A dosage form that releases a drug at pH 3 to 6 using a double coating system with at least one release promoter

Abstract

The present invention relates to a dosage form comprising a core containing at least one biologically active ingredient; an intermediate coating layer containing, inter alia, at least one alkaline agent and at least one release promoter selected from iron oxide, aluminum oxide, titanium dioxide, dimethyl sulfoxide, zinc oxide, sucrose, maltose, lactose, dextrate, glucose, fructose, dyes and any mixture thereof; and an enteric coating layer, and to a method for obtaining such a dosage form. Furthermore, the present invention relates to the use of a dosage form according to the invention for providing at least 80% drug release at a pH value of 5 within 60 minutes or at least 80% drug release at a pH value of 3 within 60 minutes.

Description

Technical Field

[0001] The present invention relates to a dosage form comprising a core containing at least one biologically active ingredient; in particular at least one alkaline agent and at least one release promoter selected from iron oxide, aluminum oxide, titanium dioxide, dimethyl sulfoxide, zinc oxide, sucrose, maltose, lactose, dextrate, glucose, fructose, dyes and any mixtures thereof in a specific intermediate coating layer; and an enteric coating layer, and a method for obtaining the dosage form. Furthermore, the present invention relates to the use of the dosage form according to the invention for providing at least 80% drug release at a pH value of 5 within 60 minutes or at least 80% drug release at a pH value of 3 within 60 minutes.

Background Art

[0002] Release and absorption in the gastrointestinal tract are preferably in the duodenum. However, for example, the sustained release time of known dosage forms described in Patent Document 1 is at least 45 minutes in phosphate buffer pH 5.5, showing only a certain degree of release. Therefore, in such a preparation, the drug passes through about 25 cm of the duodenum without being released and moves to the jejunum. Furthermore, if the trigger pH related to the duodenum is not achieved, the preparation does not release the biologically active ingredient. The release of biologically active ingredients in the duodenum is important, for example, for duodenal ulcers, but also important for systemic drug absorption, for example, because the mucus layer composition changes and thickens.

[0003] Therefore, there is a need for an enteric dosage form that shows accelerated release, particularly in the pH range of pH 3 to pH 6, preferably pH 5 to 6. The desired enteric dosage form shall be enteric and have no more than 10% drug release after 2 hours in 0.1N hydrochloric acid (HCl) in accordance with the test of the sustained release preparation described in United States Pharmacopeia (USP) 43 Monograph 711. After changing the medium to a direct test without preconditioning in a buffer medium with an appropriate pH value of pH 3 to 6, preferably pH 5 to 6, from 0.1N HCl, the drug release exceeds 80% within 30 minutes.

Prior Art Documents

Patent Documents

[0004]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0005] Surprisingly, the inventors of the present invention have found that when a certain release promoter selected from iron oxide, aluminum oxide, titanium dioxide, dimethyl sulfoxide, zinc oxide, sucrose, maltose, lactose, dextrose, glucose, fructose, dyes, or any mixture thereof is added in an amount of 0.1 to 20% by mass based on the mass of at least one polymer in the intermediate coating layer, the release is accelerated within 30 minutes at a pH value of 3 to 6, preferably pH 5 to 6.

Means for Solving the Problems

[0006] In a first aspect, the present invention is as follows: (a) a core containing at least one biologically active ingredient, (b) an intermediate coating layer (ICL) on or above the core, comprising: (i) at least one polymer, (ii) at least one alkaline agent, (iii) at least one release promoter selected from iron oxide, aluminum oxide, titanium dioxide, dimethyl sulfoxide, zinc oxide, sucrose, maltose, lactose, dextrose, glucose, fructose, dyes, or any mixture thereof; (iv) optionally, at least one lubricant; (v) optionally, at least one plasticizer; and (vi) optionally, at least one additive different from (i) to (v); comprising, wherein said at least one release promoter is present in an amount of 0.1 to 20% by mass, preferably 0.2 to 15% by mass, more preferably 0.5 to 8% by mass, most preferably 1 to 6% by mass based on the mass of said at least one polymer, and (c) an enteric coating layer (ECL) on or above said intermediate coating layer, comprising the following: (i) at least one polymer; (ii) optionally, at least one lubricant; (iii) optionally, at least one emulsifier; (iv) optionally, at least one plasticizer; (v) optionally, at least one biologically active ingredient; and (vi) optionally, at least one additive different from (i) to (v), relates to a dosage form. In one embodiment, at least one polymer of the enteric coating layer comprises or consists of two different polymers, preferably the first polymer is an anionic polymer having a Tgm ≧ 35°C, more preferably 35 to 155°C, even more preferably 80 to 145°C, most preferably 90 to 125°C; wherein the second polymer is preferably a polymer having a Tgm ≦ 30°C, more preferably ≦ 15°C. In one embodiment, the total coating amount of the coating layer is 2.0 to 30 mg / cm 2 , preferably 2.0 to 10 mg / cm 2 or 10 to 25 mg / cm 2 .

[0007] In a second aspect, the present invention relates to a method for obtaining a dosage form according to the present invention, wherein the intermediate coating layer is coated on the core by spray coating, and then the enteric coating layer is coated on said intermediate coating layer by spray coating. In a third aspect, the invention relates to the use of the polymer-coated hard shell capsules according to the invention for controlled release, i.e., for providing at least 80% drug release within 30 minutes at a pH value of 3 to 6, preferably pH 5 to 6.

Mode for Carrying Out the Invention

[0008] Polymers or polymer mixtures contained in the intermediate or enteric coating layer The following discloses polymers suitable for use as one of at least one polymer in the intermediate or at least one polymer in the enteric coating layer. At least one polymer in the intermediate coating layer and the enteric coating layer can be any of the polymers described below. The enteric coating layer preferably comprises a first polymer which is an anionic polymer having a Tgm of ≧35° C., preferably 35 to 155° C., more preferably 80 to 145° C., most preferably 90 to 125° C.; and a second polymer having a Tgm of ≦30° C., preferably ≦20° C., more preferably -10 to 20° C. Suitable anionic and neutral polymers are also described below. Expressions such as "polymers contained in the coating layer" are also used when applicable to all polymers in both coating layers. The polymer contained in the coating layer is preferably a film-forming polymer. At least one polymer of the coating layer can be selected from the group of anionic polymers, cationic polymers and neutral polymers or any mixture thereof. The selection of the general or specific polymer characteristics or embodiments disclosed herein can be combined without limitation with any other general or specific selection of the characteristics or embodiments of the materials or numerical values disclosed herein, such as capsule material, capsule size, coating thickness, biologically active ingredient, and any other characteristics or embodiments disclosed.

[0009] The coating layer may be a single layer, or may comprise or consist of two or more individual layers, and may contain one or more polymers with a total mass percentage of 10 to 100, 20 to 95, 30 to 90, preferably methacrylic acid copolymers. The ratio of monomers mentioned for each polymer generally amounts to 100% by mass in total. The intermediate coating layer and the enteric coating layer are different from each other.

[0010] In a preferred embodiment, a further coating layer, a top coating layer is included. The top coating layer contains at least one cationic polymer or at least one neutral polymer or any mixture thereof. In a preferred embodiment, the top coating layer is selected from at least one natural polymer or starch, preferably as described below or hydroxypropylmethylcellulose, and most preferably hydroxypropylmethylcellulose.

[0011] Glass transition temperature Tgm The glass transition temperature Tgm according to the present invention is preferably determined by differential scanning calorimetry (DSC) in accordance with ISO 11357-2:2013-05. The measurement is carried out at a heating rate of 20 K / min. The glass transition temperature Tgm can also be determined by the half-step height method described in DIN EN ISO 11357-2 item 10.1.2.

[0012] Anionic polymer At least one polymer contained in the coating layer may be an anionic polymer selected from the group of anionic methacrylic acid copolymers, anionic polyvinyl polymers or copolymers, and anionic celluloses.

[0013] Anionic methacrylic acid copolymer Preferably, the anionic methacrylic acid copolymer contains 25 to 95% by mass, preferably 40 to 95% by mass, particularly 60 to 40% by mass of a C1-C12 alkyl ester of acrylic acid or methacrylic acid, preferably a C1-C4 alkyl ester, and 75 to 5% by mass, preferably 60 to 5% by mass, particularly 40 to 60% by mass of a methacrylic acid monomer having an anionic group. The generally mentioned ratios total 100% by mass. However, if the properties are not essentially deteriorated or changed, a small amount of an additional vinyl copolymerizable monomer in the range of 0 to 10% by mass, for example 1 to 5% by mass, such as hydroxyethyl methacrylate or ethyl hydroxyacrylate, may be present. It is preferred that there is no additional monomer capable of vinyl copolymerization. The C1-C4 alkyl esters of acrylic acid or methacrylic acid are, in particular, methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate and butyl acrylate. The methacrylic acid monomer having an anionic group is, for example, acrylic acid, preferably methacrylic acid.

[0014] A suitable anionic methacrylic acid copolymer is one polymerized from 40 to 60% by mass of methacrylic acid and 60 to 40% by mass of methyl methacrylate or 60 to 40% by mass of ethyl acrylate (EUDRAGIT® L or EUDRAGIT® L 100 55 type). EUDRAGIT® L is a copolymer polymerized from 50% by mass of methyl methacrylate and 50% by mass of methacrylic acid. The pH value at which the release of a specific active ingredient starts in intestinal fluid or simulated intestinal fluid may be about pH 6.0. Its Tgm is >125°C. EUDRAGIT® L 100-55 is a copolymer polymerized from 50% by mass of ethyl acrylate and 50% by mass of methacrylic acid. EUDRAGIT® L 30 D-55 is a dispersion containing 30% by mass of EUDRAGIT® L 100-55.

[0015] Similarly, an anionic methacrylic acid copolymer (EUDRAGIT® S type) obtained by polymerizing 20 to 40% by mass of methacrylic acid and 80 to 60% by mass of methyl methacrylate is also suitable. The pH value at which the release of a specific active ingredient starts in intestinal fluid or simulated intestinal fluid may be about pH 7.0.

[0016] A suitable methacrylic acid copolymer is polymerized from 10 to 30% by mass of methyl methacrylate, 50 to 70% by mass of methyl acrylate, and 5 to 15% by mass of methacrylic acid (EUDRAGIT® FS type). EUDRAGIT® FS is a copolymer polymerized from 25% by mass of methyl methacrylate, 65% by mass of methyl acrylate, and 10% by mass of methacrylic acid. EUDRAGIT® FS 30 D is a dispersion containing 30% by mass of EUDRAGIT® FS.

[0017] The following: 20 to 34% by mass of methacrylic acid and / or acrylic acid 20 to 69% by mass of methyl acrylate, and 0 to 40% by mass of ethyl acrylate, and / or, where appropriate, 0 to 10% by mass of a further monomer capable of vinyl copolymerization A copolymer composed of is suitable. However, the glass transition temperature of the copolymer in accordance with ISO 11357-2:2013-05 item 3.3.3 is 60°C or lower.

[0018] The following: 20 to 33% by mass of methacrylic acid and / or acrylic acid 5 to 30% by mass of methyl acrylate, and 20 to 40% by mass of ethyl acrylate, and More than 10% to 30% by mass of butyl methacrylate, and where appropriate, 0 to 10% by mass of a further monomer capable of vinyl copolymerization A copolymer polymerized from is suitable, where the ratio of the monomers is 100% by mass in total. However, the glass transition temperature of the copolymer in accordance with ISO 11357-2:2013-05 item 3.3.3 (midpoint temperature Tm, g) is 55 to 70 °C, preferably 55 to 80 °C.

[0019] The copolymer preferably consists of 90, 95 or 99 to 100% by mass of the monomers of methacrylic acid, methyl acrylate, ethyl acrylate and butyl methacrylate in the above-mentioned amount ranges. However, provided that the properties are not substantially impaired, a small amount of further vinyl copolymerizable monomers in the range of 0 to 10% by mass, for example 1 to 5% by mass, such as methyl methacrylate, butyl acrylate, hydroxyethyl methacrylate, vinyl pyrrolidone, vinyl malonic acid, styrene, vinyl alcohol, vinyl acetate and / or their derivatives may further be present.

[0020] A further suitable anionic methacrylic acid copolymer may be a so-called core / shell polymer as described in International Publication No. 2012 / 171575 A2 or 2012 / 171576 A1. A suitable core-shell polymer is a copolymer from a two-stage emulsion polymerization process having a core of 75% by mass containing polymerization units of 30% by mass of ethyl acrylate and 70% by mass of methyl methacrylate, and a shell of 25% by mass containing polymerization units polymerized from 50% by mass of ethyl acrylate and 50% by mass of methacrylic acid. A suitable core-shell polymer may be a copolymer from a two-stage emulsion polymerization process having a core of 70 to 80% by mass containing polymerization units of 65 to 75% by mass of ethyl acrylate and 25 to 35% by mass of methyl methacrylate, and a shell of 20 to 30% by mass containing polymerization units of 45 to 55% by mass of ethyl acrylate and 45 to 55% by mass of methacrylic acid.

[0021] Anionic cellulose Anionic cellulose can be selected from carboxymethylethyl cellulose and its salts, cellulose acetate phthalate (CAP), cellulose acetate succinate (CAS), cellulose acetate trimellitate (CAT), hydroxypropylmethyl cellulose phthalate (HPMCP, HP50, HP55), hydroxypropylmethyl cellulose acetate succinate (HPMCAS-LF, -MF, -HF). The coating layer can contain one or more anionic celluloses, ethyl cellulose, and / or at least 35% by mass of amylose, preferably one or more starches having a glass transition temperature Tgm (determined by differential scanning calorimetry (DSC) according to ISO 11357-2:2013-05) of 130°C or lower, and the coating layer preferably has a thickness of about 1 to 5.8 mg / cm 2 , more preferably 2 to 5 mg / cm 2 and is present in an amount of. The coating layer can contain, in total, 10 to 100, 20 to 95, 30 to 90% by mass of one or more anionic celluloses, ethyl cellulose, and / or at least 35% by mass of amylose-containing starches.

[0022] The glass transition temperature Tgm of hydroxypropylmethyl cellulose phthalate is about 132 to 138°C (about 133°C for HP-55 type, about 137°C for HP-50 type). The glass transition temperature Tgm of hydroxypropylmethyl cellulose acetate succinate (HPMCAS) is about 120°C (119°C for AquaSolveTM L HPMCAS, 120°C for AquaSolveTM M HPMCAS, 122°C for AquaSolveTM H HPMCAS).

[0023] Anionic vinyl copolymer The anionic vinyl copolymer can be selected from unsaturated carboxylic acids other than acrylic acid or methacrylic acid, such as exemplified by polyvinyl acetate phthalate or a copolymer of vinyl acetate and crotonic acid (preferably in a ratio of 9:1).

[0024] Cationic polymer Suitable cationic methacrylic acid copolymers contained in the coating layer can be polymerized from monomers including C1-C4 alkyl esters of acrylic acid or methacrylic acid and alkyl esters of acrylic acid or methacrylic acid having a tertiary or quaternary ammonium group in the alkyl group. The cationic water-soluble methacrylic acid copolymer may be partially or completely alkyl polymerized from acrylates and / or alkyl methacrylates having a tertiary amino group in the alkyl group. Coatings containing these polymers can have the advantage of providing moisture protection to hard shell capsules. Moisture protection should be understood as a reduction in the uptake of moisture or water during storage of capsules that are easily filled and finally locked. Suitable cationic methacrylic acid copolymers may be polymerized from 30-80% by mass of C1-C4 alkyl esters of acrylic acid or methacrylic acid and 70-20% by mass of alkyl methacrylic acid monomers having a tertiary amino group in the alkyl group. Preferred cationic methacrylic acid copolymers can be polymerized from 20-30% by mass of methyl methacrylate, 20-30% by mass of butyl methacrylate, and 60-40% by mass of dimethylaminoethyl methacrylate (EUDRAGIT® E type polymer). Particularly suitable commercially available methacrylic acid copolymers having a tertiary amino group are polymerized from 25% by mass of methyl methacrylate, 25% by mass of butyl methacrylate, and 50% by mass of dimethylaminoethyl methacrylate (EUDRAGIT® E 100 or EUDRAGIT® E PO (powder form)). EUDRAGIT® E 100 and EUDRAGIT® E PO are water-soluble at pH values of less than about 5.0 and are thus also soluble in gastric juice.

[0025] A suitable methacrylic acid copolymer can be composed of 85 to 98% by mass of a free radical polymerized C1-C4 alkyl ester of acrylic acid or methacrylic acid and 15 to 2% by mass of a methacrylic acid monomer having a quaternary amino group in the alkyl group. Preferred C1-C4 alkyl esters of acrylic acid or methacrylic acid are methyl acrylate, ethyl acrylate, butyl acrylate, butyl methacrylate and methyl methacrylate. A further suitable cationic methacrylic acid polymer may contain polymerization monomer units of 2-trimethylammonium-ethyl methacrylate chloride or trimethylammonium-propyl methacrylate chloride.

[0026] A suitable copolymer may be polymerized from 50 to 70% by mass of methyl methacrylate, 20 to 40% by mass of ethyl acrylate and 7 to 2% by mass of 2-trimethylammonium ethyl methacrylate chloride. A particularly suitable copolymer is polymerized from 65% by mass of methyl methacrylate, 30% by mass of ethyl acrylate and 5% by mass of 2-trimethylammonium ethyl methacrylate chloride (EUDRAGIT® RS). A further suitable methacrylic acid copolymer can be polymerized from less than 85 to 93% by mass of a C1-C4 alkyl ester of acrylic acid or methacrylic acid and more than 7 to 15% by mass of a methacrylic acid monomer having a quaternary amino group in the alkyl group. The methacrylic acid monomer is commercially available and has been used for a long time in sustained release coatings. A particularly suitable copolymer is polymerized from 60% by mass of methyl methacrylate, 30% by mass of ethyl acrylate and 10% by mass of 2-trimethylammonium ethyl methacrylate chloride (EUDRAGIT® RL).

[0027] Neutral polymer A neutral polymer is defined as being polymerized from a neutral monomer and a monomer having less than 5% by weight, preferably less than 2% by weight, of ionic groups, or most preferably as a polymer containing no monomer having ionic groups. Neutral polymers suitable for coating hard shell capsules are methacrylate copolymers, preferably copolymers of ethyl acrylate and methyl methacrylate such as EUDRAGIT® NE or EUDRAGIT® NM, neutral celluloses such as methyl-, ethyl- or propyl ethers of cellulose, for example hydroxypropyl cellulose, polyvinylpyrrolidone, polyvinyl acetate or polyvinyl alcohol. Neutral methacrylate copolymers are often useful in mixtures with anionic methacrylic acid copolymers. Neutral methacrylate copolymers are polymerized from methacrylic acid monomers having neutral groups, especially C1-C4 alkyl groups, up to at least 95% by weight, especially up to at least 98% by weight, preferably up to at least 99% by weight, especially up to at least 99% by weight, and particularly preferably up to 100% by weight. Suitable methacrylic acid monomers having neutral groups are, for example, methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate, butyl acrylate. Preferred are methyl methacrylate, ethyl acrylate and methyl acrylate. Methacrylate monomers having anionic groups, such as acrylic acid and / or methacrylic acid, may be present in amounts of less than 5% by weight, preferably 2% by weight or less, more preferably 1% by weight or less, or in small amounts of 0.05 - 1% by weight.

[0028] Suitable examples are neutral or substantially neutral methacrylic acid copolymers polymerized from 20 - 40% by weight of ethyl acrylate, 60 - 80% by weight of methyl methacrylate, and 0 - less than 5% by weight, preferably 0 - 2% by weight or 0.05 - 1% by weight of methacrylic acid or acrylic acid. Suitable examples are neutral or substantially neutral methacrylic acid copolymers polymerized from 20 to 40% by mass of methyl methacrylate, 60 to 80% by mass of ethyl acrylate and less than 0 to 5% by mass, preferably 0 to 2 or 0.05 to 1% by mass of methacrylic acid or acrylic acid. (EUDRAGIT® NE or EUDRAGIT® NM type). EUDRAGIT® NE and EUDRAGIT® NM are copolymers containing free radical polymerization units of 28 to 32% by mass of methyl methacrylate and 68 to 72% by mass of ethyl acrylate. According to WO 01 / 68767 A1, a neutral or substantially neutral methyl acrylate copolymer produced as a dispersion using 1 to 10% by mass of a non-ionic emulsifier having an HLB value of 15.2 to 17.3 is preferred. The latter offers the advantage of no phase separation involving the formation of a crystal structure by the emulsifier (EUDRAGIT® NM type). However, according to European Patent Application No. 1571164 A2, the corresponding substantially neutral methacrylic acid copolymer having a small amount of 0.05 to 1% by mass of a monoolefinically unsaturated C3-C8 carboxylic acid can also be produced by emulsion polymerization in the presence of a relatively small amount of an anionic emulsifier, for example 0.001 to 1% by mass.

[0029] Natural polymer Particularly in the form of nutritional supplements, so-called "natural polymer" coatings are preferred by many customers. Natural polymers are based on sources from nature, plants, microorganisms or animals, and are sometimes further chemically processed. Natural polymers for coating can be selected from starches, alginates or salts of alginates, preferably sodium alginate, pectin, shellac, zein, carboxymethyl-zein, modified starches, such as EUDRAGUARD® Natural, sponge collagen, chitosan, polymers such as gellan gum, etc. Suitable polymer mixtures include ethyl cellulose and pectin, modified starch (EUDRAGUARD® Natural) and alginate and / or pectin, shellac and alginate and / or pectin, shellac and inulin, whey protein and gums (such as guar gum or tragacanth gum), zein and polyethylene glycol, sodium alginate and chitosan. Ethyl cellulose is a derivative of cellulose in which the hydroxyl groups of the glucose repeating units are converted to ethyl ether groups. Ethyl cellulose can be used as a sustained-release coating material for the disclosed capsules. The glass transition temperature Tgm of ethyl cellulose can be in the range of about 128 - 130 °C (Hui Ling Lai et al. Int. J. Pharmaceuticals 386 (2010) 178 - 184). The following describes further components that may be present in the enteric coating layer or the intermediate coating layer. Unless otherwise specified, the components are generally suitable for use in both coating layers. The amount of each component is shown taking into account the total mass of at least one polymer contained in each coating layer, unless otherwise clearly stated.

[0030] Flow promoter The flow promoters are usually lipophilic. These prevent the aggregation of the core during film formation of the film-forming polymer. At least one flow promoter is preferably selected from silica, pulverized silica, fumed silica, calcium kaolin silicate, magnesium silicate, colloidal silicon dioxide, talc, calcium stearate, magnesium stearate, zinc stearate, stearates such as sodium stearyl fumarate, starch, stearic acid, preferably talc, magnesium stearate, colloidal silicon dioxide and glycerol monostearate or mixtures thereof, more preferably glycerol monostearate and talc or mixtures thereof, which are commercially available under the trade names RXCIPIENTS® GL100 or RXCIPIENTS® GL200, for example. The standard ratio for use as a lubricant in the coating layer is in the range of 0.5 to 100% by mass, preferably 3 to 75% by mass, more preferably 5 to 50% by mass, most preferably 5 to 30% by mass, based on the total mass of at least one polymer.

[0031] Emulsifier Generally, all known emulsifiers are suitable. Nonionic emulsifiers, especially those with an HLB > 10 or HLB > 12, are preferred. The HBL value can be determined in accordance with Griffin, William C. (1954), “Calculation of HLB Values of Non-Ionic Surfactants” (PDF), Journal of the Society of Cosmetic Chemists, 5(4): 249 - 56. At least one emulsifier is preferably selected from polyglycosides, alcohols, sugars and sugar derivatives, polyethers, amines, polyethylene derivatives, alkyl sulfates (e.g., sodium dodecyl sulfate), alkyl ether sulfates, dioctyl sodium sulfosuccinate, polysorbates (e.g., polyoxyethylene (20) sorbitan monooleate), nonylphenol ethoxylate (nonoxynol - 9) and mixtures thereof.

[0032] At least one emulsifier is preferably an alkyl polyglycoside, decyl glucoside, decyl polyglucose, lauryl glucoside, octyl glucoside, N-octyl beta-D-thioglucopyranoside, cetostearyl alcohol, cetyl alcohol, stearyl alcohol, polyoxyethylene cetostearyl alcohol, cetyl stearyl alcohol, oleyl alcohol, polyglyceryl-6 dioleate, glyceryl stearate citrate, polyglyceryl-3 caprate, polyglyceryl-3 diisostearate, glyceryl isostearate, polyglyceryl-4-isostearate, glyceryl monolinoerate, dicaprylyl carbonate, alcohol polyglycol ether, polyethylene glycol ether (n = 20) of cetearyl alcohols, polyethylene glycol-6 stearate, glycol stearate, polyethylene glycol-32 stearate, polyethylene glycol-20 stearate, fatty alcohol polyglycol ether, polyethylene glycol-4 laurate, polyethylene glycol isocetyl ether (n = 20), mono- and diesters of polyethylene glycol-32 (Mw 1500 g / mol) lauric acid (C12), nonaethylene glycol, polyethylene glycol nonyl phenyl ether, octaethylene glycol monododecyl ether, pentaethylene glycol monododecyl ether, polyethylene glycol macro cetyl ether, polyethylene glycol esters of palmitic acid (C16) or stearic acid (C18) or capric acid, BRIJ (registered trademark)Polyoxyethylene fatty ethers derived from sterol alcohols such as S2, polyoxyethylene oxypropylene stearate, macrogol stearyl ether (20), diethylaminoethyl stearate, polyethylene glycol stearate, sucrose distearate, sucrose tristearate, sorbitan monostearate, sorbitan tristearate, mannitol monooleate, octaglycerol monooleate, sorbitan dioleate, polyricinoleate, polysorbates such as polysorbate 20 and polyoxyethylene (20) sorbitan monooleate (polysorbate 80), sorbitan, sorbitan monolaurate, sucrose cocoate, glycereth-2 cocoate, ethylhexyl cocoate, polypropylene glycol-3 benzyl ether myristate, sodium myristate, sodium aurothiomalate, polyethylene glycol 8 laurate, polyethylene-4 dilaurate, derived from α-hexadecyl-ω-hydroxy poly(oxyethylene), cocamidodiethanolamine, N-(2-hydroxyethyl) dodecanamide, octylphenoxypolyethoxyethanol, maltoside, 2,3-dihydroxypropyl dodecanoate, 3-[(3R,6R,9R,12R,15S,22S,25S,30aS)-6,9,15,22-tetrakis(2-amino-2-oxoethyl)-3-(4-hydroxybenzyl)-12-(hydroxymethyl)-18-(11-methyltridecyl)-1,4,7,10,13,16,20,23,26-nonaoxotriacontahydropyrrolo[1,2-g][1,4,7,10,13,16,19,22,25]nonaazacyclooctacosine-25-yl]propenamide, 2-{2-[2-(2-{2-[2-(2-{2-(4-nonylphenoxy)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}ethanol, oxy polyethoxydodecane, poloxamers such as poloxamer 188 (Pluronic® F-68) and poloxamer 407, propylene glycol monocaprylate, Type I (CapryolPGMC), polyethoxylated tallow amine, polyglycerol, polyoxyl 40 hydrogenated castor oil, surfactin, 2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]ethanol, carbomer, carbomer sodium, calcium carboxymethylcellulose, carrageenan, cholesterol, deoxycholic acid, phospholipids such as egg lecithin, gellan gum, lanolin, capric acid, waxes such as Polawax NF, Polawax A31 or Ceral PW, ester gum, deacetyl phosphate, soy lecithin, sphingomyelin, sodium phosphate, sodium lauroyl lactate, lanolin, an oxirane methyl polymer containing oxirane oxirane monobutyl ether, 1,2-dierucoyl phosphatidylcholine, dimethicone end-blocked with an average of 14 moles of propylene oxide, lauryl methicone copolyol, lauroglycol 90, white mineral oil such as amphoserine KS, a dispersion of acrylamide / sodium acryloyldimethyltaurate copolymer in isododecane, and sodium polyacrylate, or a mixture thereof. Preferred are macrogol stearyl ether (20) and polysorbate 80. In one embodiment, there is less than 3% by mass, preferably 1.5% by mass, of at least one emulsifier relative to the total mass of at least one polymer, or the emulsifier is essentially absent or absent.

[0033] Enteric or top coating layer The enteric or top coating layer may contain 10% by mass or more, 20% by mass or more, 30% by mass or more, 40% by mass or more, 50% by mass or more, 60% by mass or more, 70% by mass or more, 80% by mass or more, 90% by mass or more or 95% by mass or more of a polymer. The coating layer may contain 10 - 100, 10 - 90, 12 - 80, 15 - 80, 18 - 80, 20 - 80 or 40 - 80% by mass of a polymer. The top coating layer is disposed on top of the enteric coating layer containing at least one of the above polymers. The top coat is also preferably water-soluble or essentially water-soluble. The top coat may have a function of coloring the pharmaceutical form or the dietary supplement form, or a function of protecting from the influence of the environment, for example, moisture during storage.

[0034] Intermediate coating layer The intermediate coating layer is located on or above the capsule and contains at least one polymer, at least one alkaline agent, and at least one specific release promoter. The intermediate coating layer can contain at least one polymer in an amount of 5 to 90% by mass, preferably 10 to 70% by mass, more preferably 30 to 50% by mass, based on the total mass of the intermediate coating layer. The at least one polymer is preferably selected from cellulose such as hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxyethyl methylcellulose (HEMC), ethyl cellulose (EC), methyl cellulose (MC), cellulose ester, cellulose glycolic acid, polyethylene glycol, polyethylene oxide, polyvinyl pyrrolidone, polyvinyl acetate, polyvinyl alcohol, or a mixture thereof, and is preferably hydroxypropyl methylcellulose.

[0035] The intermediate coating layer may contain an alkaline agent in an amount of 10 to 75% by mass, preferably 10 to 50% by mass, based on the total mass of the coating layer. The alkaline agent can be an alkali or alkaline earth metal salt. The alkaline agent can be selected from calcium oxide, calcium carbonate, magnesium carbonate, magnesium oxide, sodium carbonate, sodium bicarbonate, and sodium hydroxide, or any mixture thereof. Preferred alkaline agents are magnesium oxide and / or magnesium carbonate.

[0036] At least one release promoter is selected from iron oxide, aluminum oxide, titanium dioxide, dimethyl sulfoxide, zinc oxide, sucrose, maltose, lactose, dextrose, glucose, fructose, Red 40 (E129), Blue 1 (E133), and Yellow 5 (E102), amaranth (E123), carmoisine (E122), ponceau 4R (E124) and quinoline yellow WS (E104), brilliant blue (E133), indigocarmine (E132), allura red (E129), tartrazine (E102), sunset yellow (E110), erythrosine (E127), ponceau 4R (E124), etc. dyes, or any mixture thereof, and is present in an amount of 0.1 to 20% by mass, preferably 0.2 to 15% by mass, more preferably 0.5 to 8% by mass, most preferably 1 to 6% by mass, based on the mass of at least one polymer.

[0037] The intermediate coating layer can contain at least one lubricant in an amount of preferably 2 to 50% by mass, more preferably 5 to 25% by mass, based on the total mass of the intermediate coating layer. Suitable flow promoters are the same as those described for the enteric coating layer herein. At least one flow promoter is preferably talc or glycerol. The intermediate layer can contain 1 to 95% by mass, preferably 10 to 50% by mass, of at least one additive, such as a polymer binder, a plasticizer or an anti-adhesive agent, or a combination thereof, based on the total mass of the intermediate layer. Suitable additives are the same as those described for the enteric coating layer. Preferably, the intermediate layer is disposed directly on the capsule.

[0038] Amount and thickness of the enteric and intermediate coating layers To ensure inflow prevention and processability, when a hard shell capsule, tablet or mini-tablet forms the core, the total coating amount is preferably 2.0 to 30 mg / cm 2 More preferably, particularly for hard shell capsules, it is 2.0 to 10 mg / cm 2 Or particularly for mini-tablets or tablets, it is 10 to 25 mg / cm2 It has been found that For size #0 hard shell capsules, the amount of the coating layer should not be too much. If the amount of the applied coating layer is too much, it may be difficult to process the polymer-coated pre-locked hard shell capsules in a capsule filling machine. When the amount of the coating layer is less than 5 mg / cm 2 , for example, 2 - 4 mg / cm 2 , usually, there is no problem with a standard capsule filling machine without modification. In the range of 4 - about 8 mg / cm 2 , the capsule filling machine can still be used, but the forms of the main body and the cap should be adjusted to be somewhat wider. Such adjustment can be easily carried out by a mechanic. Therefore, the capsule filling machine can be advantageously used within the range of the amount of the coating layer of about 3 - about 8 mg / cm 2 .

[0039] For size #1 hard shell capsules, the amount of the coating layer should not be too much. If the amount of the applied coating layer is too much, it may be difficult to process the polymer-coated pre-locked hard shell capsules in a capsule filling machine. When the amount of the coating layer is less than 4 mg / cm 2 , for example, 2 - 3.5 mg / cm 2 , usually, there is no problem even when using a standard capsule filling machine without modification. In the range of 3.5 - about 8 mg / cm 2 , the capsule filling machine can still be used, but the shapes of the main body and the cap should be adjusted to be somewhat wider. Such adjustment can be easily carried out by a mechanic. Therefore, the capsule filling machine can be advantageously used within the range of the amount of the coating layer of about 3 - about 8 mg / cm 2 .

[0040] For hard shell capsules of size #3, the amount of the coating layer should not be too much. If the amount of the applied coating layer is too much, this may make the subsequent processing of the polymer-coated pre-locked hard shell capsules difficult in a capsule filling machine. In the range of 2 to about 6 mg / cm 2 Although the capsule filling machine can still be used within this range, the shapes of the main body and the cap should be adjusted to be somewhat wider. Such adjustment can be easily carried out by a mechanic. Therefore, the capsule filling machine can be advantageously used within the range of the amount of the coating layer of about 3 to about 6 mg / cm 2 .

[0041] If the amount of the applied coating layer is too much, there will also be an assembly where the coating layer is excessive on the rim of the cap in the pre-lock state between the main body and the cap. In this case, when manually or mechanically opening the coated pre-locked hard shell capsule, cracks in the coating layer may occur after drying. The cracks may later cause leakage of the capsule. Finally, since the coating layer is thicker than the gap in the overlapping area between the main body and the cap, if the coating is too thick, it will be difficult or impossible to close the opened coated hard shell capsule until it is finally locked.

[0042] Generally, the amount of the coating layer (= total mass increase) on hard shell capsules, tablets or mini-tablets can be applied in the range of 0.7 to 30, 1.0 to 18, 2 to 10, 4 to 8, 1.0 to 8, 1.5 to 5.5, 1.5 to 4 mg / cm 2 . Generally, the average thickness of the coating layer on hard shell capsules, tablets or mini-tablets can be about 5 to 100, 10 to 50, 15 to 75 μm. Generally, the dry mass of the coating layer on hard shell capsules can be applied in an amount of 5 to 50, preferably 8 to 40% based on the mass of the pre-lock capsule. Using this guidance, one of ordinary skill in the art can adjust the amount of the coating layer within a range between too low an amount and too high an amount.

[0043] Biologically active ingredient The biologically active ingredient is preferably a pharmaceutical active ingredient and / or a nutraceutical active ingredient and / or a cosmetic active ingredient. Even if a specific biologically active ingredient can be included in each coating layer, it is preferred that the biologically active ingredient be included in the filling. In particular, when the biologically active ingredient is contained in liposomes, lipid nanoparticles or nucleic acids, the biologically active ingredient is contained only in the filling.

[0044] Biologically active ingredient(s) The present invention is particularly useful for sustained-release pharmaceutical or nutraceutical dosage forms having a filling of a biologically active, preferably pharmaceutically or nutraceutically active ingredient. Suitable therapeutic and chemical classes of pharmaceutical active ingredients that can be used as fillers for the described polymer-coated hard shell capsules are, for example, analgesics, antibiotics or anti-infectives, antibodies, anti-epileptics, antigens from plants, anti-rheumatics, benzimidazole derivatives, β-blockers, cardiovascular drugs, chemotherapeutic agents, CNS drugs, digitalis glycosides, gastrointestinal drugs such as proton pump inhibitors, enzymes, hormones, liquid or solid natural extracts, oligonucleotides, peptides, hormones, proteins, therapeutic bacteria, peptide, protein (metal) salts, i.e., aspartates, chlorides, urological drugs, lipid nanoparticles, liposomes, polymer nanoparticles, vaccines. In a preferred embodiment, at least one liposome or lipid nanoparticle each containing at least one polynucleotide is included.

[0045] In a preferred embodiment, the pharmaceutically active ingredient is a lipid nanoparticle or liposome each containing a polynucleotide or nucleic acid, and more preferably, the nucleic acid agent can be DNA, RNA, or a combination thereof. In certain embodiments, the nucleic acid agent can be an oligonucleotide and / or polynucleotide. In certain embodiments, the nucleic acid agent can be an oligonucleotide and / or a modified oligonucleotide (including, but not limited to, modifications via phosphorylation); an antisense oligonucleotide and / or a modified antisense oligonucleotide (including, but not limited to, modifications via phosphorylation). In certain embodiments, the nucleic acid agent can contain cDNA and / or genomic DNA. In certain embodiments, the nucleic acid agent can contain non-human DNA and / or RNA (e.g., nucleic acid sequences of viruses, bacteria, or fungi). In certain embodiments, the nucleic acid agent can be a plasmid, cosmid, gene fragment, artificial and / or natural chromosome (e.g., yeast artificial chromosome), and / or a portion thereof. In certain embodiments, the nucleic acid agent can be a functional RNA (e.g., mRNA, tRNA, rRNA, and / or ribozyme). In certain embodiments, the nucleic acid agent can be an RNAi inducer, small interfering RNA (siRNA), small hairpin RNA (shRNA), and / or microRNA (miRNA). In certain embodiments, the nucleic acid agent can be a peptide nucleic acid (PNA). In certain embodiments, the nucleic acid agent can be a polynucleotide containing synthetic analogs of nucleic acids that may or may not be modified. In certain embodiments, the nucleic acid agent can include various structural forms of DNA, including single-stranded DNA, double-stranded DNA, supercoiled DNA, and / or triple-stranded DNA; Z-DNA; and / or combinations thereof. Further suitable nucleic acids are disclosed, for example, in International Publication No. WO 2012 / 103035, which is incorporated herein by reference.

[0046] Further examples of drugs that can be used as fillers for the described polymer-coated hard shell capsules are, for example, acamprosate, aescin, amylase, acetylsalicylic acid, adrenaline, 5-aminosalicylic acid, aureomycin, bacitracin, balsalazide, beta-carotene, bicalutamide, bisacodyl, bromelain, bromelain, budesonide, calcitonin, carbamazepine, carboplatin, cephalosporin, cetrorelix, clarithromycin, chloromycetin, cimetidine, cisapride, cladribine, chlordiazepate, chromalin, 1-deaminocysteine-8-D-arginine-vasopressin, delormocycline, detirelix, dexlansoprazole, diclofenac, didanosine, digitoxin and other digitalis glycosides, dihydrostreptomycin, dimethicone, divalproex, drospirenone, duloxetine, enzyme, erythromycin, esomeprazole, estrogen, etoposide, famotidine, fluoride, garlic oil, glucagon, granulocyte colony-stimulating factor (G-CSF), heparin, hydrocortisone, human growth hormone (hGH), ibuprofen, ilaprazole, insulin, interferon, interleukin, intron A, ketoprofen, lansoprazole, leuprolide acetate triperide, lipoic acid, lithium, kinins, memantine, mesalazine, methenamine, milameline, mineral, minoprazole, naproxen, natamycin, nitrofurans, novobiocin, olsalazine, omeprazole, orotate, pancreatin, pantoprazole, parathyroid hormone, paroxetine, penicillin, perprazole, pindolol, polymyxin, potassium, pravastatin, prednisone, pregulmetacin, progabide, prosomatostatin, protease, quinapril, rabeprazole, ranitidine, ranolazine, reboxetine, rutoside, somatostatin, streptomycin, subtilin, sulfasalazine, sulfanilamide, tamsulosin, tenatoprazole, trypsin, valproic acid, vasopressin, vitamin, vitamin, zinc, its salts, derivatives, polymorphs, isomorphs, acetaminophen, codeine, gliocladin, isosorbide-5-mononitrate, lumiracoxib, metoprolol, minoxidil,Nefazodone, phenytoin, etabonate remogliflozin, rivastigmine, theophylline, cortisol, darunavir, difepipin, valacyclovir, mizoribine, ribavirin, antipyrine, glypizide, phenytoin, selegiline, theophylline, cilostazol, cimetidine, darunavir, digoxin, famotidine, fexofenadine, forskolin, indinavir, nevirapine, quinidine, ranitidine, tacrolimus, talinolol, verapamil, benazepril, cephalexin, cefadroxil, atenolol, ciprofloxacin, fluvastatin, metformin, levodopa, gabapentin, pseudoephedrine, ropivacaine, and sotalol, or mixtures or combinations thereof, preferably acetaminophen, codeine, gliocladin, isosorbide-5-mononitrate, lumiracoxib, metoprolol, minoxidil, nefazodone, phenytoin, remogliflozin etabonate, rivastigmine, theophylline, colchicine, darunavir, nifedipine, valacyclovir, mizoribine, ribavirin, antipyrine, glypizide, phenytoin, selegiline, theophylline, cilostazol, cimetidine, darunavir, digoxin, famotidine, fexofenadine, forskolin, indinavir, nevirapine, quinidine, ranitidine, tacrolimus, talinolol, verapamil, benazepril, cephalexin, cefadroxil, atenolol, ciprofloxacin, fluvastatin, metformin, levodopa, gabapentin, pseudoephedrine, ropivacaine, sotalol, or mixtures or combinations thereof may be.

[0047] It will be apparent to those skilled in the art that the terms pharmaceutical active ingredient and nutritional supplement active ingredient, excipient and composition, pharmaceutical dosage form and nutritional supplement dosage form, respectively, widely overlap. Many substances listed as dietary supplements can also be used as pharmaceutical active ingredients. Depending on the specific use and the laws and classifications of the local authorities, the same substance can be listed as a pharmaceutical composition or a nutritional supplement composition or both, as a pharmaceutical active ingredient or a nutritional supplement active ingredient. Nutritional supplements are well known to those skilled in the art. Nutraceuticals are often defined as extracts of foods that are claimed to have a medical effect on human health. Thus, nutritional supplement active ingredients can also exhibit pharmaceutical activity. Examples of nutritional supplement active ingredients can be resveratrol from grape products as an antioxidant, soluble dietary fiber products such as okra seed husks for reducing hypercholesterolemia, broccoli (sulforaphane) as an anticancer agent, and soybeans or clover (isoflavonoids) for improving arterial health. Thus, it is clear that many substances listed as nutraceuticals can also be used as pharmaceutical active ingredients. Typical nutraceuticals or nutraceutical active ingredients that can be used as fillers for the described polymer-coated hard shell capsules may also include probiotics and prebiotics. Probiotics are live microorganisms that are thought to support the health of humans or animals when consumed. Prebiotics are nutraceuticals or nutraceutical active ingredients that induce or promote the growth or activity of beneficial microorganisms in the human or animal intestine.

[0048] Examples of nutraceuticals are resveratrol from grape products, omega-3-fatty acids or proanthocyanidins from blueberries as antioxidants, soluble dietary fiber products such as okra seed husks for reducing hypercholesterolemia, broccoli (sulforaphane) as an anticancer agent, and soybeans or clover (isoflavonoids) for improving arterial health. Other examples of nutraceuticals are flavonoids, antioxidants, α-linolenic acid from flaxseeds, β-carotene from marigold petals, or anthocyanins from berries. Sometimes, the expressions "nutraceuticals" or "nutriceuticals" are used as synonyms for nutritional supplements. Preferred biological active ingredients are azacitidine, decitabine, metoprolol, mesalamine and omeprazole.

[0049] Additive The additives according to the present invention are preferably excipients, which are well known to those skilled in the art and are formulated with the biologically active ingredients contained in the coated hard shell capsules, as disclosed and claimed herein, and / or with the polymeric coating layer of the hard shell capsules. All excipients used should be safe in terms of toxicity and must be used in pharmaceuticals or dietary supplements without risk to the patient or purchaser.

[0050] The dosage form may include excipients, preferably pharmaceutical or nutritionally acceptable excipients selected from the group consisting of antioxidants, glidants, binders, flavoring agents, flow aids, fragrances, penetration enhancers, pore formers or stabilizers, or combinations thereof. Pharmaceutical or nutritionally acceptable excipients may be included in the core and / or coating layer containing the disclosed polymer. Pharmaceutical or nutritionally acceptable excipients are excipients that are permitted to be used for applications in the pharmaceutical or nutraceutical fields.

[0051] The intermediate, enteric, or top coating layer may contain, or may not contain at all (0%), additives, preferably pharmaceutical or nutritionally acceptable excipients, up to 90, up to 80, up to 70, up to 50, up to 60, up to 50, up to 40, up to 30, up to 20, up to 10, up to 5%, up to 3%, up to 1% by mass, based on the total mass of at least one polymer.

[0052] Plasticizer The intermediate coating layer and / or enteric coating layer can contain one or more plasticizers. The plasticizer reduces the glass transition temperature by physical interaction with the polymer and promotes film formation depending on the amount added. The molecular weight of suitable substances is usually 90 - 20,000 g / mol and contains one or more hydrophilic groups in the molecule, such as hydroxyl, ester, or amino groups. Examples of suitable plasticizers are alkyl citrates, alkyl phthalates, alkyl sebacates, diethyl sebacate, dibutyl sebacate, polyethylene glycol, and polypropylene glycol. Preferred plasticizers are triethyl citrate (TEC), acetyltriethyl citrate (ATEC), diethyl sebacate, dibutyl sebacate (DBS), polyethylene glycol, and polypropylene glycol, or mixtures thereof. The addition of plasticizers to the formulation can be carried out in a known manner, directly in an aqueous solution or after heat pretreatment of the mixture. It is also possible to use a mixture of plasticizers. The enteric coating layer can contain one or more plasticizers and, calculated on at least one polymer, can preferably contain up to 60% by weight, up to 30% by weight, up to 25% by weight, up to 20% by weight, up to 15% by weight, up to 10% by weight, less than 5% by weight of plasticizer, or can contain no (0%) plasticizer.

[0053] Filler Standard fillers are usually added to the formulations of the invention during processing into coating agents and binders. The amounts introduced into the pharmaceutical coating or overlay and the use of standard fillers are well known to those skilled in the art. Examples of standard fillers are release agents, stabilizers, antioxidants, pore formers, penetration enhancers, brighteners, fragrances or flavoring agents. These are used as processing aids, intended to ensure a reliable and reproducible preparation process and good long-term storage stability, or they achieve further advantageous properties in the pharmaceutical form. These are added to the polymer formulation before processing and can affect the permeability of the coating. This property can, in some cases, be used as an additional control parameter.

[0054] Dosage form The dosage form includes a core coated with an intermediate coating layer and an enteric coating layer as disclosed and can preferably be in the form of (coated) pellets (cores) or (coated) hard capsules (cores). The dosage form may be, for example, in the form of tablets, mini - tablets, pellets, pills, granules, sachets or capsules, preferably hard capsules. The dosage form may preferably be in multiple units, for example, contained in tablets, sachets or capsules.

[0055] Core The core of the dosage form contains a biologically active ingredient. The core of the dosage form may contain a biologically active ingredient distributed in a matrix structure, or bound in a binder in a coating on an internal core structure, or encapsulated in a capsule. The core can be prepared by methods such as granulation, extrusion, spheronization or hot - melt extrusion. The core may be a pellet, pill, granule, tablet, mini - tablet or capsule. The core may be an active - ingredient - containing tablet, a pellet - containing compressed tablet, a mini - tablet or a capsule (hard or soft), and may be filled with active - ingredient - containing pellets or granules, a drug solution or dispersion, a mini - tablet or a powder or a combination thereof. The core may contain, for example, uncoated pellets, neutral carrier pellets such as sugar spheres or nonpareils, on which the biologically active ingredient is bound in a binder such as lactose, polyvinylpyrrolidone or a neutral cellulose derivative such as HPC or HPMC. The binder - coating layer with the biologically active ingredient is considered a part of the core herein. The binder - coating layer of the core does not essentially affect the controlled release of the biologically active ingredient, in contrast to the intermediate - coating layer and enteric - coating layer. The core may contain uncoated pellets consisting of crystallized biologically active ingredient. The core may contain 0.1 - 100, 1 - 100, 2 - 90, 5 - 85, 10 - 70, 15 - 50% by mass of the biologically active ingredient. The core may contain 0 - 99.9, 0 - 99, 10 - 98, 15 - 95, 30 - 90 or 50 - 85% by mass of the biologically active ingredient.

[0056] The core can preferably be a hard shell capsule. Hard shell capsules for pharmaceutical or dietary supplement use are well known to those skilled in the art. A hard shell capsule is a two-piece encapsulation capsule consisting of two capsule halves, a body and a cap. The capsule body and cap materials are usually hard and sometimes brittle materials. A hard shell capsule includes a body and a cap. The body and cap are usually cylindrical with one end open and have a closed, rounded hemispherical end at the opposite end. The shape and size of the cap and body are such that the body can be nested and pushed into the open end of the cap. The body and cap include a mating region (overlap region) that potentially overlaps on the outside of the body and the inside of the cap, and this region partially overlaps when the capsule is closed in the pre-lock state and completely overlaps in the final lock state. When the cap is slid partially over the mating region of the body, the capsule is in the pre-lock state. When the cap is slid completely over the mating region of the body, the capsule is in the final lock state. Maintenance of the pre-lock or final lock state is usually supported by a snap-in lock mechanism of the body and cap, for example, mating surrounding notches or dimples, preferably elongated dimples.

[0057] Normally, the body is longer than the cap. Covering the overlapping region on the outside of the body with the cap can close or lock the capsule. In the closed state, the cap covers the overlapping region on the outside of the body in the pre-lock or final lock state. In the final lock state, the cap completely covers the overlapping region on the outside of the body, and in the pre-lock state, the cap only partially overlaps the overlapping region on the outside of the body. Sliding the cap on the body can usually be fixed at one of two different positions where the capsule is closed in the pre-lock or final lock state. Hard shell capsules are commercially available in a variety of sizes. Hard shell capsules are usually delivered as an empty container with the body and cap already in a pre-locked state and, in some cases, as separate capsule halves, body and cap. The pre-locked hard shell capsules can be supplied to a capsule filling machine, which performs the opening, filling, and closing of the capsules to the final locked state. Typically, hard shell capsules are filled with dry materials such as powders or granules or pellets or mini-tablets or sub-micron particles, or viscous liquids containing biologically active ingredients.

[0058] The cap and the body are provided with closing means which are advantageous for the pre-lock (temporary) and / or final lock of the capsule. Thus, it is possible to provide raised points on the inner wall of the cap, and on the outer wall of the body, there are provided somewhat large recessed points arranged such that when the capsule is closed, the raised points fit into the recesses. Alternatively, the raised portions may be formed on the outer wall of the body and the recessed portions may be formed on the inner wall of the cap. An arrangement where the raised portions or recessed portions are arranged in a ring shape or a spiral shape around the wall. Instead of the dot-like configuration of the raised portions and recesses, they can surround the wall of the cap or the body in an annular configuration, but advantageously, recesses and openings are provided to allow the exchange of gas into and out of the capsule. One or more raised portions may be provided in an annular arrangement around the inner wall of the cap and the outer wall of the body such that at the final lock position of the capsule, the raised portion on the cap is positioned adjacent to the raised portion on the body. Sometimes, a raised portion is formed on the outside of the body close to the open end, a recess is formed in the cap close to the open end, and at the final lock position of the capsule, the raised portion of the body latches into the recess of the cap. The raised portion is preferably such that the cap can always be opened in the pre-lock state without damaging the capsule, or, as a variant, once the cap is closed, it may not be possible to open it again without destroying the capsule. A capsule with one or more such latching mechanisms (latches) (for example, two surrounding grooves) is preferred. More preferably, a capsule having at least two such latching means for fixing the two capsule parts to different extents. In this type of component, the first latching means (dimple or notch surrounding the periphery) is formed near the opening of the capsule cap and the capsule body, and the second latching means (notch surrounding the periphery) can be further somewhat shifted towards the closed end of the capsule part. The first latching means fixes the two capsule parts more weakly than the second latching means. This variant has the advantage that after the manufacture of the empty capsule, the capsule cap and the capsule body can first be pre-lock joined to each other using the first latching mechanism. To fill the capsule, the two capsule parts are then separated again.After filling, the two capsule parts are pushed together until the second set of latches firmly fixes the capsule parts in the final locked state. Preferably, the body and the cap of the hard shell capsule each include a notch and / or a dimple surrounding the periphery in a region where the cap can slide over the body. The notch surrounding the body and the dimple of the cap are adapted to each other to provide a snap-in mechanism or a snap-in type mechanism. The dimple may be circular or elongated in the longitudinal direction (oval). The surrounding notch of the body and the surrounding notch of the cap (a closely fitting ring) also fit together to provide a snap-in or snap-in mechanism. Thereby, the capsule can be closed in either the pre-locked state or the final locked state by the snap-in mechanism. Preferably, the mating of the notch surrounding the body and the elongated dimple of the cap is used to fix the body and the cap to each other in the pre-locked state. The mating surrounding notches of the body and the cap are preferably used to fix or lock the body and the cap to each other in the final locked state. The area where the cap can slide on the body can be referred to as the overlapping area between the body and the cap, or simply the overlapping area. When the cap overlaps with the body only partially, perhaps covering 20 - 90% or 60 - 85% of the overlapping area, the hard shell capsule is only partially closed (pre - locked). Preferably, in the presence of a locking mechanism such as mating surrounding notches and / or dimples in the body and the cap, the partially closed capsule may be considered pre - locked. When the capsule is polymer - coated in the pre - locked state, the coating completely covers the outer surface including the part of the overlapping area between the body and the cap that is not covered by the cap in this pre - locked state. When the capsule is polymer - coated in the pre - locked state and then closed to the final locked state, the coating of the part of the overlapping area between the body and the cap that was not covered by the cap in the pre - locked state comes to be covered by the cap. Subsequently, the presence of the part of the coating encapsulated between the body and the cap in the final locked state is sufficient to ensure that the hard shell capsule is tightly sealed. When the cap overlaps the body, the entire overlapping area of the body, the hard shell capsule is finally closed or reaches the final locked state. Preferably, in the presence of a locking mechanism such as mating surrounding notches and / or dimples in the body and the cap, the finally closed capsule may be considered finally locked.

[0059] Normally, dimples are preferred to fix the body and the cap in the pre - locked state. As a non - restrictive rule, the mating area of the dimples is smaller than the mating area of the surrounding notches. The dimples snapped in like this can be snapped out again by applying a force smaller than the force required to snap out the snap - in fixation by mating the surrounding notches. The dimples on the body and the cap are located in the area where the cap can slide on the body and are adapted to each other in the pre-locked state by a snap-in or snap-in-place mechanism. There may be, for example, 2, 4, or preferably 6 notches or dimples distributed circularly around the cap. Normally, the dimples on the cap and the peripheral notches on the body in the area where the cap can slide on the body coincide with each other, so that as a result, they enable the capsule to be closed by a snap-in mechanism in the pre-locked state. In the pre-locked state, since the force required to open the hard shell capsule is relatively small, it can be manually or mechanically reopened without damage. Therefore, the "pre-locked state" may be referred to as "loosely capped". Normally, the surrounding notches or mating lock rings on the body and the cap in the area where the cap can slide on the body are adapted to each other, so that as a result, they enable the capsule to be closed by a snap-in mechanism in the final locked state. In the final locked state, since the force required to open the hard shell capsule is relatively large, it cannot be manually or mechanically reopened without damage or can hardly be reopened. Normally, the dimples and the surrounding notches are formed on the capsule body or the capsule cap. When the capsule parts with these protrusions and depressions are fitted together, an ideally defined uniform gap of 10 microns to 150 microns, more specifically 20 microns to 100 microns, is formed along the contact surface between the capsule body and the capsule cap disposed thereon.

[0060] Preferably, the body of the hard shell capsule includes a tapered rim. The tapered rim prevents damage caused by the rims of the body and the cap colliding when the capsule is manually or mechanically closed. In contrast to hard shell capsules, soft shell capsules are welded one-piece encapsulated capsules. Soft gel capsules are often made from blow-molded soft gel material and are usually filled with a liquid containing a biologically active ingredient by injection. The present invention is not related to welded one-piece capsules with soft shells.

[0061] Size of the hard shell capsule Closed and finally locked hard shell capsules can have an overall length in the range of about 5 - 40 mm. The diameter of the cap can be in the range of about 1.3 - 12 mm. The diameter of the body can be in the range of about 1.2 - 11 mm. The length of the cap is in the range of about 4 - 20 mm, and the length of the body is in the range of 8 - 30 mm. The filling volume can be between about 0.004 - 2 ml. The difference between the pre-lock length and the final lock length can be about 1 - 5 mm. The capsules can be divided into standard sizes, for example, sizes 000 - 5. A closed capsule of size 000 has, for example, an outer cap diameter of about 9.9 mm and an outer body diameter of about 9.5 mm, with an overall length of about 28 mm. The cap length is about 14 mm, and the body length is about 22 mm. The filling capacity is about 1.4 ml. A closed capsule of size 5 has, for example, an overall length of about 10 mm, an outer cap diameter of about 4.8 mm, and an outer body diameter of about 4.6 mm. The cap length is about 5.6 mm, and the body length is about 9.4 mm. The filling capacity is about 0.13 ml. A closed capsule of size 9 has, for example, an overall length of about 8.4 mm and an outer cap diameter of about 2.7 mm. The filling capacity is about 0.025 ml. A capsule of size 0 can have a length of about 23 - 24 mm in the pre-lock state and a length of about 20.5 - 21.5 mm in the final lock state. Thus, the difference between the pre-lock length and the final lock length can be about 2 - 3 mm.

[0062] Method for manufacturing a coated hard shell capsule A method for preparing polymer-coated hard shell capsules is described, where the hard shell capsules include a body and a cap, and where, in the closed state, the cap overlaps the body either in a pre-locked state or a final locked state. The hard shell capsules are provided in a pre-locked state and coated with a first coating solution, suspension or dispersion according to the invention, preferably by spray coating, to form an intermediate coating layer, and then optionally dried, and then coated with a coating solution, suspension or dispersion according to the invention, preferably by spray coating, to form an enteric coating layer covering the outer surface of the hard shell capsules in the pre-locked state. Further, a top coating layer can be subsequently applied after any drying step.

[0063] In a further process step, the pre-locked hard shell capsules can be provided with a filling containing a pharmaceutical or nutraceutical biologically active ingredient and closed in the final locked state. In a further process step, the pre-locked polymer-coated hard shell capsules can be opened, filled with a filling containing at least one biologically active ingredient, and closed in the final locked state. This further process step is preferably carried out by feeding the pre-locked coated hard shell capsules to a capsule filling machine, which opens the polymer-coated hard shell capsules, fills them with a filling containing at least one biologically active ingredient, and closes them in the final locked state. This further process step results in a final locked polymer-coated hard shell capsule, which is a container for at least one biologically active ingredient. The final locked polymer-coated hard shell capsule as a container for at least one biologically active ingredient is preferably in the dosage form of a pharmaceutical or dietary supplement.

[0064] The dosage form preferably includes a polymer-coated hard shell capsule in a final locked state containing a filling containing at least one biologically active ingredient, and the polymer-coated hard shell capsule includes a coating layer according to the present invention. The coating layer covers the outer surface region of the capsule in the pre-locked state, but does not cover the overlapping region where the pre-locked cap covers the body.

[0065] The coating suspension can contain an organic solvent such as acetone, isopropanol or ethanol. The concentration of the dry mass material in the organic solvent can be about 5 to 50% by mass of the polymer. A suitable spraying concentration can be about 5 to 25% by dry mass. The coating suspension can be a dispersion of the polymer in an aqueous medium such as water, or a mixture of 80% by mass or more of water and 20% by mass or less of an aqueous medium such as acetone or isopropanol. A suitable concentration of the dry mass material in the aqueous medium can be about 5 to 50% by mass. A suitable spraying concentration can be about 5 to 25% by dry mass. Spray coating is preferably performed by spraying a coating solution or dispersion onto pre-locked capsules in a drum coater or a fluidized bed coating apparatus.

[0066] Method for manufacturing a filler for a dosage form Suitable methods for preparing a filling for a dosage form, preferably for pharmaceutical or nutraceutical use, are well known to those skilled in the art. Suitable methods for preparing a filling for a dosage form, preferably for pharmaceutical or nutraceutical use, as disclosed herein, include direct compression, drying, wet or sintered granule compression, extrusion and subsequent rounding, wet or dry granulation, direct pelletization, or binding of a powder onto beads or neutral cores or active ingredient-containing particles or pellets that do not contain the active ingredient, and the application of intermediate and enteric coating layers in the form of aqueous dispersions or organic solutions in spray methods, or by fluidized bed spray granulation to form a core containing a biologically active ingredient in the form of tablets or mini-tablets.

[0067] Capsule filling machine Polymer-coated hard shell capsules are supplied to a capsule filling machine in a pre-locked state, and the capsule filling machine performs a process of separating the body and the cap, a process of filling the body with a filling material, and a process of recombining the body and the cap in a final locked state. The capsule filling machine used may be a capsule filling machine capable of manufacturing filled and closed capsules at a rate with an output of 1,000 or more filled and finally closed capsules per hour, preferably a fully automated capsule filling machine. Capsule filling machines, preferably fully automated capsule filling machines, are well known in the art and are commercially available from a certain company. The capsule filling machine used can preferably be operated at a rate with an output of 1,000 or more, preferably 10,000 or more, 100,000 or more, and from 10,000 to 500,000 filled and finally closed capsules per hour.

[0068] General operation of the capsule filling machine Prior to the capsule filling process, the capsule filling machine is provided with a sufficient number or amount of pre-coated hard shell capsules in a pre-locked state. The capsule filling machine is also provided with a sufficient amount of filling material to be filled during operation. The pre-locked hard shell capsules can fall into a supply pipe or chute by gravity. The capsules can be uniformly aligned by mechanically measuring the difference in diameter between the cap and the body. The hard shell capsules are then usually supplied to a two-fraction housing or brush in a suitable orientation. The diameter of the upper bushing or housing is usually larger than the diameter of the capsule body bushing, so the capsule cap can be held in the upper bushing while the body is drawn into the lower bushing by vacuum. When the capsule is opened / the body and the cap are separated, the upper housing and the lower housing or bush are separated to position the capsule body for filling. Next, the opened capsule body is filled with a filling material. For different filling materials such as granules, powders, pellets, or mini-tablets, various types of filling mechanisms can be applied. Capsule filling machines generally use various mechanisms for handling various dosage components and various numbers of filling stations. The dosing system is usually based on the volume or amount of the filling material determined by the capsule size and the volume of the capsule body. Manufacturers of empty capsules usually provide a reference table showing the volume capacity of the capsule body and the maximum filling mass for different capsule sizes based on the density of the filling material. After filling, the body and the cap are rejoined mechanically in the final locked state or position.

[0069] Use / Usage / Method steps In a suitable method for preparing a polymer-coated hard shell capsule in a closed state, the cap overlaps the body either in a pre-lock state or a final lock state to prepare a polymer-coated hard shell capsule suitable as a container for a biologically active ingredient (a) The step of providing the hard shell capsule is provided in the pre-lock state (b) Spray coating with a coating solution, suspension or dispersion containing components for forming an intermediate coating layer, optionally drying, and then spray coating with a coating solution, suspension or dispersion containing components for forming an enteric coating layer covering the outer surface of the hard shell capsule in the pre-lock state, optionally drying, and optionally further applying a top coating layer which includes, where the spray coating can preferably be applied using a drum coater device or a fluidized bed coating device, more preferably using a drum coater device. A suitable product temperature during the spray coating process can be in the range of about 15 to 40 °C, preferably about 23 to 30 °C. A suitable spray rate can be in the range of about 0.3 to 17.0, preferably 0.5 to 14 [g / min / kg]. After spray coating, a drying step is included. The polymer-coated hard shell capsules in the preliminary locked state can be opened in step (c), filled with a filling containing a biologically active ingredient in step (d), and then closed to the final locked state in step (e). Steps (c) to (e) can be carried out manually or preferably assisted by a suitable device, such as a capsule filling machine. Preferably, the coated hard shell capsules in the pre-locked state are supplied to a capsule filling machine, which performs the opening step (c), filling with a filling containing a biologically active ingredient in step (d), and closing of the capsules to the final locked state in step (e). The selection of the process in all of those general or specific features and embodiments as disclosed herein can be combined without limitation with any other general or specific selection and limitation of the materials or numerical features and embodiments as disclosed herein, such as polymers, capsule materials, capsule sizes, coating thicknesses, biologically active ingredients, and any other embodiments as disclosed.

[0070] Materials of the body and the cap The base materials of the main body and the cap of the hard shell capsule can be selected from hydroxypropyl methylcellulose, starch, gelatin, pullulan, and copolymers of C1-C4 alkyl esters of methacrylic acid and methacrylic acid. Hard shell capsules in which the main body and the cap contain or consist of HPMC or gelatin are preferred, and HPMC is most preferred because of its good adhesion properties to the polymer coating.

[0071] Item The present invention particularly refers to the following items. 1. The following: (a) A core containing at least one biologically active ingredient, (b) An intermediate coating layer (ICL) above or over the core, comprising the following: (i) At least one polymer, (ii) At least one alkaline agent, (iii) At least one release promoter selected from iron oxide, aluminum oxide, titanium dioxide, dimethyl sulfoxide, zinc oxide, sucrose, maltose, lactose, dextrose, glucose, fructose, dyes, or any mixture thereof; (iv) Optionally, at least one lubricant; (v) Optionally, at least one plasticizer; and (vi) Optionally, at least one additive different from (i) to (v); comprising, wherein the at least one release promoter is present in an amount of 0.1 to 20% by weight, preferably 0.2 to 15% by weight, more preferably 0.5 to 8% by weight, most preferably 1 to 6% by weight based on the mass of the at least one polymer, and (c) An enteric coating layer (ECL) on or above the intermediate coating layer, comprising the following: (i) At least one polymer; (ii) Optionally, at least one lubricant; (iii) Optionally, at least one emulsifier; (iv) Optionally, at least one plasticizer; (v) Optionally, at least one biologically active ingredient; and (vi) Optionally, at least one additive different from (i) to (v), comprising a dosage form. 2. The dosage form according to item 1, which is a coated hard shell capsule, tablet or mini-tablet. 3. The dosage form according to item 1 or 2, wherein the biologically active ingredient is a pharmaceutically active ingredient. 4. The alkali agent is as follows: (i) An alkali metal salt or an alkaline earth metal salt; or (ii) selected from calcium oxide, calcium carbonate, magnesium carbonate, magnesium oxide, sodium carbonate, sodium bicarbonate, and sodium hydroxide, or any combination thereof, preferably magnesium oxide or magnesium carbonate, more preferably magnesium oxide; and / or (iii) present in an amount of 10 to 75% by mass, preferably 15 to 50% by mass, based on the total mass of the intermediate layer, The dosage form according to any one of items 1 to 3. 5. At least one release promoter is Fe 2 O 3 , TiO 2 , lactose, disodium 2-[[4-[ethyl-[(3-sulfonatophenyl)methyl]amino]phenyl]-[4-[ethyl-[(3-sulfonatophenyl)methyl]azaniumylidene]cyclohexa-2,5-dien-1-ylidene]methyl]benzenesulfonate or any mixture thereof, the dosage form according to any one of items 1 to 4.

[0072] 6. The at least one polymer in the intermediate coating layer and / or enteric coating layer, preferably the intermediate coating layer, is selected from at least one methacrylic acid copolymer, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC) or polyvinylpyrrolidone (PVP), the dosage form according to any one of items 1 to 5. 7. The at least one polymer in the intermediate coating layer and / or enteric coating layer, preferably the enteric coating layer, is as follows: (i) A core-shell polymer obtained by a two-stage emulsion polymerization process having a core of 70 to 80% by mass containing polymerization units of 65 to 75% by mass of ethyl acrylate and 25 to 35% by mass of methyl methacrylate, and a shell of 20 to 30% by mass containing polymerization units of 45 to 55% by mass of ethyl acrylate and 45 to 55% by mass of methacrylic acid; or (ii) An anionic polymer obtained by polymerizing 25 to 95% by mass of a C1-C12 alkyl ester of acrylic acid or methacrylic acid and 75 to 5% by mass of a methacrylic acid monomer having an anionic group, or (iii) A cationic methacrylic acid copolymer obtained by polymerizing a C1-C4 alkyl ester of acrylic acid or methacrylic acid and an alkyl ester of acrylic acid or methacrylic acid having a tertiary or quaternary ammonium group in the alkyl group; or (iv) A methacrylic acid ester copolymer obtained by polymerizing methacrylic acid and ethyl acrylate, methacrylic acid and methyl methacrylate, ethyl acrylate and methyl methacrylate, or methacrylic acid and methyl acrylate and methyl methacrylate, or (v) A methacrylic acid copolymer obtained by polymerizing 40 to 60% by mass of methacrylic acid and 60 to 40% by mass of ethyl acrylate, or (vi) A methacrylic acid-based copolymer obtained by polymerizing 60 to 80% by mass of ethyl acrylate and 40 to 20% by mass of methyl methacrylate; or (vii) A methacrylic acid copolymer obtained by polymerizing 5 to 15% by mass of methacrylic acid, 60 to 70% by mass of methyl acrylate, and 20 to 30% by mass of methyl methacrylate; or a mixture thereof; The dosage form according to any one of items 1 to 5, which is as described above. 8. At least one polymer in the intermediate coating layer and / or enteric coating layer, preferably in the enteric coating layer, is as follows: (i) An anionic polymer having a Tgm of 35°C or higher, preferably 35 to 155°C, more preferably 80 to 145°C, and most preferably 90 to 125°C, and the Tgm of the second polymer is 30°C or lower, preferably less than 15°C, or (ii) A methacrylic acid copolymer obtained by copolymerizing 40 to 60% by mass of methacrylic acid and 60 to 40% by mass of ethyl acrylate, and 60 to 80% by mass, preferably 60 to 78% by mass of ethyl acrylate and 40 to 20% by mass, preferably 38 to 20% by mass of methyl methacrylate, preferably in a mass ratio of 20:1 to 1:20, and optionally polymerizing up to 2% by mass of methacrylic acid; or (iii) A methacrylic acid ester copolymer obtained by copolymerizing 5 to 15% by mass of methacrylic acid, 60 to 70% by mass of methyl acrylate, and 20 to 30% by mass of methyl methacrylate, and a methacrylic acid ester copolymer obtained by copolymerizing 40 to 60% by mass of methacrylic acid and 60 to 40% by mass of ethyl acrylate, preferably contained in a ratio of 20:1 to 1:20 by mass ratio; The dosage form according to any one of items 1 to 5, which is a mixture of. 9. The dosage form according to any one of items 1 to 5, wherein at least one polymer in the intermediate coating layer and / or enteric coating layer is selected from at least one methacrylic acid copolymer, hydroxypropylmethylcellulose (HPMC) or hydroxypropylcellulose (HPC). 10. At least one polymer in the enteric coating layer is as follows: (i) A core-shell polymer which is a copolymer obtained by a two-stage emulsion polymerization process having a core of 70 to 80% by mass containing polymerization units of 65 to 75% by mass of ethyl acrylate and 25 to 35% by mass of methyl methacrylate, and a shell of 20 to 30% by mass containing polymerization units of 45 to 55% by mass of ethyl acrylate and 45 to 55% by mass of methacrylic acid; or (ii) An anionic polymer obtained by polymerizing 25 to 95% by mass of a C1-C12 alkyl ester of acrylic acid or methacrylic acid and 75 to 5% by mass of a methacrylic acid monomer having an anionic group, or (iii) A methacrylic acid ester copolymer obtained by polymerizing methacrylic acid and ethyl acrylate, methacrylic acid and methyl methacrylate, ethyl acrylate and methyl methacrylate, or methacrylic acid and methyl acrylate and methyl methacrylate, or (iv) A methacrylic acid copolymer obtained by polymerizing 40 to 60% by mass of methacrylic acid and 60 to 40% by mass of ethyl acrylate, or (v) A methacrylic acid copolymer obtained by polymerizing 5 to 15% by mass of methacrylic acid, 60 to 70% by mass of methyl acrylate, and 20 to 30% by mass of methyl methacrylate; or a dosage form according to any one of items 1 to 5, which is any mixture of the above (i) to (v).

[0073] 11. At least one polymer in the enteric coating layer is (i) A methacrylic acid copolymer obtained by polymerizing at least two C1-C4 alkyl acrylate monomers and less than 0 to 5% by mass of methacrylic acid or acrylic acid; or (ii) A methacrylic acid copolymer obtained by polymerizing 20 to 40% by mass of ethyl acrylate, 60 to 80% by mass of methyl methacrylate, and less than 0 to 5% by mass of methacrylic acid or acrylic acid; or (iii) A methacrylic acid ester copolymer obtained by polymerizing 60 to 80% by mass of ethyl acrylate and 40 to 20% by mass of methyl methacrylate, which is a dosage form according to any one of items 1 to 10. 12. The enteric coating layer is the following: (i) A methacrylic acid ester copolymer obtained by copolymerizing 40 to 60% by mass of methacrylic acid and 40 to 60% by mass of ethyl acrylate, and (ii) A dosage form according to any one of items 1 to 5, which contains at least two polymers of a methacrylic acid ester copolymer obtained by polymerizing 60 to 78% by mass of ethyl acrylate, 20 to 38% by mass of methyl methacrylate, and in some cases, 2% by mass or less of methacrylic acid, preferably 0.1 to 2% by mass. 13. At least one polymer in the intermediate coating layer is the following: (i) Selected from celluloses such as hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxyethyl methylcellulose (HEMC), ethyl cellulose (EC), methylcellulose (MC), cellulose ester, cellulose glycolic acid, polyethylene glycol, polyethylene oxide, polyvinylpyrrolidone, polyvinyl acetate, polyvinyl alcohol, or a mixture thereof, preferably hydroxypropyl methylcellulose; and / or (ii) The dosage form according to any one of items 1 to 5, which is present in an amount of 5 to 90% by mass, preferably 10 to 70% by mass, more preferably 30 to 50% by mass, based on the total mass of the intermediate coating layer. 14. The dosage form according to any one of items 1 to 5, wherein at least one polymer in the intermediate coating layer and / or enteric coating layer is selected from at least one anionic cellulose, ethyl cellulose, or starch containing at least 35% by mass of amylose, or a mixture thereof.

[0074] 15. The dosage form according to any one of items 1 to 5, wherein at least one polymer in the intermediate coating layer and / or enteric coating layer, or in the enteric coating layer, is selected from celluloses such as hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxyethyl methylcellulose (HEMC), ethyl cellulose (EC), methylcellulose (MC), cellulose ester, cellulose glycolic acid, polyethylene glycol, polyethylene oxide, polyvinylpyrrolidone, polyvinyl acetate, polyvinyl alcohol, or a mixture thereof. 16. At least one flow promoter is present in the intermediate coating layer and / or enteric coating layer, preferably, the at least one flow promoter is the following: (i) Present in an amount of 3 to 75% by mass based on the total mass of the polymer in each coating layer, and / or (ii) silica, crushed silica, fumed silica, calcium kaolin silicate, magnesium silicate, colloidal silicon dioxide, glycerol, glycerol monostearate, talc, stearate, sodium stearyl fumarate, starch, stearic acid or mixtures thereof, preferably talc, magnesium stearate, colloidal silicon dioxide, glycerol and glycerol monostearate or mixtures thereof, more preferably an oral dosage form according to any of items 1 to 15 selected from glycerol, glycerol monostearate and talc. 17. At least one emulsifier is present in the enteric coating layer, preferably the at least one emulsifier is as follows: (i) present in an amount of less than 3% by mass, preferably less than 1.5% by mass, based on the total mass of the polymer, or not present, or (ii) present in an amount of 1.5 to 40% by mass based on the total mass of the polymer, and / or (iii) a nonionic emulsifier, preferably a nonionic emulsifier having an HLB> 10, preferably> 12; and / or (iv) is selected from polyglycosides, alcohols, sugars and sugar derivatives, polyethers, amines, polyethylene derivatives, alkyl sulfates (eg sodium dodecyl sulfate), alkyl ether sulfates, dioctyl sodium sulfosuccinate, polysorbates (eg polyoxyethylene (20) sorbitan monooleate), nonylphenol ethoxylate (nonoxynol-9) and mixtures thereof, an oral dosage form according to any of items 1 to 16. 18. At least one plasticizer is present in the intermediate coating layer and / or the enteric coating layer, preferably the at least one plasticizer is as follows: (i) present in an amount of 2 to 40% by mass based on the total mass of at least one polymer, and / or (ii) A polyethylene glycol, especially a polyethylene glycol having a mass average molecular weight Mw of 1000 to 10000 g / mol, preferably 6000 g / mol, an alkyl citrate, an alkyl phthalate, and an alkyl sebacate or a mixture thereof, preferably a polyethylene glycol having a mass average molecular weight Mw of 1000 to 10000 g / mol, diethyl sebacate, triethyl citrate (TEC), acetyltriethyl citrate (ATEC), diethyl sebacate and dibutyl sebacate (DBS) or a mixture thereof, more preferably triethyl citrate (TEC) or a polyethylene glycol having a mass average molecular weight Mw of 6000 g / mol, and the dosage form according to any one of items 1 to 17. 19. At least one additive up to 400% by mass based on the total mass of at least one polymer is contained in the intermediate coating layer and / or enteric coating layer, preferably selected from an antioxidant, a brightening agent, a flavoring agent, a flow aid, a fragrance, a penetration enhancer, a pore-forming agent or a stabilizer, or a combination thereof, and the dosage form according to any one of items 1 to 18.

[0075] 20. The core is (i) distributed in a matrix structure, or (ii) bound in a binder in a coating on the core, and the dosage form according to any one of items 1 and 3 to 19, containing a biologically active ingredient. 21. The core contains a biologically active ingredient in the filling of a hard shell capsule, and the core is the hard shell capsule, and the dosage form according to any one of items 1 to 19. 22. Use of the dosage form according to any one of items 1 to 21 for providing at least 80% drug release within 30 minutes at a pH value of 5 to 6. 23. Use of the dosage form according to any one of items 1 to 22 for providing at least 80% drug release at a pH value of 3 within 30 minutes.

[0076] [Examples] Compounds used in the experiment Table 1 Biological active ingredients and excipients used in the examples

[0077]

Table 1

Examples

[0078] Enteric coating of the pre-lock capsules in the drum coater with red iron oxide in the intermediate coating layer The enteric and top coat formulations were calculated taking into account the surface area in the pre-lock state of 545.82 mm 2 and the batch size of a total of 1,000 capsules (500 hard gel V-cap size 0 white and 500 hard gel V-cap size 0 transparent capsules). Intermediate coating VIVAPHARM® HPMC E3 was completely dispersed in water while gently stirring to prevent lumping. Magnesium oxide light, glycerol anhydrous and iron oxide red were homogenized in water for 10 minutes using a homogenizer (e.g., Ultra Turrax). The solids content should be about 10%. The excipient suspension was slowly poured into the VIVAPHARM® HPMC E3 solution while gently stirring with a conventional stirrer. The spray suspension was passed through a 0.3 mm sieve. The spray suspension was gently stirred during the coating process. Table 2 Intermediate coating

[0079]

Table 2

[0080]

Table 3

[0081]

Table 4

[0082]

Table 5

[0083]

Table 6

Example

[0084] (The present invention) Enteric coating of the pre-lock capsules in the drum coater with an increased amount of iron oxide red in the intermediate coating layer Enteric-coated and top-coated formulations are calculated considering the surface area in the unlocked state of 545.82 mm 2 and the batch size of a total of 1,000 capsules (500 Capsugel V-cap size 0 white and 500 Capsugel V-cap size 0 transparent capsules). Intermediate coating VIVAPHARM (registered trademark) HPMC E3 was completely dispersed in water while gently stirring to prevent it from clumping. Magnesium oxide light, anhydrous glycerol, and iron oxide red were homogenized in water for 10 minutes using a homogenizer (e.g., Ultra Turrax). The solid content should be approximately 10%. The excipient suspension was slowly poured into the VIVAPHARM (registered trademark) HPMC E3 solution while gently stirring with a conventional stirrer. The spray suspension was passed through a 0.3 mm sieve. The spray suspension was gently stirred during the coating process. Intermediate Coating Paint in Table 4

[0085] [Table 7] Enteric coating For the preparation of the GMS emulsion, 40% of the water was heated to 70 - 80 °C. A polysorbate 80 solution, triethyl citrate, and GMS were homogenized in the heated water for 10 minutes using a homogenizer (e.g., Ultra Turrax). The solid content was approximately 15%. The remaining 60% of the water was added with stirring into the hot GMS emulsion using a conventional stirrer and cooled to room temperature while continuously stirring. Then, the excipient suspension was slowly poured into the EUDRAGIT (registered trademark) L30D - 55 dispersion while gently stirring with a conventional stirrer. After gently stirring for 10 minutes, EUDRAGIT (registered trademark) NM30D was slowly added under continuous stirring and stirred for an additional 15 minutes. The final coating suspension was sieved through a 400 μm sieve and stirred during the coating process. The capsules were coated in the pre - locked state using a drum coater. Enteric Coating in Table 5

[0086] [Table 8] Capsule coating method The capsules are coated with a fully perforated side - vent pan coating system O’Hara M10. Bridging test : The bridging between the body and the cap of the capsule was tested. The test was carried out by holding the body and gently turning the cap of the capsule. If the capsule was damaged, a crack was heard, or the cap could not be turned without feeling it, and if the cap could not be turned at all, the capsule was a failure and bridging was determined. 100 capsules were tested. The result of this example was less than 10%, and a high applied force was required to rupture the capsule cap and the body. Dissolution test : Dissolution test (compliant with USP43<711>) The capsules were filled manually. The polymer-coated pre-lock capsules were manually filled with a 3:7 mixture of 500 mg of caffeine / lactose, closed to the final locked state, and tested in a dissolution test. Apparatus and settings:

[0087]

Table 9

[0088]

Table 10

Examples

[0089] Enteric coating of pre-lock capsules in a drum coater with FD&C Blue No. 1 (E133) in the intermediate coating layer The enteric and top coat formulations are calculated considering the surface area in the pre-lock state of 545.82 mm 2 and a batch size of a total of 1,000 capsules (500 Capsugel V-cap size 0 white and 500 Capsugel V-cap size 0 transparent capsules). Intermediate coating VIVAPHARM (registered trademark) HPMC E3 was gently stirred to prevent it from forming lumps and was completely dispersed in water. Magnesium oxide light, anhydrous glycerol, and FD&C Blue No. 1 were homogenized in water for 10 minutes using a homogenizer (e.g., Ultra Turrax). The solid content should be approximately 10%. The excipient suspension was slowly poured into the VIVAPHARM (registered trademark) HPMC E3 solution while gently stirring with a conventional stirrer. The spray suspension was passed through a 0.3 mm sieve. The spray suspension was gently stirred during the coating process. Intermediate Coating Paint in Table 6

[0090] [Table 11] Enteric coating Preparation of GMS Emulsion: 40% of water was heated to 70 - 80 °C. Polysorbate 80 solution, triethyl citrate, and GMS were homogenized in the heated water for 10 minutes using a homogenizer (e.g., Ultra Turrax). The solid content was approximately 15%. The remaining 60% of water was added to the hot GMS emulsion while stirring with a conventional stirrer and cooled to room temperature while continuously stirring. Then, the excipient suspension was slowly poured into the EUDRAGIT (registered trademark) L30D - 55 dispersion while gently stirring with a conventional stirrer. After gently stirring for 10 minutes, EUDRAGIT (registered trademark) NM30D was slowly added under continuous stirring and stirred for an additional 15 minutes. The final coating suspension was sieved through a 400 μm sieve and stirred during the coating process. The capsules were coated in the pre - locked state using a drum coater. Enteric Coating in Table 17

[0091] [Table 12] Capsule coating method The capsules are coated with a fully perforated side - vent pan coating system O’Hara M10. Bridging test : The bridging between the body and the cap of the capsule was tested. The test was carried out by holding the body and gently turning the cap of the capsule. If the capsule was damaged, a crack was audible, or the cap could not be turned without feeling it, and if the cap could not be turned at all, the capsule was a failure and bridging was determined. 100 capsules were tested. The result of this example was less than 10%, and a high applied force was required to rupture the capsule cap and the body. Dissolution test : Dissolution test (in accordance with USP43<711>) The capsules were filled manually. The polymer-coated pre-lock capsules were manually filled with a 3:7 mixture of 500 mg of caffeine / lactose, closed to the final locked state, and tested in a dissolution test. Apparatus and settings:

[0092]

Table 13

[0093]

Table 14

Example

[0094] (The present invention) Enteric coating of pre-lock capsules in a drum coater with an increased amount of titanium dioxide in the intermediate coating layer The enteric and top coat formulations are calculated considering the surface area in the pre-lock state of 545.82 mm 2 and a batch size of a total of 1,000 capsules (500 Capsugel V-cap size 0 white and 500 Capsugel V-cap size 0 transparent capsules). Intermediate coating VIVAPHARM® HPMC E3 was gently stirred to prevent agglomeration while being completely dispersed in water. Magnesium oxide light, anhydrous glycerol, and FD&C Blue No. 1 were homogenized in water for 10 minutes using a homogenizer (e.g., Ultra Turrax). The solids content should be approximately 10%. The excipient suspension was slowly poured into the VIVAPHARM® HPMC E3 solution while gently stirring with a conventional stirrer. The spray suspension was passed through a 0.3 mm sieve. The spray suspension was gently stirred during the coating process. Intermediate coating VIVAPHARM® HPMC E3 was gently stirred to prevent agglomeration while being completely dispersed in water. Magnesium oxide light, anhydrous glycerol, and titanium dioxide were homogenized in water for 10 minutes using a homogenizer (e.g., Ultra Turrax). The solids content should be approximately 10%. The excipient suspension was slowly poured into the VIVAPHARM® HPMC E3 solution while gently stirring with a conventional stirrer. The spray suspension was passed through a 0.3 mm sieve. The spray suspension was gently stirred during the coating process. Table 8: Intermediate Coating

[0095] [Table 15] Enteric coating The GMS emulsion was prepared by heating 40% of water to 70 - 80 °C. The polysorbate 80 solution, triethyl citrate and GMS were homogenized in the heated water for 10 minutes using a homogenizer (e.g., Ultra Turrax). The solid content was about 15%. The remaining 60% of water was added with stirring into the hot GMS emulsion using a conventional stirrer and cooled to room temperature while stirring continuously. Then, the excipient suspension was slowly poured into the EUDRAGIT® L30D - 55 dispersion while gently stirring with a conventional stirrer. After gently stirring for 10 minutes, EUDRAGIT® NM30D was slowly added under continuous stirring and stirred for an additional 15 minutes. The final coating suspension was sieved through a 400 μm sieve and stirred during the coating process. The capsules were coated in the pre - locked state using a drum coater. Table 9: Enteric Coating

[0096]

Table 16

[0097]

Table 17

[0098]

Table 18

Examples

[0099] Enteric coating of the pre-lock capsules in the drum coater with an increased amount of lactose in the intermediate coating layer Enteric and top coat formulations are calculated considering the surface area in the unlocked state of 545.82 mm 2 and the batch size of a total of 1,000 capsules (500 Capsugel V - cap size 0 white and 500 Capsugel V - cap size 0 transparent capsules). Intermediate coating VIVAPHARM® HPMC E3 was completely dispersed in water while gently stirring to prevent lumping. Magnesium oxide light, anhydrous glycerol and lactose were homogenized in water for 10 minutes using a homogenizer (e.g., Ultra Turrax). The solids content should be approximately 10%. The excipient suspension was slowly poured into the VIVAPHARM® HPMC E3 solution while gently stirring with a conventional stirrer. The spray suspension was passed through a 0.3 mm sieve. The spray suspension was gently stirred during the coating process. Table 10: Intermediate Coating

[0100]

Table 19

[0101]

Table 20

[0102]

Table 21

[0103] [Table 22]

Example

[0104] (Comparison) Enteric coating of the pre-lock capsules in the drum coater without a release promoter in the intermediate coating layer Enteric-coated and top-coated formulations were calculated considering the surface area in the pre-lock state of 545.82 mm 2 and the batch size of a total of 1,000 capsules (500 Capsugel V-cap size 0 white and 500 Capsugel V-cap size 0 transparent capsules). Intermediate coating VIVAPHARM® HPMC E3 was completely dispersed in water while gently stirring to prevent clumping. Magnesium oxide light, anhydrous glycerol, and anhydrous glycerol were homogenized in water for 10 minutes using a homogenizer (e.g., Ultra Turrax). The solids content should be approximately 10%. The excipient suspension was slowly poured into the VIVAPHARM® HPMC E3 solution while gently stirring with a conventional stirrer. The spray suspension was passed through a 0.3 mm sieve. The spray suspension was gently stirred during the coating process. Table 12: Intermediate coating

[0105] [Table 23] Enteric coating Preparation of GMS emulsion: 40% of water was heated to 70 - 80 °C. Polysorbate 80 solution, triethyl citrate and GMS were homogenized in the heated water for 10 minutes using a homogenizer (e.g., Ultra Turrax). The solid content was about 15%. The remaining 60% of water was added to the hot GMS emulsion with stirring using a conventional stirrer and cooled to room temperature while stirring continuously. Then, the excipient suspension was slowly poured into the EUDRAGIT® L30D - 55 dispersion while gently stirring with a conventional stirrer. After gently stirring for 10 minutes, EUDRAGIT® NM30D was slowly added under continuous stirring and stirred for an additional 15 minutes. The final coating suspension was sieved through a 400 μm sieve and stirred during the coating process. The capsules were coated in the pre - locked state using a drum coater. Table 13: Enteric coating

[0106]

Table 24

[0107]

Table 25

[0108] 4) Dissolution procedure: Acid stage: Six accurately weighed caffeine capsules were transferred to different dissolution jars, and then a dissolution test was carried out according to the parameters given in the above method (acid stage). After 1 hour and 2 hours, 10 ml aliquots were taken out and analyzed as acid stage sample solutions. Buffer stage: The capsules after the acid stage were transferred to the buffer stage medium. The dissolution test was continued according to the parameters given in the above method (buffer solution stage). The aliquots at each interval were filtered through a 0.45 μm nylon membrane syringe filter, the first few mL of the filtrate were discarded, and analyzed as buffer stage sample solutions using the following chromatographic conditions. (B) Chromatographic conditions Column: Agilent Zorbax Eclipse XDB C18 column, 150×4.6 mm, 5 μm or equivalent Mobile phase: water / ACN (80:20) Wavelength: 273 nm Column temperature: 25 °C Injection volume: 10 μL Flow rate: 1.5 ml / min

[0109]

Table 26

Example

[0110] Enteric coating of API mini tablets in the fluidized bed coater with an increased amount of lactose in the intermediate coating layer Enteric-coated and top-coated formulations are 22.14 mm 2It is calculated considering the surface area and the batch size of 750 g of API mini-tablets (concave surface with a diameter of 2.5 mm). Intermediate coating VIVAPHARM® HPMC E3 was completely dispersed in water while gently stirring to prevent lumping. Magnesium oxide light, anhydrous glycerol, and lactose were homogenized in water for 10 minutes using a homogenizer (e.g., Ultra Turrax). The solids content should be approximately 10%. The excipient suspension was slowly poured into the VIVAPHARM® HPMC E3 solution while gently stirring with a conventional stirrer. The spray suspension was passed through a 0.3 mm sieve. The spray suspension was gently stirred during the coating process. Table 14: Intermediate Coating

[0111] [Table 27] Enteric coating Triethyl citrate and talc were homogenized in water for 10 minutes using a homogenizer (e.g., Ultra Turrax). Then, the excipient suspension was slowly poured into the EUDRAGIT® L30D-55 dispersion while gently stirring with a conventional stirrer and stirred for an additional 15 minutes. The final coating suspension was sieved through a 400 μm sieve and stirred during the coating process. Table 15: Enteric Coating

[0112] [Table 28] Mini tablet coating method Process parameters for enteric coating of 750 g of mini-tablets using the GPCG-2 system

[0113] [Table 29] Dissolution test (compliant with USP 43 <711>) Dissolution system

[0114]

Table 30

[0115]

Table 31

[0116]

Table 32

Examples

[0117] (Comparative example) Enteric coating of API mini tablets in the fluidized bed coater without a release promoter in the intermediate coating layer Enteric-coated and top-coated formulations are calculated considering a surface area of 22.14 mm 2 and a batch size of a total of 750 g of API mini-tablets (concave with a diameter of 2.5 mm). Intermediate coating VIVAPHARM® HPMC E3 was gently stirred to prevent lumping while being completely dispersed in water. Magnesium oxide light, anhydrous glycerol, and lactose were homogenized in water for 10 minutes using a homogenizer (e.g., Ultra Turrax). The solid content should be approximately 10%. The excipient suspension was slowly poured into the VIVAPHARM® HPMC E3 solution while gently stirring with a conventional stirrer. The spray suspension was passed through a 0.3 mm sieve. The spray suspension was gently stirred during the coating process. Table 16: Intermediate Coating

[0118] [Table 33] Enteric coating Triethyl citrate and talc were homogenized in water for 10 minutes using a homogenizer (e.g., Ultra Turrax). Then, the excipient suspension was slowly poured into the EUDRAGIT® L30D - 55 dispersion while gently stirring with a conventional stirrer and stirred for an additional 15 minutes. The final coating suspension was sieved through a 400 μm sieve and stirred during the coating process. Table 17: Enteric Coating

[0119] [Table 34] Mini - tablet Coating Method Process Parameters for Enteric Coating of 750 g of Mini - tablets Using the GPCG - 2 System

[0120] [Table 35] Dissolution Test (in accordance with USP 43 <711>) Dissolution System

[0121] [Table 36] HPLC System Parameters

[0122]

Table 37

[0123]

Table 38

Example

[0124] (The present invention) Manufacture of caffeine mini tablets; Subsequently, sealing, intermediates and enteric coating of caffeine mini tablets (enteric coating with a 6.25% mass increase of EUDRAGIT L30D-55) Tablet Compression: A formulation blend of caffeine, MCC, lactose, Aerosil 200, and croscarmellose sodium is prepared using a Turbula mixer. Subsequently, magnesium stearate is added as a lubricant, and the total mixing time is 15 minutes. This blend is compressed using a Korsch XL compressor with a 2.5 mm multi-tip tooling. Using a compression force of approximately 17 KN, 2.5 mm circular mini-tablets with a mass of 10.0 mg, a thickness of 1.8 mm, and a hardness of 3.02 KP are manufactured. Formulation Composition:

[0125]

Table 39

[0126] Seal coating Carry out at low to medium speed for 15 minutes until all components are dissolved. Add VIVAPHARM® HPMC E3 and PEG600 to the container together with water, and gently stir to prevent lumping. The solid content should be approximately 7.5%. Pass the spray solution through a 40-mesh sieve, and gently stir to carry out the coating process. Table 18: Seal coating

[0127]

Table 40

[0128]

Table 41

[0129]

Table 42

[0130]

Table 43

[0131]

Table 44

[0132]

Table 45

[0133]

Table 46

Claims

1. The following: (a) A core containing at least one biologically active ingredient; (b) An intermediate coating layer (ICL) above or over the core, comprising the following: (i) At least one polymer; (ii) At least one alkaline agent; (iii) At least one release promoter selected from iron oxide, aluminum oxide, titanium dioxide, dimethyl sulfoxide, zinc oxide, sucrose, maltose, lactose, dextrate, glucose, fructose, dyes, or any mixture thereof; (iv) Optionally, at least one lubricant; (v) Optionally, at least one plasticizer; and (vi) Optionally, at least one additive different from (i) to (v); wherein the at least one release promoter is present at 0.1 to 20% by mass based on the mass of the at least one polymer, and (c) An enteric coating layer (ECL) above or over the intermediate coating layer, comprising the following: (i) At least one polymer; (ii) Optionally, at least one lubricant; (iii) Optionally, at least one emulsifier; (iv) Optionally, at least one plasticizer; (v) Optionally, at least one biologically active ingredient; and (vi) Optionally, at least one additive different from (i) to (v), A dosage form comprising the above.

2. The dosage form according to claim 1, which is a coated hard shell capsule, tablet or mini-tablet.

3. The dosage form according to claim 1 or 2, wherein the biologically active ingredient is a pharmaceutically active ingredient.

4. The alkaline agent is the following: (i) An alkali metal salt or alkaline earth metal salt; or (ii) Selected from calcium oxide, calcium carbonate, magnesium carbonate, magnesium oxide, sodium carbonate, sodium bicarbonate, and sodium hydroxide, or any combination thereof; or (iii) Magnesium oxide or magnesium carbonate, The dosage form according to any one of claims 1 to 3.

5. wherein the at least one release accelerator is Fe ２ O ３ , TiO ２ , lactose, disodium 2-[[4-[ethyl-[(3-sulfonatophenyl)methyl]amino]phenyl]-[4-[ethyl-[(3-sulfonatophenyl)methyl]azanidylidene]cyclohexa-2,5-dien-1-ylidene]methyl]benzenesulfonate or any mixture thereof, the dosage form according to any one of claims 1 to 4.

6. The intermediate coating layer and / or enteric coating layer, or the at least one polymer in the intermediate coating layer, is selected from at least one methacrylic acid copolymer, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), or polyvinylpyrrolidone (PVP), and the dosage form according to any one of claims 1 to 5.

7. The intermediate coating layer and / or enteric coating layer, or the at least one polymer in the enteric coating layer, is as follows: (i) A core-shell polymer which is a copolymer obtained by a two-stage emulsion polymerization process, having a core of 70 to 80% by mass containing polymerization units of 65 to 75% by mass of ethyl acrylate and 25 to 35% by mass of methyl methacrylate, and a shell of 20 to 30% by mass containing polymerization units of 45 to 55% by mass of ethyl acrylate and 45 to 55% by mass of methacrylic acid; or (ii) An anionic polymer obtained by polymerizing 25 to 95% by mass of a C1-C12 alkyl ester of acrylic acid or methacrylic acid and 75 to 5% by mass of a methacrylic acid monomer having an anionic group; or (iii) A cationic methacrylic acid copolymer obtained by polymerizing a C1-C4 alkyl ester of acrylic acid or methacrylic acid and an alkyl ester of acrylic acid or methacrylic acid having a tertiary or quaternary ammonium group in the alkyl group; or (iv) A methacrylic acid ester copolymer obtained by polymerizing methacrylic acid and ethyl acrylate, methacrylic acid and methyl methacrylate, ethyl acrylate and methyl methacrylate, or methacrylic acid and methyl acrylate and methyl methacrylate; or (v) A methacrylic acid copolymer obtained by polymerizing 40 to 60% by mass of methacrylic acid and 60 to 40% by mass of ethyl acrylate; or (vi) A methacrylic acid-based copolymer obtained by polymerizing 60 to 80% by mass of ethyl acrylate and 40 to 20% by mass of methyl methacrylate; or (vii) A methacrylic acid copolymer obtained by polymerizing 5 to 15% by mass of methacrylic acid, 60 to 70% by mass of methyl acrylate, and 20 to 30% by mass of methyl methacrylate; or a mixture thereof; and the dosage form according to any one of claims 1 to 5.

8. The intermediate coating layer and / or enteric coating layer, or at least one polymer in the enteric coating layer is as follows: (i) An anionic polymer having a Tgm of 35°C or higher, 35 to 155°C, 80 to 145°C, or 90 to 125°C, and the Tgm of the second polymer is 30°C or lower or less than 15°C, or (ii) A methacrylic acid copolymer obtained by copolymerizing 40 to 60% by mass of methacrylic acid and 60 to 40% by mass of ethyl acrylate, and 60 to 80% by mass, 60 to 78% by mass of ethyl acrylate and 40 to 20% by mass, or 38 to 20% by mass of methyl methacrylate, preferably in a mass ratio of 20:1 to 1:20, and optionally up to 2% by mass of methacrylic acid; or (iii) A methacrylic acid ester copolymer obtained by copolymerizing 5 to 15% by mass of methacrylic acid, 60 to 70% by mass of methyl acrylate, and 20 to 30% by mass of methyl methacrylate, and a methacrylic acid ester copolymer obtained by copolymerizing 40 to 60% by mass of methacrylic acid and 60 to 40% by mass of ethyl acrylate, preferably contained in a ratio of 20:1 to 1:20 by mass ratio; The dosage form according to any one of claims 1 to 5, which is a mixture of.

9. The dosage form according to any one of claims 1 to 5, wherein at least one polymer in the intermediate coating layer and / or the enteric coating layer is selected from at least one anionic cellulose, ethyl cellulose, or starch containing at least 35% by mass of amylose, or a mixture thereof.

10. The dosage form according to any one of claims 1 to 5, wherein at least one polymer in the intermediate coating layer and / or the enteric coating layer, or in the enteric coating layer is selected from cellulose such as hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), hydroxyethyl methyl cellulose (HEMC), ethyl cellulose (EC), methyl cellulose (MC), cellulose ester, cellulose glycolic acid, polyethylene glycol, polyethylene oxide, polyvinyl pyrrolidone, polyvinyl acetate, polyvinyl alcohol, or a mixture thereof.

11. The core is as follows: (i) distributed in a matrix structure, or (ii) bound in a binder in a coating on the core, The dosage form according to any one of claims 1 and 3 to 10, comprising a biologically active ingredient.

12. The dosage form according to any one of claims 1 to 10, wherein the core is a hard shell capsule, and a biologically active ingredient is contained in the filling of the hard shell capsule.

13. A method for obtaining the dosage form according to any one of claims 1 to 12, wherein the intermediate coating layer is coated on the core by spray coating, and then the enteric coating layer is coated on the intermediate coating layer by spray coating.

14. Use of the dosage form according to any one of claims 1 to 12 for providing at least 80% drug release at a pH value of 5 within 60 minutes.

15. Use of the dosage form according to any one of claims 1 to 12 for providing at least 80% drug release at a pH value of 3 within 60 minutes.

Images