TWI422398B - Colonic drug delivery formulation - Google Patents

Description

Colonic formula

The present invention relates to a delayed release formulation having a core comprising a drug and a sustained release coating, and more particularly to a sustained release formulation for releasing the drug in the colon.

Targeted administration of the drug to the colon can be used as a means of achieving local or systemic treatment. The colon is susceptible to many diseases, including inflammatory bowel disease, irritable bowel syndrome, constipation, diarrhea, infection and cancer. In such cases, targeted administration of the colon can achieve maximum therapeutic efficacy. The colon can also be used as a portal for drugs into the systemic circulation. For colonic administration, various formulations have been developed, including prodrugs and formulated dosage forms, the latter being more widely recognized because the concept has been proven to be applicable to other drugs.

The use of natural complex polysaccharides as carrier materials allows the higher number of bacteria in the colon to be fully utilized in the development of colonic dosage forms, and the natural complex polysaccharides constitute the substrate for many enzymes of colonic bacteria. These natural substances remain intact in the upper gastrointestinal tract, but are digested when entering the colon. Current related research includes amorphous amylose, pectin, chitosan and galactomannan.

Amorphous amylose is resistant to digestion by the enzymes of the upper gastrointestinal tract. However, the amorphous amylose is fermented in the colon by the action of α-amylase, which is produced by more than half of the 400 bacteria inherent in the colon.

In the administration of the colon to the colon by the bacterial enzyme method, an important attraction of using the polysaccharide is that the substance used is food grade, and therefore it is safe to use in vivo. These polysaccharides are typically used as a matrix carrier as a coating or incorporated into a core material, and when the polysaccharide enters the colon, it is digested by bacterial enzymes in the colon, resulting in release of the drug load. An example of such a formulation is an amylose coating used in EP-A-0343993 (British Technology Group International, Inc.).

However, a major limitation of this natural substance is that it over-expands in aqueous media, resulting in drug loading being filtered out in the upper gastrointestinal tract. To circumvent this problem, the natural materials are used in combination with a water impermeable substance (for example, amorphous amylose is mixed with a water insoluble cellulose polymer). However, the problem with such modifiers/mixtures is how to find the proper balance between hydration and hydrophilicity, thereby preventing improper drug release in the upper gastrointestinal tract, but at the same time allowing the enzyme to be close to the polysaccharide and ensuring the drug Released at the appropriate rate in the colon.

EP-A-0502032 (British Technology Group, Inc.) discloses an attempt to solve the problem of excessive expansion of amylose. It uses an outer coating comprising a tablet of the active compound, which comprises a film-forming cellulose or acrylate polymer and amorphous amylose. One embodiment is to first coat the active compound with an amylose inner coating and then additionally coat it with a coating of the outer layer of cellulose or acrylate polymer. Another embodiment is an outer coating having a mixture of amylose and cellulose or acrylate polymers. It is clear from the reference that, under normal circumstances, the degradation of the cellulosic material in vivo is not dependent on the pH value, and it is preferred that the above is also applicable to the acrylate material. Each of the examples disclosed in the references is a cellulose or acrylate polymer that is not pH dependent.

The Journal of Controlled Release article (Milojevic et al; 38; (1996); 75-84) reports on the results of a study on mixing a series of insoluble polymers with amylose to control amylose expansion. A series of copolymers based on cellulose and acrylate were evaluated and commercially available ethyl cellulose (Ethocel) was found. ) can effectively control the expansion. Another single coat of the study was a mixture of amylose and two pH-independent acrylic polymers, namely Eudragit RS and RL, but found that this coating does not present equally effective results. Eudragit A pH-dependent soluble coating of L100 is also used, but only in a multi-layer system that includes an inner layer coating of amylose and then Eudragit The outer layer of L100 is coated with a bioactive substance.

WO-A-99/21536 (British Science and Technology Group International Co., Ltd.) further discloses a coating composition based on amylose. The coating composition comprises a mixture of amylose and a water insoluble film forming polymer formed from a water insoluble cellulose or an acrylate polymer. As in EP-A-0502032, it is clearly indicated in the literature that the degradation of cellulosic material in vivo is generally not dependent on pH, and it is preferred that the above applies equally to acrylate materials. There appears to be a typographical error in the PCT specification because the preferred form of acrylate material mentioned is "Eudragit L, whose degradation does not depend on pH." It is generally believed that this refers to "Eudragit ^® RL", and its degradation does not depend on pH. It is not possible here to refer to Eudragit ^® L because the degradation of this polymer depends on the pH.

WO-A-99/25325 (British Technology Group International, Inc.) also discloses a sustained release coating comprising amylose and (preferably) ethylcellulose or an acrylate polymer, The degradation of the acrylate polymer does not depend on the pH. The coating composition also includes a plasticizer, and the method has particular application in the formulation of a dosage form comprising an active substance which becomes unstable at temperatures above 60 ° C and which is at a ratio of 60 °C is formed at a low temperature. It should be noted that this reference also contains typographical errors associated with the aforementioned Eudragit ^® L.

The inventors noted that the formulation disclosed in the British Science and Technology Group reference discussed above was applied to coated amylose rather than starch, and that the formulation continued to release part of the intestine.

A special sustained release coating of biologically active prednisolon sodium metasulphobenzoate is disclosed in WO-A-03/068196 (Alizyme Pharmaceutical Co., Ltd.), which comprises a glass. Glassy amylose, ethyl cellulose and dibutyl sebacate.

GB-A-2367002 (British Sugar PLC) discloses the use of polysaccharides other than amorphous amylose in a sustained release coating. Examples include guar gum, hedgehog gum, tragacanth and xanthan gum. The microparticles of the above polysaccharide are dispersed in a water-insoluble film-forming polymer matrix formed of, for example, a cellulose derivative, an acrylic polymer or a lignin.

WO-A-01/76562 (Tampereen Patenttitoimisto Oy) discloses an oral pharmaceutical formulation comprising a drug and a chitosan (a polysaccharide obtained from chitin) which controls drug release. The drug and the chitosan are mixed by mechanical force into a homogeneous phase mixture, and after the granulation, the tablet can be prepared as needed. An enteric polymer (e.g., a copolymer of methacrylic acid) may be used during the granulation process or the particles may have a porous enteric coating.

WO-A-2004/052339 (Salvona LLC) discloses a pH-dependent drug delivery system which is a free-flowing powder of solid water-repellent nanospheres, the nanospheres comprising a package A drug coated in a pH-sensitive microsphere. The nanospheres are formed by combining a drug with a waxy substance, and the pH sensitive microsphere is made of a pH sensitive polymer (eg Eudragit) The polymer) is formed by combining with a water sensitive substance such as a polysaccharide. However, the inventors believe that the very small particle size in this reference may not actually release the bioactive core beyond the position of the stomach or duodenum.

An article in the European Journal of Pharmaceutical Sciences (Akhgari et al; 28; March 2006; 307-314) reports the use of specific polymethacrylate polymers and other substances to control the expansion of inulin. The findings of the survey. The tested polymethacrylate polymer has Eudragit RS; Eudragit RL; Eudragit RS and Eudragit RL 1:1 mixture; Eudragit FS; and Eudragit RS and Eudragit S 1:1 mixture. The results showed a sustained release polymethacrylate containing inulin (Eudragit) RS and Eudragit The swelling profile of the polymer composition of RL; a polymer that is insensitive to pH is indicative of its suitability as a coating for colonic release. However, other results have been shown to include inulin and Eudragit FS or Eudragit RS and Eudragit The polymer composition of a 1:1 mixture of S (a pH-dependent polymer) is not suitable due to the presence of an undesirable expansion profile.

US-A-5422121 (R Hm GmbH) discloses an oral pharmaceutical dosage form comprising at least one active ingredient encapsulated in a shell material comprising a polysaccharide body decomposable in the colon. The outer shell material comprises a film forming polymer mixed with the polysaccharide body. The weight ratio of the polysaccharide to the film-forming polymer is between 1:2 and 5:1, preferably between 1:1 and 4:1. Examples of suitable polysaccharides include those which can be decomposed by glycosidic enzymes. Polysaccharides containing substantial amounts (preferably from about 20 wt% to 100 wt%) of galactose and mannose units are particularly suitable for mating with suitable locust bean gum and guar gum. Preferred film-forming polymers include pH-independent acrylate polymers (insoluble throughout the gastrointestinal tract) and pH-dependent acrylate polymers (insoluble in gastric juice, but at pH values greater than or equal to 5.5 is soluble in intestinal fluid). In this reference, an example of guar gum and Eudragit RL 30 D (4:1 ratio), Eudragit L 30 D (3:1 ratio), or Eudragit A mixture of S 100 (2.5:1 ratio) is used as a tablet coating.

European Journal of Pharmaceutical Sciences article (Krogars et al; 17; ( 2002); 23-30) discloses the use of film-coated Hylon ^TM VII as pastilles comprising the drug (theophylline) of use. The dissolution rate of the tablet in an acidic medium is fast, with 75% of the drug being dissolved within 15 minutes. The second film forming polymer is not included in the coating.

According to a first aspect, the present invention provides a sustained release pharmaceutical formulation comprising a core having a core and a coating for the core, the core comprising a drug, and the coating comprising a first substance and a second a mixture of substances, the first substance being susceptible to attack by colonic bacteria having a solubility threshold equal to or greater than 5, wherein the first substance comprises a starch selected from the group consisting of starch and amylose , amylopectin, chitosan, chondroitin sulfate, cyclodextrin, dextran, pullulan, carrageenan, sclerotium glucan, chitin, colloidal dextran and fructan Groups of polysaccharides.

The first substance comprises a polysaccharide body, which preferably contains a plurality of glucose units. The polysaccharide is preferably starch, amylose or amylopectin, most preferably starch.

A surprising finding is that unfavorable expansion of substances that are susceptible to attack by colonic bacteria (such as amylose) can be controlled using pH-dependent substances at pH values equal to 5 or When it is greater than 5, it will dissolve. Additionally, the inventors have unexpectedly discovered that oral pharmaceutical formulations containing a greater proportion of amylopectin coating can also release the drug in the colon.

A further technical advantage of the present invention is that (e.g., as compared to the formulation disclosed in WO-A-01/76562) substantially no drug is released for an extended period of time (i.e., when the coating is being dissolved), after which The drug will be released quite quickly. This is in contrast to homogeneous tablets in which the drug is gradually released from the beginning, rather than being delayed first, followed by a pulsatile release.

Those skilled in the art will be able to use techniques including partial general knowledge to determine whether a substance is susceptible to attack by colonic bacteria. For example, a predetermined amount of the specified substance is exposed to a sample containing the enzyme of the bacteria found in the colon, and then the weight of the specified substance is measured as a function of time.

The polysaccharide is preferably a starch. Starch is usually extracted from natural sources such as cereals, legumes and tubers. Suitable starches for use in the present invention are typical food grade starches, including rice starch, wheat starch, cereal (or corn) starch, pea starch, potato starch, sweet potato starch, tapioca starch, sorghum starch, sago starch, And bamboo 芋 starch. The use of corn starch will be exemplified as follows.

Starch is actually a mixture of two different polysaccharides (ie, amylose and amylopectin). The ratio of the two polysaccharides in different starches is different. Most natural (unmodified) corn starch has from about 20% to about 30% by weight of amylose, with the remainder being at least substantially composed of amylopectin. Starches suitable for use in the present invention typically contain at least 0.1 wt% (e.g., at least 10% or 15%), preferably at least 35 wt%, of amylose. The "high amylose content" starch refers to a starch in which at least 50% by weight of amylose is contained. Particularly suitable starches have an amylose content of between about 65 wt% and about 75 wt%, such as 70 wt% amylose.

In the starch suitable for use in the present invention, the amylopectin content may be 100%, and the more typical amylopectin content is between about 0.1 wt% and about 99.9 wt%. "low amylose content" starch, that is, starch containing no more than 50% by weight of amylose, and at least 50% by weight of amylopectin (for example, containing up to 75 wt%, or even 99 wt%) Amylopectin) is suitable. The starch may be, for example, unmodified waxy corn starch. This starch typically contains about 100% amylopectin. "Low amylose content" starch is not considered suitable because starch with low amylose content is typically degraded by pancreatic enzymes in the small intestine. Preferably, the starch contains no more than 50% by weight of amylopectin. Particularly suitable starches contain from about 25 wt% to about 35 wt% amylopectin, for example, an amylopectin content of about 30 wt%.

Those skilled in the art will be able to determine the relative proportions of amylose and amylopectin in any given starch. For example, the ratio of amylose to amylopectin in starch can be determined by using near-infrared spectroscopy ("NIR") using a calibration curve obtained from a mixture of two components of known amounts produced in the laboratory. In addition, starch can be hydrolyzed to glucose using amyloglucosidase. The result of a series of phosphorylation and oxidation reactions catalyzed by enzymes is the formation of a reduced form of nicotine indoleamine adenine dinucleotide phosphate ("NADPH"). The amount of NADPH formed has a stoichiometric ratio to the initial glucose content. Suitable test kits for this procedure are readily available (eg R-Biopharm GmbH, Germany). Another useful method involves digesting the coating with a bacterial enzyme (e.g., alpha-amylase) to produce a short chain fatty acid that can be quantified by a gas phase/liquid phase chromatograph using a capillary column. .

Although amorphous amylose may also be used in the present invention, preferred starches contain a glassy form of amylose.

Preferred starches are "off-the-shelf" starches, i.e., in the present invention, the starches need not be previously processed prior to use. Particularly suitable examples of starch "high amylose starch" includes Hylon ^TM VII (National Starch, Germany) or Eurylon ^TM 7 (Roquette, Lestrem, France) or Amylogel 03003 (Cargill, Minneapolis, USA), all the above-mentioned starches are contained An example of about 70 wt% amylose corn starch.

The invention encompasses the use of a second substance which will dissolve in a pH dependent manner. The second substance has a "pH threshold" below which the second substance has insolubility, and is soluble in the pH threshold or above the pH threshold. The pH of the surrounding medium can initiate dissolution of the second substance. As such, once the pH of the surrounding medium reaches (or exceeds) the pH threshold, the second material dissolves. Thus, no (or essentially no) second substance will dissolve below the pH threshold. Once the pH of the surrounding medium reaches (or exceeds) the pH threshold, the second substance becomes soluble. "Insoluble" means that at a given pH, 1 g of the second material requires more than 10,000 ml of solvent (peripheral medium) to dissolve. "Soluble" means that at a given pH, 1 g of the second substance needs to be 10,000 ml or less, preferably 5,000 ml or less, more preferably 1,000 ml or less, and still more preferably 100 ml or less. (The surrounding medium) can dissolve. The surrounding medium preferably refers to a medium in the gastrointestinal tract, such as gastric juice or intestinal fluid. Alternatively, the surrounding medium may be an in vitro equivalent of the medium in the gastrointestinal tract.

The normal pH of gastric juice is generally in the range of 1 to 3. The second substance is insoluble at a pH of 5 or less, and is soluble at a pH of 5 or above, and therefore, the second substance is insoluble in gastric juice. Such a substance can be considered an "enteric" substance.

The second substance is soluble at pH 5 or above pH 5, for example in intestinal fluid. The pH of the intestinal fluid gradually increases from about 6 in the duodenum to about 7 to 8 in the colon. The second substance is preferably insoluble at a pH of 6.5 or less (soluble at a pH of 6.5 or a pH of 6.5 or more), more preferably at a pH of 7 or less (dissolvable at a pH of 7 or above pH 7) ).

The pH threshold at which the substance becomes soluble can be determined by a simple titration technique which is a general knowledge to those skilled in the art.

The second material is a typical film forming polymer such as an acrylate polymer, a cellulose polymer or a polyethylene based polymer. Examples of suitable cellulosic polymers include cellulose acetate phthalate ("CAP"), cellulose acetate trimellitate ("CAT"), and hydroxypropyl methylcellulose acetate succinate. Examples of suitable polyethylene-based polymers include polyvinyl acetate phthalate ("PVAP").

The second substance is preferably a copolymer of (meth)acrylic acid and a C _1-4 alkyl (meth)acrylate, for example, a copolymer of methacrylic acid and methyl methacrylate. Such a polymer is known as a poly(methacrylic acid/methyl methacrylate) copolymer. Suitable examples of such copolymers are generally anionic and are not sustained release polymethacrylates. The ratio of carboxylic acid functional groups to methyl ester functional groups in these copolymers ("acid:ester ratio") determines at what pH the copolymer is dissolved. The acid:ester ratio can range from about 2:1 to about 1:3, such as about 1:1, or preferably about 1:2. The preferred anionic copolymer typically has a molecular weight (MW) of between about 120,000 and 150,000, preferably about 135,000.

Preferred anionic poly(methacrylic acid/methyl methacrylate) copolymers include Eudragit L (acid: ester ratio of about 1:1; molecular weight of about 135,000; pH threshold of about 6.0); Eudragit S (acid: ester ratio of about 1:2; molecular weight of about 135,000; pH threshold of about 7); and Eudragit FS (methyl acrylate/methyl methacrylate/methacrylic acid polymer; acid:ester ratio of about 1:10; molecular weight of about 220,000; pH threshold of about 7).

The second substance may be a copolymer of methacrylic acid and ethyl acrylate. Eudragit L100-55 methacrylic acid/ethyl acrylate copolymer; acid:ester ratio of about 1:1; molecular weight of about 250,000; pH threshold of about 5.5 is suitable. The Eudragit The copolymer is produced and/or distributed by Degussa AG of Darmstadt, Germany.

A mixture of film-forming polymers can be suitably used. Examples of suitable mixtures may include a mixture such as Eudragit L and Eudragit A 1:1 mixture of S. However, it is preferred to use a special film-forming polymer such as a copolymer of methacrylic acid/methyl methacrylate alone.

Eudragit It is more preferable to use S as the second substance alone.

In a preferred embodiment, it is found that a mixture of two suitable polymers in a suitable ratio can be applied to the core to coat the outer film, which can at least minimize and substantially eliminate the drug in the stomach and Release of the small intestine. Subsequent release of the drug in the colon site is thought to occur by binding active physiological sensation: that is, by the second substance (especially Eudragit Dissolution of S), and digestion of the first substance (such as starch or amylose).

The ratio of the first substance to the second substance is typically less than 99:1, and in some cases may reach 50:50. Typically, the ratio will reach 35:65, preferably from 15:85 to 35:65, such as 15:85 to 30:70. The inventors have found that the ratio of the first substance to the second substance is from about 25:75 to about 35:65, for example about 30:70, which is particularly suitable for targeted release of the drug to the colon, especially when the first substance is starch. And the second substance is Eudragit S time. The mixture of the first substance and the second substance is preferably a substantially homogeneous mixture.

A conventional excipient such as a film-forming plasticizer (for example, triethyl citrate); and an anti-adhesive agent (for example, glyceryl monostearate) may be in the form of a polymer-coated preparation, as needed. The final composition accounts for 30% of the total weight.

The thickness of the particle coating is typically from about 10 μm to about 150 μm. However, the thickness of a particular coating will depend on the composition of the coating. For example, the thickness of the coating is proportional to the amount of polysaccharide in the coating. In some embodiments, the coating comprising a ratio of about 30:70 starch content of the high amylose starch and Eudragit ^TM S, the coating thickness may be from about 70 μm to about 130 μm, preferably from about 90 μm to about 110 Mm. The thickness (in μm) of a given coating composition is independent of the size of the core.

The thickness of the coating can also be measured by the "theoretical weight gain" (TWG) of the coating formulation. The TWG of this formulation depends on a number of factors, including the composition of the coating and the size of the core to be coated. For example, in some embodiments, the core is a small lozenge (e.g., a diameter of about 8 mm), and the coating comprises starch content of the high amylose starch and Eudragit ^TM S (e.g. a ratio of about 30:70), the TWG is typically The ground is from about 4% to about 12%, such as from about 5% to about 10%, preferably from about 8% to about 9%. In some embodiments, the core is a pellet (e.g., about 1 mm in diameter) having the same coating, the TWG being from about 15% to about 35%, such as from about 20% to about 30%, preferably about 25%.

The above description of the coating comprises a mixture of the first substance and the second substance, which is meant to exclude the known multi-layered pharmaceutical dosage form (disclosed in the above-mentioned example of Milojevic et al.) wherein the active core of the multi-layered pharmaceutical dosage form is first coated An inner layer of amylose coating, followed by a layer of Eudragit The outer layer of L100 is coated. Such a multi-layer pharmaceutical dosage form does not include starch and Eudragit A mixture of L100. In the present invention, the coating is preferably a single layer of a mixture of a first substance and a second substance, and is preferably a homogeneous mixture.

However, the formulations of the present invention may have an additional layer which may be positioned between the active core and the layer comprising the sustained release composition of the present invention and/or the outer layer coated with the sustained release composition of the present invention. For example, if the sustained release composition layer includes Eudragit A mixture of L and starch is preferably added with a coating material which is released by pH and has an outer layer having a pH critical value of about 7 (for example Eudragit) S). In a preferred embodiment, the sustained release coating of the present invention is applied directly to the active core, i.e., there is no additional layer between the coating and the active core. The sustained release coating of the present invention is preferably an outer coating of the present formulation. Advantageously, it has been found that no additional outer layer is required to ensure that the composition is a sustained release composition.

Preferably, the composition forms a coating surrounding the bioactive portion, preferably a starch and Eudragit a mixture of S. The bioactive portion generally refers to a core containing a drug.

The formulation includes at least one particle having a core and a coating of the core. The formulation may include any suitable oral dosage form with a coating, including capsules, lozenges, compact tablets, pills, granules, and crystals.

The minimum diameter of each particle is typically at least about 10 ^-4 m, typically at least about 5 x 10 ^-4 m, preferably at least about 10 ^-3 m. The maximum diameter is usually no more than 30 mm, typically no more than 20 mm, preferably no more than 10 mm. In a preferred embodiment, the particles have a diameter of from 0.2 mm to about 15 mm, preferably from 1 mm to about 4 mm (for example, for pills or pocket tablets) or from 6 mm to about 12 mm. (for example, for certain tablets or capsules). The term "diameter" refers to the largest linear dimension of the entire particle.

The formulation may comprise a plurality of particles to provide a single dose of one drug (or multiple drugs), particularly in embodiments where the particles are "small", for example having a diameter of less than 5 mm. Multi-unit dosage forms including particles having a diameter of less than 3 mm are preferred.

The invention is applicable to a multiphasic drug release formulation comprising at least two particles of the same dosage form (e.g., capsules) (e.g., coated coated pills), wherein a plurality of particles It can be distinguished from another plurality of particles by coating. The coating of one of the plurality of granules may differ from the coating of the other plurality of granules in terms of coating thickness or composition thereof (e.g., ratio and/or characteristics of each component). The multi-phase drug release formulation is particularly suitable for patients with Crohn's disease who are infected in different areas of the intestine.

This "core" is usually a single solid. The core may be composed of a drug alone or may be an edible substance bead, for example, a sugar coated with a layer of a drug (or drugs). More commonly, however, the core is composed of a mixture of one (or multiple) drugs having the following additives, including fillers or dilutions, such as lactose or cellulosic materials (eg, microcrystalline cellulose). ; binding agents such as polyvinylpyrrolidone (of PVP); disintegrants, e.g. Ac-Di-Sol ^TM (i.e. croscarmellose sodium); and / or a lubricant such as magnesium stearate. The core can be a compressed granulate comprising at least some of the above materials.

According to the invention, the formulation is delayed to the intestine, preferably delayed until the colon is released. The release of a particular formulation can be continuous. However, in a preferred formulation, the release is pulsed.

If the release of the drug in the acidic medium is less than 10 wt% after 2 hours, this formulation is generally defined as a stomach resistant formulation. The formulations of the present invention typically show that in acidic media, the release of the drug is well below 10 wt% and can be considered a gastric resistant formulation. This formulation typically shows that in an acidic medium, the release of the drug is less than 1 wt%, and the formulation typically shows no acidic release in the acidic medium. When the starch is combined with the acrylate film-forming material to form a core coating, under the conditions simulating the human stomach and the small intestine environment, usually less than 5% of the drug is released after more than 5 hours. When the starch is combined with the cellulose film-forming material to form a core coating, under the conditions simulating the human stomach and the small intestine environment, usually less than 10% of the drug is released after more than 5 hours.

The time between the initial exposure to a suitable drug release and the onset of drug release is referred to as the "lag time." This "delay time" depends on a number of factors, including coating thickness and composition. The formulations of the present invention typically exhibit a delay of at least 30 minutes under conditions of the colon. In most embodiments of the invention, the delay time is from about 30 minutes to about 3 hours. In a preferred formulation, the delay time is preferably from about 45 minutes to about 2 hours.

The time between the initial exposure to a suitable drug release and the complete release of the drug also depends on a number of factors including the composition of the coating and the nature of the drug. In most embodiments of the invention, this time typically does not exceed 5 hours. In the preferred embodiment, this time typically does not exceed 4 hours.

In some embodiments, a tablet core is coated such that the tablet core has a coating of high amylose content of starch and Eudragit S (30:70) having a thickness of 8% to 9% TWG, and is initially released from the drug. The time between complete release of the drug can be below about 2 hours, preferably below 1.5 hours.

In a preferred embodiment, the core is a pellet having a diameter of about 1 mm. In another embodiment, the core is a tablet having a diameter of about 8 mm. In both cases, the coating is preferably a starch and acrylic polymer (e.g. Eudragit ^TM S) are mixed in a ratio of 30:70 mixture (Eurylon ^TM 7, for example) is a starch, high amylose content. In these two preferred embodiments, the core is coated with a coating (or coating) of about 100 μm, which is about 8% to about 9% TWG for the tablet, for the pill. It is about 27 wt% to about 32 wt% TWG.

According to a second aspect, the invention provides a formulation according to the first aspect, for use in a method of treating a human or animal body.

The core includes at least one drug. This formulation is usually used to administer a single drug as the only therapeutically active ingredient. However, in a single formulation, more than one drug can be administered.

The formulations of the present invention are designed to administer a wide variety of drugs. Suitable drugs include those known for enteral administration using known oral sustained release formulations. The invention can be used to administer a drug having a local or systemic effect.

The formulations of the present invention have particular utility in the enteral administration of a drug comprising at least one acidic functional group, such as a carboxylic acid functional group. Such drugs may be acidic drugs or zwitterionic drugs. An example of such a drug is 5-aminosalicylic acid ("5-ASA").

The nature of the drug in the formulation is clearly dependent on the conditions in which the treatment is desired. Regarding this issue, the formula is in the treatment of inflammatory bowel disease (IBD) (including Crohn's disease and ulcerative colitis), irritable bowel syndrome (IBS), constipation, diarrhea, infection, and cancer, especially colon cancer. Or there is a special application in the treatment of rectal cancer.

For the treatment or prevention of IBD, the formulation may include at least one selected from the group consisting of anti-inflammatory drugs (eg 5-ASA), steroids (eg, prednisolone, budesonide or fluticasone), immunosuppressive agents (eg, azathioprine, cyclosporine) A drug that is grouped with bacteriocin, methotrexate, and antibiotics.

For the treatment or prevention of cancer, at least one anti-tumor agent may be included in the formulation. Suitable anti-tumor agents include fluorouracil, methotrexate, dactinomycin, bleomycin, etoposide, paclitaxel, vinorelbine, and adriamycin; cisplatin, daunorubicin, VP-16, Raltitrexed, oxaliplatin, and pharmaceutically acceptable derivatives and salts thereof. For the prevention of colon and rectal cancer, mainly for patients with colitis, this formula may include anti-inflammatory drugs, 5-ASA.

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

Pharmaceutically acceptable derivatives and/or salts thereof can also be used in the formulation. An example of a suitable salt of prednisolone is methylprednisolone sodium succinate. In addition, another example is fluticasone propionate.

The present invention has particular application in the treatment of IBD (especially, ulcerative colitis) or in the prevention of colon cancer or rectal cancer (mainly, colitis patients), both of which use 5-ASA. The colon can be used as an entry point for the drug to enter the systemic circulation. This is particularly advantageous for peptide and protein drugs that are unstable in the upper gastrointestinal tract. The invention is also applicable to chronotherapy.

In a third aspect, the invention provides a method of colon-targeted administration comprising administering to a patient a formulation as defined above.

In a fourth aspect, the present invention provides a medicament for the treatment or prevention of IBD (particularly, ulcerative colitis), IBS, constipation, diarrhea, infection, and cancer using the formulation defined above.

The present invention also provides a medicament for the treatment of IBD comprising a formulation as defined above using at least one drug selected from the group consisting of anti-inflammatory drugs and steroids. Further, the present invention also provides a medicament comprising the above defined formula for the treatment of cancer using at least one antitumor drug. Further, the present invention also provides a medicament comprising 5-ASA for the preparation of a formulation comprising the above definition for preventing colon cancer or rectal cancer.

In a fifth aspect, the invention provides a method of treating or preventing IBD or cancer comprising administering to a patient a therapeutic amount of the above defined formula.

An effective therapeutic amount of the drug or various drugs is typically included in the formulation, and the effective therapeutic amount is from about 0.01% to about 99% by weight based on the total weight of the formulation. The actual dosage will be determined by those skilled in the art using his general knowledge. By way of example, however, a "low" dose formulation typically includes no more than 20 wt% of the drug, preferably from about 1 wt% to about 10 wt% of the drug, for example about 5 wt% of the drug. A "high" dose formulation typically includes at least 40 wt% of the drug, preferably from about 45 wt% to about 80 wt% of the drug, such as about 50 wt% or about 80 wt% of the drug.

In a sixth aspect, the invention provides a method of preparing a sustained release pharmaceutical formulation according to the first aspect, the method comprising: forming a core comprising at least one drug; and coating the core with a polymeric coating article, the polymeric coating The article comprises a mixture of a first substance and a second substance, the first substance being susceptible to attack by colonic bacteria having a pH of 5 or a pH value above 5, wherein the first substance comprises One selected from the group consisting of starch, amylose, amylopectin, chitosan, chondroitin sulfate, cyclodextrin, dextran, pullulan, carrageenan, scleroglucan, chitin, colloidal state A polysaccharide of a group of dextran and fructan. Preferred polysaccharide systems are as detailed above. Preferably, the core is spray coated with the polymeric coating article.

In some embodiments, the core is formed from compressed granules, the method preferably comprising the steps of: dry blending the drug with at least one excipient to form a dry mixture; and wetting at least a portion of the dry mixture Granulating to form a wet granule; pressing at least a portion of the wet granule to form a core; and spraying the core with a polymeric coating article to form a sustained release pharmaceutical formulation. Preferably, a fluidized bed sprayer is used and the core is spray coated with a polymeric coating article to form granules of the formulation.

In a preferred embodiment, the method comprises the steps of: forming an aqueous dispersion comprising the first material; forming an alcoholic solution or an aqueous solution comprising the second material; and preferably by dropping, The polymeric coating article is formed by adding at least a portion of the aqueous dispersion comprising the first material to at least a portion of the alcoholic solution or the aqueous solution comprising the second material.

The first substance is typically dispersed in a solution of at least one alcohol, preferably a C ₁ to C ₆ alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, 2-butanol, and mixtures thereof, In particular, n-butanol is used alone, followed by the addition of water, usually with sufficient agitation. The resulting aqueous dispersion is usually heated to boiling and then cooled overnight with stirring. Alcohols are used to solvate the first material in preparation for forming an aqueous dispersion. Alternatively, the material can be dispersed directly in water.

The second substance is typically dissolved in at least one solvent, such as water or an organic solvent. The organic solvent may be an alcohol such as methanol, ethanol, isopropanol, propylene glycol, butyl glycol, acetone, methyl glycol acetate, and mixtures thereof, such as a mixture of acetone and isopropanol (for example, the ratio is About 4:6). The second substance is preferably dissolved in ethanol under high speed agitation (preferably, the concentration is 85% to 98%).

The polymeric coating article is preferably formed by adding an appropriate amount of aqueous dispersion droplets to the alcohol solution under rapid agitation. In addition, excipients (eg, plasticizers (eg, triethyl citrate)) and/or lubricants (eg, glyceryl monostearate) are typically added to the polymeric coating article with agitation.

The above and other objects, features, aspects and advantages of the present invention will become apparent from

The embodiments of the present invention will be described in more detail below with reference to the drawings, which can be implemented by those skilled in the art after having studied this specification.

Embodiment 1

Preparation of prednisolone tablets Prednisolone tablets (200 mg, 8 mm diameter and standard double concave) were formulated according to the following formula:

The prednisolone is dry blended with the excipients and then wet granulated. Particles having a size of 500-710 μm were pressed by a single punching machine (Manesty, UK).

The Eurylon ^TM 7 starch was dispersed in n-butanol, followed by sufficient stirring was added water. The resulting dispersion was then heated to boiling and then cooled overnight with stirring. In the cooled dispersion, the percentage of solids is calculated based on the final weight of the dispersion which evaporates during heating.

Eudragit Formulation of S solution

Eudragit S solution is Eudragit by stirring at high speed The S 100 polymer was prepared by dissolving in 96% ethanol. The resulting solution had a polymer solids content of about 6%.

Starch-Eudragit Mixed coating dispersion

Will be the right amount of starch dispersion and Eudragit The solutions are mixed to give the desired ratio (based on the dry polymer material). Always add the starch to Eudragit with rapid stirring In solution. The resulting dispersion was stirred for 2 hours before the addition of the excipient, and stirring was continued for another 2 hours after the addition of the excipient. The excipients added are:

The final mixed polymeric coating article was applied as a film to the tablet using a fluid bed sprayer. The coating thickness was evaluated as an increase in weight percent (% TWG) of the coated tablet.

The parameters of this spray are as follows:

In vitro test The starch dispersion was prepared from Eurylon 7, a "high amylose content" starch, and then with Eudragit The S solution was mixed in ethanol. The composition of the coating dispersion and the preparation method thereof have been described above. Multiple starches / Eudragit A combination of S was prepared which contained 15%, 20%, 25%, 30% and 35% starch, respectively. Then Eudragit ^{The /} starch mixed coating dispersion was applied as a film to the prednisolone tablet prepared according to the method described above. The tablets are coated to have different thicknesses which are calculated based on the total weight gain of the polymer to determine the optimum coating thickness. The proportion of starch in the coating mixture which produces a high quality film is as high as 30%.

The coated tablets are then subjected to an in vitro test for drug release in buffer solutions of different pH values. Best starch / Eudragit S ratio and coating weight gain are mainly based on the dissolution profile of the present invention and the conventional Eudragit Comparison of S coated lozenges.

The results are shown in Figures 1-7.

It has been surprisingly found that these tablets, which are mixed in a film form, are capable of releasing the drug in HCl which mimics the pH of the human gastric juice medium of 1.2 (see the left part of the graph of Figures 1-6).

These coated lozenges were able to release the drug for 12 hours in a simulated human intestinal fluid medium at pH 6.8 (see Figure 6). Mixed amylose/water insoluble Eudragit used in in vitro tests The acrylate polymers based on RL and RS products exhibit uncontrolled swelling and rapid drug release in acids and buffers (Milojevic et al., 1996).

The drug release profile of the coated tablet was shown in Figures 1 to 5 in a buffer medium having a pH of 7.0. According to the analysis of the dissolution profile, coated with 30% starch / Eudragit Tablets with a film thickness equivalent to 8.3% TWG were considered to be the best and further tested to evaluate the digestibility of the starch component in the film.

The tablet was subjected to solubility measurement in a buffer containing pH of 6.8 of 50 U(units)/ml α-amylase extracted from Bacillus licheniformis (see Fig. 7). Solubility measurements were also performed in a medium containing pancreatin at pH 6.8 to test whether the starch was digestible in the presence of pancreatic alpha-amylase (see Figure 6).

The solubility measurement in the presence of the enzyme showed that the starch component in the membrane was indigestible in the presence of pancreatin (indicating tolerance in the small intestine), but in the presence of alpha-amylase from Bacillus licheniformis In the case, the drug begins to release within 3 hours. These results provide evidence that mixed membranes are resistant to drug release under conditions that mimic the gastrointestinal tract of the human body, but in the presence of bacterial enzymes, the mixed membrane is digestible (even at pH below) Eudragit In the case of a pH threshold at which the S polymer is dissolved).

In vivo study of healthy volunteers in starch/Eudragit After the surprising success of the in vitro study of S-mixed film-coated tablets, the performance of the dosage forms in healthy individuals was tested. The lozenges were radiolabeled with In-111 and eight healthy male volunteers were given the lozenges at three different times. The position and disintegration position of the tablet in the gastrointestinal tract is tracked by a gamma camera.

Table 1 shows the collapse time and position of these tablets with mixed membranes. The results show that the targeted administration to the colon is surprisingly excellent because the disintegration of the lozenge mainly occurs in the colon.

Evidence from the results of research on healthy volunteers indicates starch and Eudragit 30% starch to 70% Eudragit The ratio of S is mixed while being applied to the tablet with about 8.3% TWG, which is capable of withstanding the disintegration of the tablet in the stomach and small intestine, but causes the tablet to collapse in the colon.

Table 1 shows 30% starch and 70% Eudragit The location and time of disintegration of S-coated lozenges in eight healthy male volunteers at three different times.

The nomenclature in Table 1 explains "Fasted" - fasting; "Pre-fed" - fasting, but dine 30 minutes after dosing; and "Fed" - after breakfast. "ICJ" - ileal colon junction; "AC" - ascending colon; "HF" - hepatic flexure; and "SF" - splenic flexure.

Embodiment 2

According to the procedure of Example 1, a tablet containing 200% by weight of prednisolone substituted with 5 wt% of 5-aminosalicylic acid (5-ASA) (weight 200 mg; diameter 8 mm; standard double concave surface) was prepared, and Use includes 70% Eudragit S: 30% starch (Eurylon ^TM 7) of the polymer mixture of 5%, 6%, 7% and 8.3% of TwG coated onto the tablet.

5-ASA lozenges having different weight gains of 5%, 6%, 7%, and 8.3% were tested in vitro for drug release in a buffer having a pH of 6.8 in the presence of α-amylase. Figure 8 shows that the 5-ASA tablet applied to 8.3% TWG did not release 5-ASA for about 9 hours, but almost all of the 5-ASA was released after 11 hours.

Each 5-ASA lozenge with a different TWG was subsequently tested in vitro in the presence of 50 U/ml alpha-amylase. Figure 9 shows that in the presence of alpha-amylase, drug release is greatly accelerated for all different TWGs.

The 5-ASA tablet coated to 7% TWG showed a similar delay time (about 2) to a tablet containing 5 wt% prednisolone applied to 8.3% TWG in a buffer of pH 6.8. hour). Without wishing to be bound by any particular theory, this result can be explained by the fact that when 5-ASA is dissolved in a near neutral buffer, it exhibits acidity, thus, relative to the host medium, 5-ASA The pH of the boundary layer of the tablet core/polymer is lowered, thus delaying the dissolution of the polymer coating (coating).

Embodiment 3

According to the procedure of Example 1, a lozenge containing 5 wt% prednisolone (weight 200 mg; diameter 8 mm; standard double concave surface) was prepared, and the use included 70% Eudragit S: A polymer mixture of 30% starch was applied to the tablet at 8.3% TWG. Starch used is a high amylose content maize starch ^{(Eurylon TM 7; ~ 70 wt} % amylose) or one starch content of the low amylose (natural maize starch; ~ 27 wt% amylose; Sigma, Poole, One of the UK).

The tablets were tested in vitro for drug release in a pH 7 buffer containing no amylase, and then in a buffer of pH 6.8 with and without 50 U/ml α-amylase. , an in vitro test for drug release was performed.

Figures 10 and 11 show that if a "low" amylose content of starch is used, the drug is released at a faster rate. Figure 11 shows that for a tablet containing a low amylose content of starch, there is a delay of about 2.5 hours in the small intestine, which is shorter than the delay of the tablet containing the high amylose content of the starch. . This result can be explained as follows: amylopectin is more water soluble than amylose. Thus, the higher the proportion of amylopectin, the faster the coating (or coating) dissolves in the aqueous solution. Figure 12 shows that in the presence of alpha-amylase, the rate of drug release will be substantially faster.

A coated lozenge having a starch having a low amylose content has also been demonstrated (using the same procedure as for Figure 6) without being digested by the pancreaticin for a few hours, which further confirms the low amylose content The tolerance of starch in the small intestine. When amylopectin is a substrate for pancreatic amylase (present in pancreatic hormone), such tolerance is surprising, and therefore, the digestive power and drug release of the coating can be expected.

Embodiment 4

According to the procedure of Example 1, a lozenge containing 5 wt% prednisolone (weight 200 mg; diameter 8 mm; standard double concave surface) was prepared, and the use included 70% Eudragit S: 30% starch (Eurylon ^TM 7) of a polymer mixture of 8.3% TWG coated onto the tablet.

The tablets were first tested in vitro for drug release in a buffer containing no amylase at a pH of 5.5, and then in a buffer of the same pH containing 50 U/ml α-amylase. In vitro testing of drug release.

Figure 13 shows the delay time just below 4 hours under the conditions of the small intestine. However, in the presence of alpha-amylase, the delay time was approximately 3 hours (Figure 14). The results show that the coating system can be used for drug release into the proximal small intestine.

Embodiment 5

According to the procedure of Example 1, a tablet containing 5 wt% prednisolone (weight 200 mg; diameter 8 mm; standard biconcave) was prepared, and 70% hydroxypropylmethylcellulose succinate acetate was used ("HPMCAS""): 30% starch (Eurylon ^TM 7) a polymer mixture of 8.3% TWG coated onto the tablet. The HPMCAS (ShinEtsu, Japan) used was a particulate grade HG with a pH threshold of 6.8. The HPMCAS-HG was dissolved in a 90% ethanol solution, and then an aqueous dispersion of starch was added thereto.

The tablets were first tested in vitro in a buffer of pH 6.5 containing no amylase and then in a buffer of the same pH containing 50 U/ml of α-amylase. Further tablets were tested in vitro for drug release in a buffer pH 6.8 containing no amylase.

Figure 15 shows that under the pH threshold of HMPCAS-HG, the coating has a tendency to swell, allowing the drug to diffuse slowly from the formulation before the coating dissolves, followed by a burst-release of the drug. In a buffer having a pH of 6.5 without alpha-amylase, the delay time before diffusion occurs is about 2 hours, which is sufficient for the drug to be released until the distal small intestine. The spread will continue for about another 4.5 hours, with the result that almost 40% of the drug will spread out before the sudden release of the drug.

In the presence of alpha-amylase, diffusion begins in a buffer of pH 6.5 without delay and releases 20% of the drug prior to drug burst release (Figure 16). However, at pH 6.8, this diffusion phenomenon does not exist, presumably due to the faster dissolution of the entire system (Figure 17).

It will be apparent to those skilled in the art that various modifications and changes can be made without departing from the spirit and scope of the invention. Therefore, the present invention includes such modifications and variations, and is included in the scope of the appended claims and their equivalents.

Figure 1 is a graph showing a mixed film coated prednisolone tablet with a TWG of 5% and a Eudragit with a TWG of 5% in a pH 7 buffer. The dissolution characteristic curve of the S-coated tablet; FIG. 2 is a graph showing the dissolution characteristics of the mixed film-coated tablet as shown in FIG. 1, but the TWG is 6%; FIG. 3 is a view of FIG. The dissolution profile of the mixed film coated tablet, but the TWG is 7.4%; FIG. 4 is a graph showing the dissolution characteristics of the mixed film coated tablet as shown in FIG. 1, but the TWG is 8.3%; 5 is a prednisolone tablet coated with 30% starch: 70% Eudragit S to a plurality of polymer weight gains in a buffer of pH 7, and Eudragit with a TWG of 5%. The dissolution profile of the S-coated tablet; Figure 6 is a plot of 30% Eudragit S coated with 30% Eudragit S in a buffer of pH 6.8 in the presence and absence of pancreatin. The dissolution profile of the pine pellets; Figure 7 is a diagram showing the drug release profile of prednisolone tablet with 8.3% TWG in a buffer containing 50 U/ml amylase and a pH of 6.8; It is a dissolution profile of a 5-ASA tablet coated with 30% starch: 70% Eudragit S with a TWG of 8.3% in a pH 6.8 buffer; Figure 9 is a representation of 50 U/ml. A dissolution profile of a 5-ASA tablet that is coated with a 30% starch: 70% Eudragit S to a plurality of polymer weights in a buffer of amylase and pH 6.8; Figure 10 is a graph showing pH 7 Dissolution profile of 70% Eudragit S: 30% 70% or 27 wt% amylose-coated prednisolone in a buffer; Figure 11 is a plot at pH In the buffer of 6.8, the dissolution profile of the prednisolone tablet in Fig. 10; Fig. 12 is a description of the buffer having a pH of 6.8 containing 50 U/ml amylase, Figure 10 is a dissolution profile of the prednisolone tablet; Figure 13 is a graph showing prednisone coated with 70% Eudragit S: 30% starch with a TWG of 8.3% in a pH 5.5 buffer. The dissolution profile of the lozenge; FIG. 14 is a graph showing the dissolution characteristics of the prednisolone tablet in the buffer containing 50 U/ml amylase and having a pH of 5.5; FIG. Is a dissolution profile of prednisolone tablets coated with 70% HPMCAS-HG: 30% starch in a buffer of pH 6.5; Figure 16 is a diagram showing the inclusion of 50 U/ml amylase In the buffer of pH 6.5, the dissolution profile of the prednisolone tablet in Figure 15; and Figure 17 shows the prednisolone in the buffer of pH 6.8, as shown in Figure 15. A dissolution profile of the tablet.

Claims (33)

A sustained release pharmaceutical formulation for releasing a drug in the colon, comprising a particle having a core and a coating for the core, the core comprising a drug, and the coating comprising a mixture of a first substance and a second substance The first substance is susceptible to attack by colonic bacteria, and the second substance is a film forming polymer material having a pH value equal to or greater than 5, wherein the first substance is amylopectin or contains no more than 75 wt% amylose starch. The sustained release pharmaceutical formulation of claim 1, wherein the first substance is a starch comprising at least about 35% amylose. The sustained release pharmaceutical formulation according to claim 1, wherein the first substance is amylopectin. The sustained release pharmaceutical formulation of claim 1, wherein the second substance is an acrylate polymer. The sustained release pharmaceutical formulation according to claim 1, wherein the second substance is a copolymer of an anionic (meth)acrylic acid and a C _1-4 alkyl (meth)acrylate. The sustained release pharmaceutical formulation according to claim 4, wherein the second substance is a copolymer of anionic methacrylic acid and methyl methacrylate. The sustained release pharmaceutical formulation according to claim 6, wherein the ratio of methacrylic acid to methyl methacrylate is about 1:2. The sustained release drug formulation of claim 1, wherein the second substance is Eudragit ^® S. The sustained release pharmaceutical formulation according to claim 5, wherein the second substance is a copolymer of methacrylic acid and ethyl acrylate. The sustained release pharmaceutical formulation according to claim 1, wherein the second substance is a cellulose polymer or a polyethylene-based polymer. The sustained-release pharmaceutical formulation according to claim 10, wherein the cellulose polymer is cellulose acetate phthalate ("CAP"), cellulose acetate trimellitate ("CAT"), or Hydroxypropyl methylcellulose acetate succinate. The sustained release pharmaceutical formulation according to claim 10, wherein the polyethylene-based polymer is polyvinyl acetate phthalate ("PVAP"). The sustained release drug formulation of claim 1, wherein the ratio of the first substance to the second substance reaches about 50:50. The sustained release pharmaceutical formulation of claim 1, wherein the ratio of the first substance to the second substance reaches about 35:65. The sustained release drug formulation of claim 1, wherein the ratio of the first substance to the second substance is from 15:85 to 35:65. The sustained release pharmaceutical formulation of claim 1, wherein the particles have a minimum diameter of at least about 5 x 10 ^-4 m. The sustained release pharmaceutical formulation of claim 1, wherein the thickness of the coating is 5% to 10% as measured by the theoretical weight gain ("TWG") of the coating formulation. The sustained release pharmaceutical formulation according to claim 1, wherein the thickness of the coating is 15% to 35% as measured by the theoretical weight gain of the coating formulation. The sustained release pharmaceutical formulation of claim 1, wherein the coating has a thickness of from about 10 μm to about 150 μm. The sustained release pharmaceutical formulation of claim 1, wherein the drug comprises at least one acidic functional group. The sustained release drug formulation according to claim 1, wherein the drug is an anti-inflammatory drug. The sustained release pharmaceutical formulation according to claim 20 or 21, wherein the drug is 5-aminosalicylic acid. The sustained release drug formulation of claim 1, wherein the drug is a steroid. The sustained release pharmaceutical formulation according to claim 23, wherein the drug is selected from the group consisting of prednisolone, budesonide, fluticasone, and derivatives thereof. The sustained release drug formulation according to claim 1, wherein the drug is an antitumor drug. The sustained release drug formulation of claim 1, which is used in a medical method for treating a human or an animal. A sustained release pharmaceutical formulation as described in claim 21 or 23, which is for use in the preparation of a medicament for the treatment of inflammatory bowel disease. A sustained-release pharmaceutical formulation as described in claim 25, which is for use in the preparation of a medicament for treating cancer. A sustained-release pharmaceutical formulation as described in claim 22, which is for use in the preparation of a medicament for preventing cancer. A method for preparing a sustained release pharmaceutical formulation according to claim 1, comprising the steps of: forming a core comprising at least one drug; and coating the core with a polymeric coating article, the polymeric coating article comprising a mixture of a first substance and a second substance, the first substance being susceptible to attack by colonic bacteria, the second substance being a film-forming polymeric substance having a pH threshold of pH 5 or above pH 5 Wherein the first substance is amylopectin or a starch containing no more than 75 wt% amylose. The preparation method of claim 30, wherein the core is sprayed using the polymer coating article. The preparation method of claim 30 or 31, comprising: forming an aqueous dispersion containing the first substance; forming an alcohol solution or an aqueous solution containing the second substance; and adding at least a part of the content The aqueous dispersion of the first material is added to at least a portion of the alcohol solution or the aqueous solution containing the second material to form the polymeric coating article. A sustained release pharmaceutical formulation according to any one of claims 1 to 27 for use in the preparation of a medicament for targeted release of colon after administration to a patient.