JP6700220B2 - Delayed release drug formulation - Google Patents

Description

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

  Targeting drugs to the intestine is well known and has been known for over 100 years. The colon can be used as a means to achieve local or systemic treatment, but the drug target is usually the small intestine. The requirements for coating the drug depend on its target site. In order to reach the colon, it is necessary for the drug to 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 it in the small intestine.

  Coated products for release in the small intestine typically use polymeric 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, allowing the polymer coating to collapse or dissolve. 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. 5,837,086 is one of a number of references that disclose partial neutralization of carboxyl groups to lower the pH at which disintegration occurs. U.S. Pat. No. 5,837,037 discloses tablets having an inner coat of partially neutralized material and an outer coat of lesser or no neutralization. This is said to result in disintegration earlier in transit from the stomach.

  Release of drugs in the colon typically requires another approach. The colon is prone to many disease states, including inflammatory bowel disease, irritable bowel syndrome, constipation, diarrhea, infections and carcinomas. In such conditions, drugs targeting the colon will maximize the therapeutic efficacy of the treatment. The colon can also serve as an entrance to the drug for entry into the systemic circulation. Various formulations, such as prodrugs and drug formulations, have been developed for colon drug delivery, and the latter has become more prevalent because the once proven concept can be applied to other drugs.

  The higher bacterial population within the colon has also been exploited in the development of colon drug delivery dosage forms through the use of natural polysaccharides as carrier materials that make up substrates for many enzymes of resident colonic bacteria. .. These materials can pass through the digestive tract region upstream, but are digested when they enter the colon. Those that have been investigated so far include amylose, pectin, chitosan, and galactomannan.

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

  One major attraction of using polysaccharides in this bacterial enzyme approach to colon drug delivery is that the materials used are food grade and 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 where they are digested by colonic bacterial enzymes leading to release of the drug load. An example of such a formulation that employs 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 leaching of drug load in the upstream gastrointestinal tract. To avoid this problem, natural materials have been used as a mixture with various impermeable materials.

  US Pat. No. 6,037,058 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 polymeric material used is a pH independent release polymeric material.

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

  A further amylose-based coating composition is 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. Pat. No. 5,837,058 also discloses a delayed release coating comprising amylose and (preferably) ethylcellulose or alternatively an insoluble acrylate polymer. The coating composition also includes a plasticizer, the method finds particular application in the preparation of dosage forms containing active materials that are unstable at temperatures above 60° C., but at temperatures below 60° C. Is formed.

  U.S. Pat. No. 5,837,037 discloses certain delayed release coatings for bioactive sodium prednisolone metasulfobenzoate, including glassy amylose, ethyl cellulose 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. Microparticles 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 the release thereof. The drug and chitosan are mixed into a homogeneous mechanical powder mixture, which is granulated and then optionally tableted. Granulation may be carried out 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. 6,096,049 discloses a pH dependent drug release system which is a free flowing powder of solid hydrophobic nanospheres containing 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 regarding the use of certain polymethacrylate polymers, inter alia, to control the swelling of inulin. The polymethacrylate polymers tested were Eudragit® RS; Eudragit® RL; 1:1 mixture of Eudragit® RS and Eudragit® RL; Eudragit® FS; and Eudragit®. It was a 1:1 mixture of (registered trademark) RS and Eudragit (registered trademark) S.

  U.S. Pat. No. 6,096,849 discloses an oral dosage form having a core containing at least one active ingredient in an outer shell material containing a colon-degrading polysaccharide as an admixture with a film-forming polymer. The weight ratio of polysaccharide to film forming polymer is 1:2 to 5:1, preferably 1:1 to 4:1. A gastric resistant separation layer can be used to prevent premature diffusion of the active ingredient from the core. This reference specifically exemplifies a tablet having an inner separation layer of Eudragit® L30D with an outer layer comprising Eudragit® L30D and guar gum (Example 2).

  U.S. Pat. No. 6,096,849 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 an aqueous medium at a pH of about 5 to about 6.3, and the outer coating layer is an aqueous polymer 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, hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose 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. Pat. No. 5,837,037 discloses colon drug delivery formulations using a mixture of a pH dependent film forming polymeric material and a polysaccharide such as starch. This formulation is known to exhibit delayed release followed by relatively rapid release of the drug, but it would be preferable if the drug release were more rapid in the colon.

US Patent Application Publication No. 2008/0200482 International Publication No. 2008/135090 Pamphlet European Patent Application Publication No. 03433993 (BTG International Limited) European Patent Application Publication No. 0502032 (British Technology Group Ltd) International Publication No. 99/21536 (BTG International Limited) Brochure International Publication No. 99/25325 (BTG International Limited) Pamphlet International Publication No. 03/068196 (Alizyme Therapeutics Ltd) Pamphlet British Patent No. 2366002 (British Sugar PLC) Pamphlet of International Publication No. 01/76562 (Tampereen Patenttimisto Oy) International Publication No. 2004/052339 (Salvona LLC) Pamphlet US Pat. No. 5,422,121 (Roehm GmbH) International Publication No. 96/36321 Pamphlet International Publication No. 2007/122374 Pamphlet

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

  An object is to provide a delayed release preparation having a drug-containing core and a delayed release coating. In particular, the challenge is to provide a delayed release formulation for delivering drugs 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 a patient's colon, the formulation comprising a core containing the drug and an outer layer and an inner layer. An outer layer comprising 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 comprising: It comprises a third polymeric material which is a nonionic polymer soluble in intestinal fluid or gastrointestinal fluid, and said inner layer comprises at least one additive selected from buffers and bases.

  In an alternative of the first aspect, the coating comprises an outer layer and at least one layer selected from the group consisting of a separating layer and an inner layer between the core and the outer layer. When present, the separating layer comprises a nonionic polymer that is soluble in intestinal fluid or gastrointestinal fluid. The outer layer is a coating preparation formed by combining a first polymeric material in an aqueous medium with a second polymeric material in an organic medium, either directly on the inner layer or when the inner layer is not present. Is applied directly to the separating layer.

  We have found that intestinal fluid or gastrointestinal fluid soluble polymers, such as an inner layer comprising a partially or fully neutralized polycarboxylic acid polymer, and a first polymer susceptible to attack by colonic bacteria. The material, eg, the polysaccharide, and a second polymeric material having a pH threshold above about pH 6, eg, to the same extent as the polymer of the inner layer but not neutralized or partially to a lesser extent than the third polymeric material. A coating having an outer layer of a mixture with a polycarboxylic acid polymer that has been neutralized, exhibits superior colonic release properties over similar coatings designed for site-specific release in the colon. I have found In this regard, drug release from the formulations according to the invention appears to be accelerated in the colon when compared to similar colon release formulations. Without being bound to a particular theory, we find that once intestinal fluid or gastrointestinal fluid penetrates into the outer layer, the inner layer begins to dissolve before the outer layer, and between the core and outer layer. We believe that a flow region will be formed. The flow region not only promotes dissolution and/or disintegration of the outer layer from the inside, but it also softens and begins to rupture the core, resulting in faster release of the drug from the core when the outer layer decomposes.

  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. Preferably. It is particularly preferred that the first polymeric 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 (meth)acrylic acid alkyl ester.

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

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

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

  A further technical advantage of the present invention is that the drug is long-term (ie as long as the coating is intact and dissolution/comparison with the formulation disclosed in WO 01/76562). It means that there is virtually no release (during the disintegration), after which the drug is released relatively quickly. This is in contrast to homogeneous tablets, where the drug release profile is graded from the beginning 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 colon environment.

First Polymeric Material The first polymeric material typically comprises a polysaccharide, eg, a polyglucoside, which preferably contains 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. Is. More preferably the polysaccharide is starch, amylose or amylopectin, most preferably starch.

  One of ordinary skill in the art can use techniques that are part of common sense to determine 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 an enzyme from a bacterium found in the colon and the change in weight of that material over time determined.

  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, Examples include 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 can have these two polysaccharides in different proportions. Most natural (unmodified) corn starches have from about 20% to about 30% by weight amylose, the balance being 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% amylose.

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

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

  A preferred starch has no more than 50% by weight amylopectin. As indicated above, a particularly suitable starch is a "high amylose" starch having about 25% to about 45% by weight amylopectin, such as about 30% or about 40% by weight amylopectin. In particular, starches having about 40% to about 50% amylopectin by weight are also suitable.

  One of ordinary skill in the art can determine the relative proportions of amylose and amylopectin for any starch. For example, using near-infrared (“NIR”) spectroscopy, the amylose and amylopectin contents of starch were calibrated by NIR using a laboratory-made mixture of known amounts of these two components. It can be determined using lines. In addition, amyloglucosidase can be used to hydrolyze starch to glucose. As a result of a series of enzyme-catalyzed phosphorylation and oxidation reactions, reduced nicotinamide adenine dinucleotide phosphate (“NADPH”) is formed. The amount of NADPH formed is in a stoichiometric relationship with the original glucose content. Suitable test kits for this procedure are available (eg 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 give short chain fatty acids (“SCFA”) that can be quantified by gas liquid chromatography using a capillary column. Including making.

  The preferred starch has amylose in its glassy form, but amylose in its amorphous form may also be used in connection with the present invention.

  Preferred starches are "off-the-shelf" starches, ie starches which do not require any processing prior to use in the context of the present invention. Examples of particularly suitable "high amylose" starches are Hylon™ VII (National Starch, Germany), Eurylon™ 6 (or VI) or Amylo NI-460 or Amylo N-400 (Roquette, Restron, France), Or Amylogel 03003 (Cargill, Minneapolis, USA), all of which are examples of corn starch having from 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 material is a pH-sensitive film-forming polymer, ie it has a “pH threshold” that is insoluble in aqueous media below its pH and soluble in aqueous media above its pH. Thus, the pH of the surrounding medium induces dissolution of the second polymeric material, and below the pH threshold, the second polymeric material does not dissolve (substantially at all). 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. Furthermore, the term "soluble" means that 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, so that 1 g of polymeric material dissolves at a given pH. Is used to mean that it requires a solvent or surrounding medium.

  By "ambient medium" we mean gastric and intestinal fluid, or an aqueous solution designed to reproduce gastric or intestinal fluid in vitro.

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

  The second polymeric material has a pH threshold of pH 6 or higher, and more preferably about pH 6.5 or higher. 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 it is generally 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, that is, it is insoluble below pH 6.5, soluble above about pH 6.5, and more preferably about pH 7. That is, it is 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 hydroxypropylmethyl cellulose acetate succinate (HPMC-AS). An example of a suitable polyvinyl-based polymer is polyvinyl acetate phthalate (PVAP).

The second material is preferably an "anionic" polymeric material, i.e. a polymeric material containing groups capable of ionizing in an aqueous medium to form anions (see below), more preferably a (meth)acrylic. A copolymer of an acid and a C _1-4 alkyl ester of (meth)acrylic acid, for example, a copolymer of methacrylic acid and methacrylic acid methyl ester. 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 sustained release. The ratio of carboxylic acid groups to methyl ester groups in these copolymers ("acid:ester ratio") determines the pH at which the copolymer is soluble. The acid:ester ratio can be about 2:1 to about 1:3, such as about 1:1 or preferably about 1:2. The molecular weight ("MW") of the preferred anionic copolymers is typically 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) copolymers have a molecular weight of about 125,000 g/mol. Suitable examples of such polymers have an acid:ester ratio of about 1:1 and a pH threshold of about pH 6, or an acid:ester ratio of about 1:2 and a pH threshold of about pH 7.

  An 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 the trade name Eudragit( It is marketed under the 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 commercially available under the trade name Eudragit( (Registered trademark) S is commercially available. 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, for example about 320,000 g/mol. Suitable examples of such copolymers have 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 the form of powders, marketed under the trade name Eudragit® L100-55 or in the form of aqueous dispersions (30 %) and is marketed 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, for example about 280,000 g/mol. A suitable example of such a copolymer has a ratio of methyl acrylate:methyl methacrylate:methacrylic acid of about 7:3:1, thereby providing an acid:ester ratio of about 1:10 and a pH threshold of about pH 7. To do.

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

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

  Mixtures of film-forming polymeric materials may optionally be used. 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 about 1:99 to about 99:1, such as about 10:90 to about 90:10. Or about 25:75 to about 75:25, or about 40:60 to about 60:40, for example about 50:50, by weight of the polymer may be present in the blend.

  An example of a suitable mixture may include a mixture of Eudragit® L and Eudragit® S, for example a 1:1 mixture. A further example may be a blend of Eudragit S and Eudragit FS, eg a 50:50 blend.

  For the avoidance of doubt, the terms “mixture” and “blend” are used interchangeably herein in the context of a mixture or blend of polymers that form a second polymeric material.

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

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

  The mixture of the first polymeric material and the second polymeric material 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 an amount of 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 about 10 μm to about 150 μm. However, the specific coating thickness will depend on the composition of the coating. For example, coating thickness 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 about 70 μm to about 130 μm, and preferably 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 is typically on the order of about 5×10 −4 m to about 25 mm diameter core, based on the dry weight of the total polymeric material, for a core having a diameter of about 5×10 −4 m to about 25 mm. Equivalent to 2 mg/cm ² to about 10 mg/cm ² , preferably about 2 mg/cm ² to about 8 mg/cm ² , and most preferably about 4 mg/cm ² to about 8 mg/cm ² , for example about 7 mg/cm ² . is there.

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 and intestinal fluid (referred to herein as gastrointestinal fluid).

  By "gastric fluid" we mean the aqueous fluid in the stomach of mammals, especially humans. This fluid contains up to about 0.1 N hydrochloric acid and substantial amounts of potassium chloride and sodium chloride and plays an important role in digestion by activating digestive enzymes to denature ingested proteins. Gastric acid is produced by the cells lining the stomach and prevents the other cells from producing bicarbonate, which acts as a buffer, to make the gastric juices too acidic.

  By "intestinal fluid" we mean the 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, namely those found in the duodenum (or "duodenal juice"), those found in the jejunum (or "jejunal fluid"), and those found in the ileum (or " Ileal fluid"), as well as fluids found in the large intestine, such as "colonic fluid".

  One of ordinary skill in the art can readily determine if a polymer is soluble in gastric and/or intestinal fluids. If the polymer is soluble in water (or an aqueous solution), such as a buffer solution, at a pH of 1-3, 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. If 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.

  In principle, any pharmaceutically acceptable water-soluble film-forming polymer is 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 with a pH threshold. In such an embodiment, 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 0.5-3.5 pH units only. Low. The pH threshold of the third polymeric material is typically about pH 4.5 to about pH 7.5.

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

  Suitable polymers for use as the third polymeric material include pharmacologically acceptable nonionic 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 buffers and bases. In particular, the inner layer of these embodiments preferably comprises a base and optionally a buffer. In a preferred embodiment, the inner layer comprises 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 nonionic polymer, or a mixture of anionic and nonionic polymers. Examples of suitable mixtures include a mixture of Eudragit® L and Eudragit® S, for example a 1:1 mixture, and a mixture of Eudragit® S and HPMC, for example a 1:1 mixture. I can name you. 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 below the outer layer when intestinal fluid begins to penetrate the outer layer. Without wishing to be bound by any particular theory, we have found that the alkaline environment causes the outer layer to dissolve and thus disintegrate because the pH of the alkaline environment is above the pH threshold of the second polymeric material. It is believed to promote and thereby accelerate the release of drug from the formulation once the outer coating dissolves and/or disintegrates.

  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 physiologically such as triethanolamine, sodium bicarbonate, potassium carbonate, trisodium phosphate, trisodium citrate or triethylamine. Organic bases such as acceptable amines may be mentioned. Generally hydroxide bases, especially sodium hydroxide, are preferred.

  In embodiments where the third polymeric material is a nonionic polymer, the inner layer typically comprises either a base, or more typically a combination of base and buffer.

  The amount of base present in the inner layer depends, at least in part, on the final pH of the inner-coated preparation before coating the core of a given batch, the number of cores to be coated in the batch, the coating process of the batch. It 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 Inner coating preferably comprises at least one buffer. The purpose of the buffer is to provide or increase the pH buffer capacity below the outer layer when intestinal fluid begins to penetrate the outer layer. Without wishing to be bound by any particular theory, we believe that the buffering agent enhances the buffering 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 in which the base is present in the inner layer, the buffer aids in maintaining an alkaline environment below the outer layer once the intestinal fluid has penetrated into the outer layer.

  The buffering agent may be a pharmaceutically 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 carboxylic acid salt, or a mixture of carboxylic acids, carboxylic acid salts or both.

  Buffering agents may also be inorganic salts such as alkali metal salts, alkaline earth metal salts, ammonium salts, and soluble metal salts. Examples of the metal of the soluble metal salt 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 their high buffer capacity at the pH of the coating solution, eg pH 8.

  The buffer(s) are usually present in the inner layer in an amount of from about 0.1 to 20% by weight, based on the dry weight of the third polymeric material, for example from about 0.1 to about 4% by weight, preferably about 0. 0.1 to about 3% by weight, and more preferably about 1% by weight.

Inner Layer In addition to the buffer and/or base, the inner layer contains an additive selected from a plasticizer (such as triethyl citrate), an antiblocking agent (such as GMS), and a surfactant (such as polysorbate 80). , Conventional polymer film additives may be included.

The thickness of the inner coating of the core is typically 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, drying the third polymeric material. Equivalent to about ² mg/cm ² to about 10 mg/cm ² , preferably about 2 mg/cm ² to about 8 mg/cm ² , and most preferably about 3 mg/cm ² to about 7 mg/cm ^{2 by} weight. .

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

  The formulation according to the invention may also be incompatible in the composition of the core with the delayed release coating. In such cases, it may be desirable to include a separation layer to separate the core from the coating. For example, the invention includes embodiments in which the inner layer provides an alkaline environment that is believed to aid dissolution and disintegration of the outer layer. However, the inner layer may be incompatible with the core if the core contains a drug with acidic groups. 5ASA is an example of a drug having an acidic group. In such cases, it will typically be appropriate to include a separation layer.

  Any suitable separating layer known to those skilled in the art may be used. In one preferred embodiment, the separation layer comprises a nonionic 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 nonionic polymers may also be used. HPMC or PVA are preferred. The separation layer may further contain 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 such as 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 a encapsulated content. 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 nonpareil beads or dragee.

  The core may consist solely of the drug(s), or more usually, the drug(s) and at least one pharmacologically acceptable additive. In this context, the core is typically a tablet or pellet, with the drug(s) and fillers or diluents, eg cellulosic materials such as lactose or microcrystalline cellulose; binders, eg polyvinylpyrrolidone (“PVP”). )) or hydroxypropyl methylcellulose (HPMC); disintegrants such as croscarmellose sodium (eg Ac-Di-Sol™) and sodium starch glycolate (eg Explotab™); and/or lubricants such as stearin. Composed of a mixture of magnesium acid and talc. The core may be a compressed granule containing at least some of these substances.

  The core may be uncoated or, as mentioned above, the core itself may include a coating, such as a separating layer onto which the inner layer is applied.

  The minimum diameter of each core is typically at least about 10-4 m, usually at least about 5x10-4 m, and preferably at least about 10-3 m. 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 minitablets) or about 15 mm to about 25 mm (eg for particular tablets or capsules). Have. 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 coated cores less than 3 mm in diameter may be preferred.

  The present invention is a multiphasic drug release formulation comprising at least two populations of coated cores, eg coated pellets, within the same dosage form, eg capsule, wherein one population of coated cores is provided in the other, or in another. From each coated core population, it has applications in formulations that are distinguished by its coating. The coatings may differ from one population to another in terms of coating thickness or composition, such as the ratio of components and/or the identity of the components. Multiphasic drug release formulations may be particularly suitable for Crohn's disease patients, who are affected by various areas along the intestine.

  Release from formulations 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 from initial exposure to conditions suitable for drug release to the onset of drug release is known as the "lag time". Rag time depends on a number of factors, including coating thickness and composition, and can 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 the majority of embodiments, the lag time is about 10 minutes to about 8 hours. For example, in a fecal slurry at pH 6.8, the lag time can be about 10 minutes to about 2 hours, such as about 30 minutes to about 1.5 hours. Complete release of the drug may be achieved within 5 hours, eg within 4 hours, after exposure to these conditions.

  A formulation is usually defined as gastric resistant if the drug release after 2 hours in 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 usually exhibit less than 1% by weight drug release in acidic media and typically show substantially no drug release in acidic media. 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 15-25 mm. The outer layer preferably comprises a 30:70 mixture of 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. Comprising a fully neutralized polymethacrylate polymer, such as Eudragit™ S, applied from an inner coating preparation having. The core is preferably coated with an inner layer to a thickness of from 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 the outer layer. Coated to a thickness of about 4 to about 8 mg/cm ² (based on dry weight of 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 comprises at least one drug. 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 various 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 that have local or systemic effects.

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

  The identity of the drug(s) in the formulation obviously depends on the condition being treated. In this context, the formulation has 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 formulations may include anti-inflammatory agents (eg 5ASA (also known as mesalazine or mesalamine), 4ASA, sulfasalazine and balsalazide); non-steroidal anti-inflammatory agents (eg ibuprofen and diclofenac). At least one selected from the group consisting of: steroids (eg prednisolone, budesonide or fluticasone); immunosuppressants (eg azathioprine, cyclosporine, and methotrexate); antibiotics; and biological agents including peptides, proteins and antibody fragments. The species may include a drug. 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 antineoplastic drug. Suitable antitumor 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 cancer or colon cancer, mainly in patients with colitis, the formulation may include the anti-inflammatory agent 5ASA.

  For the treatment or prevention of IBS, constipation, diarrhea or infectious diseases, the formulation may comprise at least one active agent suitable for treating or preventing these pathologies.

  Pharmacologically acceptable derivatives and/or salts of drugs 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 invention has particular use in either the treatment of IBD (particularly ulcerative colitis) or the prevention of colon cancer or colon cancer (mainly in patients with colitis), both using 5ASA. The present invention also has use as an entrance to the entry of drugs into the systemic circulation through the colon. 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 a formulation as described above.

  In a fourth aspect of the 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 (particularly ulcerative colitis), IBS, constipation, diarrhea, infections 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, including the formulations described above, for use in the treatment of IBD. In addition, the use of at least one antineoplastic agent in the manufacture of a medicament, including the above-mentioned formulation, for use in the treatment of carcinoma is also provided. Further provided is the use of 5ASA in the manufacture of a medicament, including the formulations described above, for use in the prevention of colon cancer or colon cancer.

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

  The formulation will typically contain a therapeutically effective amount of the drug or drugs, 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 those of ordinary skill in the art using routine common sense. However, by way of example, a "low" dose formulation will typically contain no more than about 20% by weight of the drug, and preferably about 1% to about 10% by weight, for example about 5% by weight of the drug. A "high" dose formulation will typically include at least 40% by weight of drug, and preferably from about 45% to about 85% by weight, for example about 50% or about 80% by weight drug.

Method According to a sixth aspect of the invention there is provided a method for producing a delayed release drug formulation for oral administration for delivering a drug to the colon according to the first aspect. This method
Forming a core containing the drug,
Coating the core using an inner-coated preparation containing a third polymeric material as described above in a solvent system to form an inner-coated core,
Coating the inner coated core with an outer coated 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 greater in a solvent system to form the outer coated core. Including doing
The third polymeric material is a nonionic polymer and the inner coating preparation comprises at least one additive selected from the group consisting of buffers and bases.

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

  In embodiments where the third polymeric material is a nonionic polymer, the pH of the inner coating preparation is preferably such that it is at least 0.5 pH units above the pH threshold of the second polymeric material prior to coating. 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. It

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

In an alternative of the sixth aspect of the present invention there is provided a method of manufacturing a delayed release drug formulation for oral administration for delivering a drug to the colon according to the first aspect, the method comprising:
Forming a core containing the drug,
Separation layer coating preparation containing a nonionic polymer soluble in intestinal fluid or gastrointestinal fluid in a solvent system, and inner layer coating preparation containing a third polymer material soluble in intestinal fluid or gastrointestinal fluid in a solvent system An aqueous preparation of a first polymeric material, wherein the core is coated with at least one coating preparation selected from the group consisting of products to form an intermediate coated core, and which is susceptible to attack by colonic bacteria. Combining with an organic preparation of a second polymeric material having a pH threshold of about pH 6 or higher to form an outer layer coated preparation,
Coating the intermediate coated core with the outer layer coated preparation to form an outer layer coated core,
The third polymeric material is a nonionic polymer and the inner coating preparation comprises at least one additive selected from buffers and bases.

  In embodiments according to this alternative aspect, the core may be directly coated with either the separation layer coated preparation or the inner layer coated preparation to form the intermediate coated core. Alternatively, the core is directly coated with the separation layer coated preparation to form a separation layer coated core, which is then directly coated with the inner layer coated preparation to produce the intermediate coated core. It may be formed.

  In an alternative embodiment having both a separating layer and an inner layer and the third polymeric material of the inner layer is a nonionic polymer, a different nonionic polymer may be used. However, in these embodiments, it may be preferred to use the same nonionic polymer as the nonionic polymer of the separation layer for the third polymeric material.

Organic medium, C ₁ -C ₄ alcohol, methyl glycol, butyl glycol, acetone, methyl glycol acetate, and may be selected from the group consisting of mixtures. However, it is preferred that the organic medium comprises ethanol. In a preferred embodiment, the organic medium is 85-98% ethanol, for example about 96% ethanol.

  The organic medium may contain from about 2% to about 10%, for example about 6% polymer solids.

Aqueous medium, water, C ₁ -C ₆ alcohol, and may be selected from the group consisting of mixtures. However, the aqueous medium is preferably water and a _C 1 -C ₆ alcohol, preferably a mixture of butan-1-ol. The ratio of water to alcohol in such a mixture is at least 5:1, preferably about 11:1.

The outer layer may have a thickness based on the total polymeric material of from about 2 mg/cm ² , for example about 5 mg/cm ² to about 10 mg/cm ² , for example about 7 mg/cm ² .

  The outer layer may have a total weight gain (TWG) thickness of about 3% to about 8%, for example about 5%.

  Either method may be used to prepare any of the preferred formulations described above.

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

  The dependence of drug release on gastric status is colloquially known as the "dietary effect." For oral dosage forms intended for site-specific release of the drug in the colon, such dietary effects can result in premature release of the drug in the small intestine. Such release can lead to an undesired increase in systemic side effects, which can adversely affect patient compliance. Clearly, significant dietary effects are undesirable for oral delayed release dosage forms.

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

  An example of FeSSGF is described in Jantratid et al., (2008) “Dissolution media simulating conditions in the proximal human gastrointestinal tract: 25 conditions in the human proximal gastrointestinal tract. ):1663-1676). Briefly, this example of FeSSGF is composed of a mixture of milk and acetic acid/sodium acetate buffer (50:50) and sodium chloride.

  As an example, we have shown that coated 800 mg 5ASA tablets (coated with a single coating of EudragitS) were exposed to this simulated fed state condition in vitro as compared to the simulated fasted state condition. In comparison, it was observed to show a shorter lag. Earlier initial release of 5ASA may result in drug absorption in the small intestine, which may lead to increased systemic side effects. Similar effects were also obtained in vitro and in vivo for 1200 mg 5ASA tablet formulations of Lialda®/Mezavant® from Cosmo Pharmaceuticals/Shire where site-specific colonic release of 5ASA is contemplated. Observed in.

  The inventors have found that the above-mentioned formulations according to the invention in which the outer layer is applied from a “semi-organic” coating preparation show a similar release profile after both fasted and fed-mimetic gastric conditions. . Increased tlag in the fed state may at least reduce and even eliminate unwanted dietary effects, which in turn leads to a reduction in the occurrence of systemic side effects that the dosage form may take with or with the diet. It can be taken at any time without, which may lead to improved patient compliance.

  As described above for the alternative method, a "semi-organic" coating preparation is prepared from an aqueous dispersion of a first polymeric material and an organic (typically ethanol-based) solution of a second polymeric material. .. The preferred first polymeric material and second polymeric material, and their relative proportions, are as described above.

Effect of alcohol Alcohol-induced early release (dose dumping) was observed for the coated 5ASA dosage form (Fadda et al., (2008) "Implement of release from release reinforcement formulas"). alcohol (impairment 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 40% ethanol in 0.1 N HCl for 2 hours, the formulations according to the invention are more resistant to alcohol-induced degradation in the stomach and thus the effect of alcohol. It shows that you don't wear much. Further studies are proposed to confirm this preliminary result.

(A) Single layer of Eudragit® S only (Comparative Example 1), (b) Single layer of 30:70 mixture of starch and Eudragit® S (Comparative Example 2), (c) Complete medium Wa Eudragit(R) S inner layer and Eudragit(R) S outer layer (Comparative Example 3), or (d) fully neutralized Eudragit(R) S inner layer and starch and Eudragit(R). An outer layer of a 30:70 mixture with S (Example 1), 400 mg of 5ASA tablets coated with 0.1 N HCl for 2 hours, then in Kreb's buffer (pH 7.4) 8 FIG. 6 is a graph comparing drug release from tablets with respect to time upon time exposure. (A) Monolayer of a 30:70 mixture of starch and Eudragit® S (Comparative Example 2), (b) Inner layer of fully neutralized Eudragit® S and exterior 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). FIG. 4 is a graph comparing drug release from 400 mg 5ASA tablets over time when 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 upon exposure of 400 mg 5ASA tablets coated with an outer layer of a 30:70 mixture with ®S (Example 1) to a fecal slurry pH 6.5 for 24 hours. It is the graph which compared. 400 mg 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) were placed in Hanks pH 6.8 (Example 5). Figure 3 is a graph showing drug release from tablets upon exposure to Hanks) buffer. (A) inner layer of fully neutralized Eudragit® L30D-55 and outer layer of a 30:70 mixture of starch and Eudragit® S (Example 2), and (b) Eudragit®. ) 1200 mg of 5ASA tablets coated with an inner layer of L30D-55 (unneutralized) and an outer layer of a 30:70 mixture of starch and Eudragit® S (Comparative Example 4), with 0.1 N HCl. 2 is a graph comparing the drug release from the tablets with respect to time after exposure for 2 hours to Krebs buffer (pH 7) for 10 hours. 5 is a graph comparing the drug release from the tablets of Example 2 and Comparative Example 4 with respect to time when exposed to a fecal slurry of 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®. ) 1200 N 5ASA tablets coated with 0.1N of an inner layer of L30D-55 (unneutralized) and an outer layer of a 3:1 mixture of guar gum and Eudragit® L30D-55 (Comparative Example 5). 2 is a graph comparing drug release from tablets versus time upon 2 hours of HCl exposure and then 10 hours exposure to Krebs buffer (pH 7.4). FIG. 6 is a graph comparing the drug release from the tablets of Example 3 and Comparative Example 5 when exposed to 0.1 N HCl for 2 hours and then to Hanks buffer (pH 6.8) for 10 hours. 5 is a graph comparing the drug release from the tablets of Example 3 and Comparative Example 5 when exposed to the fecal slurry having a pH of 6.5 for 24 hours. (A) Separation layer of polyvinyl alcohol (OpadryII85F), inner layer of polyvinyl alcohol (OpadryII85F) adjusted to pH 8 and 20% buffer salt, and starch of blend of Eudragit® S/Eudragit® FS An outer layer of a 70:30 mixture with (Example 4), and (b) a separating layer made of polyvinyl alcohol (OpadryII85F) and a blend of Eudragit® S/Eudragit® FS with starch. An outer layer made with a 70:30 mixture (Comparative Example 6), coated with 1200 mg of 5ASA tablets upon exposure to 0.1 N HCl for 2 hours and then to Krebs buffer (pH 7.4) for 10 hours. 5 is a graph comparing drug release from tablets against time. With a separating layer of HPMC, an inner layer of neutralized Eudragit® S and an outer layer of 30:70 starch: Eudragit® S applied from a “semi-organic” coating preparation (Example 5). Figure 5 is a graph comparing drug release from tablets upon exposure of coated 1200 mg 5ASA tablets to FeSSGF at pH 5 for 4 hours (fed state) and then to Hanks buffer at pH 6.8 for 10 hours ( Only the steps of Hanks buffer are presented). 1200 mg of 5ASA tablets coated with a separating layer of HPMC and an outer layer of 30:70 starch: Eudragit® S (Comparative Example 7) applied from a “semi-organic” coating preparation (a) Tablets against time when exposed to 0.1 N HCl for 2 hours (fasted state) or (b) for 4 hours FeSSGF at pH 5 for 4 hours (fed state) followed by 10 hours exposure to pH 6.8 Hanks buffer. FIG. 6 is a graph comparing drug release from A. (only presented with Hanks buffer step). 1200 mg of 5ASA tablets coated with a separating layer of HPMC and an outer layer of 30:70 starch: Eudragit® S (Comparative Example 8) applied from an aqueous coating preparation, (a) 0.1 N Drug release from tablets over time upon exposure to HCl for 2 hours (fasted state) or (b) FeSSGF at pH 5 for 4 hours (fed state) followed by 10 hours exposure to pH 6.8 Hanks buffer. Is a graph comparing (only the stage of Hanks buffer was presented). With a separating layer of HPMC, an inner layer of neutralized Eudragit® S and an outer layer of 50:50 starch: Eudragit® S applied from a “semi-organic” coating preparation (Example 6) The coated 1200 mg 5ASA tablets were exposed to (a) 0.1N HCl for 2 hours (fasted state) or (b) FeSSGF at pH 5 for 4 hours (fed state) followed by Hank's buffer at pH 6.8. Fig. 6 is a graph comparing drug release from tablets upon 10-hour exposure to solution (only the Hanks buffer stage is presented). With a separating layer of HPMC, an inner layer of neutralized Eudragit® S and a 30:70 starch applied from the “semi-organic” coating preparation: outer layer of Eudragit® S (Example 7). Coated 400 mg 5ASA tablets were exposed to (a) 0.1 N HCl for 2 hours (fasted state) or (b) FeSSGF at pH 5 for 4 hours (fed state) followed by Hank's buffer at pH 6.8. Fig. 6 is a graph comparing drug release from tablets upon 10-hour exposure to solution (only the Hanks buffer stage is presented). An inner layer of neutralized Eudragit® S and a 30:70 starch applied from a “semi-organic” coating preparation: 400 mg of an outer layer of Eudragit® S (Example 1) coated 5ASA tablets were exposed to (a) 0.1 N HCl for 2 hours (fasted state) or (b) FeSSGF at pH 5 for 4 hours (fed state) followed by 10 hours exposure to Hanks buffer at pH 6.8. 3 is a graph comparing the drug release from the tablets with respect to time (only the Hanks buffer step is presented).

  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 (Karlskouga, 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). Polyvinylpyrrolidone (PVP) was purchased from ISP Global Technologies (Cologne, Germany). Magnesium stearate was purchased from Peter Greven (Bad Muenster Eifel, 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 An oval shaped 400 mg 5ASA tablet core with dimensions 14.5 x 5.7 mm was prepared by fluid bed granulation followed by blending and compression. Each tablet contains 76.9 wt% 5ASA (400 mg; drug); 14.7 wt% lactose (filler); 1.7 wt% PVP (binder); 3.5 wt% sodium starch glycolate ( Disintegrant); and 2% by weight talc and 1.2% by weight 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 5ASA tablet cores 1200 mg 5ASA tablet cores (having dimensions 21 x 10 mm) that were oval shaped by wet granulation were prepared. Each tablet contained 85.7 wt% 5ASA (1200 mg), 9.2 wt% microcrystalline cellulose, 1.7 wt% HPMC, 2.9 wt% sodium starch glycolate, and 0.5 wt%. 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 70:30 mixture of Eudragit® S and starch)
Inner Layer The inner coating layer was applied using an aqueous preparation of Eudragit®-S100 whose pH was adjusted to pH 8. The composition of the inner layer was also 50% triethyl citrate (dry polymer weight basis), 10% potassium dihydrogen phosphate (dry polymer weight basis), 10% glyceryl monostearate (GMS; dry polymer weight basis) and It contained 40% polysorbate 80 (based on GMS weight). The pH was adjusted with 1 M NaOH until pH 8 was obtained. Potassium dihydrogen phosphate and triethyl citrate were dissolved in distilled water, then Eudragit®-S100 was dispersed under mechanical stirring. The pH of this dispersion was then adjusted to pH 8 with 1M NaOH and mixing continued for 1 hour.

  The GMS dispersion was prepared at a concentration of 10% w/w. Polysorbate 80 (40%, GMS weight basis) was dissolved in distilled water and then 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 at room temperature with stirring.

This GMS dispersion is added to the neutralized Eudragit®-S100 solution and the final preparation is made into 400 mg 5ASA tablet cores using a fluid bed spray coater until the coating amount reaches 5 mg polymer/cm ^2. Coated. The total solid content of the coating solution is 10%. The coating parameters were as follows: spray rate 20 ml/min/kg tablets, 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, then cooled with stirring overnight. The% solids of the cooled preparation was calculated based on the final weight of the dispersion (taking into account 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®-S100 solution, resulting in 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.

  GMS was added in the form of a dispersion prepared at a concentration of 5% w/w. Polysorbate 80 (40%, GMS weight basis) was dissolved in distilled water and then 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 at room temperature with stirring.

The final preparation was coated on 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 tablets, atomization pressure 0.2 bar, and charge temperature 40°C.

Example 2 [or Comparative Example 9] (separation layer/inner layer of neutralized Eudragit® L30D-55/outer layer of 70:30 mixture of Eudragit® S and starch)
Separation Layer A separation layer containing a mixture of HPMC and 20% polyethylene glycol 6000 (PEG6000) (dry polymer weight basis) was used.

HPMC was dissolved in water under magnetic stirring and then PEG6000 was added to form a coated preparation. The coating preparation was sprayed onto 1200 mg 5ASA cores using a pan coater to achieve a coating amount of 3 mg polymer/cm ² to form a separating layer coated tablet.

The coating parameters were as follows: spraying rate 3.1 g/min/kg tablet core, spraying pressure 0.7 bar, air supply 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 adjusted to pH8. The composition of the inner layer also included 20% TEC (dry polymer weight basis), 1% potassium dihydrogen phosphate (dry polymer weight basis) and 50% talc (dry polymer weight basis). 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® L30D-55 dispersion was added under mechanical stirring and mixed for 15 minutes. The pH was then adjusted to pH 8 with 1M NaOH and the solution continued to stir for 1 hour. Talc was then added to this solution and mixing was continued for an additional 30 minutes to form an internally coated preparation. This inner-coated preparation was coated on the separating layer-coated tablets using a pan coater until the coating amount reached 5 mg polymer/cm ² to obtain inner layer-coated tablets. The total solids 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 solvent). It is the total weight of solids used. One skilled in the art will understand that the dissolution of solids in some solvent does not affect the total solids of the preparation.

The 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 overnight with stirring.

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

  The aqueous Eudragit® S100 solution was added to the starch dispersion to give a starch:Eudragit® S ratio of 30:70. The mixture is stirred for 1 hour, 60% TEC (based on Eudragit® S polymer weight), 50% talc (based on Eudragit® S polymer weight), 13.18% red iron oxide (Eudragit®). ) S polymer weight basis) and 2.27% yellow iron oxide (Eudragit® S polymer weight basis) were added and mixed for another 30 minutes.

The final preparation was sprayed onto the inner layer coated tablet by a pan coater until 7.14 mg 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, atomization pressure 0.4 bar, air supply 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 (PEG6000) (dry polymer weight basis).

The HPMC polymer was dissolved in water under magnetic stirring and then PEG6000 was added to form a separating layer coated preparation. The coated preparation was sprayed on a 1200 mg 5ASA tablet core using a pan coater to achieve a coating amount of 3 mg polymer/cm ² to form a separating layer coated tablet.

The coating parameters were as follows: spray rate 2.7 g/min/kg tablet core, spray pressure 0.7 bar, air supply 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 with pH adjusted to pH 8. The composition of the inner layer also included 20% TEC (dry polymer weight basis), 1% potassium dihydrogen phosphate (dry polymer weight basis), and 50% talc (dry polymer weight basis). Adjust pH with 1 M NaOH until pH 8 is obtained.

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

The coating parameters were as follows: spraying rate 2.7 g/min/kg tablet core, atomization pressure 0.6 bar, air supply 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. Guar gum was dispersed in a mixture of water and isopropanol (50:50) with talc for 15 minutes and then homogenized for 5 minutes. The Eudragit L30D-55 solution was then added to this guar gum dispersion and the resulting mixture was stirred for 20 minutes to form the outer layer coated preparation. The coated preparations were sprayed on the inner-layer coated tablets in a pan coater until the coating amount reached 9.71 total polymer/cm ² (weight ratio dry matter to weight 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: spraying rate 8.0 g/min/kg tablet core, atomization pressure 0.6 bar, air charge 75 m ³ /h/kg tablet core, and product temperature 29°C.

Example 4 [or Comparative Example 10] (separation layer/inner layer of PVA with buffer and base/outer layer of 70:30 mixture of Eudragit® S and FS blend (50:50) and starch. )
Separation Layer The separation layer is composed of polyvinyl alcohol, that is, PVA (Opadry85F).

  The polymer was suspended in water under magnetic stirring so as to achieve a solids concentration of 10% of the final weight of the dispersion, forming a separating layer coated preparation.

  The coated preparation was sprayed onto 1200 mg of 5ASA tablet cores using a pan coating machine to achieve a coating amount of 2% based on the weight of uncoated tablets to form a separating layer coated tablet.

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

Inner Layer The inner layer is composed of polyvinyl alcohol (Opadry85F) and 20% potassium dihydrogen phosphate (Opadry85F standard).

  Potassium dihydrogen phosphate was dissolved in water under magnetic stirring and then polyvinyl alcohol (Opadry85F) 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 the inner layer coated preparation. The coated preparation was sprayed onto the separating layer coated tablets using a pan coater until the coating amount reached 2% based on the weight of the uncoated tablets to form inner layer coated tablets.

The coating parameters were as follows: spraying rate 8.2 g/min/kg tablet core, spraying pressure 0.7 bar, air supply 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.

  An aqueous dispersion of Eudragit® S100 was prepared by dispersing Eudragit® S100 in water under high speed stirring, then portioned with 1N ammonia (formed by diluting a 25% ammonia solution). Neutralized (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 dispersion of this Eudragit® S100/Eudragit® FS30D blend and the mixture was stirred for a further 30 minutes. The mixture contained a 30:70 ratio of starch:Eudragit S100/Eudragit FS30D blend.

  50% talc (based on Eudragit® polymer weight), 13.18% red iron oxide (based on Eudragit® polymer weight) and 2.27% yellow iron oxide (based on Eudragit® polymer weight) Suspension in water was formed under high shear homogenization and this suspension was added to the starch/Eudragit® blend mixture and mixing continued for a further 30 minutes to form the outer layer coated preparation.

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

The coating parameters were as follows: spraying rate 8.5 g/min/kg tablet core, spraying pressure 0.7 bar, air supply 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: spraying 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 (dry polymer weight basis) and 1% (not 10%) potassium dihydrogen phosphate (dry polymer weight basis) coating The preparation is coated on a separate layer-coated 1200 mg tablet using a perforated pan coater, the coating parameters are as follows: spraying rate 2.9 g/min/kg tablet, spraying pressure 0.6 bar, An internal coating layer was formed as in Example 1 except that the air charge was 16.3 m ³ /h/kg tablets and the product temperature was 33°C.

Outer layer 13.18% red iron oxide (Eudragit polymer weight basis) and 2.27% yellow iron oxide (Eudragit polymer weight basis) were suspended in ethanol under high shear homogenization and the suspension was treated with starch and Eudragit. And mixing it for another 30 minutes before adding GMS and coating the coated preparation on 1200 mg 5ASA tablets coated with an inner layer using a perforated pan coater, and The spray coating parameters were as follows: spraying speed 3.1 g/min/kg tablets, spraying pressure 0.4 bar, air supply 21.7 m ³ /h/kg tablets, and product temperature 34° C. An outer coating layer was formed in the same manner as in Example 1 except that.

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 1200 mg of 5ASA tablet cores as described in Example 3.

Inner Layer As described in Example 5, the inner layer was formed on a 1200 mg 5ASA tablet core with a separate coating.

Outer layer Corn starch:butan-1-ol:water ratio of 1:1:about 9.5, starch:Eudragit S ratio of 50:50, and spray parameters as follows: spraying Velocity 7.4 g/min/kg tablets, spray pressure 0.4 bar, air charge 40 m ³ /h/kg tablets, and product temperature 34° C., except as described in Example 5. 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 70:30 mixture of Eudragit® S and starch)
Separation Layer Using a fluidized bed spray coating machine, the coating parameters were as follows: spraying rate 3.1 g/min/kg tablets, spray pressure 0.2 bar, and air supply temperature 40°C. The separating layer was applied to 400 mg 5ASA tablet cores using the procedure described in Example 3.

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

Outer layer 13.18% red iron oxide (Eudragit polymer weight basis) and 2.27% yellow iron oxide (Eudragit polymer weight basis) were suspended in ethanol under high shear homogenization and the suspension was treated with starch and Eudragit. Same as Example 1 except that it was added to the mixture of ##STR1## and mixed for an additional 30 minutes before GMS was added and the outer coating layer preparation was coated on the inner layer coated 400 mg 5ASA tablet core. Then, an outer coating layer was formed. The coating parameters were as follows: spraying rate 11 ml/min/kg tablets, spraying 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 (dry polymer weight basis), 10% glyceryl monostearate (dry polymer weight basis), and 40% polysorbate 80 (GMS weight basis). Briefly, triethyl citrate was dissolved in 96% ethanol, then Eudragit®-S100 was dissolved under mechanical stirring and mixing was continued for 1 hour.

  GMS was added in the form of a dispersion prepared at a concentration of 10% w/w. Polysorbate 80 (40%, GMS weight basis) was dissolved in distilled water and then 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 at room temperature with stirring.

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 amount of 5 mg polymer/cm ² . The coating parameters were as follows: spraying rate 16 ml/min/kg tablets, spraying 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. The 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 cooled overnight with stirring. The% solids of the cooled preparation was calculated on the basis of the final weight of the dispersion (taking into account evaporation during heating).

  The organic Eudragit®-S solution was prepared by dissolving Eudragit®-S100 in 96% ethanol under rapid stirring. The final solution contained about 6% polymer solids. The starch dispersion was added dropwise to the Eudragit®-S100 solution, resulting in a starch:Eudragit S ratio of 30:70. 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%, GMS weight basis) was dissolved in distilled water and then 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 at room temperature with stirring.

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

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

  The GMS dispersion was prepared at a concentration of 10% w/w. Polysorbate 80 (40%, GMS weight basis) was dissolved in distilled water and then 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 at room temperature with stirring.

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

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

  The GMS dispersion was prepared at a concentration of 10% w/w. Polysorbate 80 (40%, GMS weight basis) was dissolved in distilled water and then 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 at room temperature with stirring.

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® A coating amount of ™)-S polymer/cm ² was obtained. The coating parameters were as follows: spraying rate 16 ml/min/kg tablets, spraying pressure 0.2 bar, and air supply temperature 40°C.

Comparative Example 4 (separation layer/inner layer of Eudragit® L30D-55/outer layer of a 70:30 mixture of Eudragit® S/starch)
Separation Layer The separation layer is formed from a mixture of HPMC and 20% polyethylene glycol 6000 (PEG6000) (dry polymer weight basis).

The polymer was dissolved in water under magnetic stirring and then PEG6000 was added to form a separating layer coated preparation. The coated preparation was sprayed onto 1200 mg 5ASA tablet cores using a pan coater to give a coating amount of 3 mg polymer/cm ² to form a separating 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 comprises 20% TEC (dry polymer weight basis) and 50% talc (dry polymer weight basis).

Eudragit L30D-55 was diluted with distilled water, then TEC and talc suspension was added and mixed for 1 hour to form an inner layer coated preparation. The coated preparation was coated on a separating layer coated tablet using a pan coater 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: spraying rate 6.125 g/min/kg tablet core, spraying pressure 0.6 bar, air supply 100 m ³ /h/kg tablet core, and product temperature 33°C.

Outer Layer The outer layer is made from a mixture of an aqueous starch dispersion and an 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 overnight with stirring.

  Eudragit® S100 was dispersed in water under rapid stirring and then partially (15-20%) neutralized with 1N ammonia (obtained by diluting a 25% ammonia solution) to form aqueous Eudragit®. A redispersion of Trademark) S was prepared.

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

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

Comparative Example 5 (separation layer/inner layer of Eudragit L30D-55/outer layer of a 1:3 mixture of Eudragit L30D-55/guar gum).
Separation Layer A separation layer is applied from a mixture of HPMC and 20% polyethylene glycol 6000 (PEG6000) (dry polymer weight basis).

The HPMC polymer was dissolved in water under magnetic stirring and then PEG6000 was added to form a separating layer coated preparation. The coated preparation was sprayed onto 1200 mg of 5ASA tablet cores using a pan coater to achieve a coating weight of 3 mg polymer/cm ² to form a separating layer coated tablet.

The coating parameters were as follows: spray rate 2.7 g/min/kg tablet core, spray pressure 0.7 bar, air supply 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 included 20% TEC (dry polymer weight basis) and 50% talc (dry polymer weight basis).

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 coated preparation. The coated preparation was coated on a separating layer coated tablet using a pan coater 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, atomization pressure 0.6 bar, air supply 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 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 this guar gum dispersion and stirred for 20 minutes to form the outer layer coated preparation. The coated preparation was sprayed on 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 tablets were dried at 40° C. for 2 hours to form tablets of Comparative Example 5.

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

Comparative Example 6 (Separating 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 (Opadry85F) was suspended in water under magnetic stirring to achieve a solids concentration of 10% based on the final weight of the suspension, forming a separating layer coated preparation.

  The coated preparation was sprayed onto 1200 mg of 5ASA tablet cores using a pan coater to achieve a coating amount of 2% based on the weight of uncoated tablet to form a separating layer coated tablet.

The coating parameters were as follows: spray rate 6.45 g/min/kg tablets, spray pressure 0.6 bar, air charge 62.5 m ³ /h/kg tablet cores, 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 under stirring overnight.

  By dispersing Eudragit® S100 in water under rapid stirring and then partially (15-20%) neutralizing with 1N 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 dispersion of the Eudragit® S100/Eudragit® FS30D blend and the mixture was stirred for a further 30 minutes. The mixture contained a 30:70 ratio of starch:Eudragit S100/Eudragit FS30D blend.

  50% talc (based on Eudragit® polymer weight), 13.18% red iron oxide (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 another 30 minutes to form an outer layer coated preparation.

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

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

Comparative Example 7 [or Example 8] (separation layer/starch: Eudragit S (30:70) outer layer)
Separation Layer Separation layer coated 1200 mg 5ASA tablet cores were 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 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, then cooled with stirring overnight. The% solids of the cooled preparation was calculated on the basis of the final weight of the dispersion (taking into account 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 obtain 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% red iron oxide (based on Eudragit polymer weight) and 2.27% yellow iron oxide (based on Eudragit polymer weight) were suspended in ethanol under high shear homogenization and the suspension was a mixture of 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%, GMS weight basis) was dissolved in distilled water and then 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 at room temperature with stirring. The final preparation was coated on a separating layer coated tablet core using a perforated pan coater 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 tablets, spray pressure 0.4 bar, air charge 21.7 m ³ /h/kg tablets, and product temperature 34°C.

Comparative Example 8 (separation layer/starch: Eudragit S (30:70) outer layer)
Separation Layer Separation layer coated 1200 mg 5ASA tablet cores were 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.

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

The outer layer coated preparation was sprayed on the inner layer coated 1200 mg 5ASA tablet cores 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 cores, spray pressure 0.4 bar, air supply 100 m ³ /h/kg tablet cores, product temperature 35°C.

Drug Release Test #1-Effect of pH Only In vitro dissolution studies were performed with a USP Type II instrument using a paddle speed of 50 rpm and a media temperature of 37±0.5°C. The 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 infusion of 5% CO ₂ /95% O ₂ . Absorbance measurements were taken every 5 minutes at an absorption wavelength of 301 nm in HCl and 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 NaHCO ₃ . Only the measurements taken at 15 minute intervals are shown in FIG.

Fermentation assay used to test the drug release test #2-pH 6.8 faecal slurry formulation was as described in Hughes et al. And in vitro fermentation of β-glucan derived from barley)”, 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 stools (3 different donors) 40% w/w in phosphate buffered saline (pH 6.8). Was mixed in a 1:1 ratio with the fecal slurry prepared by homogenizing at a concentration of. The final concentration of the prepared fecal slurry (diluted with basal medium) was 20% w/w. Donors had not received antibiotic treatment for at least 3 months prior to conducting this study with slurries.

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

Drug Release Test #3-pH 6.5 Fecal Slurry Similar to Drug Release Test #2, but the pH of the fecal slurry was maintained at pH 6.5.

Drug Release Test #4-Hanks Buffer pH 6.8 Dissolution In vitro dissolution studies were performed with a USP Type II instrument using a paddle speed of 50 rpm and a media temperature of 37±0.5°C. The 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 infusion of 5% CO ₂ /95% O ₂ . Absorbance measurements were taken every 5 minutes at an absorption wavelength of 301 nm in HCl and 330 nm in Hanks buffer pH 6.8. The composition per liter of Hank's buffer is 0.06 g of KH ₂ PO ₄ , 0.06 g of Na ₂ HPO ₄ .2H ₂ O, 8.0 g of NaCl, 0.4 g of KCl, 0.2 g of MgSO _4. 7H ₂ O, 0.139 g CaCl ₂ .2H ₂ O and 0.350 g NaHCO ₃ .

Drug release test #5-Hank's buffer pH 6.8 after imitation fed/fasted state
An in vitro dissolution study was conducted on a USP Type II instrument using a paddle speed of 50 rpm and a media temperature of 37±0.5°C. When simulating the "fasted" condition, the study was conducted in the manner described in Drug Release Test #4.

  When mimicking the "fed" state, tablets were first tested in fed state mimicking 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 Jantrid et al. (2008).

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

Results The results shown in Figures 1 to 4 demonstrate that the coated tablets according to the invention are significantly superior to the tablets of the comparative example. In this regard, the tablets according to the invention have a pH (pH 7.4) higher than the pH threshold (pH 7) of the second polymeric material and a pH lower (pH 6.8 or pH 6. Accelerated drug release is observed in both 5).

  The aqueous solution at pH 7.4 (drug release test #1; FIG. 1) did not release 5ASA from any of the test tablets during the 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 happened significantly earlier than was the case from WO2007/122374, which is a site-specific colon release formulation described in US Pat. The release profile of 5ASA from Example 1 closely follows that of Comparative Example 3. This similar release profile can be explained by the similarity of the formulations themselves (Example 1 differs only by the presence of starch in the outer coating) and the lack of colonic enzymes that digest starch in the surrounding medium. .

  In the fecal slurry at pH 6.8 (drug release test #2; FIG. 2), the initial release of 5ASA from the tablets of Example 1 occurred after 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 only a substantial release from the tablets of Comparative Example 3 occurred after 6 hours. Furthermore, the tablets of Comparative Example 2 showed complete release after about 5 hours and the tablets 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 colonic conditions from tablets having an outer layer containing a mixture of starch and EudragitS. 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 pH 6.5 (drug release test #3; FIG. 3), the initial release of 5ASA from the tablets of Example 1 occurred after about 2 hours, while the initial release from the comparative tablets occurred at about 8. It was after hours. Furthermore, even though the pH of the surrounding medium was significantly below 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 tablets of Comparative Example 3 was less than 10% after 24 hours. These results show that the presence of starch in the outer layer releases a significant amount of active agent when exposed to colonic enzymes, even though the pH of the surrounding medium is well below the pH threshold of the second polymeric material. Is possible.

  The person skilled in the art will notice that not all of the active substance has been released after 8 hours despite the loss of the integrity of the coating of Example 1. The inventors believe that this is because the test is in vitro. The tablets, in vivo, are exposed to the mechanical pressure exerted as a result of colonic motility, which should contribute to the complete disintegration of the tablets.

  We also observed that less than 10% of 5ASA was released from the tablets of Example 1 when exposed to an aqueous solution of pH 6.8 for 24 hours (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 the colonic enzyme in the surrounding medium is necessary and is resistant to the conditions of the small intestine. It demonstrates that premature drug release is effectively prevented.

  Accelerated drug release under colonic conditions also includes neutralized Eudragit® L30D-55 in the inner layer and starch in the outer layer when compared to a comparable formulation in which the inner layer is not neutralized. Also observed is a formulation of the invention comprising a 30:70 mixture of /Eudragit® S100. As shown in FIG. 5, no release is observed from any of the formulations when exposed to 0.1 M HCl for 2 hours. However, upon exposure to Krebs buffer at pH 7.4, an initial release from the formulation according to the invention (Example 2) is observed after 30 minutes, whereas an initial release from the comparative formulation (Comparative formulation 4) is up to about 150 minutes. It won't happen. A similar acceleration of initial release was observed when these formulations were exposed to a fecal slurry at pH 6.5, with the initial release from tablets with a non-neutralized inner layer (Comparative Example 4) occurring after about 4 hours. In contrast, the initial release from tablets with a neutralized inner layer (Example 2) occurs after about 2 hours (Figure 6).

  The formulations according to the invention also demonstrate distinct advantages over the formulations exemplified in US Pat. No. 5,422,121. In this regard, we have shown that tablet cores were first coated with an inner layer of Eudragit® L30D and then with an outer layer of a 1:3 mixture of Eudragit® L30D and guar gum, US The formulation of Example 2 of Japanese Patent No. 5422121 (Patent Document 11) was reproduced as faithfully as possible (Comparative Example 5), and the drug release from this formulation under different conditions was performed according to an embodiment of the present invention ( The inner layer according to Example 3) was compared to a comparable formulation in which Eudragit® L30D was completely neutralized. Under all colon conditions tested, initial drug release was accelerated with formulations with neutralized inner layers (see Figures 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 in which the inner layer contained neither base nor 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, provided that In embodiments where the inner layer contains base and buffer, it was demonstrated that the initial release can be reduced from 4 hours to 3 hours when exposed to Grubbs buffer (FIG. 10).

  Incomplete drug release was observed in some of the test experiments after 10 hours in colonic conditions (see especially Figures 8 and 9). The present inventors have found that this observation indicates that high dose (1200 mg) tablets were tested in these experiments and that the volume of buffer (Krebs and Hanks buffer) used was low or of the fecal slurry used. It should be pointed out that, due to the limited volume (210 ml), this may be explained by the fact that the sink condition may not have been reached.

  In contrast, the tablets of Examples 5-7 do not show significant release early when exposed to simulated fed state conditions over the test period (Figures 11, 14, and 15). Furthermore, the tablets of Example 7 do not show a significant "dietary effect" when exposed to simulated fed and fasted conditions for 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 the simulated fed and fasted states are very similar (Example 7; Figure 15) or almost identical (Example 6; Figure 14).

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

  Therefore, it can be seen that the delayed release formulation according to the present invention is significantly superior to similar formulations.

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

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

Claims (27)

A method of making an oral delayed release drug formulation for delivering a drug to the colon, said method comprising:
Forming a core containing the drug,
The core using an inner layer coated preparation comprising (i) a third polymeric material that is a nonionic polymer soluble in intestinal fluid or gastrointestinal fluid, and (ii) a buffering agent that is an inorganic salt in a solvent system. To form an intermediate coated core,
Polysaccharides selected from the group consisting of starch, amylose, amylopectin, chitosan, chondroitin sulphate, cyclodextrin, dextran, pullulan, carrageenan, scleroglucan, chitin, curdlan and levan in an aqueous medium susceptible to attack by colonic bacteria. And a second polymeric material that is an enteric film-forming polymer having a pH threshold of pH 6.5 or greater in an organic medium, the second polymeric material being a second polymeric material of the first polymeric material. Forming an outer layer coated preparation having a weight ratio to polymeric material of at least 25:75 and not more than 60:40,
Coating the intermediate coated core with the outer layer coated preparation to form an outer layer coated core,
Method. By covering the core directly with separation layer coating preparation to form a separation layer covering the core, by coating directly with then the inner layer coating preparations this, to form the intermediate coating cores, The method of claim 1.   The method of claim 1 or claim 2, wherein the solvent system of the inner layer coated preparation is aqueous.   4. The method according to any of claims 1 to 3, wherein the pH of the inner layer coated preparation is adjusted with a base to be pH 7.5 to pH 10.   5. The method of claim 4, wherein the pH of the inner layer coated preparation is adjusted with a base to be pH 7.5-pH 8.5.   6. The method of claim 4 or claim 5, wherein the pH of the inner layer coated preparation is adjusted to pH 8 with a base.   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 7. The method according to any one of Items 1 to 6.   The method according to any one of claims 4 to 7, wherein the base is a hydroxide.   9. The method according to any of claims 4-8, wherein the base is sodium hydroxide. The organic medium is, C ₁ -C ₄ alcohol, methyl glycol, butyl glycol, acetone, is selected from the group consisting of methyl glycol acetate, and mixtures thereof The method of any of claims 1-9.   11. The method according to any of claims 1-10, wherein the organic medium comprises ethanol. The method according to any of claims 1 to 11, wherein the organic medium is 85-98 v/v % ethanol. The organic medium contains 2% to 10% by weight of polymer solids relative to the final weight of the dispersion, the method according to any one of claims 1 to 12. 14. Method according to any of claims 1 to 13, wherein the organic medium contains 6% by weight of polymer solids, based on the final weight of the dispersion . Wherein the aqueous medium is water, C ₁ -C ₆ alcohol, and is selected from the group consisting of mixtures A method according to any one of claims 1 to 14. The aqueous medium is a mixture of _water, C 1 -C ₆ alcohol, and preferably butan-1-ol, The method according to any one of claims 1 to 15. 17. The method according to claim 16, wherein the weight ratio of water to alcohol in the mixture is at least 5:1, preferably 11:1. 18. The method of any of claims 1-17, wherein a weight ratio of the first polymeric material to the second polymeric material is present in the outer layer at 25:75 to 35:65. 19. The method of claim 18, wherein a weight ratio of the first polymeric material to the second polymeric material is present in the outer layer at 30:70.   18. The method of any of claims 1-17, wherein a weight ratio of the first polymeric material to the second polymeric material is present in the outer layer at 40:60 to 60:40.   21. The method of claim 20, wherein a weight ratio of the first polymeric material to the second polymeric material is present in the outer layer at 50:50. The method according to any of claims 1 to 21 , wherein the first polymeric material is starch. Said second polymeric material, the molecular weight of 125,000 g / mol, 1: 2 acid: esters ratios, and poly (methacrylic acid / methyl methacrylate) copolymer with a pH threshold of pH 7, according to claim 1 to 22 The method described in either. The nonionic polymer of the inner layer is methyl cellulose (MC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), poly(ethylene oxide)-graft-polyvinyl alcohol, polyvinylpyrrolidone (PVP), polyethylene glycol ( PEG), and is selected from the group consisting of polyvinyl alcohol (PVA), the method of any of claims 1-23. The buffering agent is a phosphoric acid salt A process according to any one of claims 1-24. Wherein the buffer is potassium dihydrogen phosphate A method according to any of claims 1 to 25. The buffering agent is present in the inner layer in an amount of 0.1 wt% to 20 wt% based on the dry weight of the third polymeric material A method according to any one of claims 1 to 26.

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