight of amylose and at least 50% by weight of amylopectin, for example up to 75% by weight amylopectin, and even up to 99% by weight amylopectin, are also suitable. The starch may be, for example, unmodified waxy corn starch. It typically contains about 100% amylopectin.

  Preferred starches have up to 50% by weight of amylopectin. As indicated above, particularly suitable starches are "high amylose" starches having about 25% to about 45% by weight amylopectin, for example about 30% or about 40% by weight amylopectin. In particular, starches having about 40% to about 50% by weight amylopectin are also suitable.

  One skilled in the art can determine the relative proportions of amylose and amylopectin in any starch. For example, using near-infrared ("NIR") spectroscopy, the amylose and amylopectin contents of starch can be determined by NIR using a laboratory-produced mixture of known amounts of these two components. It can be determined using a line. In addition, starch can be hydrolyzed to glucose using amyloglucosidase. A series of enzyme-catalyzed phosphorylation and oxidation reactions results in the formation of reduced nicotinamide adenine dinucleotide phosphate ("NADPH"). The amount of NADPH formed is stoichiometric with the original glucose content. Test kits suitable for this procedure are available (e.g., R-Biopharm, Germany). Another method that can be used is to subject the coating to digestion with a bacterial enzyme, such as α-amylase, to obtain short chain fatty acids (“SCFA”) that can be quantified by gas-liquid chromatography using a capillary column. Including making.

  A preferred starch has amylose in its glassy form, but amylose in its amorphous form may also be used in the context of the present invention.

  Preferred starches are "off-the-shelf" starches, that is, starches that do not require any processing before use in the context of the present invention. Examples of particularly suitable “high amylose” starches include Hylon ™ VII (National Starch, Germany), Eurylon ™ 6 (or VI) or Amylo NI-460 or Amylo N-400 (Roquette, Lestron, France), Or Amylogel 03003 (Cargill, Minneapolis, USA), all of which are examples of corn starch having about 50% to about 75% amylose by weight.

Second Polymeric Material The present invention involves the use of a second polymeric material that dissolves in a pH dependent manner. The second polymeric material is a pH-sensitive, film-forming polymer, ie, has a "pH threshold" below which its pH is insoluble in aqueous media and above which it is soluble in aqueous media. Thus, the pH of the surrounding medium induces dissolution of the second polymeric material, below which the second polymeric material does not (substantially) dissolve. Once the pH of the surrounding medium reaches (or exceeds) the pH threshold, the second polymeric material becomes soluble.

  Throughout this specification, the term "insoluble" is used to mean that 1 g of polymeric material requires more than 10,000 ml of solvent or "ambient medium" to dissolve at a given pH. In addition, the term "soluble" refers to less than 10,000 ml, preferably less than 5,000 ml, more preferably less than 1000 ml, even more preferably less than 100 ml or 10 ml for 1 g of the polymeric material to dissolve at a given pH. Used to mean that a solvent or surrounding medium is required.

  By "ambient medium" we mean gastric and intestinal fluids, or aqueous solutions designed to reproduce gastric or intestinal fluids in vitro.

  The normal pH of gastric juice is usually in the range of pH 1-3. The second polymeric material is insoluble below pH 6, is soluble above about pH 6, and is therefore usually insoluble in gastric juice. Such materials are sometimes referred to as gastric resistant or "enteric" materials.

  The second polymeric material has a pH threshold above about pH 6, and more preferably above about pH 6.5. The second polymeric material typically has a pH threshold of about pH 8 or less, such as about pH 7.5 or less, and preferably about pH 7.2 or less. Preferably, the second polymeric material has a pH threshold within the pH range found in intestinal fluid. The pH of intestinal fluid varies from person to person, but in healthy humans generally is about pH 5-6 in the duodenum, about 6-8 in the jejunum, about 7-8 in the ileum, and about 6-8 in the colon. The second polymeric material preferably has a pH threshold of about 6.5, ie, is insoluble below pH 6.5, soluble above about pH 6.5, and more preferably has a pH threshold of about 7. Ie, insoluble below pH 7 and soluble above about pH 7.

  The pH threshold at which a material becomes soluble can be determined by simple titration techniques, which will be part of the common general knowledge of those skilled in the art.

  The second polymeric material is typically a film-forming polymeric material, such as a polymethacrylate polymer, a cellulosic polymer or a polyvinyl-based polymer. Examples of suitable cellulose polymers include cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), and hydroxypropyl methylcellulose acetate succinate (HPMC-AS). An example of a suitable polyvinyl-based polymer is polyvinyl acetate phthalate (PVAP).

The second polymeric material is preferably an "anionic" polymeric material, i.e. a polymeric material containing groups capable of ionizing in an aqueous medium to form an anion (see below), more preferably (meth) Copolymers of acrylic acid and (meth) acrylic acid C _1-4 alkyl esters, for example, copolymers of methacrylic acid and methyl methacrylate. Such polymers are known as poly (methacrylic acid / methyl methacrylate) copolymers. A preferred example of such a copolymer is polymethacrylate, which is usually anionic and not slow release. The ratio of carboxylic acid groups to methyl ester groups ("acid: ester ratio") in these copolymers determines the pH at which the copolymer is soluble. The acid: ester ratio can be from about 2: 1 to about 1: 3, such as about 1: 1, or preferably about 1: 2. Preferred anionic copolymers typically have a molecular weight ("MW") of about 120,000 to 150,000 g / mol, preferably about 125,000 g / mol or about 135,000 g / mol.

  Preferred anionic poly (methacrylic acid / methyl methacrylate) copolymer has a molecular weight of about 125,000 g / mol. Preferred examples of such polymers have an acid: ester ratio of about 1: 1 and a pH threshold of about pH 6, or have an acid: ester ratio of about 1: 2 and a pH threshold of about pH 7.

  A specific example of a suitable anionic poly (methacrylic acid / methyl methacrylate) copolymer having a molecular weight of about 125,000 g / mol, an acid: ester ratio of about 1: 1 and a pH threshold of about pH 6 is available under the trade name Eudragit ( (Registered trademark) L. The polymer is available in powder form (Eudragit® L100) or as an organic solution (12.5%) (Eudragit® L12.5).

  A specific example of a suitable anionic poly (methacrylic acid / methyl methacrylate) copolymer having a molecular weight of about 125,000 g / mol, an acid: ester ratio of about 1: 2, and a pH threshold of about pH 7 is available under the trade name Eudragit ( (Registered trademark) S. The polymer is available in powder form (Eudragit® S100) or as an organic solution (12.5%) (Eudragit® S12.5).

  The second polymeric material may be a copolymer of methacrylic acid and ethyl acrylate. Preferred poly (methacrylic acid / ethyl acrylate) copolymers have a molecular weight of about 300,000 to 350,000 g / mol, such as about 320,000 g / mol. A preferred example of such a copolymer has an acid: ester ratio of about 1: 1 and a pH threshold of about pH 5.5.

  Specific examples of suitable anionic poly (methacrylic acid / ethyl acrylate) copolymers are available in powder form, commercially available under the trade name Eudragit® L100-55, or in the form of an aqueous dispersion (30 %) And is commercially available under the trade name Eudragit® L30D-55.

  The second polymeric material may be a copolymer of methyl acrylate, methyl methacrylate and methacrylic acid. Preferred poly (methyl acrylate / methyl methacrylate / methacrylic acid) copolymers have a molecular weight of about 250,000 to about 300,000 g / mol, such as about 280,000 g / mol. A preferred example of such a copolymer has a ratio of about 7: 3: 1 methyl acrylate: methyl methacrylate: methacrylic acid, thereby providing an acid: ester ratio of about 1:10 and a pH threshold of about pH 7. I do.

  A specific example of a suitable anionic poly (methyl acrylate / methyl methacrylate / ethyl acrylate) copolymer is available in the form of an aqueous dispersion (30%) and is sold under the trade name Eudragit® FS30D ing.

  Eudragit® copolymers are manufactured and / or sold by Evonik (Darmstadt, Germany).

  Mixtures of film-forming polymeric materials may be used as appropriate. For example, the second polymeric material may be a blend of at least two different polymers having a pH threshold of about pH 6 or higher. Preferably, the polymers in the blend are different polymethacrylate polymers. In embodiments where the second polymeric material is a blend of two different polymers having a pH threshold of about pH 6 or greater, the polymer is from about 1:99 to about 99: 1, for example, from about 10:90 to about 90:10. Or 25:75 to about 75:25, or about 40:60 to about 60:40, such as about 50:50 polymer weight ratio, may be present in the blend.

  One example of a suitable mixture may include a mixture of Eudragit® L and Eudragit® S, for example a 1: 1 mixture. As a further example, a blend of Eudragit S and Eudragit FS, such as a 50:50 blend, may be mentioned.

  For the avoidance of doubt, the terms "mixture" and "blend" are used interchangeably herein in the context of a mixture or blend of polymers forming a second polymeric material.

  However, the use of certain film-forming polymeric materials, such as poly (methacrylic acid / methyl methacrylate) copolymer alone, is preferred. Particularly preferred is the use of Eudragit® S alone as the second polymeric material.

Outer layer The ratio of the first polymer material to the second polymer material is typically at least 1:99, such as at least 10:90, and preferably at least 25:75. This ratio is typically less than 99: 1, for example less than 75:25, and preferably less than 60:40. In some embodiments, this ratio can be 35:65 or less. In some preferred embodiments, the ratio is between 10:90 and 75:25, for example between 10:90 and 60:40, and preferably between 25:75 and 60:40. In some particularly preferred embodiments, this ratio is between 15:85 and 35:65, such as between 25:75 and 35:65, and preferably about 30:70. In another particularly preferred embodiment, the ratio is from 40:60 to about 60:40, such as about 50:50.

  The mixture of the first and second polymeric materials is preferably substantially homogeneous.

  If desired, conventional additives such as additives selected from plasticizers for film formation (eg, triethyl citrate), antiblocking agents (such as glyceryl monostearate or GMS) and surfactants (such as polysorbate 80). May be included in amounts up to 30% by weight of the final composition of the outer coating preparation.

  The thickness of the outer coating of the core is typically from about 10 μm to about 150 μm. However, the specific coating thickness will depend on the composition of the coating. For example, the thickness of the coating is directly proportional to the amount of polysaccharide in the coating. Thus, in embodiments where the coating comprises high amylose starch and Eudragit ™ S in a ratio of about 30:70, the thickness of the coating can be from about 70 μm to about 130 μm, and preferably from about 90 μm to about 110 μm. The thickness (in μm) of a given coating composition is independent of core size.

The thickness of the outer coating is independent of the size of the core, but typically for cores having a diameter of about 5 × 10 −4 m to about 25 mm, based on the dry weight of the total polymer material, 2 mg / cm ² ~ about 10 mg / cm ^2, preferably about 2 mg / cm ² ~ about 8 mg / cm ^2, and most preferably equivalent to about 4 mg / cm ² ~ about 8 mg / cm ^2.

Third polymeric material The formulation according to the invention further has an inner layer located between the core and the outer layer. The inner layer comprises a third polymeric material that is insoluble in gastric fluid and may be soluble in intestinal fluid, but is preferably soluble in both gastric fluid and intestinal fluid (referred to herein as gastrointestinal fluid).

  By "gastric juice" we mean the aqueous fluid in the stomach of a mammal, especially a human. This fluid contains up to about 0.1 N hydrochloric acid and substantial amounts of potassium and sodium chlorides and plays an important role in digestion by activating digestive enzymes and denaturing ingested proteins. Stomach acid is produced by cells lining the stomach and other cells produce bicarbonate, which acts as a buffer, preventing gastric juice from becoming too acidic.

  By "intestinal fluid" we mean fluid in the lumen of the intestine of mammals, especially humans. Intestinal fluid is a pale yellow aqueous fluid secreted by the glands lining the intestinal wall. Intestinal fluid includes fluids found in the small intestine, i.e., fluids found in the duodenum (or "duodenal fluid"), fluids found in the jejunum (or "jejunal fluid"), and fluids found in the ileum (or " Ileal fluid "), as well as fluids found in the large intestine, such as" colon fluid ".

  One skilled in the art can easily determine whether the polymer is soluble in gastric and / or intestinal fluids. If the polymer is soluble in water (or an aqueous solution) at a pH of 1 to 3, such as a buffer solution, the polymer will typically be soluble in gastric fluid. Similarly, if the polymer is soluble in water (or an aqueous solution, such as a buffer solution) at a pH of 5-8, the polymer will typically be soluble in intestinal fluid. Alternatively, the composition of gastric and intestinal fluids is known and can be replicated in vitro. Where the polymer is soluble in vitro in artificial gastric or intestinal fluid, it will typically be soluble in gastric or intestinal fluid, respectively, in vivo.

  Any pharmacologically acceptable water-soluble film-forming polymer is in principle suitable for use as the third polymeric material. The solubility of the water-soluble polymer may be pH-dependent, ie, the third polymeric material may be a pH-sensitive polymer having a pH threshold. In such embodiments, the pH threshold of the third polymeric material is lower than the pH threshold of the second polymeric material, typically at least 0.5 pH units, and preferably only 0.5-3.5 pH units. Low. The pH threshold of the third polymeric material is typically between about pH 4.5 and about pH 7.5.

  The third polymeric material can be soluble in at least one fluid selected from gastric, duodenal, jejunal, and ileal fluids. However, in a preferred embodiment, the solubility of the third polymeric material in water is pH independent, at least within the range of pH found in the intestine. In a preferred embodiment, the third polymeric material is soluble in fluid at any point in the stomach and intestines, ie, is soluble in gastrointestinal fluids.

  Suitable polymers for use as the third polymeric material include pharmacologically acceptable non-ionic polymers, ie, pharmacologically acceptable polymers that do not ionize in aqueous media. In these embodiments, the inner layer further comprises at least one additive selected from a buffer and a base. In particular, the inner layer of these embodiments preferably comprises a base and optionally a buffer. In a preferred embodiment, the inner layer contains both a buffer and a base. Suitable examples of buffers and bases are discussed below.

  Examples of suitable nonionic polymers include methylcellulose (MC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), poly (ethylene oxide) -graft-polyvinyl alcohol, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG) ) And polyvinyl alcohol (PVA).

  Mixtures of film-forming polymeric materials may be used if desired. The polymer component in such a mixture may be an anionic polymer, a non-ionic polymer, or a mixture of an anionic polymer and a non-ionic polymer. Examples of suitable mixtures include mixtures of Eudragit® L and Eudragit® S, such as a 1: 1 mixture, and mixtures of Eudragit® S and HPMC, such as a 1: 1 mixture. May be mentioned. However, the use of certain film-forming polymeric materials, such as poly (methacrylic acid / methyl methacrylate) copolymers, especially Eudragit® S, alone is preferred.

Base In a preferred embodiment, the inner layer comprises at least one base. The purpose of the base is to provide an alkaline environment beneath the outer layer when intestinal fluid begins to penetrate the outer layer. Without being bound by any particular theory, we believe that because the pH of the alkaline environment is above the pH threshold of the second polymeric material, the alkaline environment may also cause dissolution of the outer layer, and thus collapse. It is believed that it accelerates the release of the drug from the formulation once the outer coating has dissolved and / or disintegrated.

  In principle, any pharmacologically 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 physiological bases such as triethanolamine, sodium bicarbonate, potassium carbonate, trisodium phosphate, trisodium citrate or triethylamine. Organic bases such as acceptable amines are included. Generally, a hydroxide base, especially sodium hydroxide, is preferred.

  In embodiments where the third polymeric material is a non-ionic polymer, the inner layer typically includes either a base or, more typically, a combination of a base and a buffer.

  The amount of base present in the inner layer is determined, at least in part, by the final pH of the inner coating preparation prior to coating the core of a given batch, the number of cores to be coated in the batch, the coating process of the batch. Will depend on the efficiency of the coating process in terms of the amount of internal coating preparation used and the amount of coating preparation discarded.

Buffer The inner coating preferably comprises at least one buffer. The purpose of the buffer is to provide or increase the pH buffer capacity beneath the outer layer when intestinal fluid begins to penetrate the outer layer. Without being bound by a particular theory, we believe that the buffer increases the buffer capacity in dissolving the inner layer and aids in ionizing and dissolving the polymer in the outer layer. . It is believed that for a given pH, the higher the buffer capacity, the faster the rate of polymer dissolution. In embodiments where the base is present in the inner layer, the buffer aids in maintaining an alkaline environment beneath the outer layer once intestinal fluid has penetrated the outer layer.

  The buffering agent may be a pharmacologically acceptable non-polymeric carboxylic acid, for example an organic acid such as a carboxylic acid having 1 to 16, preferably 1 to 3 carbon atoms. Suitable carboxylic acids are disclosed in WO 2008/135090. Citric acid is an example of such a carboxylic acid. The carboxylic acid may be used in the form of a carboxylate, or a mixture of carboxylic acids, carboxylate salts or both.

  The buffer may also be an inorganic salt such as an alkali metal salt, an alkaline earth metal salt, an ammonium salt, and a soluble metal salt. The metals of the soluble metal salts include manganese, iron, copper, zinc and molybdenum. More 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 and organic acid buffers due to the high buffer capacity of the coating solution at pH, eg, pH 8.

  The buffer (s) will typically be present in the inner layer at about 0.1 to about 20% by weight, based on the dry weight of the third polymeric material, for example about 0.1 to about 4% by weight, preferably about It is present in an amount from 0.1 to about 3% by weight, and more preferably about 1% by weight.

Inner Layer In addition to the buffer and / or the base, the inner layer contains additives selected from plasticizers (such as triethyl citrate), anti-blocking agents (such as GMS), and surfactants (such as polysorbate 80). And conventional polymer film additives.

The thickness of the inner coating of the core is typically from about 10 μm to about 150 μm. Like the outer layer, the thickness of the inner layer is independent of the size of the core, but typically for cores having a diameter of about 0.2 mm to about 30 mm, the drying of the third polymeric material based on the weight, about 2 mg / cm ² ~ about 10 mg / cm ^2, preferably about 2 mg / cm ² ~ about 8 mg / cm ^2, and most preferably equivalent to about 3 mg / cm ² ~ about 7 mg / cm ² .

Optional Additional Layers The formulations of the present invention may have additional (or separation) layers between the active core and an upper coating layer that coats the inner and / or outer layers.

  Formulations according to the present invention may have a core composition that is incompatible with the delayed release coating. In such cases, it may be desirable to include a separating layer to separate the core from the coating. For example, the invention encompasses embodiments where the inner layer provides an alkaline environment that is believed to assist in dissolving and disintegrating the outer layer. However, if the core contains a drug with acidic groups, the inner layer may be incompatible with the core. One example of a drug having an acidic group is 5ASA. In such cases, it will typically be appropriate to include a separating layer.

  Any suitable separation layer known to those skilled in the art may be used. In one preferred embodiment, the separation layer comprises a non-ionic polymer. Suitable nonionic polymers include methylcellulose (MC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), poly (ethylene oxide) -graft-polyvinyl alcohol, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), And polyvinyl alcohol (PVA). Mixtures of non-ionic polymers may also be used. HPMC or PVA is preferred. The separation layer may further include polyethylene glycol.

  The formulation may also include an intermediate layer between the outer and inner layers, provided that the intermediate layer does not adversely affect the release characteristics of the formulation. However, the outer layer is usually provided in contact with the inner layer; in other words, the outer layer is usually applied directly to the inner layer, ie there is usually no intermediate layer separating the inner and outer layers.

Core "Core" is the solid to which the inner layer is applied. The core may be in any suitable dosage form, for example, tablets, pellets, granules, microparticles, hard or soft capsules, or microcapsules. In a preferred embodiment, the core is a tablet or capsule.

  The core contains the drug (s). The drug (s) may be contained within the core body, for example, within a matrix of tablets or pellets, or within the contents encapsulated within a capsule. Alternatively, the drug may be in a coating applied to the core, for example when the core is a bead of an edible substance such as sugar, for example when the core is in the form of non-pareil beads or dragees.

  The core may consist solely of the drug (s), or more usually the drug (s) and at least one pharmaceutically acceptable excipient. In this context, the core is typically a tablet or pellet, with the drug (s) and a filler or diluent, for example, a cellulosic material such as lactose or microcrystalline cellulose; a binder, for example, polyvinylpyrrolidone ("PVP"). ") Or hydroxypropyl methylcellulose (HPMC); disintegrants such as croscarmellose sodium (e.g., Ac-Di-Sol (TM)) and sodium starch glycolate (e.g., Explotab (TM)); and / or lubricants, such as stearin Consists of a mixture with magnesium acid and talc. The core may be a compressed granule containing at least some of these materials.

  The core may be uncoated, or, as described above, the core itself may include a coating, such as a separation layer on which the inner layer is applied.

  The minimum diameter of each core is typically at least about 10-4m, usually at least about 5x10-4m, and preferably at least about 10-3m. The maximum diameter is usually 30 mm or less, typically 25 mm or less, preferably 20 mm or less. In a preferred embodiment, the core has a diameter of about 0.2 mm to about 25 mm, and preferably about 0.2 mm to about 4 mm (eg, for pellets or mini-tablets) or about 15 mm to about 25 mm (eg, for certain tablets or capsules). Having. The term "diameter" refers to the largest linear dimension through the core.

  The formulation may include a plurality of coated cores (coated cores) to provide a single dose of drug (s), especially in embodiments where the cores are “small”, eg, less than 5 mm in diameter. . Multiple unit dosage forms containing a coated core of less than 3 mm in diameter may be preferred.

  The present invention is a multiphasic drug release formulation comprising at least two populations of a coated core, eg, a coated pellet, in the same dosage form, eg, a capsule, wherein one population of the coated core is used as the other, or other, From each coated core population, it has a use in the formulation that is distinguished by its coating. The coatings may differ between the populations in terms of coating thickness or composition, for example, component ratios and / or component identities. A polyphasic drug release formulation would be particularly suitable for Crohn's disease patients, where various areas are affected along the intestine.

  Release from a formulation according to the invention is typically delayed at least to the distal ileum, and preferably to the colon. Release from some formulations may be sustained. However, in preferred formulations, the release is pulsatile.

  The time between the first exposure to conditions suitable for drug release and the start of drug release is known as "lag time". Lag time depends on a number of factors, including the thickness and composition of the coating, and may vary from patient to patient. The formulations according to the invention usually show a lag time of at least 10 minutes in colonic conditions. In most embodiments, the lag time is from about 10 minutes to about 8 hours. For example, in a fecal slurry at pH 6.8, the lag time can be from about 10 minutes to about 2 hours, for example, from about 30 minutes to about 1.5 hours. Complete release of the drug can be achieved within 5 hours, such as within 4 hours, after exposure to these conditions.

  Formulations are usually defined as gastric resistant if the drug release after 2 hours in an acidic medium is less than 10% by weight. Formulations according to the present invention typically show much less than 10% by weight drug release in acidic media and may be considered gastric resistant. These formulations typically exhibit less than 1% by weight of drug release in the acidic medium, and typically exhibit substantially no drug release in the acidic medium. When starch is combined with an acrylate film forming material to form the outer layer of the core coating, typically less than 5% drug release occurs over 5 hours under conditions that mimic the stomach and small intestine.

In one embodiment, the core is a tablet having a diameter of 15 to 25 mm. The outer layer preferably comprises a 30:70 mixture of a high amylose starch such as Eurylon ™ VII or VI and a polymethacrylate polymer such as Eudragit ™ S, and the inner layer preferably has a pH of about 8. It contains a fully neutralized polymethacrylate polymer, such as Eudragit ™ S, applied from an internal coating preparation having. The core is preferably coated with an inner layer to a thickness of about 3 to about 7 mg / cm ² (based on the dry weight of the polymethacrylate polymer) to form an inner layer coated core, which is then coated with an outer layer. It is coated to a thickness of about 4 to about 8 mg / cm ² (based on the dry weight of the polymethacrylate polymer).

Various Aspects According to a second aspect of the present invention there is provided a formulation according to the first aspect for use in a method of medical treatment of the human or animal body by therapy.

  The core contains at least one drug. The formulations are typically used to administer a single drug as the sole therapeutically active ingredient. However, more than one drug may be administered in a single formulation.

  The formulations of the present invention are designed to administer a variety of drugs. Suitable drugs include those known to be administered enterally using known delayed release oral formulations. The present invention can be used to administer drugs with local or systemic effects.

  The formulations of the present invention have particular use in intestinal administration of drugs containing at least one acidic group, such as a carboxylic acid group. Such a drug may be an acidic drug or a zwitterionic drug. One example of such a drug is 5-aminosalicylic acid (5ASA or mesalazine).

The identity of the drug (s) in the formulation will obviously depend on the condition being treated.
In this context, the formulations have particular use in the treatment of IBD (including Crohn's disease and ulcerative colitis), IBS, constipation, diarrhea, infections, and carcinomas, especially colon or colon cancer.

  For the treatment or prevention of IBD, the formulation may be an anti-inflammatory agent (eg, 5ASA (or also known as mesalazine or mesalamine), 4ASA, sulfasalazine and balsalazide); non-steroidal anti-inflammatory agents (eg, ibuprofen and diclofenac) Steroids (eg, prednisolone, budesonide or fluticasone); immunosuppressants (eg, azathioprine, cyclosporine, and methotrexate); antibiotics; and biological agents, including peptides, proteins and antibody fragments. It may include certain drugs. Suitable examples of biological agents include alkaline phosphatase and anti-TNF antibodies such as infliximab, adalimumab, certolizumab pegol, golimumab and ustekinumab.

  For the treatment or prevention of cancer, the formulation may include at least one anti-tumor agent. Suitable antineoplastic agents include fluorouracil, methotrexate, dactinomycin, bleomycin, etoposide, taxol, vincristine, doxorubicin, cisplatin, daunorubicin, VP-16, raltitrexed, oxaliplatin, and pharmaceutically acceptable derivatives thereof. And salts. For the prevention of colon or colon cancer, mainly in patients suffering from colitis, the formulation may comprise the anti-inflammatory agent 5ASA.

  For the treatment or prevention of IBS, constipation, diarrhea or infectious diseases, the formulation may contain at least one active agent suitable for the treatment or prevention of these conditions.

  Pharmacologically acceptable derivatives and / or salts of the drug may also be used in the formulation. One example of a suitable salt of prednisolone is methylprednisolone sodium succinate. A further example is fluticasone propionate.

  The present invention has particular use in either the treatment of IBD (particularly ulcerative colitis) or the prevention of colon or colon cancer (primarily in colitis patients), both using 5ASA. The invention also has use as an entry point into the transfer of drugs through the colon into the systemic circulation. This is particularly advantageous for peptide and protein drugs that are unstable in the upstream gastrointestinal tract. The present invention may also be used for chronotherapeutic purposes.

  In a third aspect of the invention, there is provided a method of targeting a drug to the colon comprising administering to a patient the formulation described above.

  In a fourth aspect of the present invention there is provided the use of a formulation as described above in the manufacture of a medicament for the treatment or prevention of IBD (especially ulcerative colitis), IBS, constipation, diarrhea, infection, and cancer. .

  Also provided is the use of at least one drug selected from anti-inflammatory agents and steroids in the manufacture of a medicament comprising a formulation as described above for use in treating IBD. In addition, there is also provided the use of at least one anti-tumor agent in the manufacture of a medicament, including a formulation as described above for use in treating carcinoma. Further provided is the use of 5ASA in the manufacture of a medicament, including a formulation as described above, for use in preventing colon or colon cancer.

  In a fifth aspect of the present invention, there is also provided a method of medical treatment or prevention of IBD or carcinoma, comprising administering to a patient a therapeutic amount of a formulation as described above.

  The formulation will typically contain a therapeutically effective amount of each or each drug, which may be from about 0.01% to about 99% by weight, based on the total weight of the formulation. The actual dose will be determined by one of ordinary skill in the art using common general knowledge. However, by way of example, a "low" dose formulation typically contains no more than about 20% by weight of the drug, and preferably contains about 1% to about 10% by weight of the drug, for example about 5% by weight. "High" dose formulations typically contain at least 40% by weight of the drug, and preferably from about 45% to about 85% by weight, for example about 50% or about 80% by weight of the drug.

Method According to a sixth aspect of the present invention there is provided a method for manufacturing a delayed release drug formulation for oral administration for delivering a drug to the colon according to the first aspect. This method
Form a core containing the drug,
Coating said core using an inner coating preparation comprising a third polymeric material as described above in a solvent system to form an inner coated core;
Coating the inner coating core with an outer coating preparation comprising a first polymeric material susceptible to attack by colonic bacteria and a second polymeric material having a pH threshold of about pH 6 or higher in a solvent system to form an outer coating core Including
The third polymeric material is a non-ionic polymer, and the internal coating preparation includes at least one additive selected from the group consisting of a buffer and a base.

  The solvent system of the inner coating preparation is preferably aqueous.

  In embodiments where the third polymeric material is a non-ionic polymer, the pH of the inner coating preparation is preferably at least 0.5 pH units above the pH threshold of the second polymeric material prior to coating. It is adjusted to.

  The pH of the inner coating preparation is preferably adjusted to about pH 7.5 to about pH 10, such as about pH 7.5 to about pH 8.5, preferably about pH 7.8 to about pH 8.2, and more preferably about pH 8. You.

  The outer coating can be applied using the method described in WO 2007/122374.

Effect of Diet The drug release profile from conventional delayed release dosage forms often depends on the condition of the stomach, ie, whether the stomach is in a "fed" or "fasted" state. Briefly, "fed state" leads to an increase in stomach residence time, which can affect the lag, the time to initial release of the drug from the dosage form. In addition, fast in vivo lysis after leaving the stomach can result in an increase in Cmax, the peak plasma concentration of the drug.

  The dependence of drug release on gastric status is colloquially known as the "effect of a meal", and conventional dosage forms may be administered either on an empty stomach or with food or shortly after a meal. It is often the case that administration should be carried out. Clearly, a pronounced dietary effect is in principle undesirable when an oral dosage form can be administered, and can adversely affect patient compliance due to premature drug release.

  The fasted and fed states are mimicked in vitro by first exposing the dosage form to 0.1 N HCl for 2 hours (fasted state) or 4 hours to fed state mimic gastric fluid at pH 5 (FeSSGF). Can be. After a simulated fasting or fed state, the tablets are further exposed to a Hanks buffer at pH 6.8 that mimics the conditions in the small intestine for at least 4 hours. As in the examples discussed below, exposing the tablet to more than 4 hours, for example, 10 hours, provides an indication of the "robustness" of the tablet.

  An example of FeSSGF is Jantratid et al., (2008) "Dissolution media simulating conditions in the proximal human gastrointestinal tract: dissolving in the proximal stomach of a human gastrointestinal tract. ): 1663-1676). Briefly, this example of FeSSGF consists of a mixture of milk and acetic acid / sodium acetate buffer (50:50) and sodium chloride.

  As an example, the inventors have determined that a coated 800 mg 5ASA tablet (coated with a single coating of Eudragit S) was exposed in vitro to this simulated fed condition, A shorter lag was observed. Earlier initial release of 5ASA may result in drug absorption in the small intestine, which may lead to increased systemic side effects. A similar effect is also seen with the 1200 mg 5ASA tablet formulation of Lialda® / Mezavant® from Cosmo Pharmaceuticals / Shire where site-specific colonic release of 5ASA is contemplated, both in vitro and in vivo. Observed in.

  We have found that the above-described formulation according to the invention, in which the outer layer is applied from a "semi-organic" coating preparation, shows a similar release profile after both fasting and fed mimicking gastric conditions. . Increasing lag in the fed state may at least reduce or even eliminate the effects of undesirable diets, which in turn may lead to a reduction in the occurrence of systemic side effects, and the dosage form may be taken with or along with the diet. May be taken at any time without the drug, which may lead to improved patient compliance.

  "Semi-organic" coating preparations are prepared from an aqueous dispersion of a first polymeric material and an organic (typically ethanol-based) solution of a second polymeric material. Preferred first and second polymer materials and their relative proportions are as described above.

Influence of Alcohol For the coated 5ASA dosage form, alcohol-induced early release (dose dumping) was observed (Fadda et al., (2008) "Impairment of drug release from modified information formation reference"). alcohol (disorder of drug release from release-improving formulations in the presence of alcohol) "Int. J. Pharm. 360; 171-176). Preliminary results show that when exposed to 0.1N 40% ethanol in HCl for 2 hours, the formulations according to the invention are more resistant to alcohol-induced degradation in the stomach and therefore the effect of alcohol It does not suffer much. Further studies are proposed to confirm this preliminary result.

(A) a single layer of Eudragit® S alone (Comparative Example 1), (b) a single layer of a 30:70 mixture of starch and Eudragit® S (Comparative Example 2), (c) complete Inner layer of Eudragit® S and outer layer of Eudragit® S (Comparative Example 3), or (d) Inner layer of fully neutralized Eudragit® S and starch and Eudragit® 400 mg of 5ASA tablets coated with an outer layer of a 30:70 mixture with S (Example 1) in 0.1N HCl for 2 hours and then in Kreb's buffer (pH 7.4). 5 is a graph comparing drug release from tablets over time upon time exposure. (A) a single layer of a 30:70 mixture of starch and Eudragit® S (Comparative Example 2), (b) an inner layer of fully neutralized Eudragit® S and an outer layer of Eudragit® S Coated with a layer (Comparative Example 3), or (c) an inner layer of fully neutralized Eudragit® S and an outer layer of a 30:70 mixture of starch and Eudragit® S (Example 1). Figure 4 is a graph comparing drug release from tablets over time when a 400 mg 5ASA tablet was exposed to fecal slurry at pH 6.8 for 24 hours. (A) Inner layer of fully neutralized Eudragit® S and outer layer of Eudragit® S (Comparative Example 3) and (b) Inner layer of fully neutralized Eudragit® S and starch and Eudragit Drug release from tablets over time when 400 mg of 5ASA tablets coated with an outer layer of a 30:70 mixture with S (Example 1) were exposed to a fecal slurry at pH 6.5 for 24 hours 5 is a graph comparing. 400 mg of 5ASA tablets coated with an inner layer of fully neutralized Eudragit® S and an outer layer of a 30:70 mixture of starch and Eudragit® S (Example 1) with Hanks pH 6.8 ( 5 is a graph showing drug release from tablets over time upon exposure to Hanks buffer. (A) an inner layer of fully neutralized Eudragit® L30D-55 and an outer layer of a 30:70 mixture of starch and Eudragit® S (Example 2), and (b) Eudragit® 1.) 1200 mg of 5ASA tablets coated with 0.1 N HCl with an inner layer of L30D-55 (non-neutralized) and an outer layer of a 30:70 mixture of starch and Eudragit® S (Comparative Example 4) 7 is a graph comparing drug release from tablets over time when exposed to Krebs buffer (pH 7) for 2 hours and then for 10 hours. 9 is a graph comparing the release of drug from the tablets over time when the tablets of Example 2 and Comparative Example 4 were exposed to fecal slurry at pH 6.5 for 24 hours. (A) an inner layer of neutralized Eudragit® L30D-55 and an outer layer of a 3: 1 mixture of guar gum and Eudragit® L30D-55 (Example 3), and (b) Eudragit® 1.) 1200 mg of 5ASA tablets coated with 0.1N of an inner layer of L30D-55 (non-neutralized) and an outer layer of a 3: 1 mixture of guar gum and Eudragit® L30D-55 (Comparative Example 5). 3 is a graph comparing drug release from tablets over time upon exposure to 2 hours of HCl and then 10 hours of Krebs buffer (pH 7.4). FIG. 11 is a graph comparing the drug release from the tablets over time when the tablets of Example 3 and Comparative Example 5 were exposed to 0.1 N HCl for 2 hours and then to Hanks buffer (pH 6.8) for 10 hours. FIG. 9 is a graph comparing the release of drug from the tablet with respect to time when the tablets of Example 3 and Comparative Example 5 were exposed to fecal slurry at pH 6.5 for 24 hours. (A) Separation layer of polyvinyl alcohol (Opadry II 85F), inner layer of polyvinyl alcohol (Opadry II 85F) adjusted to pH 8 and 20% buffer salt, and starch of blend of Eudragit® S / Eudragit® FS With the outer layer of a 70:30 mixture (Example 4), and (b) a starch of a blend of Eudragit® S / Eudragit® FS with a separating layer made of polyvinyl alcohol (Opadry II 85F). A 1200 mg 5ASA tablet coated with an outer layer made of a 70:30 mixture (Comparative Example 6) was exposed to 0.1 N HCl for 2 hours and then to Krebs buffer (pH 7.4) for 10 hours. Compare drug release from tablets against time It is a graph. With a separating layer of HPMC, an inner layer of neutralized Eudragit® S and an outer layer of 30:70 starch: Eudragit® S (Example 5) applied from a “semi-organic” coating preparation. FIG. 4 is a graph comparing drug release from tablets over time when a coated 1200 mg 5ASA tablet was exposed to FeSSGF at pH 5 for 4 hours (fed) and then to Hanks buffer at pH 6.8 for 10 hours (FIG. Only the Hanks buffer stage is shown). A 1200 mg 5ASA tablet coated with an outer layer of 30:70 starch: Eudragit® S (Comparative Example 7) applied from a separating layer of HPMC and a “semi-organic” coating preparation was prepared by (a) Tablets against time when exposed to 0.1N HCl for 2 hours (fasted) or (b) exposed to FeSSGF at pH 5 for 4 hours (fed) and then exposed to Hank's buffer at pH 6.8 for 10 hours FIG. 5 is a graph comparing drug release from S.A. (only the Hanks buffer stage is shown). A 1200 mg 5ASA tablet coated with a 30:70 starch: Eudragit® S outer layer (Comparative Example 8) applied from a separating layer of HPMC and an aqueous coating preparation was prepared by: Drug release from tablets over time upon exposure to HCl for 2 hours (fasted state) or (b) pH 5 FeSSGF for 4 hours (fed state), followed by exposure to pH 6.8 Hanks buffer for 10 hours. Is a graph comparing (only the Hanks buffer stage is shown). With a separating layer of HPMC, an inner layer of neutralized Eudragit® S and an outer layer of 50:50 starch: Eudragit® S (Example 6) applied from a “semi-organic” coating preparation. The coated 1200 mg 5ASA tablets are exposed to (a) 0.1N HCl for 2 hours (fasted) or (b) pH 5 FeSSGF for 4 hours (fed), followed by Hanks buffer at pH 6.8. Figure 4 is a graph comparing drug release from tablets over time upon exposure to liquid for 10 hours (only the Hanks buffer stage is presented). With a separating layer of HPMC, an inner layer of neutralized Eudragit® S and an outer layer of 30:70 starch: Eudragit® S (Example 7) applied from a “semi-organic” coating preparation. The coated 400 mg 5ASA tablets are exposed to (a) 0.1N HCl for 2 hours (fasted) or (b) pH5 FeSSGF for 4 hours (fed), followed by Hanks buffer pH 6.8. Figure 4 is a graph comparing drug release from tablets over time upon exposure to liquid for 10 hours (only the Hanks buffer stage is presented). 400 mg coated with an inner layer of neutralized Eudragit® S and an outer layer of 30:70 starch: Eudragit® S (Example 1) applied from a “semi-organic” coating preparation 5ASA tablets are exposed to (a) 0.1N HCl for 2 hours (fasted) or (b) pH5 FeSSGF for 4 hours (fed), followed by exposure to pH 6.8 Hanks buffer for 10 hours. 7 is a graph comparing the release of drug from the tablet over time when performing (only the Hanks buffer stage is shown).

  Here, a preferred embodiment of the present invention will be described with reference to the drawings.

Materials 5-Aminosalicylic acid (Mesalazine EP) was purchased from Cambrex Karlskoga (Karlskuga, Sweden). Lactose (Tabletose 80) was purchased from Meggle (Hamburg, Germany). Sodium starch glycolate (Explotab ™) was purchased from JRS Pharma (Rosenberg, Germany). Talc was purchased from Luzenac Deutschland (Dusseldorf, Germany). Polyvinyl pyrrolidone (PVP) was purchased from ISP Global Technologies (Cologne, Germany). Magnesium stearate was purchased from Peter Greven (Bad Münstereifel, Germany). Eudragit® S100, Eudragit® L30D-55 and Eudragit® FS30D were all purchased from Evonik (Darmstadt, Germany). Corn starch (NI-460 and Eurylon VI or 6) was purchased from Roquette (Restron, France). Polysorbate 80, butan-1-ol and sodium hydroxide were all purchased from Sigma-Aldrich (Books, Switzerland). Potassium dihydrogen phosphate, glyceryl monostearate (GMS), triethyl citrate (TEC) and ammonia solution (25%) were all purchased from VWR International LTD (Pool, UK).

Preparation of 400 mg 5ASA Tablet Core A 400 mg 5ASA tablet core formed into an oval shape with dimensions of 14.5 x 5.7 mm was prepared by fluid bed granulation followed by blending and compression. Each tablet contains 76.9% by weight of 5ASA (400 mg; drug); 14.7% by weight of lactose (filler); 1.7% by weight of PVP (binder); 3.5% by weight of sodium starch glycolate ( Disintegrant); and 2% by weight of talc and 1.2% by weight of magnesium stearate (lubricant).

  The resulting tablet cores were coated as described in Examples 1, 8 and 9 below and Comparative Examples 1-3 and 9.

Preparation of 1200 mg of 5ASA tablet core 1200 mg of 5ASA tablet core (having a size of 21 x 10 mm), which was formed into an oval shape by wet granulation, was prepared. Each tablet has 85.7% by weight of 5ASA (1200 mg), 9.2% by weight of microcrystalline cellulose, 1.7% by weight of HPMC, 2.9% by weight of sodium starch glycolate, and 0.5% by weight of It contained magnesium stearate.

  The resulting tablet cores were coated as described in Examples 2-7 and 10 below and Comparative Examples 4-7.

Example 1 (inner layer of neutralized Eudragit® S / outer layer of a 70:30 mixture of Eudragit® S and starch)
Inner Layer The inner coating layer was applied using an aqueous preparation of Eudragit®-S100 with the pH adjusted to pH8. The composition of the inner layer may also include 50% triethyl citrate (based on dry polymer weight), 10% potassium dihydrogen phosphate (based on dry polymer weight), 10% glyceryl monostearate (GMS; based on dry polymer weight) and It contained 40% polysorbate 80 (GMS weight basis). The pH was adjusted with 1 M NaOH until pH 8 was obtained. Potassium dihydrogen phosphate and triethyl citrate were dissolved in distilled water, and then Eudragit®-S100 was dispersed under mechanical stirring. Next, the pH of this dispersion was adjusted to pH 8 using 1 M NaOH, and mixing was continued for 1 hour.

  A GMS dispersion was prepared at a concentration of 10% w / w. Polysorbate 80 (40%, based on GMS weight) was dissolved in distilled water and then the GMS was dispersed. The dispersion was then heated at 75 ° C. for 15 minutes under strong magnetic stirring to form an emulsion. The emulsion was cooled with stirring at room temperature.

This GMS dispersion is added to the neutralized Eudragit®-S100 solution and the final preparation is applied to a 400 mg 5ASA tablet core using a fluid bed spray coater until the coating amount reaches 5 mg polymer / cm ^2. Coated. The total solids of the coating solution is 10%. The coating parameters were as follows: spray rate 20 ml / min / kg tablet, spray pressure 0.2 bar and air supply temperature 40 ° C.

Outer Layer The outer coating layer was applied from a mixture of an aqueous starch dispersion and an organic Eudragit®-S100 solution.

  An aqueous starch dispersion was prepared by dispersing corn starch in butan-1-ol under magnetic stirring and then in water. The ratio of corn starch: butan-1-ol: water was 1: 2: 22. The resulting dispersion was heated to boiling and then cooled with stirring overnight. The percent solids of the cooled preparation was calculated based on the final weight of the dispersion (considering evaporation during heating).

  An organic Eudragit®-S100 solution was prepared by dissolving Eudragit®-S100 in 96% ethanol under high speed stirring. The final solution contained about 6% polymer solids. The starch dispersion was added dropwise to the Eudragit (R) -S100 solution to give a 30:70 starch: Eudragit (R) -S ratio. The mixture was mixed for 2 hours, 20% triethyl citrate (based on total polymer weight) and 5% glyceryl monostearate (GMS, based on total polymer weight) were added and mixed for an additional 2 hours.

  GMS was added in the form of a dispersion prepared at a concentration of 5% w / w. Polysorbate 80 (40%, based on GMS weight) was dissolved in distilled water and then the GMS was dispersed. The dispersion was then heated at 75 ° C. for 15 minutes under strong magnetic stirring to form an emulsion. The emulsion was cooled with stirring at room temperature.

The final preparation was coated onto a 5ASA tablet core, previously coated with an inner coating layer, using a fluid bed spray coater until a coating with 7 mg total polymer / cm ² was obtained. The spray coating parameters were as follows: spray rate 14 ml / min / kg tablet, spray pressure 0.2 bar, and air temperature 40 ° C.

Example 2 (separation layer / inner layer of neutralized Eudragit® L30D-55 / outer layer of a 70:30 mixture of Eudragit® S and starch)
Separation Layer A separation layer containing a mixture of HPMC and 20% polyethylene glycol 6000 (PEG 6000) (by dry polymer weight) was used.

HPMC was dissolved in water under magnetic stirring, then PEG 6000 was added to form a coating preparation. The coated preparation was sprayed onto a 1200 mg 5ASA core using a pan coating machine to achieve a coating weight of 3 mg polymer / cm ² to form a separation layer coated tablet.

The coating parameters were as follows: spray rate 3.1 g / min / kg tablet core, spray pressure 0.7 bar, air charge 19 m ³ / h / kg tablet core, and product temperature 35 ° C.

Inner Layer The inner layer was applied from an aqueous coating preparation of Eudragit® L30D-55 with the pH adjusted to pH8. The composition of the inner layer also comprised 20% TEC (based on dry polymer weight), 1% potassium dihydrogen phosphate (based on dry polymer weight) and 50% talc (based on dry polymer weight). The pH was adjusted with 1 M NaOH until pH 8 was obtained.

Potassium dihydrogen phosphate and TEC were dissolved in distilled water for 15 minutes, then Eudragit (R) L30D-55 dispersion was added under mechanical stirring and mixed for 15 minutes. The pH was then adjusted to pH 8 with 1 M NaOH and the solution was kept stirring for 1 hour. Talc was then added to the solution and mixing continued for another 30 minutes to form an internal coating preparation. This inner coating preparation was coated on a separation layer coated tablet using a pan coating machine until the coating amount reached 5 mg polymer / cm ² to obtain an inner layer coated tablet. The total solids content of the inner coating preparation was 10% (by weight).

  As used herein, the “total solids” of a suspension, dispersion, or other preparation refers to the formation of the preparation, as a percentage of the total weight of the preparation (solids and solvents). The total weight of solids used. Those skilled in the art will appreciate that the dissolution of a solid in some solvent will not affect the total solids of the preparation.

Coating parameters were as follows: spray rate 6.75 g / min / kg tablet core, spray pressure 0.6 bar, air charge 75 m ³ / h / kg tablet core, and product temperature 31 ° C.

Outer layer The outer layer was applied from a mixture of an aqueous starch dispersion and an aqueous Eudragit® S100 solution.

  An aqueous starch dispersion was prepared by dispersing corn starch in butan-1-ol, followed by water, under magnetic stirring. The ratio of corn starch: butan-1-ol: water was 1: 2: 22. The resulting dispersion was heated to boiling under reflux and then cooled while stirring overnight.

  An aqueous Eudragit® S100 solution was prepared by dispersing Eudragit® S100 in water under high speed stirring, and then partially using a 1N ammonia solution (obtained by dilution of a 25% ammonia solution). (15-20%).

  An aqueous Eudragit® S100 solution was added to the starch dispersion to give a 30:70 starch: Eudragit® S ratio. The mixture was stirred for 1 hour, 60% TEC (by weight of Eudragit® S polymer), 50% of talc (by weight of Eudragit® S polymer), 13.18% of bengara (by weight of Eudragit®). A) S polymer weight) and 2.27% yellow iron oxide (Eudragit® S polymer weight basis) and mixed for an additional 30 minutes.

The final preparation was sprayed onto the inner layer coated tablet by a pan coater until 7.14 mg of total polymer / cm ² was obtained to make the coated tablet of Example 2.

The coating parameters were as follows: spray rate 6.175 g / min / kg tablet core, spray pressure 0.4 bar, air charge 100 m ³ / h / kg tablet core, and product temperature 35 ° C.

Example 3 (separation layer / inner layer of neutralized Eudragit® L30D-55 / outer layer of a 1: 3 mixture of Eudragit® L30D-55 and guar gum)
Separation Layer The separation layer is formed by a mixture of HPMC and 20% polyethylene glycol 6000 (PEG 6000) (based on dry polymer weight).

The HPMC polymer was dissolved in water under magnetic stirring and then PEG 6000 was added to form a separation layer coating preparation. The coated preparation was sprayed onto a 1200 mg 5ASA tablet core using a pan coating machine to achieve a coating weight of 3 mg polymer / cm ² to form a separation layer coated tablet.

The coating parameters were as follows: spray rate 2.7 g / min / kg tablet core, spray pressure 0.7 bar, air charge 16 m ³ / h / kg tablet core, and product temperature 35 ° C.

Inner Layer The inner layer is applied from an aqueous preparation of Eudragit L30D-55 whose pH has been adjusted to pH8. The composition of the inner layer also includes 20% TEC (by dry polymer weight), 1% potassium dihydrogen phosphate (by dry polymer weight), and 50% talc (by dry polymer weight). Adjust the pH with 1 M NaOH until a pH of 8 is obtained.

Potassium dihydrogen phosphate and TEC were dissolved in distilled water while stirring for 15 minutes, and then Eudragit L30D-55 dispersion was added under mechanical stirring and mixed for 15 minutes. The pH was then adjusted to pH 8 with 1 M NaOH and the solution was kept mixing for 1 hour. Talc was then added and mixing continued for an additional 30 minutes to form an inner layer coating preparation. The inner layer coated preparation was coated on the separation layer coated tablet using a pan coating machine until the coating amount reached 5 mg polymer / cm ² to form an inner layer coated tablet. The total solids of the final preparation is 10%.

The coating parameters were as follows: spray rate 2.7 g / min / kg tablet core, spray pressure 0.6 bar, air charge 30 m ³ / h / kg tablet core, and product temperature 31 ° C.

Outer Layer The outer layer is applied from a mixture of Eudragit® L30D-55 and guar gum.

Eudragit L30D-55 was dissolved in isopropanol. The guar gum was dispersed with talc in a mixture of water and isopropanol (50:50) for 15 minutes and then homogenized for 5 minutes. The Eudragit L30D-55 solution was then added to the guar gum dispersion and the resulting mixture was stirred for 20 minutes to form an outer layer coating preparation. The coated preparation was sprayed onto the inner layer coated tablets in a pan coater until the coating amount reached 9.71 total polymer / cm ² (weight ratio between dry substances 1: 3). The coated tablets were dried at 40 ° C. for 2 hours to form tablets of Example 3.

The coating parameters were as follows: spray rate 8.0 g / min / kg tablet core, spray pressure 0.6 bar, air charge 75 m ³ / h / kg tablet core, and product temperature 29 ° C.

Example 4 (separation layer / inner layer of PVA with buffer and base / outer layer of a blend of Eudragit® S and FS (50:50) and a 70:30 mixture of starch)
Separation Layer The separation layer is composed of polyvinyl alcohol, that is, PVA (Opadry 85F).

  The polymer was suspended in water under magnetic stirring to achieve a solids concentration of 10% of the final weight of the dispersion to form a separation layer coating preparation.

  The coated preparation was sprayed onto a 1200 mg 5ASA tablet core using a pan coating machine to achieve a 2% coating weight based on the weight of the uncoated tablet, forming a separate layer coated tablet.

Coating parameters were as follows: spray rate 6.45 g / min / kg tablet, spray pressure 0.6 bar, air charge 62.5 m ³ / h / kg tablet core, and product temperature 40 ° C.

Inner Layer The inner layer is composed of polyvinyl alcohol (Opadry 85F) and 20% potassium dihydrogen phosphate (based on Opadry 85F).

  Potassium dihydrogen phosphate was dissolved in water under magnetic stirring, and then polyvinyl alcohol (Opadry 85F) was added to form a suspension. The pH of this suspension was then adjusted to pH 8 with 1 M NaOH and the mixture was kept stirring for 1 hour to form an inner layer coating preparation. The coated preparation was sprayed onto the separated layer coated tablet using a pan coating machine until the coating amount reached 2% by weight of the uncoated tablet to form an inner layer coated tablet.

The coating parameters were as follows: spray rate 8.2 g / min / kg tablet core, spray pressure 0.7 bar, air charge 62.5 m ³ / h / kg tablet core, and product temperature 40 ° C. .

Outer Layer The outer layer formulation is applied from a mixture of an aqueous starch dispersion and an aqueous dispersion of a 50:50 blend of Eudragit® S100 and Eudragit® FS30D (dry polymer basis).

  An aqueous starch dispersion was prepared by dispersing corn starch (Eurylon 6) in butan-1-ol under magnetic stirring. Water was added with continued stirring. The ratio of corn starch: butan-1-ol: water was 1: 2: 22. The resulting dispersion was heated to boiling under reflux and then cooled while stirring overnight.

  An aqueous dispersion of Eudragit® S100 was prepared by dispersing Eudragit® S100 in water under high-speed stirring, and then portioned with 1N ammonia (formed by diluting a 25% ammonia solution). (15-20%). TEC was added to this dispersion and mixed for 30 minutes. Eudragit® FS30D was added to form a 50:50 blend with Eudragit® S100, and mixing was continued for another 30 minutes.

  The starch dispersion was added to the Eudragit® S100 / Eudragit® FS30D blend dispersion and the mixture was stirred for an additional 30 minutes. The mixture contained a 30:70 starch: Eudragit S100 / Eudragit FS30D blend ratio.

  50% talc (based on Eudragit® polymer weight), 13.18% bengara (based on Eudragit® polymer weight) and 2.27% yellow iron oxide (based on Eudragit® polymer weight) Was formed under high shear homogenization and this suspension was added to the starch / Eudragit® blend mixture and mixing was continued for an additional 30 minutes to form an outer layer coating preparation.

The coated preparation was sprayed onto the inner layer coated tablet in a pan coater until 5.2 mg Eudragit® polymer blend / cm ² was obtained to form the tablet of Example 4.

The coating parameters were as follows: spray rate 8.5 g / min / kg tablet core, spray pressure 0.7 bar, air charge 62.5 m ³ / h / kg tablet core, and product temperature 41 ° C. .

Example 5 (separation layer / inner layer of neutralized Eudragit® S / outer layer of a 70:30 mixture of Eudragit® S and starch)
Separation layer A separation layer was formed as in Example 3, but the coating parameters were as follows: spray rate 2.33 g / min / kg tablet core, spray pressure 0.7 bar, air charge 16. 3 m ³ / h / kg tablet core, and product temperature 33 ° C.

Inner Layer The composition of the inner layer comprises 70% (not 50%) triethyl citrate (based on dry polymer weight) and 1% (not 10%) potassium dihydrogen phosphate (based on dry polymer weight) and is coated. The preparation is coated on a 1200 mg tablet coated with a separating layer using a perforated pan coating machine, the coating parameters are as follows: spraying speed 2.9 g / min / kg tablet, spray pressure 0.6 bar, An inner coating layer was formed in the same manner as in Example 1 except that the supplied air amount was 16.3 m ³ / h / kg tablet and the product temperature was 33 ° C.

Outer layer 13.18% Bengala (Eudragit polymer weight basis) and 2.27% yellow iron oxide (Eudragit polymer weight basis) are suspended in ethanol under high shear homogenization, and this suspension is mixed with starch and Eudragit. And the mixture was further mixed for 30 minutes before adding the GMS and coating the coated preparation onto 1200 mg 5ASA tablets with an inner layer coating using a perforated pan coater and spraying. The coating parameters were as follows: spray rate 3.1 g / min / kg tablet, spray pressure 0.4 bar, air charge 21.7 m ³ / h / kg tablet, and product temperature 34 ° C. Except for this, the outer coating layer was formed in the same manner as in Example 1.

Example 6 (separation layer / inner layer of neutralized Eudragit® S / outer layer of a 50:50 mixture of Eudragit® S and starch)
Separation Layer A separation layer was formed on a 1200 mg 5ASA tablet core as described in Example 3.

Inner Layer The inner layer was formed on a 1200 mg 5ASA tablet core coated with a separate layer as described in Example 5.

Outer layer The ratio of corn starch: butan-1-ol: water was 1: 1: about 9.5, the ratio of starch: EudragitS was 50:50, and the spray parameters were as follows: spraying As described in Example 5, except that the rate was 7.4 g / min / kg tablets, spray pressure 0.4 bar, air charge 40 m ³ / h / kg tablets, and the product temperature was 34 ° C. An outer coating layer was formed on the inner layer coated 5ASA tablet core.

Example 7 (separation layer / inner layer of neutralized Eudragit® S / outer layer of a 70:30 mixture of Eudragit® S and starch)
Separator layer Using a fluid bed spray coating machine, except that the coating parameters were as follows: spray rate 3.1 g / min / kg tablet, spray pressure 0.2 bar, and air temperature 40 ° C. The separation layer was applied to a 400 mg 5ASA tablet core using the procedure described in Example 3.

Inner Layer The composition of the inner layer contained 70% (not 50%) triethyl citrate (by dry polymer weight) and 1% (not 10%) potassium dihydrogen phosphate (dry polymer weight). Except for this, the inner coating layer was applied as described in Example 1. In addition, the inner coating layer preparation was coated on a 400 mg 5ASA tablet core coated with a separate layer.

Outer layer 13.18% Bengala (Eudragit polymer weight basis) and 2.27% yellow iron oxide (Eudragit polymer weight basis) are suspended in ethanol under high shear homogenization, and this suspension is mixed with starch and Eudragit. As in Example 1 except that it was mixed for an additional 30 minutes before adding GMS and coating the outer coating layer preparation onto a 400 mg 5ASA tablet core with an inner layer coating. Then, an outer coating layer was formed. The coating parameters were as follows: spray rate 11 ml / min / kg tablet, spray pressure 0.2 bar and air supply temperature 40 ° C.

Comparative Example 1 (single layer coating of Eudragit® S)
A coating layer containing Eudragit®-S100 was applied as an organic coating composition. The coating composition contained 20% triethyl citrate (by dry polymer weight), 10% glyceryl monostearate (by dry polymer weight), and 40% polysorbate 80 (by GMS weight). Briefly, triethyl citrate was dissolved in 96% ethanol, then Eudragit®-S100 was dissolved under mechanical stirring, and mixing continued for 1 hour.

  GMS was added in the form of a dispersion prepared at a concentration of 10% w / w. Polysorbate 80 (40%, based on GMS weight) was dissolved in distilled water and then the GMS was dispersed. The preparation was heated at 75 ° C. for 15 minutes under strong magnetic stirring to form an emulsion. The emulsion was cooled with stirring at room temperature.

This GMS dispersion was added to the organic Eudragit®-S solution and the final coating solution was coated on a 5ASA tablet core using a fluid bed spray coater to give a coating weight of 5 mg polymer / cm ² . The coating parameters were as follows: spray rate 16 ml / min / kg tablet, spray pressure 0.2 bar and air supply temperature 40 ° C.

Comparative Example 2 (single layer coating of a 70:30 mixture of Eudragit® S and starch)
The coating layer composition contains a mixture of an aqueous starch dispersion and an organic Eudragit®-S100 solution. Aqueous starch dispersions were prepared by dispersing corn starch in butan-1-ol under magnetic stirring and then in water. The ratio of corn starch: butan-1-ol: water was 1: 2: 22. The resulting dispersion was heated to boiling and cooled with stirring overnight. The percent solids of the cooled preparation was calculated based on the final weight of the dispersion (considering evaporation during heating).

  Organic Eudragit®-S solution was prepared by dissolving Eudragit®-S100 in 96% ethanol under high speed stirring. The final solution contained about 6% polymer solids. The starch dispersion was added dropwise to the Eudragit®-S100 solution to give a 30:70 starch: Eudragit S ratio. The mixture was mixed for 2 hours, 20% triethyl citrate (based on total polymer weight) and 5% glyceryl monostearate (based on total polymer weight) were added and the mixture was mixed for an additional 2 hours.

  GMS was added in the form of a dispersion prepared at a concentration of 5% w / w. Polysorbate 80 (40%, based on GMS weight) was dissolved in distilled water and then the GMS was dispersed. The preparation was then heated at 75 ° C. for 15 minutes under strong magnetic stirring to form an emulsion. The emulsion was cooled with stirring at room temperature.

The final preparation was coated on a 5ASA tablet core with a fluid bed spray coater until 7 mg Eudragit®-S polymer / cm ² was obtained. The spray coating parameters were as follows: spray rate 14 ml / min / kg tablet, spray pressure 0.2 bar and air supply temperature 40 ° C.

Comparative Example 3 (Inner layer of neutralized Eudragit® S / outer layer of Eudragit® S)
Inner Layer The inner coating layer is constituted by an aqueous preparation of Eudragit®-S100, the pH of which has been adjusted to pH8. The composition of the inner layer also includes 50% triethyl citrate (by dry polymer weight), 10% potassium dihydrogen phosphate (by dry polymer weight), 10% glyceryl monostearate (by dry polymer weight) and 40%. % Polysorbate 80 (GMS weight basis). The pH was adjusted with 1 M NaOH until a pH of 8 was obtained. Potassium dihydrogen phosphate and triethyl citrate were dissolved in distilled water, and then Eudragit®-S100 was dispersed under mechanical stirring. The pH was adjusted to pH 8 using 1 M NaOH and mixing continued for 1 hour.

  The GMS dispersion was prepared at a concentration of 10% w / w. Polysorbate 80 (40%, based on GMS weight) was dissolved in distilled water and then the GMS was dispersed. The preparation was then heated under strong magnetic stirring at 75 ° C. for 15 minutes to form an emulsion. The emulsion was cooled with stirring at room temperature.

This GMS dispersion is added to the neutralized Eudragit®-S solution and the final preparation is coated on a 5ASA tablet core using a fluid bed spray coater until the coating amount reaches 5 mg polymer / cm ^2. Coated. The total solids of the coating solution is 10%. The coating parameters were as follows: spray rate 20 ml / min / kg tablet, spray pressure 0.2 bar and air supply temperature 40 ° C.

Outer Layer The outer coating layer is composed of Eudragit®-S100 and is applied as an organic solution. The coating solution contains 20% triethyl citrate (by dry polymer weight), 10% glyceryl monostearate (by dry polymer weight), and 40% polysorbate 80 (by GMS weight). Briefly, triethyl citrate was dissolved in 96% ethanol, then Eudragit®-S100 was dissolved under mechanical stirring and mixing was continued for 1 hour.

  The GMS dispersion was prepared at a concentration of 10% w / w. Polysorbate 80 (40%, based on GMS weight) was dissolved in distilled water and then the GMS was dispersed. The dispersion was then heated at 75 ° C. for 15 minutes under strong magnetic stirring to form an emulsion. The emulsion was cooled with stirring at room temperature.

This GMS preparation was added to the Eudragit® S100 solution and the final coating solution was coated on a 5ASA tablet core previously coated with an inner coating layer using a fluid bed spray coater to give 5 mg of Eudragit® (Trademark) -S polymer / cm ² was obtained. The coating parameters were as follows: spray rate 16 ml / min / kg tablet, spray pressure 0.2 bar and air supply temperature 40 ° C.

Comparative Example 4 (separation layer / inner layer of Eudragit® L30D-55 / outer layer of 70:30 mixture of Eudragit® S / starch)
Separation Layer The separation layer is formed from a mixture of HPMC and 20% polyethylene glycol 6000 (PEG 6000) (based on dry polymer weight).

The polymer was dissolved in water under magnetic stirring and then PEG 6000 was added to form a separation layer coating preparation. The coating preparation was sprayed onto 1200 mg of 5ASA tablet core using a pan coating machine to obtain a coating amount of 3 mg polymer / cm ² to form a separation layer coated tablet.

The coating parameters were as follows: spray rate 2.7 g / min / kg tablet core; spray pressure 0.7 bar; air charge 16 m ³ / h / kg tablet core; and product temperature 35 ° C.

Inner Layer The inner layer is made from a standard (non-neutralized) aqueous preparation of Eudragit L30D-55. The composition of the inner layer also includes 20% TEC (by dry polymer weight) and 50% talc (by dry polymer weight).

Eudragit L30D-55 was diluted with distilled water, then TEC and talc suspension were added and mixed for 1 hour to form an inner layer coating preparation. This coated preparation was coated on a separation layer coated tablet using a pan coating machine until the coating amount reached 5 mg polymer / cm ² to form an inner layer coated tablet. The total solids of the final preparation is 10%.

Coating parameters were as follows: spray rate 6.125 g / min / kg tablet core, spray pressure 0.6 bar, air charge 100 m ³ / h / kg tablet core, and product temperature 33 ° C.

Outer Layer The outer layer is made from a mixture of aqueous starch dispersion and aqueous Eudragit® S100 redispersion.

  An aqueous starch dispersion was prepared by dispersing corn starch in butan-1-ol and then in water under magnetic stirring. The ratio of corn starch: butan-1-ol: water was 1: 2: 22. The resulting dispersion was heated to boiling under reflux and then cooled under stirring overnight.

  The aqueous Eudragit® S100 is dispersed in water under high speed stirring and then partially (15-20%) neutralized with 1N ammonia (obtained by dilution of a 25% ammonia solution). A redispersion of TM) S was prepared.

This redispersion of aqueous Eudragit® S was added to the starch dispersion to give a 30:70 starch: Eudragit S ratio. The mixture is stirred for 1 hour, 60% TEC (based on Eudragit® S-polymer), 50% talc (based on Eudragit® S-polymer), 13.18% bengara (based on Eudragit®). S polymer weight) and 2.27% yellow iron oxide (by Eudragit® S polymer weight) and the mixture was stirred for an additional 30 minutes to form an outer layer coating preparation. The tablet of Comparative Example 4 was made by spraying the outer layer coated preparation onto the inner layer coated tablet with a pan coater until 7.14 mg total polymer / cm ² was obtained.

The coating parameters were as follows: spray rate 10.0 g / min, spray pressure 0.4 bar, air charge 100 m ³ / h / kg tablet core, and product temperature 35 ° C.

Comparative Example 5 (separation layer / inner layer of Eudragit L30D-55 / outer layer of 1: 3 mixture of Eudragit L30D-55 / guar gum)
Separation Layer The separation layer is applied from a mixture of HPMC and 20% polyethylene glycol 6000 (PEG 6000) (based on dry polymer weight).

The HPMC polymer was dissolved in water under magnetic stirring and then PEG 6000 was added to form a separation layer coating preparation. The coated preparation was sprayed onto 1200 mg of 5ASA tablet core using a pan coating machine to achieve a coating weight of 3 mg polymer / cm ² to form a separation layer coated tablet.

The coating parameters were as follows: spray rate 2.7 g / min / kg tablet core, spray pressure 0.7 bar, air charge 16 m ³ / h / kg tablet core, and product temperature 35 ° C.

Inner Layer The inner layer was applied from a standard (non-neutralized) aqueous preparation of Eudragit L30D-55. The composition of the inner layer also contained 20% TEC (by dry polymer weight) and 50% talc (by dry polymer weight).

Eudragit L30D-55 was diluted with distilled water, then TEC and talc were added to form a mixture, which was stirred for 1 hour to form an inner layer coating preparation. The coated preparation was coated on a separation layer coated tablet using a pan coating machine until the coating amount reached 5 mg polymer / cm ² to form an inner layer coated tablet. The total solids of the final preparation is 10% based on the final weight of the suspension.

The coating parameters were as follows: spray rate 2.45 g / min / kg tablet core, spray pressure 0.6 bar, air charge 25 m ³ / h / kg tablet core, and product temperature 33 ° C.

Outer Layer The outer layer contains a mixture of Eudragit L30D-55 and guar gum.

Eudragit L30D-55 was dissolved in isopropanol and guar gum with talc was dispersed in a mixture of water and isopropanol (50:50) for 15 minutes and then homogenized for 5 minutes. The Eudragit L30D-55 solution was then added to the guar gum dispersion and stirred for 20 minutes to form an outer layer coating preparation. The coated preparation was sprayed onto the inner layer coated tablets in a pan coater until a total polymer / cm ^{2 of} 9.71 (1: 3 dry matter weight ratio) was obtained. The coated tablet was dried at 40 ° C. for 2 hours to form a tablet of Comparative Example 5.

The coating parameters were as follows: spray rate 8.0 g / min / kg tablet core, spray pressure 0.6 bar, air charge 75 m ³ / h / kg tablet core, and product temperature 29 ° C.

Comparative Example 6 (Separation layer / outer layer of a 70:30 mixture of Eudragit® S and FS blend (50:50) and starch)
Separation layer The separation layer was composed of polyvinyl alcohol (Opadry85F).

  Polyvinyl alcohol (Opadry 85F) was suspended in water under magnetic stirring to achieve a solids concentration of 10% based on the final weight of the suspension, forming a separation layer coating preparation.

  The coated preparation was sprayed onto a 1200 mg 5ASA tablet core using a pan coating machine to achieve a 2% coating weight based on the weight of the uncoated tablet, forming a separate layer coated tablet.

Coating parameters were as follows: spray rate 6.45 g / min / kg tablet, spray pressure 0.6 bar, air charge 62.5 m ³ / h / kg tablet core, and product temperature 40 ° C.

Outer Layer The outer layer formulation is applied from a mixture of an aqueous starch dispersion and an aqueous dispersion of a 50:50 blend of Eudragit® S100 and Eudragit® FS30D (dry polymer basis).

  An aqueous starch dispersion was prepared by dispersing corn starch (Eurylon 6) in butan-1-ol under magnetic stirring. Water was added with continued stirring. The ratio of corn starch: butan-1-ol: water was 1: 2: 22. The resulting dispersion was heated to boiling under reflux and then cooled overnight with stirring.

  By dispersing Eudragit® S100 in water under high speed stirring and then partially neutralizing (15-20%) with 1 N ammonia (formed by diluting a 25% ammonia solution) An aqueous dispersion of Eudragit® S100 was prepared. TEC was added to this dispersion and mixed for 30 minutes. Eudragit® FS30D was added to form a 50:50 blend with Eudragit® S100, and mixing was continued for another 30 minutes.

  The starch dispersion was added to the Eudragit® S100 / Eudragit® FS30D blend dispersion and the mixture was stirred for an additional 30 minutes. The mixture contained a 30:70 starch: Eudragit S100 / Eudragit FS30D blend ratio.

  50% talc (based on Eudragit® polymer weight), 13.18% bengara (based on Eudragit® polymer weight) and 2.27% yellow iron oxide (based on Eudragit® polymer weight) Was formed under high shear homogenization and this suspension was added to the starch / Eudragit® blend mixture and mixing continued for an additional 30 minutes to form an outer layer coating preparation.

The coated preparation was sprayed on a separating layer coated tablet in a pan coating machine until 5.2 mg Eudragit® polymer blend / cm ² was obtained to form the tablet of Example 4.

The coating parameters were as follows: spray rate 8.5 g / min / kg tablet core, spray pressure 0.7 bar, air charge 62.5 m ³ / h / kg tablet core, and product temperature 41 ° C. .

Comparative Example 7 (separation layer / starch: outer layer of Eudragit S (30:70))
Separation Layer A 1200 mg 5ASA tablet core coated with a separation layer was prepared as in Comparative Example 4.

Outer Layer The outer coating layer was applied to the inner coated tablet core from a mixture of an aqueous starch dispersion and an organic Eudragit® S100 solution.

  An aqueous starch dispersion was prepared by dispersing corn starch in butan-1-ol and then in water under magnetic stirring. The ratio of corn starch: butan-1-ol: water was 1: 2: 22. The resulting dispersion was heated to boiling and then cooled with stirring overnight. The percent solids of the cooled preparation was calculated based on the final weight of the dispersion (considering evaporation during heating).

  An organic Eudragit® S100 solution was prepared by dissolving Eudragit® S100 in 96% ethanol under high speed stirring. The final solution contained about 6% polymer solids. A starch dispersion was added dropwise to the Eudragit® S100 solution to give a 30:70 starch: Eudragit® S ratio.

  The mixture was mixed for 2 hours, 20% triethyl citrate (based on total polymer weight) and 5% glyceryl monostearate (GMS, based on total polymer weight) were added and mixed for an additional 2 hours. 13.18% Bengala (by weight of Eudragit polymer) and 2.27% of yellow iron oxide (by weight of Eudragit polymer) are suspended in ethanol under high shear homogenization, and this suspension is mixed with starch and Eudragit. And mixed for an additional 30 minutes.

GMS was added in the form of an emulsion prepared at a concentration of 5% w / w. Polysorbate 80 (40%, based on GMS weight) was dissolved in distilled water and then the GMS was dispersed. The dispersion was then heated at 75 ° C. for 15 minutes under strong magnetic stirring to form an emulsion. The emulsion was cooled with stirring at room temperature. The final preparation was coated on a separating layer coated tablet core using a perforated pan coating machine until a coating with 5 mg Eudragit® S polymer / cm ² was obtained. The spray coating parameters were as follows: spray rate 3.1 g / min / kg tablet, spray pressure 0.4 bar, air charge 21.7 m ³ / h / kg tablet, and product temperature 34 ° C.

Comparative Example 8 (separation layer / starch: outer layer of Eudragit S (30:70))
A 1200 mg 5ASA tablet core coated with a separation layer was prepared as in Comparative Example 4.

Outer Layer The outer layer is applied from a mixture of an aqueous starch dispersion and an aqueous Eudragit S100 redispersion.

  An aqueous starch dispersion was prepared as described in Example 1.

  An aqueous Eudragit S redispersion was prepared by dispersing Eudragit S100 in water under high speed stirring and then partially neutralizing with 1N ammonia obtained by dilution of 25% ammonia.

  This aqueous EudragitS redispersion was added to the starch dispersion to give a 30:70 ratio of starch to EudragitS. This is mixed for 1 hour, 60% TEC (based on Eudragit S polymer), 50% talc (based on Eudragit S polymer), 13.18% bengara (based on Eudragit S polymer) and 2.27% yellow iron oxide (Eudragit S polymer weight basis) was added and mixed for an additional 30 minutes to form an outer layer coating preparation.

The outer layer coating preparation was sprayed on a 1200 mg 5ASA tablet core with an inner layer coating in a pan coater until 7.14 mg total polymer / cm ² was obtained. The coating parameters were as follows: spray rate 6.175 g / min. kg tablet core, spray pressure 0.4 bar, air charge 100 m ³ / h / kg tablet core, and product temperature 35 ° C.

Drug Release Test # 1-Effect of pH Only In vitro dissolution studies were performed on a USP Type II instrument using a paddle speed of 50 rpm and a media temperature of 37 ± 0.5 ° C. Tablets were tested first in 0.1 M HCl for 2 hours and then in Krebs buffer (pH 7.4) for 8 or 10 hours. The pH of the buffer was stabilized at 7.4 ± 0.05 by continuous injection of 5% CO ₂ /95% O ₂ . Every 5 minutes, the absorbance was measured at an absorption wavelength of 301 nm in HCl and at 330 nm in Krebs buffer. Composition per Krebs Buffer 1 liter, 0.16 g of _KH 2 _PO 4, NaCl of 6.9 g, KCl of 0.35g, MgSO ₄ · _7H 2 O of 0.29g, CaCl ₂ · 2H of 0.376g ₂ O, and 2.1 g of NaHCO ₃ . Only measurements taken at 15 minute intervals are shown in FIG.

Drug Release Test # 2-pH 6.8 Fecal Slurry The fermentation assay used to test the formulation is described by Hughes et al. ("In vitro fermentation of at and barley derived beta-glucans by human faecal microbiota by human faecal microbiota. And in vitro fermentation of barley-derived β-glucan), FEMS Microbiol. Ecol .; 2008; 64 (3); pp. 482-493).

  The basal medium used to allow bacterial growth was prepared according to Hughes et al., And fresh human stool (3 different donors) was added at 40% w / w in phosphate buffered saline (pH 6.8). Was mixed with the stool slurry prepared by homogenizing at a concentration of 1: 1. The final concentration of the prepared stool slurry (diluted with the basal medium) was 20% w / w. Donors had not received antibiotic treatment for at least three months prior to conducting this study using the slurry.

  The tablets were tested in 210 ml fecal slurry under continuous stirring adjusted to the desired pH. The test was performed in an anaerobic chamber (37 ° C. and 70% RH). Samples were analyzed for 5ASA content by HPLC with a UV detector.

Drug Release Test # 3-Fecal Slurry at pH 6.5 Same as Drug Release Test # 2, except that the pH of the fecal slurry was maintained at pH 6.5.

Drug Release Test # 4-Dissolution in Hanks Buffer pH 6.8 In vitro dissolution studies were performed on a USP Type II apparatus using a paddle speed of 50 rpm and a medium temperature of 37 ± 0.5 ° C. Tablets were tested first in 0.1 M HCl for 2 hours and then in Hanks buffer (pH 6.8) for 8 or 10 hours. The pH of the buffer was stabilized at 6.8 ± 0.05 by continuous injection of 5% CO2 / 95% O2. Every 5 minutes, absorbance measurements were taken at an absorption wavelength of 301 nm in HCl and 330 nm in Hanks buffer pH 6.8. The composition of Hanks buffer per liter, 0.06 g of _{KH 2 PO 4, Na 2 HPO} 4 · 2H 2 O in 0.06 g, NaCl of 8.0 g, 0.4 g of KCl, 0.2 g MgSO ₄ in 7H ₂ O, 0.139 g CaCl ₂ .2H ₂ O and 0.350 g NaHCO ₃ .

Drug Release Test # 5-Hanks Buffer pH 6.8 After Simulated Feeding / Fasting State
In vitro dissolution studies were performed on a USP Type II apparatus using a paddle speed of 50 rpm and a media temperature of 37 ± 0.5 ° C. When simulating the “fasted” state, the study was performed as described in Drug Release Test # 4.

  When mimicking the "fed" state, the tablets were first tested in fed state mimic gastric fluid (FeSSGF) at pH 5.0 for 4 hours and then in Hanks buffer (pH 6.8) for 10 hours. FeSSGF is as described in the aforementioned Jantrid et al. (2008).

Drug release test # 5-40% ethanol in 0.1 N HCl (v / v)
The coated tablets were tested in a disintegrator for 2 hours using a 0.1N HCl water-alcohol solution (40% ethanol). At the end of 2 hours, the morphology of the tablets was evaluated visually for the presence of cracks and / or swelling.

Results The results shown in FIGS. 1-4 demonstrate that the coated tablets according to the invention are significantly better than the tablets of the comparative example. In this regard, for the tablet according to the invention, relative to the comparative tablet, a pH higher than the pH threshold (pH 7.4) of the second polymeric material (pH 7.4) and a pH lower than the pH threshold (pH 6.8 or pH 6.8). Acceleration of drug release is observed in both 5).

  In the aqueous solution at pH 7.4 (drug release test # 1; FIG. 1), no 5ASA was released from any of the test tablets during 2 hours of exposing the tablets to simulated gastric conditions. However, once the tablets were exposed to pH 7.4, the initial release of 5ASA from the tablets of Example 1 was from Comparative Example 1 (which is a conventional site-specific colon release formulation) and Comparative Example 2 ( It should be noted that this occurred significantly earlier than from the case of WO 2007/122374, which is a site-specific colon release formulation described in WO-A-2007 / 122374. The release profile of 5ASA from Example 1 closely follows that of Comparative Example 3. This similar release profile may be explained by the similarity of the formulation itself (Example 1 differs only in the presence of starch in the outer coating) and the absence of starch enzymes in the surrounding medium to digest starch. .

  In the stool slurry at pH 6.8 (drug release test # 2; FIG. 2), the initial release of 5ASA from the tablet of Example 1 occurred about 1 hour, and the complete release occurred about 3 hours after the initial release. In contrast, the initial release from the tablets of Comparative Examples 2 and 3 occurred after about 2 hours, and substantial release from the tablets of Comparative Example 3 only occurred after 6 hours. In addition, the tablet of Comparative Example 2 showed complete release after about 5 hours, and the tablet of Comparative Example 3 showed less than 40% release over 24 hours. These results indicate that the presence of the inner soluble layer accelerates drug release under colony conditions from tablets with an outer layer containing a mixture of starch and Eudragit S. These results also show that in the absence of polysaccharide in the outer layer (Comparative Example 3), the release under colonic conditions is not complete.

  In the fecal slurry at pH 6.5 (drug release test # 3; FIG. 3), the initial release of 5ASA from the tablet of Example 1 occurred after about 2 hours, while the initial release from the comparative tablet occurred in about 8 hours. Hours later. Furthermore, even when the pH of the surrounding medium was significantly lower than the pH threshold of Eudragit S, the tablets according to Example 1 released about 40% of 5ASA after about 8 hours. In contrast, the 5ASA released by the tablet of Comparative Example 3 was less than 10% after 24 hours. These results indicate that even when the pH of the surrounding medium is well below the pH threshold of the second polymeric material, the presence of starch in the outer layer releases a significant amount of active substance when exposed to colonic enzymes. Is possible.

  One skilled in the art will note that despite the loss of integrity of the coating of Example 1, not all of the active was released after 8 hours. We believe this is because the test is in vitro. The tablets are exposed in vivo to the applied mechanical pressure as a result of colonic motility, which should contribute to the complete disintegration of the tablet.

  We also observed that when the tablet of Example 1 was exposed to an aqueous solution at pH 6.8 for 24 hours, less than 10% of 5ASA was released from the tablet (drug release test # 4; (See FIG. 4). This result indicates that in order to achieve a significant release of the active substance from the tablets according to the invention, the presence of colonic enzymes in the surrounding medium is necessary and that they are resistant to small intestinal conditions, It demonstrates that premature drug release is effectively prevented.

  The accelerated drug release under colonic conditions also indicated that the inner layer contained neutralized Eudragit® L30D-55 and the outer layer contained starch when compared to a comparable formulation where the inner layer was not neutralized. / Eudragit® S100 is also observed in formulations of the invention comprising a 30:70 mixture. As shown in FIG. 5, no release is observed from either formulation when exposed to 0.1 M HCl for 2 hours. However, upon exposure to Krebs buffer pH 7.4, the initial release from the formulation according to the invention (Example 2) is observed after 30 minutes, whereas the initial release from the comparative formulation (Comparative formulation 4) is up to about 150 minutes. Does not happen. A similar acceleration of the initial release is observed when these formulations are exposed to a fecal slurry at pH 6.5, with the initial release from a tablet with a non-neutralized inner layer (Comparative Example 4) occurring after about 4 hours In contrast, the initial release from a tablet with a neutralized inner layer (Example 2) occurs after about 2 hours (FIG. 6).

  The formulation according to the invention also demonstrates distinct advantages over the formulation exemplified in US Pat. No. 5,422,121. In this regard, we believe that the tablet core was first coated with an inner layer of Eudragit® L30D and then coated with an outer layer of a 1: 3 mixture of Eudragit® L30D and guar gum. The preparation of Example 2 of Patent No. 5422121 (Patent Document 11) was reproduced as faithfully as possible (Comparative Example 5), and the drug release from this preparation over time under different conditions was measured using an embodiment of the present invention ( The comparison was made against an equivalent formulation in which the inner layer Eudragit® L30D according to Example 3) was completely neutralized. Under all colon conditions tested, initial drug release was accelerated with the formulation having a neutralized inner layer (see FIGS. 7-9).

  Formulations having an inner layer comprising a nonionic polymer, a base and a buffer also show accelerated initial drug release when compared to a comparable formulation wherein the inner layer does not contain a base or a buffer. In this regard, we have an inner PVA polymer layer and an outer layer comprising a 70:30 mixture of Eudragit® S / Eudragit® FS (50:50) blend and starch. In embodiments where the inner layer contains a base and a buffer, it was demonstrated that the initial release could be reduced from 4 hours to 3 hours when exposed to Grebs buffer (FIG. 10).

  In some of the test experiments after 10 hours in colonic conditions, incomplete drug release was observed (see especially FIGS. 8 and 9). We observed that this observation indicates that high dose (1200 mg) tablets were tested in these experiments and that the volume of buffer used (Krebs and Hanks buffer) was low or that the stool slurry used was It should be pointed out that, due to the limited volume (210 mL), the sink conditions may not have been achieved.

  In contrast, the tablets of Examples 5-7 do not show significant early release when exposed to simulated feeding conditions over the duration of the study (FIGS. 11, 14, and 15). Furthermore, the tablets of Example 7 do not show a significant "dietary effect" when exposed to simulated feeding and fasting conditions over the duration of the study (Figure 15). In other words, not only do these tablets show less than 10% drug release by the end of the study, but the release profiles in both simulated fed and fasted states are very similar (Example 7; 15) or almost the same (Example 6; FIG. 14).

  These results seem to support the conclusion that by providing tablets with a coating according to the present invention, the dietary effects associated with coated 5ASA tablets can be reduced or even eliminated. . In particular, these results indicate that dietary effects can be eliminated by applying an outer coating containing a "semi-organic" coating preparation rather than an aqueous coating preparation (Example 1; FIG. 16). It seems to indicate.

  Thus, it can be seen that the delayed release formulation according to the present invention is significantly better than similar formulations.

  Although the present invention has been described with reference to preferred embodiments, it should be understood that various modifications can be made within the spirit or scope of the invention as set forth in the following claims.

In this specification, unless expressly indicated otherwise, the term "or" refers to the operator "exclusive OR", which requires that only one of the stated conditions be satisfied. On the other hand, it is used to mean an operator that returns a true value when either or both of the conditions are satisfied. The term "comprising" is used in the meaning of "including" rather than "consisting of". The teachings of all the above prior art teachings are incorporated herein by reference. Any knowledge of these preceding published documents herein should not be construed as an admission or statement that their teachings were common general in Australia and elsewhere at the time of filing this application. Absent.

Claims (26)

A delayed release drug formulation for oral administration for delivering a drug to a patient's colon, said formulation comprising:
Including a core containing a drug, and a coating for the core including an outer layer and an inner layer,
The outer layer is a polysaccharide selected from the group consisting of starch, amylose, amylopectin, chitosan, chondroitin sulfate, cyclodextrin, dextran, pullulan, carrageenan, scleroglucan, chitin, curdlan and levan, which are susceptible to attack by colonic bacteria. wherein the first polymeric material is a mixture of the second polymeric material is a film-forming polymer enteric having a pH threshold p H 6.5 or higher,
The ratio of the first polymer material to the second polymer material is at least 25:75 and is present in the outer layer at 60:40 or less;
The delayed release drug, wherein the inner layer includes a third polymer material that is a nonionic polymer soluble in intestinal fluid or gastrointestinal fluid, and the inner layer includes at least one buffer that is an inorganic salt. Formulation.   The nonionic polymer may be methylcellulose (MC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), poly (ethylene oxide) -graft-polyvinyl alcohol, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), The delayed release drug formulation according to claim 1, wherein the drug formulation is selected from the group consisting of: and polyvinyl alcohol (PVA).   3. The delayed release drug formulation according to claim 1 or 2, wherein the buffer is selected from the group consisting of alkali metal salts, alkaline earth metal salts, ammonium salts, and soluble metal salts.   The delayed release drug formulation according to any one of claims 1 to 3, wherein the buffer is a phosphate.   The delayed release drug formulation according to any one of claims 1 to 4, wherein the buffer is potassium dihydrogen phosphate. The buffering agent is, based on the dry weight of the third polymeric material 0. 6. The delayed release drug formulation according to any of the preceding claims, wherein the formulation is present in the inner layer in an amount of 1% to 20 % by weight.   7. The delayed release drug formulation according to claims 1 to 6, wherein the inner layer comprises at least one base.   Wherein the base is selected from the group consisting of hydroxide bases, alkali metal bicarbonates, alkali metal carbonates, alkali metal phosphates, alkali metal citrates, or physiologically acceptable amines. Item 8. The delayed-release drug preparation according to Item 7.   9. The delayed release drug formulation according to claim 7, wherein the base is a hydroxide base.   The delayed release drug formulation according to any one of claims 7 to 9, wherein the base is sodium hydroxide. It said second polymeric material is a blend of at least two different polymers having p H 6.5 or more pH threshold, delayed release drug formulation according to any one of claims 1 to 10.   12. The delayed release drug formulation according to claim 11, wherein the polymers in the blend are different polymethacrylate polymers. Two different polymers in the blend, 4 0:60 6 0: present in a ratio of 4 0, delayed release drug formulation according to claim 11 or 12.   14. The delayed release drug formulation according to any of claims 11 to 13, wherein the two different polymers in the blend are present in a ratio of 50:50. 15. The delayed release drug formulation according to any of the preceding claims , wherein the ratio of the first polymer material to the second polymer material is present in the outer layer from 25:75 to 35:65. .   17. The delayed release drug formulation of claim 15, wherein the ratio of the first polymeric material to the second polymeric material is present in the outer layer at a ratio of 30:70. The ratio for the second polymeric material of the first polymeric material, 40: 60 to 60: existing outside layer 40, a delayed release drug formulation as claimed in any of claims 1-14. 18. The delayed release drug formulation according to claim 17, wherein the ratio of the first polymeric material to the second polymeric material is present in the outer layer at a ratio of 50:50.
A method of making a delayed release drug formulation for oral administration for delivering a drug to the colon according to claim 1, wherein the method comprises:
Form a core containing the drug,
Using an inner coating preparation comprising a third polymeric material, which is a nonionic polymer soluble in intestinal or gastrointestinal fluid, in a solvent system and comprising at least one buffer, which is an inorganic salt, the core is prepared using the inner coating preparation. To form an inner coating core,
A first polysaccharide selected from the group consisting of starch, amylose, amylopectin, chitosan, chondroitin sulfate, cyclodextrin, dextran, pullulan, carrageenan, scleroglucan, chitin, curdlan and leban, which are susceptible to attack by colonic bacteria. and a second polymeric material is a film-forming polymer enteric having a polymeric material and p H 6.5 or more pH threshold covering the inner coating core with an outer coating preparation comprising a solvent system, external coating core Forming a
The ratio of the first polymer material to the second polymer material is at least 25:75 and is present in the outer layer at 60:40 or less;
Method. 20. The method of claim 19 , wherein the solvent system of the inner coating preparation is aqueous. The pH inside the coating preparation is adjusted using a base so that the p H7.5 ~p H1 0, The method of claim 19 or claim 20.   22. The method according to claim 21, wherein the pH of the inner coating preparation is adjusted with a base to be between pH 7.5 and pH 8.5.   23. The method according to claim 21 or claim 22, wherein the pH of the inner coating preparation is adjusted to a pH of 8 with a base. Wherein the base is selected from the group consisting of hydroxide bases, alkali metal bicarbonates, alkali metal carbonates, alkali metal phosphates, alkali metal citrates, or physiologically acceptable amines. Item 24. The method according to any one of Items 21 to 23 . The method according to any one of claims 21 to 24 , wherein the base is a hydroxide. The method according to any one of claims 21 to 25 , wherein the base is sodium hydroxide.

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