Dosage form for releasing drug at pH 3 to 6 using two-layer coating system with at least one release accelerator

Abstract

The present invention relates to a dosage form comprising a core comprising at least one bioactive ingredient, a specific intermediate coating layer and an enteric coating layer, and a method for obtaining said dosage form, the specific intermediate coating layer comprises in particular at least one basic substance and at least one release accelerator selected from iron oxide, aluminum oxide, titanium dioxide, dimethyl sulfoxide, zinc oxide, sucrose, maltose, lactose, glucose binding agents, glucose, fructose, dyes or any mixture thereof. Furthermore, the invention relates to the use of a dosage form according to the invention for providing at least 80% drug release at pH 5 within 60 min or at least 80% drug release at pH 3 within 60 min.

Description

Technical Field

[0001] The present invention relates to a dosage form and a method for obtaining the same, the dosage form comprising a core, a specific intermediate coating layer and an enteric coating layer, the core comprising at least one biologically active ingredient, the specific intermediate coating layer in particular comprising at least one alkaline substance and at least one release accelerator selected from iron oxide, aluminum oxide, titanium dioxide, dimethyl sulfoxide, zinc oxide, sucrose, maltose, lactose, dextrates, glucose, fructose, dyes or any mixture thereof. In addition, the present invention relates to the use of the dosage form according to the invention for providing at least 80% drug release at pH 3-6 within 30 min. Background Art

[0002] The favorable position for release and absorption in the gastrointestinal tract is the duodenum. However, known dosage forms, such as those described in EP application number 22170267.3, show a lag time of at least 45 minutes in phosphate buffer at pH 5.5 and therefore only a certain release. Therefore, such a preparation is most likely to pass through about 25 cm of the duodenum into the adjacent jejunum without any drug release. In addition, such a preparation will not release the biologically active ingredient because the trigger pH relevant for the duodenum is often not reached.

[0003] The release of bioactive ingredients in the duodenum is important, for example, in duodenal ulcers as well as in systemic drug absorption, for example as the mucus layer changes in composition and increases in thickness.

[0004] Therefore, enteric dosage forms showing accelerated release in a pH range of particularly pH 3-6, preferably pH 5-6, are needed. According to the test for delayed release preparations as described in the United States Pharmacopeia (USP) 43 Monograph 711, a desired enteric dosage form should be an enteric dosage form with a drug release of no more than 10% after 2 hours in 0.1N hydrochloric acid (HCl). After the medium is changed from 0.1N HCl to a buffer medium having a relevant pH value of pH 3-6, preferably pH 5-6, or directly tested in the buffer medium without pretreatment, the drug release should exceed 80% within 30 minutes.

[0005] The inventors of the present invention surprisingly found that the addition of certain specific release accelerators selected from iron oxide, aluminum oxide, titanium dioxide, dimethyl sulfoxide, zinc oxide, sucrose, maltose, lactose, dextrates, glucose, fructose, dyes or any mixtures thereof in an amount of 0.1-20 wt. % based on the weight of the at least one polymer in the intermediate coating layer leads to accelerated release within 30 minutes at pH values ​​of 3-6, preferably pH 5-6. Summary of the invention

[0006] In a first aspect, the present invention relates to a dosage form comprising

[0007] a) a core comprising at least one biologically active ingredient,

[0008] b) an intermediate coating layer (ICL) on or above the core, the intermediate coating layer comprising

[0009] i) at least one polymer;

[0010] ii) at least one alkaline substance;

[0011] iii) at least one release accelerating agent selected from the group consisting of iron oxide, aluminum oxide, titanium dioxide, dimethyl sulfoxide, zinc oxide, sucrose, maltose, lactose, dextrates, glucose, fructose, dyes, or any mixture thereof;

[0012] iv) optionally at least one glidant

[0013] v) optionally at least one plasticizer; and

[0014] vi) optionally at least one additive different from i) to v); wherein

[0015] The at least one release accelerating agent is present in 0.1-20 wt%, preferably 0.2-15 wt%, more preferably 0.5-8 wt%, most preferably 1-6 wt%, based on the weight of the at least one polymer; and

[0016] c) an enteric coating layer (ECL) on or above the intermediate coating layer, the enteric coating layer comprising

[0017] i) at least one polymer;

[0018] ii) optionally at least one glidant;

[0019] iii) optionally at least one emulsifier;

[0020] iv) optionally at least one plasticizer;

[0021] v) optionally at least one biologically active ingredient; and

[0022] vi) optionally at least one additive different from i) to v).

[0023] In one embodiment, the at least one polymer of the enteric coating layer comprises or consists of two different polymers, preferably, wherein the first polymer is an anionic polymer with a Tgm ≥ 35°C, more preferably 35-155°C, even more preferably 80-145°C, most preferably 90-125°C; and wherein the second polymer is preferably a polymer with a Tgm ≤ 30°C, more preferably ≤ 15°C.

[0024] In one embodiment, the total coating amount of the one or more coating layers is 2.0-30 mg / cm 2 , preferably 2.0-10 mg / cm 2 or 10-25 mg / cm 2 .

[0025] In a second aspect, the present invention relates to a method for obtaining said dosage form according to the present invention, wherein said intermediate coating layer is coated on said core via spray coating and thereafter said enteric coating layer is coated on said intermediate coating layer via spray coating.

[0026] In a third aspect, the present invention relates to the use of a polymer coated hard shell capsule according to the present invention for delayed release, ie for providing at least 80% drug release within 30 min at pH 3-6, preferably pH 5-6. DETAILED DESCRIPTION OF THE INVENTION

[0028] The polymer or polymer mixture contained in the intermediate coating layer or the enteric coating layer

[0029] The following discloses polymers suitable for use as one of the at least one polymer in the intermediate coating layer or the at least one polymer in the enteric coating layer. The at least one polymer in the intermediate coating layer and the enteric coating layer can be any of the following polymers. The enteric coating layer preferably requires a first polymer, wherein the first polymer is an anionic polymer with a Tgm ≥ 35°C, preferably 35-155°C, more preferably 80-145°C, and most preferably 90-125°C; and a second polymer, wherein the second polymer is a polymer with a Tgm ≤ 30°C, preferably ≤ 20°C, and more preferably -10 to 20°C. Suitable anionic polymers and neutral polymers are also described below. If applicable to all polymers of both coating layers, the expression "polymer contained in / constituting the coating layer" etc. is used.

[0030] The polymer comprised in the coating layer is preferably a film-forming polymer.

[0031] The at least one polymer of the coating layer may be selected from anionic polymers, cationic polymers and neutral polymers or any mixture thereof.

[0032] Selections of general or specific polymer features or embodiments as disclosed herein may be combined without limitation with any other general or specific selections of material or numerical features or embodiments as disclosed herein, such as capsule material, capsule size, coating thickness, bioactive ingredient, and any other features or embodiments as disclosed.

[0033] The coating layer may be a single layer or may comprise or consist of two or more separate layers, and may comprise a total of 10-100 wt%, 20-95 wt%, 30-90 wt% of one or more polymers, preferably (meth)acrylate copolymers.

[0034] The monomer proportions mentioned for the individual polymers generally add up to 100% by weight.

[0035] The intermediate coating layer and the enteric coating layer are different from each other.

[0036] In a preferred embodiment, another coating layer, i.e. a top coating layer, is contained. The top coating layer comprises 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 hydroxypropyl methylcellulose, most preferably hydroxypropyl methylcellulose.

[0037] Glass transition temperature Tgm

[0038] The glass transition temperature Tgm according to the invention is preferably determined by differential scanning calorimetry (DSC) according to ISO 11357-2:2013-05. The determination 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 as described in Section 10.1.2 of DIN EN ISO 11357-2.

[0039] Anionic polymer

[0040] The at least one polymer contained in the coating layer may be an anionic polymer selected from anionic (meth)acrylate copolymers, anionic polyvinyl polymers or copolymers, and anionic cellulose.

[0041] Anionic (meth)acrylate copolymer

[0042] Preferably, the anionic (meth)acrylate copolymer comprises 25-95% by weight, preferably 40-95% by weight, in particular 60-40% by weight of free-radically polymerized C1- to C12-alkyl esters, preferably C1- to C4-alkyl esters of acrylic acid or methacrylic acid and 75-5% by weight, preferably 60-5% by weight, in particular 40-60% by weight of (meth)acrylate monomers with anionic groups. The proportions mentioned usually add up to 100% by weight. However, small amounts of other monomers capable of vinyl copolymerization, such as, for example, hydroxyethyl methacrylate or hydroxyethyl acrylate, may also be present in addition without causing impairment or modification of the essential properties, such as 0-10% by weight, for example 1-5% by weight. Preferably, no other monomers capable of vinyl copolymerization are present.

[0043] C1- to 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.

[0044] The (meth)acrylate monomer having an anionic group is, for example, acrylic acid, preferably methacrylic acid.

[0045] Suitable anionic (meth)acrylate copolymers are those obtained by polymerization of 40-60 wt % methacrylic acid and 60-40 wt % methyl methacrylate or 60-40 wt % ethyl acrylate ( L or L 100 55 type).

[0046] L is a copolymer formed by polymerizing 50 wt% methyl methacrylate and 50 wt% methacrylic acid. The pH value at which the specific active ingredient begins to be released in intestinal fluid or simulated intestinal fluid can be expressed as about pH 6.0. Its Tgm>125°C.

[0047] L 100-55 is a copolymer obtained by polymerizing 50 wt% ethyl acrylate and 50 wt% methacrylic acid. L 30D-55 contains 30% by weight Dispersion of L 100-55.

[0048] Likewise, suitable are anionic (meth)acrylate copolymers ( S type). The pH value at which the release of a particular active ingredient begins in intestinal fluid or simulated intestinal fluid can be expressed as being at about pH 7.0.

[0049] Suitable (meth)acrylate copolymers are prepared by polymerizing 10-30 wt% methyl methacrylate, 50-70 wt% methyl acrylate and 5-15 wt% methacrylic acid ( FS type).

[0050] FS is a copolymer obtained by polymerizing 25 wt% methyl methacrylate, 65 wt% methyl acrylate and 10 wt% methacrylic acid. FS 30 D contains 30% by weight Dispersion of FS.

[0051] Suitable are copolymers comprising:

[0052] 20-34% by weight of methacrylic acid and / or acrylic acid,

[0053] 20-69% by weight of methyl acrylate, and

[0054] 0-40% by weight of ethyl acrylate, and / or, where appropriate,

[0055] 0-10% by weight of other monomers capable of vinyl copolymerization,

[0056] Provided that the glass transition temperature of the copolymer according to ISO 11357-2:2013-05, subsection 3.3.3 does not exceed 60°C.

[0057] Suitable copolymers are those formed by polymerization of:

[0058] 20-33% by weight of methacrylic acid and / or acrylic acid,

[0059] 5-30% by weight of methyl acrylate, and

[0060] 20-40 wt% ethyl acrylate, and

[0061] from more than 10 to 30% by weight of butyl methacrylate and, where appropriate,

[0062] 0-10% by weight of other monomers capable of vinyl copolymerization,

[0063] The total weight of the monomers is 100%.

[0064] Provided that the glass transition temperature (midpoint temperature Tm,g) of the copolymer according to ISO 11357-2:2013-05, subsection 3.3.3 is 55-70°C.

[0065] The copolymers are preferably composed of 90, 95 or 99-100% by weight of the monomers methacrylic acid, methyl acrylate, ethyl acrylate and butyl methacrylate in the above-mentioned amount range. However, small amounts of other monomers capable of vinyl copolymerization, such as, for example, methyl methacrylate, butyl acrylate, hydroxyethyl methacrylate, vinylpyrrolidone, vinylmalonic acid, styrene, vinyl alcohol, vinyl acetate and / or their derivatives, may additionally be present in amounts of 0-10% by weight, for example 1-5% by weight, without this necessarily resulting in impairment of the essential properties.

[0066] Other suitable anionic (meth)acrylate copolymers may be so-called core / shell polymers as described in WO 2012 / 171575 A2 or WO 2012 / 171576 A1. Suitable core-shell polymers are copolymers from a two-stage emulsion polymerization process, having a core of 75 wt. % polymerized units comprising 30 wt. % ethyl acrylate and 70 wt. % methyl methacrylate, and a shell of 25 wt. % polymerized units polymerized from 50 wt. % ethyl acrylate and 50 wt. % methacrylic acid.

[0067] A suitable core-shell polymer may be a copolymer from a two-stage emulsion polymerization process having a 70-80 wt% core and a 20-30 wt% shell, the core comprising polymerized units of 65-75 wt% ethyl acrylate and 25-35 wt% methyl methacrylate, and the shell comprising polymerized units of 45-55 wt% ethyl acrylate and 45-55 wt% methacrylic acid.

[0068] Anionic cellulose

[0069] The anionic cellulose may be selected from carboxymethylethylcellulose and its salts, cellulose acetate phthalate (CAP), cellulose acetate succinate (CAS), cellulose acetate trimellitate (CAT), hydroxypropyl methylcellulose phthalate (HPMCP, HP50, HP55), hydroxypropyl methylcellulose acetate succinate (HPMCAS-LF, -MF, -HF).

[0070] The coating layer may comprise one or more anionic cellulose, ethyl cellulose and / or one or more starches comprising at least 35 wt. % amylose, preferably having a glass transition temperature Tgm of 130° C. or less (determined by differential scanning calorimetry (DSC) according to ISO 11357-2:2013-05), wherein the coating layer is preferably present in an amount of about 1-5.8 mg / cm 2 , more preferably 2-5 mg / cm 2 The amount exists.

[0071] The coating layer may comprise a total of 10-100 wt%, 20-95 wt%, 30-90 wt% of one or more anionic celluloses, ethyl cellulose and / or one or more starches comprising at least 35 wt% amylose.

[0072] The glass transition temperature Tgm of hydroxypropylmethylcellulose phthalate is about 132-138°C (about 133°C for HP-55 type and about 137°C for HP-50 type).

[0073] The glass transition temperature Tgm of hydroxypropylmethylcellulose acetate succinate (HPMCAS) is about 120°C (119°C for AquaSolve™ L HPMCAS, 120°C for AquaSolve™ M HPMCAS, and 122°C for AquaSolve™ H HPMCAS).

[0074] Anionic vinyl copolymer

[0075] The anionic vinyl copolymer may be selected from unsaturated carboxylic acids other than acrylic acid or methacrylic acid, exemplified by polyvinyl acetate phthalate, or a copolymer of vinyl acetate and crotonic acid, preferably in a ratio of 9:1.

[0076] Cationic polymers

[0077] Suitable cationic (meth)acrylate copolymers included in the coating layer may be polymerized from monomers comprising C1- to C4-alkyl esters of acrylic acid or methacrylic acid and alkyl esters of acrylic acid or methacrylic acid having a tertiary amino group or a quaternary ammonium group in the alkyl group. The cationic water-soluble (meth)acrylate copolymer may be partially or completely polymerized from alkyl acrylates and / or alkyl methacrylates having a tertiary amino group in the alkyl group. Coatings comprising these types of polymers may have the advantage of providing moisture protection for the hard shell capsule. Moisture protection is understood to be a reduction in moisture or water absorption during storage of the filled and finally locked capsules.

[0078] Suitable cationic (meth)acrylate copolymers can be polymerized from 30-80% by weight of C1- to C4-alkyl acrylate or methacrylate and 70-20% by weight of alkyl (meth)acrylate monomers having a tertiary amino group in the alkyl group.

[0079] A preferred cationic (meth)acrylate copolymer can be polymerized from 20-30 wt% of methyl methacrylate, 20-30 wt% of butyl methacrylate and 60-40 wt% of dimethylaminoethyl methacrylate ( E-type polymer).

[0080] A particularly suitable commercially available (meth)acrylate copolymer having tertiary amino groups is obtained by polymerizing 25% by weight of methyl methacrylate, 25% by weight of butyl methacrylate and 50% by weight of dimethylaminoethyl methacrylate ( E 100 or E PO (powder form)). E 100 and E PO is water soluble below about pH 5.0 and is therefore also soluble in gastric fluid.

[0081] Suitable (meth)acrylate copolymers may contain 85-98 wt% of a free radical polymerized C1 to C4 alkyl acrylate or methacrylate and 15-2 wt% of a (meth)acrylate monomer having a quaternary amino group in the alkyl group.

[0082] Preferred C1 to C4 alkyl esters of acrylic or methacrylic acid are methyl acrylate, ethyl acrylate, butyl acrylate, butyl methacrylate and methyl methacrylate.

[0083] Other suitable cationic (meth)acrylate polymers may contain polymerized monomer units of 2-trimethylammonium-ethyl methacrylate chloride or trimethylammonium-propyl methacrylate chloride.

[0084] Suitable copolymers may be polymerized from 50-70 weight percent methyl methacrylate, 20-40 weight percent ethyl acrylate, and 7-2 weight percent 2-trimethylammoniumethyl methacrylate chloride.

[0085] A particularly suitable copolymer is obtained by polymerizing 65% by weight of methyl methacrylate, 30% by weight of ethyl acrylate and 5% by weight of 2-trimethylammoniumethyl methacrylate chloride ( RS).

[0086] Other suitable (meth)acrylate copolymers can be polymerized from 85 wt% to less than 93 wt% of C1 to C4 alkyl esters of acrylic acid or methacrylic acid and greater than 7 wt% to 15 wt% of (meth)acrylate monomers having a quaternary amino group in the alkyl group. Such (meth)acrylate monomers are commercially available and have long been used for sustained-release coatings.

[0087] A particularly suitable copolymer is obtained by polymerizing 60% by weight of methyl methacrylate, 30% by weight of ethyl acrylate and 10% by weight of 2-trimethylammoniumethyl methacrylate chloride ( RL).

[0088] Neutral polymer

[0089] Neutral polymers are defined as polymers polymerized from neutral monomers and less than 5 wt % (preferably less than 2 wt % or most preferably no) monomers having ionic groups.

[0090] Suitable neutral polymers for use in the hard shell capsule coating are methacrylate copolymers (preferably copolymers of ethyl acrylate and methyl methacrylate, such as NE or NM), neutral cellulose (such as methyl ether, ethyl ether or propyl ether of cellulose, for example hydroxypropyl cellulose), polyvinyl pyrrolidone, polyvinyl acetate or polyvinyl alcohol.

[0091] Neutral methacrylate copolymers are often useful when mixed with anionic (meth)acrylate copolymers.

[0092] The neutral methacrylate copolymer is polymerized from (meth)acrylate monomers having neutral groups, especially C1- to C4-alkyl groups, at least to an extent of more than 95% by weight, in particular to an extent of at least 98% by weight, preferably to an extent of at least 99% by weight, in particular to an extent of at least 99% by weight, and more preferably to an extent of 100% by weight.

[0093] Suitable (meth)acrylate monomers having a neutral group are, for example, methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate, butyl acrylate. Preference is given to methyl methacrylate, ethyl acrylate and methyl acrylate.

[0094] The methacrylate monomer having an anionic group, such as acrylic acid and / or methacrylic acid, may be present in a small amount of less than 5 wt%, preferably not more than 2 wt%, more preferably not more than 1 wt%, or 0.05-1 wt%.

[0095] Suitable examples are neutral or substantially neutral (meth)acrylate copolymers polymerized from 20-40 wt % ethyl acrylate, 60-80 wt % methyl methacrylate and 0 to less than 5 wt %, preferably 0-2 wt % or 0.05-1 wt % methacrylic acid or acrylic acid.

[0096] Suitable examples are neutral or substantially neutral (meth)acrylate copolymers (hereinafter referred to as "co-polymers") polymerized from 20-40 wt % of methyl methacrylate, 60-80 wt % of ethyl acrylate and 0 to less than 5 wt %, preferably 0-2 wt % or 0.05-1 wt % of methacrylic acid or acrylic acid. NE or

[0097] NM type).

[0098] NE and NM is a copolymer comprising free radically polymerized units of 28-32 wt % methyl methacrylate and 68-72 wt % ethyl acrylate.

[0099] Preference is given to neutral or substantially neutral methyl acrylate copolymers which have been prepared as dispersions according to WO 01 / 68767 A1 using 1 to 10% by weight of a nonionic emulsifier having an HLB value of 15.2 to 17.3. The latter offer the advantage that, in the presence of the emulsifier ( NM type) forms a crystal structure without phase separation.

[0100] However, according to EP 1 571 164 A2, corresponding substantially neutral (meth)acrylate copolymers with small proportions of monoethylenically unsaturated C3-C8-carboxylic acids of 0.05 to 1% by weight can also be prepared by emulsion polymerization in the presence of relatively small amounts of anionic emulsifiers, for example 0.001 to 1% by weight.

[0101] Natural polymers

[0102] Especially for nutraceutical dosage forms, many consumers prefer so-called "natural polymer" coatings. Natural polymers are based on sources from nature, i.e. plants, microorganisms or animals, but are sometimes further chemically processed. The natural polymers used for coatings can be selected from, for example, starch, alginates, or salts of alginates (preferably sodium alginate), pectin, shellac, zein, carboxymethyl-zein, modified starches (e.g. Natural), sponge collagen, chitosan, gellan gum polymer. Suitable polymer mixtures may include: ethyl cellulose and pectin, modified starch ( Natural) and alginate and / or pectin, shellac and alginate and / or pectin, shellac and inulin, whey protein and a gum (such as guar or tragacanth), zein and polyethylene glycol, sodium alginate and chitosan.

[0103] Ethyl cellulose is a cellulose derivative in which some of the hydroxyl groups of the repeating glucose units are converted into ethyl ether groups. Ethyl cellulose can be used as a delayed 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).

[0104] Other components that may be present in the enteric coating layer or the intermediate coating layer are described below.

[0105] Unless expressly stated otherwise, these components are generally suitable for both coating layers.Unless expressly stated otherwise, the amount of each component is indicated based on the total weight of the at least one polymer contained in each coating layer.

[0106] Glidants

[0107] Glidants are generally of lipophilic nature. They prevent core agglomeration during film formation of the film-forming polymer.

[0108] The at least one glidant is preferably selected from silicon dioxide, for example those sold under the trade name GL100 or GL200 commercially available silicon dioxide, ground silicon dioxide, fumed silica, kaolin calcium silicate, magnesium silicate, colloidal silicon dioxide, talc, stearates such as calcium stearate, magnesium stearate, zinc stearate, sodium stearyl fumarate, starch, stearic acid, preferably talc, magnesium stearate, colloidal silicon dioxide and glyceryl monostearate or a mixture thereof, more preferably glyceryl monostearate and talc or a mixture thereof.

[0109] The standard usage ratio of the glidant in the coating layer is 0.5-100 wt %, preferably 3-75 wt %, more preferably 5-50 wt %, most preferably 5-30 wt %, relative to the total weight of the at least one polymer.

[0110] Emulsifier

[0111] In general, all known emulsifiers are suitable. Preference is given to nonionic emulsifiers, in particular emulsifiers with HLB>10 or HLB>12. The HLB value can be determined according to Griffin, William C. (1954), "Calculation of HLB Values ​​of Non-Ionic Surfactants" (PDF), Journal of the Society of Cosmetic Chemists, 5(4):249-56.

[0112] The at least one emulsifier is preferably selected from polysaccharides, alcohols, sugars and sugar derivatives, polyethers, amines, polyethylene derivatives, alkyl sulfates (e.g. sodium lauryl sulfate), alkyl ether sulfates, dioctyl sodium sulfosuccinate, polysorbates (e.g. polyoxyethylene (20) sorbitan monooleate), nonylphenol ethoxylate (nonoxynol-9), and mixtures thereof.

[0113] The at least one emulsifier is preferably selected from alkyl polyglycosides, decyl glucoside, decyl polyglucose, lauryl glucoside, octyl glucoside, N-octyl β-D-thiopyranoglucoside, cetearyl alcohol, cetyl alcohol, stearyl alcohol, polyoxyethylene cetearyl alcohol, cetostearyl alcohol, oleyl alcohol, polyglyceryl-6-dioleate, glyceryl stearate citrate, polyglyceryl-3-decanoate, polyglyceryl-3-diisostearate, glyceryl isostearate, polyglyceryl-4-isostearate, glyceryl monolinoleate, dicaprylyl carbonate, alcohol polyglycol ether, polyethylene glycol ether of cetearyl alcohol (n=20), polyethylene glycol-6 stearate, glycol stearate ... stearate), polyethylene glycol-32 stearate, polyethylene glycol-20 stearate, fatty alcohol polyethylene glycol ethers, polyethylene glycol-4 laurate, polyethylene glycol isocetyl ether (n=20), polyethylene glycol-32 (Mw 1500 g / mol) monoester and diester of lauric acid (C12), nonaethylene glycol, polyethylene glycol nonylphenyl ether, octaethylene glycol monododecyl ether, pentaethylene glycol monododecyl ether, polyethylene glycol macrocetyl ether, polyethylene glycol esters of palmitic acid (C16) or stearic acid (C18) or caprylic acid, polyoxyethylene fatty ethers derived from stearyl alcohols such as BRIJ S2, polyoxyethylene oxypropylene stearate, macrogol stearyl ether (20), diethylaminoethyl stearate, macrogol stearate, sucrose distearate, sucrose tristearate, sorbitan monostearate, sorbitan tristearate, mannose monooleate, octaglycerol monooleate monooleate), sorbitan dioleate, polyricinoleate, polysorbates such as polysorbate 20 and polyoxyethylene (20) sorbitan monooleate (polysorbate 80), sorbitan, sorbitan monolaurate, sucrose cocoate, glyceryl cocoate-2, ethylhexyl cocoate, polypropylene glycol-3 benzyl ether myristate, sodium myristate, sodium gold thiomalate, polyethylene glycol 8 laurate, polyethylene glycol-4 dilaurate, alpha-hexadecene -ω-hydroxypoly(ethylene oxide), cocamide diethanolamine, N-(2-hydroxyethyl) dodecanoamide, 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-nonaoxotriahydropyrrolo[1,2-g][1,4,7,10,13,16,19,22,25]nonaazacyclooctadec-25-yl]acrylamide (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-nonaoxotriacontahydrop yrrolo[1,2-g][1,4,7,10,13,16,19,22,25]nonaazacyclooctacosin-25-yl]propenamide), 2-{2-[2-(2-{2-[2-(2-{2-[2-(4-nonylphenoxy)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}ethoxy)ethoxy]ethoxy}ethanol, oxypolyethoxydodecane, poloxamers such as poloxamer 188 (Pluronic F-68) and poloxamer 407, propylene glycol monocaprylate type I (Capryol PGMC), polyethoxylated tallow amine, polyglycerol, polyoxyethylene 40 hydrogenated castor oil, surfactin, 2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]ethanol, carbomer, carbomer sodium, carboxymethylcellulose calcium, carrageenan, cholesterol, deoxycholic acid, phospholipids such as eggphospholipids, gellan gum, lanolin, capric acid, waxes such as Polawax NF, Polawax A31 or Ceral Pw, ester gum, dea-cetyl phosphate, soy lecithin, sphingomyelin, sodium phosphate, sodium lauroyl lactylate, lanolin, methyl-polymer with oxirane monobutyl ether ether), 1,2-dierucoylphosphatidylcholine, polydimethylsiloxane terminated with an average of 14 moles of propylene oxide, laurylmethicone copolyol, lauroglycol 90, liquid paraffin such as Amphocerine KS, dispersion of acrylamide / sodium acryloyldimethyltaurate copolymer in isohexadecane, and sodium polyacrylate, or mixtures thereof. Preferred are polyethylene glycol stearyl ether (20) and polysorbate 80. ,

[0114] In one embodiment, less than 3 wt%, preferably 1.5 wt%, of at least one emulsifier is present, or essentially no emulsifier is present, based on the total weight of the at least one polymer.

[0115] Enteric coating or top coating

[0116] The enteric coating layer or top coating layer can comprise 10 wt % or more, 20 wt % or more, 30 wt % or more, 40 wt % or more, 50 wt % or more, 60 wt % or more, 70 wt % or more, 80 wt % or more, 90 wt % or more, or 95 wt % or more of the polymer. The coating layer can comprise 10-100 wt %, 10-90 wt %, 12-80 wt %, 15-80 wt %, 18-80 wt %, 20-80 wt % or 40-80 wt % of the polymer.

[0117] The top coating layer is located on the enteric coating layer and comprises at least one polymer as described above. The top coating is also preferably water-soluble or substantially water-soluble. The top coating may have the function of coloring the drug or nutraceutical form, or protecting it from environmental influences (e.g., moisture during storage).

[0118] Middle coating layer

[0119] The intermediate coating layer is located on or above the capsule and comprises at least one polymer, at least one alkaline substance and at least one specific release accelerating agent.

[0120] Based on the total weight of the intermediate coating layer, the intermediate coating layer may contain 5-90 wt %, preferably 10-70 wt %, more preferably 30-50 wt % of the at least one polymer. The at least one polymer is preferably 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 esters, cellulose glycolates, polyethylene glycol, polyethylene oxide, polyvinyl pyrrolidone, polyvinyl acetate, polyvinyl alcohol, or mixtures thereof, preferably hydroxypropyl methyl cellulose.

[0121] The intermediate coating layer may contain 10-75 wt %, preferably 10-50 wt % of the basic substance, based on the total weight of the coating layer.

[0122] The alkaline substance may be an alkali or alkaline earth metal salt. The alkaline substance may be selected from calcium oxide, calcium carbonate, magnesium carbonate, magnesium oxide, sodium carbonate, sodium bicarbonate and sodium hydroxide, or any mixture thereof. Preferably the alkaline substance is magnesium oxide and / or magnesium carbonate.

[0123] The at least one release accelerator is selected from iron oxide, aluminum oxide, titanium dioxide, dimethyl sulfoxide, zinc oxide, sucrose, maltose, lactose, dextrates, glucose, fructose, dyes such as Red 40 (E129), Blue 1 (E133) and Yellow 5 (E102), Amaranth (E123), Azorubin (E122), Ponceau 4R (E124) and Quinoline Yellow WS (E104), Brilliant Blue (E133), Indigo Carmine (E132), Allura Red (E129), Tartrazine (E102), Sunset Yellow (E110), Erythrosine (E127), Ponceau 4R (E124), or any mixture thereof, and is present in 0.1-20 wt %, preferably 0.2-15 wt %, more preferably 0.5-8 wt %, and most preferably 1-6 wt %, based on the weight of the at least one polymer.

[0124] The intermediate coating layer may contain at least one glidant, preferably in an amount of 2-50 wt %, more preferably 5-25 wt %, based on the total weight of the intermediate coating layer. Suitable glidants are the same as those described herein for the enteric coating layer. The at least one glidant is preferably talc or glycerol.

[0125] Based on the total weight of the intermediate layer, the intermediate layer may contain 1-95 wt%, preferably 10-50 wt% of at least one additive, such as a polymer binder, a plasticizer or an anti-adherent, or a combination thereof. Suitable additives are the same as those described for the enteric coating layer.

[0126] Preferably, the intermediate layer is located directly on the capsule.

[0127] The amount and thickness of the enteric coating layer and the intermediate coating layer

[0128] To ensure influx prevention and processability, when a hard shell capsule, tablet or mini-tablet forms the core, it has been found that the total coating amount is preferably 2.0-30 mg / cm 2 , especially for hard shell capsules, more preferably 2.0-10 mg / cm 2 , or 10-25 mg / cm3 especially for small tablets or tablets 2 .

[0129] For hard shell capsules of size #0, the amount of the coating layer should not be too high. If the amount of the coating layer applied is too high, this may result in difficulty in subsequently processing the polymer coated pre-locked hard shell capsules in the capsule filling machine. If the amount of the coating layer is less than 5 mg / cm 2 , for example 2-4 mg / cm 2 , standard capsule filling machines without modification will not usually present a problem. 2 Up to about 8 mg / cm 2 The capsule filling machine can still be used within the range of about 3 mg / cm, however the form of the body and cap should be adjusted to be slightly wider. Such adjustments can be easily made by a mechanical engineer. 2 About 8mg / cm 2 Within the range of the amount of coating layer, a capsule filling machine can be advantageously used.

[0130] For hard shell capsule size #1, the amount of coating layer should not be too high. If the amount of coating layer applied is too high, this may lead to difficulty in the subsequent processing of the polymer coated pre-locked hard shell capsule in the capsule filling machine. If the amount of coating layer is less than 4 mg / cm 2 , for example, 2-3.5 mg / cm 2 , standard capsule filling machines without modification will not usually present a problem. 2 Up to about 8 mg / cm 2 The capsule filling machine can still be used within the range of about 3 mg / cm, however the form of the body and cap should be adjusted to be slightly wider. Such adjustments can be easily made by a mechanical engineer. 2 About 8mg / cm 2 Within the range of the amount of coating layer, a capsule filling machine can be advantageously used.

[0131] For hard shell capsule size #3, the amount of coating layer should not be too high. If the amount of coating layer applied is too high, this may lead to difficulty in the subsequent processing of the polymer coated pre-locked hard shell capsule in the capsule filling machine. 2 Up to about 6 mg / cm 2 The capsule filling machine can still be used within the range of about 3 mg / cm, however the form of the body and cap should be adjusted to be slightly wider. Such adjustments can be easily made by a mechanical engineer. 2 About 6 mg / cm 2 Within the range of the amount of coating layer, a capsule filling machine can be advantageously used.

[0132] If the amount of the coating layer applied is too high, there will also be too much assembly of the coating layer at the flange of the cap when the gap between the body and the cap is in the pre-locked state. This may lead to cracks in the coating layer when the coated pre-locked hard shell capsule is opened manually or in a machine after drying. The cracks may cause the capsule to leak subsequently. Finally, too thick a coating may make it difficult or impossible to close the opened coated hard shell capsule to the final locked state because the coating layer is thicker than the gap in the overlap area between the body and the cap.

[0133] Generally speaking, the coating layer on the hard shell capsule, tablet or mini-tablet can be 0.7-30 mg / cm 2 1.0-18mg / cm 2 , 2-10mg / cm 2 , 4-8mg / cm 2 1.0-8mg / cm 2 1.5-5.5mg / cm 2 1.5-4mg / cm 2 Amount (= total weight gain) is applied.

[0134] Generally speaking, the coating layer on the hard shell capsule, tablet or mini-tablet may have an average thickness of about 5-100 μm, 10-50 μm, 15-75 μm.

[0135] Generally speaking, the coating layer on the hard shell capsule may be applied in an amount of 5-50%, preferably 8-40% dry weight relative to the weight of the pre-locked capsule.

[0136] With this guidance, a person skilled in the art will be able to adjust the amount of the coating layer within the range between too low and too high.

[0137] Bioactive ingredients

[0138] The bioactive ingredient is preferably a pharmaceutical active ingredient and / or a nutraceutical active ingredient and / or a cosmetic active ingredient. Although each coating layer may contain a specific bioactive ingredient, it is preferred that the bioactive ingredient is contained in the filler. In particular, if the bioactive ingredient is contained in a liposome, a lipid nanoparticle or a nucleic acid, the bioactive ingredient is only contained in the filler.

[0139] Bioactive ingredients

[0140] The present invention is particularly useful for delayed release formulated pharmaceutical or nutraceutical dosage forms having a fill of a biologically active, preferably pharmaceutically or nutraceutical active ingredient.

[0141] Suitable therapeutic and chemical classes of pharmaceutical active ingredients that can be used as fillers for the polymer coated hard shell capsules are, for example: analgesics, antibiotics or anti-infectives, antibodies, anti-epileptics, antigens from plants, anti-rheumatic drugs, benzimidazole derivatives, beta blockers, cardiovascular drugs, chemotherapeutic drugs, CNS drugs, digitalis glycosides, gastrointestinal drugs such as proton pump inhibitors, enzymes, hormones, liquid or solid natural extracts, oligonucleotides, peptides, hormones, proteins, therapeutic bacteria, peptides, protein (metal) salts, i.e., aspartate, chloride, urology drugs, lipid nanoparticles, liposomes, polymer nanoparticles, vaccines. In a preferred embodiment, at least one liposome or lipid nanoparticle is contained, each of which contains at least one polynucleotide.

[0142] In a preferred embodiment, the pharmaceutical active ingredient is a lipid nanoparticle or a liposome, each of which contains a polynucleotide or a nucleic acid, and more preferably, the nucleic acid agent can be DNA, RNA or a combination thereof. In some embodiments, the nucleic acid agent can be an oligonucleotide and / or a polynucleotide. In some embodiments, the nucleic acid agent can be an oligonucleotide and / or a modified oligonucleotide (including but not limited to being modified by phosphorylation); an antisense oligonucleotide and / or a modified antisense oligonucleotide (including but not limited to being modified by phosphorylation). In some embodiments, the nucleic acid agent can include cDNA and / or genomic DNA. In some embodiments, the nucleic acid agent can include non-human DNA and / or RNA (e.g., viral, bacterial or fungal nucleic acid sequences). In some embodiments, the nucleic acid agent can be a plasmid, a cosmid, a gene fragment, an artificial and / or natural chromosome (e.g., a yeast artificial chromosome), and / or a part thereof. In some embodiments, the nucleic acid agent can be a functional RNA (e.g., mRNA, tRNA, rRNA and / or a ribozyme). In some embodiments, the nucleic acid agent can be an RNAi inducer, a small interfering RNA (siRNA), a short hairpin RNA (shRNA) and / or a micro RNA (miRNA). In some embodiments, the nucleic acid agent can be a peptide nucleic acid (PNA). In some embodiments, the nucleic acid agent can be a polynucleotide comprising a synthetic analog of nucleic acid, which can be modified or unmodified. In some embodiments, the nucleic acid agent can include various structural forms of DNA, including single-stranded DNA, double-stranded DNA, supercoiled DNA and / or triple-helix DNA; Z-DNA; and / or combinations thereof. In addition, suitable nucleic acids are disclosed, for example, in WO 2012103035 A1, which is incorporated by reference.

[0143] Other examples of drugs that can be used as fillers for the polymer coated hard shell capsules are, for example, acamprosate, aescin, amylase, acetylsalicylic acid, epinephrine, 5-aminosalicylic acid, chlortetracycline, bacitracin, balsalazine, beta carotene, bicalutamid, bisacodyl, bromelain, bromelain, budesonide, calcitonin, carbamacipine, carboplatin, cephalosporins, cetrorelix, clarithromycin, chloramphenicol, cimetidine, cisapride, cladribine, chloramphenicol ... acid, cromalyn, 1-deaminocysteine-8-D-arginine-vasopressin, deramciclane, detirelizine, dexlansoprazole, diclofenac, didanosine, digitoxin and other digitalis glycosides, dihydrostreptomycin, polydimethylsiloxane, divalproex, drospirenone, duloxetine, enzymes, erythromycin, esomeprazole, estrogens, etoposide, famotidine, fluoride, garlic oil, glucagon, granulocyte colony-stimulating agent G-CSF, heparin, hydrocortisone, human growth hormone (hGH), ibuprofen, ilaprazole, insulin, interferon, interleukin, intron A, ketoprofen, lansoprazole, leuprolidacetat lipase, lipoic acid, lithium, kinins, memantine, mesalamine, methenamine, miramerine, minerals, minoprazole, naproxen, natamycin, nitrofurantoin, novobiocin, olsala zine), omeprazole, orothates, pancreatic enzymes, pantoprazole, parathyroid hormone, paroxetine, penicillin, perprazol, pindolol, polymyxin, potassium, pravastatin, prednisone, preglumetacin, progab, pro-somatostatin, protease, quinapril, rabeprazole, ranitidine butyl, ranolazine, reboxetine, rutin (rutosid), somatostatin, streptomycin, subtilisin, sulfasalazine, sulfonamide, tamsulosin, tenatoprazole, thrypsine, valproic acid, vasopressin, vitamins, zinc, including their salts, derivatives, polymorphs, isomorphs, acetaminophen, codeine, griseofulvin, isosorbide 5-mononitrate, lumiracoxib, metoprolol, minoxidil, nefazodone, phenytoin, remogliflozin etabonate (remogliflozin etabonate etabonate), rivastigmine, theophylline, colchicine, darunavir, nifedipine, valacyclovir, mizoribine, ribavirin, antipyrine, glipizine, phenytoin, selegiline, theophylline, cilostazol, cimetidine, darunavir, digoxin, famotidine, fexofenadine, forskolin, indinavir, nevirapine, quinidine, ranitidine, tacrolimus, talinolol, verapamil, benazepril, cefadroxil, cephalexin, atenolol, ciprofloxacin, fluvastatin, metformin, levodopa, gabapentin, pseudoephedrine, ropivacaine and sotalol, or mixtures or combinations thereof.Preferably, acetaminophen, codeine, griseofulvin, isosorbide 5-mononitrate, lumiracoxib, metoprolol, minoxidil, nefazodone, phenytoin, repagliflozin etabonate, rivastigmine, theophylline, colchicine, darunavir, nifedipine, valacyclovir, mizoribine, ribavirin, antipyrine, glipizine, phenytoin, selegiline, theophylline, cilostazol, cimetidine, darunavir, digoxin , famotidine, fexofenadine, forskolin, indinavir, nevirapine, quinidine, ranitidine, tacrolimus, talinolol, verapamil, benazepril, cefadroxil, cephalexin, atenolol, ciprofloxacin, fluvastatin, metformin, levodopa, gabapentin, pseudoephedrine, ropivacaine and sotalol, or mixtures or combinations thereof.

[0144] It is obvious to those skilled in the art that there is extensive overlap between the terms drug and nutraceutical active ingredients, excipients and compositions, respective drug or nutraceutical dosage forms. Many substances that are classified as nutraceuticals can also be used as drug active ingredients. Depending on the specific application and local authority legislation and classification, the same substance can be classified as a drug or nutraceutical active ingredient, a drug or nutraceutical composition, or even both, respectively.

[0145] Nutrients are well known to those skilled in the art. Nutrients are often limited to food extracts that are said to have a medical effect on human health. Therefore, nutraceutical active ingredients may also exhibit pharmaceutical activity: examples of nutraceutical active ingredients may be resveratrol from grape products as antioxidants, soluble dietary fiber products such as psyllium seed husks for alleviating hypercholesterolemia, broccoli (sulfane) as anticancer drugs, and soybeans or alfalfa (isoflavones) for improving arterial health. Therefore, it is clear that many substances listed as nutraceuticals may also be used as pharmaceutically active ingredients.

[0146] Typical nutraceuticals or nutraceutical active ingredients that can be used as fillers for the polymer-coated hard shell capsules may also include probiotics and prebiotics. Probiotics are live microorganisms believed to support human or animal health when ingested. Prebiotics are nutraceuticals or nutraceutical active ingredients that induce or promote the growth or activity of beneficial microorganisms in the human or animal intestines.

[0147] Examples of nutraceuticals are resveratrol from grape products as antioxidants, omega-3-fatty acids or proanthocyanidins from blueberries, soluble dietary fiber products such as psyllium seed husks for reducing hypercholesterolemia, broccoli (sulfanes) as anticancer agents and soy or alfalfa (isoflavonoids) for improving arterial health. Other examples of nutraceuticals are flavonoids, antioxidants, alpha-linoleic acid from flaxseed, beta-carotene from marigold petals or anthocyanins from berries. The expressions neutraceutical or nutriceutical are sometimes used as synonyms for nutraceuticals.

[0148] Preferred biologically active ingredients are azacitidine, decitabine, metoprolol, mesalazine and omeprazole.

[0149] additive

[0150] The additives according to the present invention are preferably excipients, which are well known to those skilled in the art and are often formulated with the biologically active ingredients contained in the coated hard shell capsule and / or with the polymer coating layer of the hard shell capsule as disclosed and claimed herein. All excipients used must be toxicologically safe and need to be used in medicines or nutraceuticals without risk to patients or consumers.

[0151] The dosage form may include an excipient, preferably an excipient acceptable to a drug or nutraceutical, selected from an antioxidant, a brightener, a binder, a flavoring agent, a flow aid, a flavor, a penetration enhancer, a pore former, or a stabilizer, or a combination thereof. The excipient acceptable to the drug or nutraceutical may be included in the core and / or in the coating layer comprising the polymer as disclosed. The excipient acceptable to a drug or nutraceutical is an excipient that is permitted for use in the field of drugs or nutraceuticals.

[0152] Based on the total weight of the at least one polymer, the intermediate coating layer, the enteric coating layer or the top coating layer may contain up to 90 wt.-%, up to 80 wt.-%, up to 70 wt.-%, up to 50 wt.-%, up to 60 wt.-%, up to 50 wt.-%, up to 40 wt.-%, up to 30 wt.-%, up to 20 wt.-%, up to 10 wt.-%, up to 5 wt.-%, up to 3 wt.-%, up to 1 wt.-% additives, or be completely free (0%) of additives (preferably pharmaceutically or nutraceutical acceptable excipients).

[0153] Plasticizers

[0154] The intermediate coating layer and / or the enteric coating layer can comprise one or more plasticizers. Plasticizer realizes the reduction of glass transition temperature by physical interaction with polymer, and promotes film formation, which depends on addition. Suitable material has the molecular weight of 90-20000g / mol conventionally and comprises one or more hydrophilic groups, for example hydroxyl, ester group or amino in molecule.

[0155] Examples of suitable plasticizers are selected from alkyl citrates, alkyl phthalates, alkyl sebacates, diethyl sebacate, dibutyl sebacate, polyethylene glycol and polypropylene glycol. Preferred plasticizers are triethyl citrate (TEC), acetyl triethyl citrate (ATEC), diethyl sebacate, dibutyl sebacate (DBS), polyethylene glycol and polypropylene glycol, or mixtures thereof.

[0156] The plasticizer can be added to the formulation in a known manner directly in an aqueous solution or after the mixture is subjected to a thermal pretreatment. A mixture of plasticizers can also be used. The enteric coating layer can contain one or more plasticizers, based on the at least one polymer, preferably at most 60 wt %, at most 30 wt %, at most 25 wt %, at most 20 wt %, at most 15 wt %, at most 10 wt %, at most 5 wt %, less than 5 wt % plasticizer, or can be completely free of (0%) plasticizer.

[0157] filler

[0158] Standard fillers are usually added to the preparation of the present invention during the processing of coatings and adhesives. The introduction quantity and use of standard fillers in drug coatings or coverings are familiar to those skilled in the art. Examples of standard fillers are release agents, stabilizers, antioxidants, pore formers, penetration enhancers, brighteners, essences or flavorings. They are used as processing aids and are intended to ensure reliable and reproducible preparation processes and good long-term storage stability, or they realize additional favorable properties in pharmaceutical form. They are added to polymer formulations before processing and can affect the permeability of the coating. If necessary, this property can be used as an additional control parameter.

[0159] Dosage form

[0160] The dosage form comprises the core coated with the intermediate coating layer and the enteric coating layer as disclosed, and may preferably be in the form of a (coated) pellet (core) or a (coated) hard capsule (core).

[0161] The dosage form may have, for example, the form of a tablet, a mini-tablet, a mini-pellet, a pill, a granule, a sachet or a capsule, preferably a hard capsule. The dosage form may also be contained, preferably in multiple units, for example in a tablet, in a sachet or in a capsule.

[0162] nuclear

[0163] The core of the dosage form comprises a biologically active ingredient.

[0164] The core of the dosage form may comprise the biologically active ingredient distributed in a matrix structure, or in a binder in a coating bonded to an internal core structure, or encapsulated in a capsule.

[0165] The core may be prepared by methods such as pelletizing, extrusion, spheronization or hot melt extrusion.

[0166] The core can be a pellet, a pill, a granule, a tablet, a small piece or a capsule. The core can be a tablet containing an active ingredient, a compressed tablet containing a pellet, a small piece or a capsule (hard or soft), which can be filled with a pellet or granule containing an active ingredient, a drug solution or dispersion, a small piece or a powder, or a combination thereof.

[0167] The core can include, for example, uncoated pellets, neutral carrier pellets, such as sugar spheres or blank pellet cores (non-pareil), and the bioactive component is bonded in the adhesive thereon, such as lactose, polyvinyl pyrrolidone or neutral cellulose derivatives such as HPC or HPMC. The adhesive-coating layer with the bioactive component is considered as a part of the core in this article. Contrary to the intermediate coating layer and the enteric coating layer, the adhesive-coating layer of the core has basically no influence on the controlled release of the bioactive component. The core can also include the uncoated pellets consisting of the bioactive component of crystallization.

[0168] The core may comprise 0.1-100 wt%, 1-100 wt%, 2-90 wt%, 5-85 wt%, 10-70 wt%, 15-50 wt% of the bioactive ingredient. The core may comprise 0-99.9 wt%, 0-99 wt%, 10-98 wt%, 15-95 wt%, 30-90 wt% or 50-85 wt% of the bioactive ingredient.

[0169] The core may preferably be a hard shell capsule. Hard shell capsules for pharmaceutical or nutraceutical purposes are well known to those skilled in the art. A hard shell capsule is a two-piece encapsulated capsule consisting of two capsule halves, referred to as a body and a cap. The capsule body and the cap material are usually made of hard and sometimes brittle materials. The hard shell capsule comprises a body and a cap. The body and the cap are usually in the form of a cylindrical opening at one end, with a closed circular hemispherical end at the opposite end. The cap and the body are shaped and sized so that the body can be telescoped into the open end of the cap by its open end.

[0170] The body and the cap include a potentially overlapping matching area (overlapping area) on the outside of the body and the inside of the cap, which partially overlaps when the capsule is closed in the pre-locking state and completely overlaps when the capsule is closed in the final locking state. When the cap partially slides over the overlapping matching area of ​​the body, the capsule is in the pre-locking state. When the cap completely slides over the overlapping matching area of ​​the body, the capsule is in the final locking state. The maintenance of the pre-locking state or the final locking state is usually supported by a snap-in locking mechanism of the body and the cap, such as a matching surrounding notch or dimple, preferably an elongated dimple.

[0171] Typically, the body is longer than the cap. The outer overlapping area of ​​the body can be covered by the cap to facilitate closing or locking the capsule. In the closed state, the cap covers the outer overlapping area of ​​the body in a pre-locking state or in a final locked state. In the final locked state, the cap completely covers the outer overlapping area of ​​the body, and in the pre-locking state, the cap only partially overlaps the outer overlapping area of ​​the body. The cap can be slid over the body and is usually fixed in one of two different positions, in which the capsule is closed in a pre-locking state or in a final locked state.

[0172] Hard shell capsules of different sizes are commercially available. Hard shell capsules are usually supplied as empty containers, with the body and cap positioned in a pre-locked state, and as required as separate half capsules, i.e., body and cap. The pre-locked hard shell capsules can be provided to a capsule filling machine, which opens, fills and closes the capsules to a final locked state. Typically, hard shell capsules are filled with dry material, such as powders or granules, or pellets, or small pieces, or submicron particles, or viscous liquids containing bioactive ingredients.

[0173] The cap and the main body are provided with a closure device that is conducive to the pre-locking (temporary) and / or final locking of the capsule. Therefore, convex points (elevated points) can be provided on the inner wall of the cap, and slightly larger concave points (indented points) can be provided on the outer wall of the main body, and these points are arranged so that the protrusions (elevations) fit into the recesses (indentations) when the capsule is closed. Alternatively, a protrusion can be formed on the outer wall of the main body and a recess can be formed on the inner wall of the cap. Wherein the arrangement of the protrusion or recess is arranged in a ring or spiral around the wall. Instead of the point-shaped structure of the protrusion or recess, these can be surrounded by the cap or the wall of the main body in an annular structure, although it is advantageous to provide grooves and openings to allow gas exchange in and out of the capsule. One or more protrusions can be provided in an annular arrangement around the inner wall of the cap and the outer wall of the main body, so that in the final locking position of the capsule, the protrusion on the cap is adjacent to the protrusion on the main body. Sometimes a projection is formed on the outside of the body near the open end and a recess is formed in the cap near the open end, so that the projection on the body locks into the recess in the cap in the final locked position of the capsule. The projection can make it possible to open the cap at any time in the pre-locked state without damaging the capsule, or alternatively, make it impossible to open the capsule again without destroying it once it has been closed. Capsules with one or more such locking mechanisms (latches) (e.g. two surrounding grooves) are preferred. More preferred are capsules with at least two such locking devices, which fix the two capsule parts to different degrees. In some of these cases, the first locking (recess or surrounding recess) device can be formed close to the opening in the capsule cap and the capsule body, and the second locking (surrounding recess) can be moved slightly further towards the closed end of the capsule part. The first locking device fixes the two capsule parts weaker than the second locking device. The advantage of this variant is that after the production of the empty capsule, the capsule cap and the capsule body can initially be pre-locked and joined together using the first locking mechanism. In order 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 locking catches securely fix the capsule parts in the final locked state.

[0174] Preferably, the body and the cap of the hard shell capsule each contain a surrounding recess and / or a dimple in the area where the cap can slide over the body. The surrounding recess of the body and the dimple of the cap match each other to provide a snap-in or snap-in-place mechanism. The dimple can be circular or longitudinally elongated (oval). The surrounding recess of the body and the surrounding recess of the cap (closely matched ring) also match each other to provide a snap-in or snap-in-place mechanism. This allows the capsule to be closed in a pre-locked state or a final locked state by the snap-in-place mechanism.

[0175] Preferably, the body and the cap are fixed to each other in a pre-locked state using the matching surrounding notches of the body and the elongated recesses of the cap. Preferably, the body and the cap are fixed to each other or locked in a final locked state using the matching surrounding notches of the body and the cap.

[0176] The area over which the cap can slide over the body can be referred to as the overlapping area of ​​the body and the cap, or simply the overlapping area. If the cap only partially overlaps the body, perhaps 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 matching surrounding notches and / or dimples in the body and the cap, the partially closed capsule can be referred to as pre-locked. When the capsule is polymer-coated in the pre-locked state, the coating completely covers the outer surface, including the portion of the overlapping area of ​​the body and the cap that is not overlapped by the cap in this pre-locked state. When the capsule is polymer-coated in the pre-locked state and is subsequently closed to the final locked state, the coating of the portion of the overlapping area of ​​the body and the cap that is not overlapped by the cap in the pre-locked state will be overlapped by the cap. Then the presence of that portion of the coating encapsulated between the body and the cap in the final locked state is sufficient to tightly seal the hard shell capsule.

[0177] If the cap overlaps the body over the entire overlapping area of ​​the body, the hard shell capsule is finally closed or in a final locked state. Preferably, the final closed capsule can be called a final locked capsule in the presence of a locking mechanism such as matching surrounding notches and / or dimples in the body and the cap.

[0178] Generally, it is preferred that the recess is used to fix the body and the cap in the pre-locked state. As a non-binding rule, the matching area of ​​the recess is smaller than the matching area of ​​the surrounding recess. Therefore, the inserted recess can be disengaged again by applying a smaller force than the force required to disengage the locking by the matching surrounding recess.

[0179] The recesses of the body and the cap are located in the area where the cap can slide over the body, and they match each other in a pre-locked state by a snap-in or snap-in-place mechanism. There may be, for example, 2, 4 or preferably 6 notches or recesses distributed around the cap.

[0180] Typically, in the area where the cap can slide over the body, the recess of the cap and the surrounding recess of the body match each other so that they allow the capsule to be closed to the pre-locked state by a snap-in-place mechanism. In the pre-locked state, the hard shell capsule can be reopened manually or by machine without damage due to the relatively low force required for opening. Therefore, the "pre-locked state" is sometimes also called "loosely capped".

[0181] Typically, in the area where the cap can be slid over the body, the surrounding recesses or matching locking rings of the body and the cap match each other so that they allow the capsule to be closed into a final locked state by a click-in-place mechanism. In the final locked state, the hard-shell capsule cannot be reopened without damage manually or by machine, or only with difficulty, due to the high forces required for opening.

[0182] The dimples and surrounding recesses are usually formed in the capsule body or the capsule cap. When the capsule parts provided with these protrusions and recesses are matched with each other, an ideally defined uniform gap of 10 microns to 150 microns, more particularly 20 microns to 100 microns, is formed along the contact surface between the capsule body and the capsule cap placed thereon.

[0183] Preferably, the body of the hard shell capsule comprises a tapered rim. The tapered rim prevents the rim of the body and the rim of the cap from colliding and being damaged when the capsule is closed manually or by machine.

[0184] Unlike hard shell capsules, soft shell capsules are welded one-piece encapsulated capsules. Soft gel capsules are often made of blow-molded soft gelling material and are usually filled with a liquid containing a biologically active ingredient by injection. The present invention does not relate to welded soft shell one-piece encapsulated capsules.

[0185] Hard shell capsule size

[0186] The closed final locked hard shell capsule can have a total length of about 5-40mm. The diameter of the cap can be in the range of about 1.3-12mm. The diameter of the body can be in the range of about 1.2-11mm. The length of the cap can be in the range of about 4-20mm, and the length of the body is in the range of 8-30mm. The filling volume can be between about 0.004-2mL. The difference between the pre-locking length and the final locking length can be about 1-5mm.

[0187] Capsules can be divided into standardized sizes, such as 000 to 5. A closed capsule size 000 has, for example, a total length of about 28 mm, and an outer diameter of the cap of about 9.9 mm and an outer diameter of the body of about 9.5 mm. The length of the cap is about 14 mm, and the length of the body is about 22 mm. The filling volume is about 1.4 mL.

[0188] A size 5 closed capsule has, for example, a total length of about 10 mm and a cap outer diameter of about 4.8 mm and a body outer diameter of about 4.6 mm. The length of the cap is about 5.6 mm and the length of the body is about 9.4 mm. The filling volume is about 0.13 mL.

[0189] A size 9 closed capsule has, for example, an overall length of about 8.4 mm and an outer cap diameter of about 2.7 mm. The fill volume is about 0.025 mL.

[0190] A size 0 capsule may exhibit a length of about 23-24 mm in the pre-locked state and about 20.5-21.5 mm in the final locked state. Thus, the difference between the pre-locked length and the final locked length may be about 2-3 mm.

[0191] Process for preparing coated hard shell capsules

[0192] Described is a process for preparing a polymer coated hard shell capsule, wherein the hard shell capsule comprises a body and a cap, wherein in the closed state, the cap overlaps the body in a pre-locked state or a final locked state, wherein the hard shell capsule is provided in a pre-locked state and coated with a first coating solution, suspension or dispersion according to the present invention, preferably spray coated, to form an intermediate coating layer, and then optionally dried and coated with a coating solution, suspension or dispersion according to the present invention, preferably spray coated, to form an enteric coating layer, which covers the outer surface of the hard shell capsule in the pre-locked state. In addition, after an optional drying step, a top coating layer can be subsequently applied.

[0193] In a further process step, the pre-locked hard shell capsule can be provided with a fill containing a pharmaceutical or nutraceutical bioactive ingredient and closed to a final locked state.

[0194] In such an additional process step, the polymer coated hard shell capsule in the pre-locked state can be opened, filled with a fill material comprising at least one biologically active ingredient, and closed to a final locked state. This additional process step is preferably performed as follows: the coated hard shell capsule in the pre-locked state is provided to a capsule filling machine, which performs the opening, filling and closing of the polymer coated hard shell capsule to the final locked state.

[0195] This additional 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 which serves as a container for at least one biologically active ingredient is preferably a pharmaceutical or nutraceutical dosage form.

[0196] The dosage form preferably comprises a polymer-coated hard shell capsule in a final locked state, the polymer-coated hard shell capsule containing a fill comprising at least one biologically active ingredient, wherein the polymer-coated hard shell capsule comprises a coating layer according to the present invention, wherein the coating layer covers the outer surface area of ​​the capsule in the pre-locked state but does not cover the overlapping area where the cap covers the body in the pre-locked state.

[0197] The coating suspension may contain an organic solvent, such as acetone, isopropanol or ethanol. The concentration of dry weight material in the organic solvent may be about 5-50% by weight based on the weight of the polymer. Suitable spray concentrations may be about 5-25% by dry weight.

[0198] The coating suspension can be a dispersion of a polymer in an aqueous medium, and the aqueous medium is, for example, water, or a mixture of 80% by weight or more of water and 20% by weight or less of a water-soluble solvent such as acetone or isopropanol. The suitable concentration of the dry weight material in the aqueous medium can be about 5-50% by weight. Suitable spray concentrations can be about 5-25% by dry weight.

[0199] Spray coating is preferably performed by spraying the coating solution or dispersion onto pre-locked capsules in a drum coater or fluidized bed coating equipment.

[0200] Process for preparing the filling material for the dosage form

[0201] Suitable processes for preparing fillers for preferred pharmaceutical or nutraceutical dosage forms are well known to those skilled in the art. Suitable processes for preparing fillers for dosage forms (preferably pharmaceutical or nutraceutical dosage forms) as disclosed herein may be by direct compression, compression of dry, wet or sintered granules, by extrusion and subsequent rounding, by wet or dry granulation, by direct pelleting or by bonding the powder to beads or neutral cores of inactive ingredients or particles or pellets containing active ingredients to form a core containing the biologically active ingredient in tablet or tablet form, and applying the intermediate coating layer and enteric coating layer in the form of an aqueous dispersion or an organic solution during spraying or by fluidized bed spray granulation.

[0202] Capsule filling machine

[0203] The polymer coated hard shell capsule in a pre-locked state is provided to a capsule filling machine, which performs the steps of separating a body and a cap, filling the body with a filler, and re-engaging the body and the cap into a final locked state.

[0204] The capsule filling machine used may be a capsule filling machine, preferably a fully automatic capsule filling machine, capable of preparing filled and closed capsules at an output speed of 1000 or more filled and finally closed capsules per hour. Capsule filling machines, preferably fully automatic capsule filling machines, are well known in the art and can be purchased from a number of companies.

[0205] The capsule filling machine used may preferably be operated with an output speed of 1000 or more, preferably 10000 or more, 100000 or more, 100000 to 500000 filled and finally closed capsules per hour.

[0206] Capsule filling machine general operation

[0207] Prior to the capsule filling process, a sufficient number or amount of pre-coated hard shell capsules in a pre-locked state are provided to the capsule filling machine. A sufficient amount of filler is also provided to the capsule filling machine to be filled during operation.

[0208] The hard shell capsule in the pre-locked state can fall into a feed tube or chute by gravity. The capsule can be evenly aligned by mechanically measuring the diameter difference between the cap and the body. The hard shell capsule is then typically fed into a two-section housing or brushing in the proper orientation.

[0209] The diameter of the upper sleeve or shell is usually larger than the diameter of the capsule body sleeve; therefore, the capsule cap can remain in the upper sleeve while the body is pulled into the lower sleeve by the vacuum. Once the capsule is opened / body and cap separated, the upper and lower shells or sleeves are separated to position the capsule body for filling.

[0210] The opened capsule body is then filled with filler. For different fillers, such as granules, powders, pellets or tablets, various types of filling mechanisms can be applied. Capsule filling machines usually use various mechanisms to operate various dosage ingredients and various numbers of filling stations. Dosing systems are usually based on the filler volume or amount determined by the capsule size and the capacity of the capsule body. Empty capsule manufacturers usually provide reference tables that indicate the volume capacity of their capsule bodies and the maximum fill weight of different capsule sizes based on the density of the filler material. After filling, the body and the cap are reengaged into a final locked state or position by the machine.

[0211] Purpose / Usage / Methods and Steps

[0212] In a suitable process for preparing a polymer-coated hard shell capsule in a closed state, the cap is overlapped with the body in a pre-locked state or a final locked state, for preparing a polymer-coated hard shell capsule suitable as a container for a biologically active ingredient, which comprises the following steps:

[0213] a) providing said hard shell capsule in a pre-locked state, and

[0214] b) spray coating with a coating solution, suspension or dispersion containing the components that will form the intermediate coating layer, optionally drying, and then spray coating with a coating solution, suspension or dispersion containing the components that will form the enteric coating layer covering the outer surface of the hard shell capsule in the pre-locked state, optionally drying, and optionally further applying a top coating layer.

[0215] The spray coating may preferably be applied using a drum coater apparatus or a fluidized bed coating apparatus, more preferably a drum coater apparatus. Suitable product temperatures during the spray coating process may be in the range of about 15-40° C., preferably about 23-30° C. Suitable spray rates may be in the range of about 0.3-17.0 [g / min / kg], preferably 0.5-14 [g / min / kg]. After spray coating, a drying step is included.

[0216] The polymer-coated hard shell capsule in the pre-locked state can be opened in step c), filled with a fill material including a bioactive ingredient in step d), and then closed to a final locked state in step e).

[0217] Steps c) to e) can be performed manually or preferably supported by a suitable device such as a capsule filling machine. Preferably, the coated hard shell capsule in a pre-locked state is provided to a capsule filling machine, which performs opening step c), filling with a fill material comprising a biologically active ingredient in step d) and closing the capsule to a final locked state in step e).

[0218] Selection of processes in all of their general or specific features and embodiments as disclosed herein may be combined without restriction with any other general or specific selection of materials or numerical features and embodiments as disclosed herein, such as polymers, capsule materials, capsule size, coating thickness, bioactive ingredients, and any other embodiments as disclosed.

[0219] Body and cap material

[0220] The base material of the body and the cap of the hard shell capsule can be selected from hydroxypropyl methylcellulose, starch, gelatin, pullulan, and copolymers of C1- to C4-alkyl esters of (meth)acrylic acid and (meth)acrylic acid. Preferred are hard shell capsules in which the body and the cap comprise or consist of HPMC or gelatin, most preferably HPMC due to good adhesion properties to the polymer coating.

[0221] Terms

[0222] The present invention particularly relates to the following clauses:

[0223] 1. A dosage form, comprising

[0224] a) a core comprising at least one biologically active ingredient,

[0225] b) an intermediate coating layer (ICL) on or over the core, the intermediate coating layer comprising

[0226] i) at least one polymer;

[0227] ii) at least one alkaline substance;

[0228] iii) at least one release accelerating agent selected from the group consisting of iron oxide, aluminum oxide, titanium dioxide, dimethyl sulfoxide, zinc oxide, sucrose, maltose, lactose, dextrates, glucose, fructose, dyes, or any mixture thereof;

[0229] iv) optionally at least one glidant;

[0230] v) optionally at least one plasticizer; and

[0231] vi) optionally at least one additive different from i) to v); wherein

[0232] The at least one release accelerating agent is present in 0.1-20 wt%, preferably 0.2-15 wt%, more preferably 0.5-8 wt%, most preferably 1-6 wt%, based on the weight of the at least one polymer; and

[0233] c) an enteric coating layer (ECL) on or above the intermediate coating layer, the enteric coating layer comprising

[0234] i) at least one polymer;

[0235] ii) optionally at least one glidant;

[0236] iii) optionally at least one emulsifier;

[0237] iv) optionally at least one plasticizer;

[0238] v) optionally at least one biologically active ingredient; and

[0239] vi) optionally at least one additive different from i) to v).

[0240] 2. The dosage form according to any of the preceding clauses, wherein the dosage form is a coated hard shell capsule, tablet or minitablet.

[0241] 3. A dosage form according to clause 1 or 2, wherein the biologically active ingredient is a pharmaceutically active ingredient.

[0242] 4. The dosage form according to any one of the preceding clauses, wherein the alkaline substance

[0243] i) is an alkali or alkaline earth metal salt; or

[0244] 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

[0245] iii) is present in 10-75 wt %, preferably 15-50 wt %, based on the total weight of the intermediate layer.

[0246] 5. The dosage form according to any of the preceding clauses, wherein the at least one release accelerator is Fe2O3, TiO2, lactose, disodium 2-[[4-[ethyl-[(3-sulfonated phenyl)methyl]amino]phenyl]-[4-[ethyl-[(3-sulfonated phenyl)methyl]ammoniumylidene]cyclohexa-2,5-diene-1-ylidene]methyl]benzenesulfonate, or any mixture thereof.

[0247] 6. The dosage form according to any of the preceding clauses, wherein the at least one polymer in the intermediate coating layer and / or the enteric coating layer, preferably the intermediate coating layer, is selected from at least one (meth)acrylate copolymer, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC) or polyvinylpyrrolidone (PVP).

[0248] 7. The dosage form according to any one of clauses 1 to 5, wherein the at least one polymer in the intermediate coating layer and / or the enteric coating layer, preferably the enteric coating layer, is

[0249] i) a core-shell polymer, which is a copolymer obtained by a two-stage emulsion polymerization process, having 70-80 wt% of a core and 20-30 wt% of a shell, the core comprising 65-75 wt% of polymerized units of ethyl acrylate and 25-35 wt% of methyl methacrylate, and the shell comprising 45-55 wt% of polymerized units of ethyl acrylate and 45-55 wt% of methacrylic acid; or

[0250] ii) anionic polymers obtained by polymerizing 25 to 95% by weight of a C1- to C12-alkyl ester of acrylic acid or methacrylic acid and 75 to 5% by weight of a (meth)acrylate monomer having an anionic group; or

[0251] iii) cationic (meth)acrylate copolymers obtained by polymerizing C1- to C4-alkyl esters of acrylic acid or methacrylic acid and alkyl esters of acrylic acid or methacrylic acid having a tertiary amino group or a quaternary ammonium group in the alkyl group; or

[0252] iv) a (meth)acrylate copolymer obtained by polymerizing methacrylic acid and ethyl acrylate, methacrylic acid and methyl methacrylate, ethyl acrylate and methyl methacrylate, or methacrylic acid, methyl acrylate and methyl methacrylate; or

[0253] v) a (meth)acrylate copolymer obtained by polymerizing 40-60 wt. % of methacrylic acid and 60-40 wt. % of ethyl acrylate; or

[0254] vi) a (meth)acrylate copolymer obtained by polymerizing 60-80 wt. % of ethyl acrylate and 40-20 wt. % of methyl methacrylate; or

[0255] vii) A (meth)acrylate copolymer obtained by polymerizing 5-15 wt% of methacrylic acid, 60-70 wt% of methyl acrylate and 20-30 wt% of methyl methacrylate; or a mixture thereof.

[0256] 8. The dosage form according to any one of clauses 1 to 5, wherein the at least one polymer in the intermediate coating layer and / or the enteric coating layer, preferably the enteric coating layer, is a mixture as listed below:

[0257] i) an anionic polymer and a second polymer, the anionic polymer has a Tgm ≥ 35°C, preferably 35-155°C, more preferably 80-145°C, most preferably 90-125°C, and the second polymer is a polymer with a Tgm ≤ 30°C, preferably < 15°C; or

[0258] ii) (meth)acrylate copolymers obtained by copolymerizing 40 to 60% by weight of methacrylic acid and 60 to 40% by weight of ethyl acrylate and (meth)acrylate copolymers obtained by polymerizing 60 to 80% by weight, preferably 60 to 78% by weight of ethyl acrylate and 40 to 20% by weight, preferably 38 to 20% by weight of methyl methacrylate, preferably in a weight ratio of 20:1 to 1:20 and optionally up to 2% by weight of (meth)acrylic acid; or

[0259] iii) (meth)acrylate copolymers obtained by copolymerizing 5-15 wt% of methacrylic acid, 60-70 wt% of methyl acrylate and 20-30 wt% of methyl methacrylate, and (meth)acrylate copolymers obtained by copolymerizing 40-60 wt% of methacrylic acid and 60-40 wt% of ethyl acrylate, preferably in a weight ratio of 20:1 to 1:20.

[0260] 9. The dosage form according to any of clauses 1 to 5, wherein the at least one polymer in the intermediate coating layer and / or the enteric coating layer is selected from at least one (meth)acrylate copolymer, hydroxypropyl methylcellulose (HPMC) or hydroxypropyl cellulose (HPC).

[0261] 10. The dosage form according to any one of clauses 1 to 5, wherein the at least one polymer in the enteric coating layer is

[0262] i) a core-shell polymer, which is a copolymer obtained by a two-stage emulsion polymerization process, having 70-80 wt% of a core and 20-30 wt% of a shell, the core comprising 65-75 wt% of polymerized units of ethyl acrylate and 25-35 wt% of methyl methacrylate, and the shell comprising 45-55 wt% of polymerized units of ethyl acrylate and 45-55 wt% of methacrylic acid; or

[0263] ii) anionic polymers obtained by polymerizing 25 to 95% by weight of a C1- to C12-alkyl ester of acrylic acid or methacrylic acid and 75 to 5% by weight of a (meth)acrylate monomer having an anionic group; or

[0264] iii) a (meth)acrylate copolymer obtained by polymerizing methacrylic acid and ethyl acrylate, methacrylic acid and methyl methacrylate, ethyl acrylate and methyl methacrylate, or methacrylic acid, methyl acrylate and methyl methacrylate; or

[0265] iv) a (meth)acrylate copolymer obtained by polymerizing 40-60 wt% of methacrylic acid and 60-40 wt% of ethyl acrylate; or

[0266] v) (meth)acrylate copolymers obtained by polymerizing 5-15 wt% of methacrylic acid, 60-70 wt% of methyl acrylate and 20-30 wt% of methyl methacrylate; or any mixture of i) to v).

[0267] 11. The dosage form according to any of the preceding clauses, wherein the at least one polymer in the enteric coating layer is

[0268] i) (meth)acrylate copolymers obtained by polymerizing at least two C1- to C4-alkyl acrylate monomers and 0 to less than 5% by weight of methacrylic acid or acrylic acid; or

[0269] ii) a (meth)acrylate copolymer obtained by polymerizing 20-40 wt% of ethyl acrylate, 60-80 wt% of methyl methacrylate and 0 to less than 5 wt% of methacrylic acid or acrylic acid; or

[0270] iii) a (meth)acrylate copolymer obtained by polymerizing 60-80 wt% of ethyl acrylate and 40-20 wt% of methyl methacrylate.

[0271] 12. The dosage form according to any one of clauses 1 to 5, wherein the enteric coating layer comprises at least two polymers:

[0272] i) a (meth)acrylate copolymer obtained by copolymerizing 40-60 wt % of methacrylic acid and 40-60 wt % of ethyl acrylate, and

[0273] ii) (Meth)acrylate copolymers obtained by polymerizing 60 to 78% by weight of ethyl acrylate and 20 to 38% by weight of methyl methacrylate and optionally up to 2% by weight, preferably 0.1 to 2% by weight, of (meth)acrylic acid.

[0274] 13. The dosage form according to any one of clauses 1 to 5, wherein the at least one polymer in the intermediate coating layer

[0275] i) 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 esters, cellulose glycolates, polyethylene glycol, polyethylene oxide, polyvinyl pyrrolidone, polyvinyl acetate, polyvinyl alcohol, or mixtures thereof, preferably hydroxypropyl methyl cellulose; and / or

[0276] ii) is present in an amount of 5-90 wt%, preferably 10-70 wt%, more preferably 30-50 wt%, based on the total weight of the intermediate coating layer.

[0277] 14. The dosage form according to any of clauses 1 to 5, wherein the 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 comprising at least 35 wt.% amylose, or mixtures thereof.

[0278] 15. The dosage form according to any of clauses 1 to 5, wherein the at least one polymer in the intermediate coating layer and / or the enteric coating layer, preferably the intermediate 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 esters, cellulose glycolates, polyethylene glycol, polyethylene oxide, polyvinyl pyrrolidone, polyvinyl acetate, polyvinyl alcohol, or mixtures thereof.

[0279] 16. The dosage form according to any of the preceding clauses, wherein at least one glidant is present in the intermediate coating layer and / or the enteric coating layer, wherein preferably, the at least one glidant

[0280] i) is present in an amount of 3-75% by weight based on the total weight of the polymer in each coating layer, and / or

[0281] ii) is selected from silicon dioxide, ground silicon dioxide, fumed silica, kaolin calcium silicate, magnesium silicate, colloidal silicon dioxide, glycerol, glyceryl monostearate, talc, stearate, sodium stearyl fumarate, starch, stearic acid, or a mixture thereof, preferably talc, magnesium stearate, colloidal silicon dioxide, glycerol and glyceryl monostearate, or a mixture thereof, more preferably glycerol, glyceryl monostearate and talc.

[0282] 17. The dosage form according to any of the preceding clauses, wherein at least one emulsifier is present in the enteric coating layer, wherein preferably, the at least one emulsifier

[0283] i) is present in an amount of less than 3 wt%, preferably less than 1.5 wt%, based on the total weight of the polymer, or is absent; or

[0284] ii) is present in an amount of 1.5 to 40 wt. %, based on the total weight of the polymer; and / or

[0285] iii) is a nonionic emulsifier, preferably a nonionic emulsifier with HLB>10, preferably>12; and / or

[0286] iv) is selected from polysaccharides, alcohols, sugars and sugar derivatives, polyethers, amines, polyethylene derivatives, alkyl sulfates (e.g. sodium lauryl sulfate), alkyl ether sulfates, dioctyl sodium sulfosuccinate, polysorbates (e.g. polyoxyethylene (20) sorbitan monooleate), nonylphenol ethoxylate (nonoxynol-9), and mixtures thereof.

[0287] 18. The dosage form according to any of the preceding clauses, wherein at least one plasticizer is present in the intermediate coating layer and / or the enteric coating layer, wherein preferably, the at least one plasticizer

[0288] i) is present in an amount of 2 to 40% by weight, based on the total weight of the at least one polymer, and / or

[0289] ii) is selected from polyethylene glycol, in particular polyethylene glycol having a weight average molecular weight Mw of 1000-10000 g / mol, preferably 6000 g / mol, alkyl citrate, alkyl phthalate and alkyl sebacate, or mixtures thereof, preferably polyethylene glycol having a weight average molecular weight Mw of 1000-10000 g / mol, diethyl sebacate, triethyl citrate (TEC), acetylcitrate triethyl ester (ATEC), diethyl sebacate and dibutyl sebacate (DBS), or mixtures thereof, more preferably triethyl citrate (TEC) or polyethylene glycol having a weight average molecular weight Mw of 6000 g / mol.

[0290] 19. A dosage form according to any of the preceding clauses, wherein up to 400 wt % of at least one additive, based on the total weight of the at least one polymer, is contained in the intermediate coating layer and / or the enteric coating layer, preferably selected from antioxidants, brighteners, flavoring agents, flow aids, fragrances, penetration enhancers, pore formers or stabilizers, or combinations thereof.

[0291] 20. The dosage form according to any one of clauses 1 and 3-19, wherein the core comprises a biologically active ingredient

[0292] i) distributed in a matrix structure; or

[0293] ii) bound in a binder in a coating on the core.

[0294] 21. The dosage form according to any one of clauses 1 to 19, wherein the core comprises the biologically active ingredient in the fill of a hard shell capsule, wherein the core is the hard shell capsule.

[0295] 22. Use of a dosage form according to any of the preceding clauses to provide at least 80% drug release within 30 min at pH 5-6.

[0296] 23. Use of a dosage form according to any of the preceding clauses to provide at least 80% drug release at pH 3 within 30 min.

[0297]

[0298] Example 1: (Invention) Enteric coating of pre-locked capsules in a drum coater with red iron oxide in the middle coating layer

[0299] Considering 545.82mm 2 The enteric coating and top coating formulations were calculated based on the surface area of ​​the capsules in the pre-locked state and a batch size of 1000 capsules in total (500 Capsugel V-Caps Size 0 white capsules and 500 Capsugel V-Caps Size 0 clear capsules).

[0300] Intermediate coating

[0301] While stirring gently HPMC E3 is fully dispersed in water to prevent agglomeration. Use a homogenizer (such as Ultra Turrax) to homogenize light magnesium oxide, anhydrous glycerol and red iron oxide in water for 10 minutes. The solid content should be about 10%. Slowly pour the excipient suspension into the mixture while stirring gently with a conventional stirrer. HPMC E3 solution. The spray suspension was passed through a 0.3 mm sieve. The spray suspension was gently stirred during the coating process.

[0302] Table 2: Intermediate coating

[0303]

[0304] *Amount based on dry polymer substance [%]

[0305] Enteric coating

[0306] Preparation of GMS emulsion: Heat 40% of the water to 70-80°C. Homogenize the polysorbate 80 solution, triethyl citrate and GMS in the heated water for 10 minutes using a homogenizer (e.g. Ultra Turrax). The solid content is about 15%. Stir the remaining 60% of the water into the hot GMS emulsion using a conventional stirrer and cool to room temperature while continuing to stir. Then slowly pour the excipient suspension into the mixture while gently stirring with a conventional stirrer. L 30D-55 dispersion. After gentle stirring for 10 minutes, slowly add NM 30D and stirred for another 15 minutes. The final coating suspension was sieved through a 400 μm sieve and stirred during the coating process. The pre-locked state capsules were coated using a drum coater.

[0307] Table 3: Enteric coating

[0308]

[0309] *Amount based on dry polymer substance [%]

[0310] Capsule coating process

[0311] Capsules were coated in a fully perforated side-vended pan coating system O'Hara M10.

[0312] Bridging test:

[0313] The bridging between the body and the cap of the capsule is tested. The test is performed by holding the body and gently twisting the cap of the capsule. If the cap cannot be twisted without damaging the capsule, hearing or feeling a crack, and if the cap cannot be twisted at all, the capsule fails and the bridging is determined. 100 capsules are tested.

[0314] The result of this embodiment is that less than 10% require significant force to separate the capsule cap and body.

[0315] Dissolution test:

[0316] Dissolution test (according to USP 43 <711> )

[0317] Manual filling of capsules. The polymer coated pre-locked capsules were manually filled with 500 mg of a caffeine / lactose 3:7 mixture, closed to a final locked state, and tested in a dissolution test.

[0318] Equipment and Setup:

[0319]

[0320]

[0321] Composition and preparation of dissolution medium

[0322] 0.1N HCl (1 L):

[0323] 1. Mix 8.5 ml of concentrated hydrochloric acid in 1000 ml of deionized water and mix well.

[0324] 2. Check the pH and adjust it to 1.2 if necessary.

[0325] Phosphate buffer pH 5.5 (10 L):

[0326] 1. Mix and dilute 108.87 grams of potassium phosphate monohydrate into 4 liters of deionized water to create a 0.2 M solution labeled potassium dihydrogen phosphate monohydrate solution.

[0327] 2. To prepare 0.2M NaOH solution, take 200mL of 1.0N NaOH solution and dilute to 1 liter.

[0328] 3. Take 2.5 liters of potassium phosphate solution into a 10 liter container and add 180 mL of 0.2 M NaOH solution.

[0329] 4. Dilute the volume to 10 L with deionized water, check the pH, and adjust it to pH 5.5 with 1N NaOH or 1N HCl solution.

[0330] Dissolution Procedure:

[0331] Acid phase: Three accurately weighed caffeine capsules were transferred to different dissolution tanks and then subjected to dissolution testing according to the parameters given in the above method (acid phase). After 2 hours, a 10 mL aliquot was removed and analyzed as the acid phase sample solution.

[0332] Buffer Phase: Transfer the capsules after the acid phase to the buffer phase medium. Continue the dissolution test according to the parameters given in the above method (buffer phase). Filter an aliquot of each interval through a 0.45 μm nylon membrane syringe filter (discard the first few milliliters of filtrate) and analyze as the buffer phase sample solution using the following chromatographic conditions.

[0333] 1. Caffeine capsules (white capsules) were dissolved in 900 mL 0.1N HCl for 2 hours, followed by dissolution in 900 mL pH 5.5 phosphate buffer.

[0334]

[0335] 2. Caffeine capsules (transparent capsules) were dissolved in 900 mL 0.1N HCl for 2 hours, followed by dissolution in 900 mL pH 5.5 phosphate buffer.

[0336]

[0337] Example 2: (Invention) Enteric coating of pre-locked capsules in a drum coater with an increased amount of red iron oxide in the intermediate coating layer

[0338] Considering 545.82mm 2 The enteric coating and top coating formulations were calculated based on the surface area of ​​the capsules in the pre-locked state and a batch size of 1000 capsules in total (500 Capsugel V-Caps Size 0 white capsules and 500 Capsugel V-Caps Size 0 clear capsules).

[0339] Intermediate coating

[0340] While stirring gently HPMC E3 is fully dispersed in water to prevent agglomeration. Use a homogenizer (such as Ultra Turrax) to homogenize light magnesium oxide, anhydrous glycerol and red iron oxide in water for 10 minutes. The solid content should be about 10%. Slowly pour the excipient suspension into the mixture while stirring gently with a conventional stirrer. HPMC E3 solution. The spray suspension was passed through a 0.3 mm sieve. The spray suspension was gently stirred during the coating process.

[0341] Table 4: Intermediate coating

[0342]

[0343] Enteric coating

[0344] Preparation of GMS emulsion: Heat 40% of the water to 70-80°C. Homogenize the polysorbate 80 solution, triethyl citrate and GMS in the heated water for 10 minutes using a homogenizer (e.g. Ultra Turrax). The solid content is about 15%. Stir the remaining 60% of the water into the hot GMS emulsion using a conventional stirrer and cool to room temperature while continuing to stir. Then slowly pour the excipient suspension into the mixture while gently stirring with a conventional stirrer. L 30D-55 dispersion. After gentle stirring for 10 minutes, slowly add NM 30D and stirred for another 15 minutes. The final coating suspension was sieved through a 400 μm sieve and stirred during the coating process. The pre-locked state capsules were coated using a drum coater.

[0345] Table 5: Enteric coating

[0346]

[0347] *Amount based on dry polymer substance [%]

[0348] Capsule coating process

[0349] Capsules were coated in a fully perforated side vented pan coating system O'Hara M10.

[0350] Bridging test:

[0351] The bridging between the body and the cap of the capsule is tested. The test is performed by holding the body and gently twisting the cap of the capsule. If the cap cannot be twisted without damaging the capsule, hearing or feeling a crack, and if the cap cannot be twisted at all, the capsule fails and the bridging is determined. 100 capsules are tested.

[0352] The result of this embodiment is that less than 10% require significant force to separate the capsule cap and body.

[0353] Dissolution test:

[0354] Dissolution test (according to USP 43 <711> )

[0355] Manual filling of capsules. The polymer coated pre-locked capsules were manually filled with 500 mg of a caffeine / lactose 3:7 mixture, closed to a final locked state, and tested in a dissolution test.

[0356] Equipment and Setup:

[0357] parameter condition Device USP Apparatus I (40 mesh basket) Dissolution bath temperature 37±0.5℃ Basket speed 75rpm Acid stage (optional) 900mL 0.1N HCl Buffer stage 900 mL phosphate buffer pH 5.5 Detection wavelength 272nm Data System OptDiss 405UV Fiber Instrument ID CCD-DI-10027 dissolution bath Distek 2500 Diluent for preparation of caffeine standard solution 100% Methanol

[0358] Composition and preparation of dissolution medium

[0359] 0.1N HCl (1 L):

[0360] 1. Mix 8.5 ml of concentrated hydrochloric acid in 1000 ml of deionized water and mix well.

[0361] 2. Check the pH and adjust it to 1.2 if necessary.

[0362] Phosphate buffer pH 5.5 (10 L):

[0363] 1. Mix and dilute 108.87 grams of potassium phosphate monohydrate into 4 liters of deionized water to create a 0.2 M solution labeled potassium dihydrogen phosphate monohydrate solution.

[0364] 2. To prepare 0.2M NaOH solution, take 200mL of 1.0N NaOH solution and dilute to 1 liter.

[0365] 3. Take 2.5 liters of potassium phosphate solution into a 10 liter container and add 180 mL of 0.2 M NaOH solution.

[0366] 4. Dilute the volume to 10 L with deionized water, check the pH, and adjust it to pH 5.5 with 1N NaOH or 1N HCl solution.

[0367] Dissolution Procedure:

[0368] Acid phase: Three accurately weighed caffeine capsules were transferred to different dissolution tanks and then subjected to dissolution testing according to the parameters given in the above method (acid phase). After 2 hours, a 10 mL aliquot was removed and analyzed as the acid phase sample solution.

[0369] Buffer Phase: Transfer the capsules after the acid phase to the buffer phase medium. Continue the dissolution test according to the parameters given in the above method (buffer phase). Filter an aliquot of each interval through a 0.45 μm nylon membrane syringe filter (discard the first few milliliters of filtrate) and analyze as the buffer phase sample solution using the following chromatographic conditions.

[0370] 1. Caffeine capsules (white capsules) were dissolved in 900 mL 0.1N HCl for 2 hours, followed by dissolution in 900 mL pH 5.5 phosphate buffer.

[0371] medium Time (min) Sample 1 Sample 2 Sample 3 average value 0.1N HCl 0 0 0 0 0 0.1N HCl 120 0 0 0 0.0 pH 5.5 125 33.4 58.8 60.3 50.8 pH 5.5 130 62.4 99.9 74.1 78.8 pH 5.5 135 97.5 105.1 83.4 95.3 pH 5.5 150 106.1 106 105.9 106.0 pH 5.5 165 106.3 106.1 105.9 106.1

[0372] Example 3: (Invention) Enteric coating of pre-locked capsules in a drum coater with FD&C Blue No. 1 (E133) in the middle coating layer

[0373] Considering 545.82mm 2 The enteric coating and top coating formulations were calculated based on the surface area of ​​the capsules in the pre-locked state and a batch size of 1000 capsules in total (500 Capsugel V-Caps Size 0 white capsules and 500 Capsugel V-Caps Size 0 clear capsules).

[0374] Intermediate coating

[0375] While stirring gently HPMC E3 is fully dispersed in water to prevent agglomeration. Homogenize light magnesium oxide, anhydrous glycerol and FD&C blue No. 1 in water using a homogenizer (e.g. Ultra Turrax) for 10 minutes. The solid content should be about 10%. Slowly pour the excipient suspension into the mixture while stirring gently with a conventional stirrer. HPMC E3 solution. The spray suspension was passed through a 0.3 mm sieve. The spray suspension was gently stirred during the coating process.

[0376] Table 6: Intermediate coating

[0377]

[0378] Enteric coating

[0379] Preparation of GMS emulsion: Heat 40% of the water to 70-80°C. Homogenize the polysorbate 80 solution, triethyl citrate and GMS in the heated water for 10 minutes using a homogenizer (e.g. Ultra Turrax). The solid content is about 15%. Stir the remaining 60% of the water into the hot GMS emulsion using a conventional stirrer and cool to room temperature while continuing to stir. Then slowly pour the excipient suspension into the mixture while gently stirring with a conventional stirrer. L 30D-55 dispersion. After gentle stirring for 10 minutes, slowly add NM 30D and stirred for another 15 minutes. The final coating suspension was sieved through a 400 μm sieve and stirred during the coating process. The pre-locked state capsules were coated using a drum coater.

[0380] Table 7: Enteric coating

[0381]

[0382] *Amount based on dry polymer substance [%]

[0383] Capsule coating process

[0384] Capsules were coated in a fully perforated side vented pan coating system O'Hara M10.

[0385] Bridging test:

[0386] The bridging between the body and the cap of the capsule is tested. The test is performed by holding the body and gently twisting the cap of the capsule. If the cap cannot be twisted without damaging the capsule, hearing or feeling a crack, and if the cap cannot be twisted at all, the capsule fails and the bridging is determined. 100 capsules are tested.

[0387] The result of this embodiment is that less than 10% require significant force to separate the capsule cap and body.

[0388] Dissolution test:

[0389] Dissolution test (according to USP 43 <711> )

[0390] Manual filling of capsules. The polymer coated pre-locked capsules were manually filled with 500 mg of a caffeine / lactose 3:7 mixture, closed to a final locked state, and tested in a dissolution test.

[0391] Equipment and Setup:

[0392]

[0393]

[0394] Composition and preparation of dissolution medium

[0395] 0.1N HCl (1 L):

[0396] 1. Mix 8.5 ml of concentrated hydrochloric acid in 1000 ml of deionized water and mix well.

[0397] 2. Check the pH and adjust it to 1.2 if necessary.

[0398] Phosphate buffer pH 5.5 (10 L):

[0399] 1. Mix and dilute 108.87 grams of potassium phosphate monohydrate into 4 liters of deionized water to create a 0.2 M solution labeled potassium dihydrogen phosphate monohydrate solution.

[0400] 2. To prepare 0.2M NaOH solution, take 200mL of 1.0N NaOH solution and dilute to 1 liter.

[0401] 3. Take 2.5 liters of potassium phosphate solution into a 10 liter container and add 180 mL of 0.2 M NaOH solution.

[0402] 4. Dilute the volume to 10 L with deionized water, check the pH, and adjust it to pH 5.5 with 1N NaOH or 1N HCl solution.

[0403] Dissolution Procedure:

[0404] Acid phase: Three accurately weighed caffeine capsules were transferred to different dissolution tanks and then subjected to dissolution testing according to the parameters given in the above method (acid phase). After 2 hours, a 10 mL aliquot was removed and analyzed as the acid phase sample solution.

[0405] Buffer Phase: Transfer the capsules after the acid phase to the buffer phase medium. Continue the dissolution test according to the parameters given in the above method (buffer phase). Filter an aliquot of each interval through a 0.45 μm nylon membrane syringe filter (discard the first few milliliters of filtrate) and analyze the remaining buffer phase sample solution using the following chromatographic conditions.

[0406] 1. Caffeine capsules (transparent capsules) were dissolved in 900 mL 0.1N HCl for 2 hours, followed by dissolution in 900 mL pH 5.5 phosphate buffer at 75 RPM USPI (40 mesh)

[0407]

[0408] Example 4: Enteric coating of pre-locked capsules in a drum coater (invention) with increased amounts of titanium dioxide in the middle coating layer

[0409] Considering 545.82mm 2 The enteric coating and top coating formulations were calculated based on the surface area of ​​the capsules in the pre-locked state and a batch size of 1000 capsules in total (500 Capsugel V-Caps Size 0 white capsules and 500 Capsugel V-Caps Size 0 clear capsules).

[0410] Intermediate coating

[0411] While stirring gently HPMC E3 is fully dispersed in water to prevent agglomeration. Homogenize light magnesium oxide, anhydrous glycerol and titanium dioxide in water for 10 minutes using a homogenizer (e.g. Ultra Turrax). The solid content should be about 10%. Slowly pour the excipient suspension into the mixture while stirring gently with a conventional stirrer. HPMC E3 solution. The spray suspension was passed through a 0.3 mm sieve. The spray suspension was gently stirred during the coating process.

[0412] Table 8: Intermediate coating

[0413]

[0414] Enteric coating

[0415] Preparation of GMS emulsion: Heat 40% of the water to 70-80°C. Homogenize the polysorbate 80 solution, triethyl citrate and GMS in the heated water for 10 minutes using a homogenizer (e.g. Ultra Turrax). The solid content is about 15%. Stir the remaining 60% of the water into the hot GMS emulsion using a conventional stirrer and cool to room temperature while continuing to stir. Then slowly pour the excipient suspension into the mixture while gently stirring with a conventional stirrer. L 30D-55 dispersion. After gentle stirring for 10 minutes, slowly add NM 30D and stirred for another 15 minutes. The final coating suspension was sieved through a 400 μm sieve and stirred during the coating process. The pre-locked state capsules were coated using a drum coater.

[0416] Table 9: Enteric Coating

[0417]

[0418]

[0419] *Amount based on dry polymer substance [%]

[0420] Capsule coating process

[0421] Capsules were coated in a fully perforated side vented pan coating system O'Hara M10.

[0422] Bridging test:

[0423] The bridging between the body and the cap of the capsule is tested. The test is performed by holding the body and gently twisting the cap of the capsule. If the cap cannot be twisted without damaging the capsule, hearing or feeling a crack, and if the cap cannot be twisted at all, the capsule fails and the bridging is determined. 100 capsules are tested.

[0424] result:

[0425] The result of this embodiment is that less than 10% require significant force to separate the capsule cap and body.

[0426] Dissolution test:

[0427] Dissolution test (according to USP 43 <711> )

[0428] Manual filling of capsules. The polymer coated pre-locked capsules were manually filled with 500 mg of a caffeine / lactose 3:7 mixture, closed to a final locked state, and tested in a dissolution test.

[0429] Equipment and Setup:

[0430] parameter condition Device USP Apparatus I (40 mesh basket) Dissolution bath temperature 37±0.5℃ Basket speed 75rpm Acid stage (optional) 900mL 0.1N HCl Buffer stage 900 mL phosphate buffer pH 5.5 Detection wavelength 272nm Data System OptDiss 405UV Fiber Instrument ID CCD-DI-10027 dissolution bath Distek 2500 Diluent for preparation of caffeine standard solution 100% Methanol

[0431] Composition and preparation of dissolution medium

[0432] 0.1N HCl (1 L):

[0433] 1. Mix 8.5 ml of concentrated hydrochloric acid in 1000 ml of deionized water and mix well.

[0434] 2. Check the pH and adjust it to 1.2 if necessary.

[0435] Phosphate buffer pH 5.5 (10 L):

[0436] 1. Mix and dilute 108.87 grams of potassium phosphate monohydrate into 4 liters of deionized water to create a 0.2 M solution labeled potassium dihydrogen phosphate monohydrate solution.

[0437] 2. To prepare 0.2M NaOH solution, take 200mL of 1.0N NaOH solution and dilute to 1 liter.

[0438] 3. Take 2.5 liters of potassium phosphate solution into a 10 liter container and add 180 mL of 0.2 M NaOH solution.

[0439] 4. Dilute the volume to 10 L with deionized water, check the pH, and adjust it to pH 5.5 with 1N NaOH or 1N HCl solution.

[0440] Dissolution Procedure:

[0441] Acid phase: Three accurately weighed caffeine capsules were transferred to different dissolution tanks and then subjected to dissolution testing according to the parameters given in the above method (acid phase). After 2 hours, a 10 mL aliquot was removed and analyzed as the acid phase sample solution.

[0442] Buffer Phase: Transfer the capsules after the acid phase to the buffer phase medium. Continue the dissolution test according to the parameters given in the above method (buffer phase). Filter an aliquot of each interval through a 0.45 μm nylon membrane syringe filter (discard the first few milliliters of filtrate) and analyze as the buffer phase sample solution using the following chromatographic conditions.

[0443] 1. Caffeine capsules (white capsules) were dissolved in 900 mL 0.1N HCl for 2 hours, followed by dissolution in 900 mL pH 5.5 phosphate buffer.

[0444]

[0445] Example 5: Enteric coating of pre-locked capsules in a drum coater with increased amounts of lactose in the middle coating layer (of the present invention)

[0446] Considering 545.82mm 2 The enteric coating and top coating formulations were calculated based on the surface area of ​​the capsules in the pre-locked state and a batch size of 1000 capsules in total (500 Capsugel V-Caps Size 0 white capsules and 500 Capsugel V-Caps Size 0 clear capsules).

[0447] Intermediate coating

[0448] While stirring gently HPMC E3 is fully dispersed in water to prevent agglomeration. Homogenize light magnesium oxide, anhydrous glycerol and lactose in water using a homogenizer (e.g. Ultra Turrax) for 10 minutes. The solid content should be about 10%. Slowly pour the excipient suspension into the mixture while stirring gently with a conventional stirrer. HPMCE3 solution. The spray suspension was passed through a 0.3 mm sieve. The spray suspension was gently stirred during the coating process.

[0449] Table 10: Intermediate coating

[0450]

[0451] Enteric coating

[0452] Preparation of GMS emulsion: Heat 40% of the water to 70-80°C. Homogenize the polysorbate 80 solution, triethyl citrate and GMS in the heated water for 10 minutes using a homogenizer (e.g. Ultra Turrax). The solid content is about 15%. Stir the remaining 60% of the water into the hot GMS emulsion using a conventional stirrer and cool to room temperature while continuing to stir. Then slowly pour the excipient suspension into the mixture while gently stirring with a conventional stirrer. L 30D-55 dispersion. After gentle stirring for 10 minutes, slowly add NM 30D and stirred for another 15 minutes. The final coating suspension was sieved through a 400 μm sieve and stirred during the coating process. The pre-locked state capsules were coated using a drum coater.

[0453] Table 11: Enteric Coating

[0454]

[0455]

[0456] *Amount based on dry polymer substance [%]

[0457] Capsule coating process

[0458] Capsules were coated in a fully perforated side vented pan coating system O'Hara M10.

[0459] Bridging test:

[0460] The bridging between the body and the cap of the capsule is tested. The test is performed by holding the body and gently twisting the cap of the capsule. If the cap cannot be twisted without damaging the capsule, hearing or feeling a crack, and if the cap cannot be twisted at all, the capsule fails and the bridging is determined. 100 capsules are tested.

[0461] The results for this example showed that less than 10% of the cases required a significant force to separate the capsule cap and body.

[0462] Dissolution test:

[0463] Dissolution test (according to USP 43 <711> )

[0464] Manual filling of capsules. The polymer coated pre-locked capsules were manually filled with 500 mg of a caffeine / lactose mixture 3:7, closed to a final locked state, and tested in a dissolution test.

[0465] Equipment and Setup:

[0466] parameter condition Device USP Apparatus I (40 mesh basket) Dissolution bath temperature 37±0.5℃ Basket speed 75 rpm Acid stage (optional) 900 mL 0.1N HCl Buffer stage 900 mL phosphate buffer pH 5.5 Detection wavelength 272 nm Data System OptDiss 405 UV Fiber Instrument ID CCD-DI-10027 dissolution bath Distek 2500 Diluent for preparation of caffeine standard solution 100% Methanol

[0467] Composition and preparation of dissolution medium

[0468] 0.1 N HCl (1 L):

[0469] 1. Mix 8.5 ml of concentrated hydrochloric acid in 1000 ml of deionized water and mix well.

[0470] 2. Check the pH and adjust it to 1.2 if necessary.

[0471] Phosphate buffer pH 5.5 (10 L):

[0472] 1. Mix and dilute 108.87 grams of potassium phosphate monohydrate into 4 liters of deionized water to create a 0.2 M solution labeled potassium dihydrogen phosphate monohydrate solution.

[0473] 2. To prepare 0.2 M NaOH solution, take 200 mL of 1.0 N NaOH solution and dilute to 1 liter.

[0474] 3. Take 2.5 liters of potassium phosphate solution into a 10-liter container. Add 180 mL of 0.2 M NaOH solution.

[0475] 4. Dilute the volume to 10 L with deionized water, check the pH, and adjust it to pH 5.5 with 1 N NaOH or 1 N HCl solution.

[0476] Dissolution Procedure:

[0477] Acid phase: Three accurately weighed caffeine capsules were transferred to different dissolution tanks and then subjected to dissolution testing according to the parameters given in the above method (acid phase). After 2 hours, a 10 mL aliquot was removed and analyzed as the acid phase sample solution.

[0478] Buffer Phase: Transfer the capsules after the acid phase to the buffer phase medium. Continue the dissolution test according to the parameters given in the above method (buffer phase). Filter each interval aliquot through a 0.45 μm nylon membrane syringe filter, discard the first few milliliters of filtrate, and analyze the remaining as the buffer phase sample solution using the following chromatographic conditions.

[0479] 1. Caffeine capsules (white capsules) were dissolved in 900 mL 0.1N HCl for 2 hours, followed by dissolution in 900 mL pH 5.5 phosphate buffer.

[0480] medium Time (min) Sample 1 Sample 2 Sample 3 average value 0.1N HCl 0.0 0.0 0.0 0.0 0.0 0.1N HCl 120 0.0 0.0 0.0 0.0 pH 5.5 125 50.6 6.8 20.8 26.1 pH 5.5 130 77.0 19.3 38.1 44.8 pH 5.5 135 85.7 50.4 63.0 66.4 pH 5.5 150 95.0 95.5 95.8 95.4 pH 5.5 165 95.1 98.5 96.8 96.8

[0481] Example 6: (Comparative) Enteric Coating of Pre-Locked Capsules in a Drum Coater Without Release Accelerator in the Intermediate Coating Layer

[0482] Considering 545.82mm 2 The enteric coating and top coating formulations were calculated based on the surface area of ​​the capsules in the pre-locked state and a batch size of 1000 capsules in total (500 Capsugel V-Caps Size 0 white capsules and 500 Capsugel V-Caps Size 0 clear capsules).

[0483] Intermediate coating

[0484] While stirring gently HPMC E3 is fully dispersed in water to prevent caking. Use a homogenizer (such as Ultra Turrax) to homogenize light magnesium oxide and anhydrous glycerol in water for 10 minutes. The solid content should be about 10%. Slowly pour the excipient suspension into the mixture while stirring gently with a conventional stirrer. HPMC E3 solution. The spray suspension was passed through a 0.3 mm sieve. The spray suspension was gently stirred during the coating process.

[0485] Table 12: Intermediate coating

[0486]

[0487]

[0488] Enteric coating

[0489] Preparation of GMS emulsion: Heat 40% of the water to 70-80°C. Homogenize the polysorbate 80 solution, triethyl citrate and GMS in the heated water for 10 minutes using a homogenizer (e.g. Ultra Turrax). The solid content is about 15%. Stir the remaining 60% of the water into the hot GMS emulsion using a conventional stirrer and cool to room temperature while continuing to stir. Then slowly pour the excipient suspension into the mixture while gently stirring with a conventional stirrer. L 30 D-55 dispersion. After gentle stirring for 10 minutes, slowly add NM30 D and stirred for another 15 minutes. The final coating suspension was sieved through a 400 μm sieve and stirred during the coating process. The pre-locked state capsules were coated using a drum coater.

[0490] Table 13: Enteric Coating

[0491]

[0492] *Amount based on dry polymer substance [%]

[0493] Capsule coating process for intermediate coating and enteric coating:

[0494]

[0495] Bridging test:

[0496] The bridging between the body and the cap of the capsule is tested. The test is performed by holding the body and gently twisting the cap of the capsule. If the cap cannot be twisted without damaging the capsule, hearing or feeling a crack, and if the cap cannot be twisted at all, the capsule fails and the bridging is determined. 100 capsules are tested.

[0497] The result of this embodiment is that less than 10% require significant force to separate the capsule cap and body.

[0498] Dissolution test:

[0499] A) Dissolution conditions

[0500] 1) Dissolution parameters

[0501] Device: USPI type

[0502] Dissolution media: 2-hour acid phase followed by a complete change to 2-hour buffer phase

[0503] Sampling point: acid stage medium; 60min, 120min

[0504] Buffer stage medium; 10min, 20min, 30min, 45min, 60min, 120min

[0505] Medium volume: 750 mL for acid phase and 1000 mL for buffer phase

[0506] Speed: 100rpm

[0507] Temperature: 37℃±0.5℃

[0508] Discharge volume: 10mL

[0509] 2) Dissolution medium

[0510] I. Acid phase medium - 0.1N HCl; Buffer phase medium - pH 5.0 buffer, or

[0511] II. Acid phase medium - 0.1N HCl; Buffer phase medium - pH 4.5 buffer, or

[0512] III. Acid phase medium - 0.1N HCl; Buffer phase medium - pH 3.0 buffer

[0513] 3) Composition of the buffer phase medium

[0514] I. Buffer Phase Medium - pH 5.0 Buffer

[0515] Weigh 1g of potassium dihydrogen phosphate (KH2PO4), 2g of anhydrous potassium dihydrogen phosphate (K2HPO4) and 8.5g of sodium chloride (NaCl) and transfer to a 1-liter beaker. Add 500mL of water to dissolve the salts and make up the volume to 1000mL with water. Adjust the pH to 5.0+0.05 using orthophosphoric acid.

[0516] II. Buffer Phase Medium - pH 4.5 Buffer

[0517] Weigh 1g of potassium dihydrogen phosphate (KH2PO4), 2g of anhydrous potassium dihydrogen phosphate (K2HPO4) and 8.5g of sodium chloride (NaCl) and transfer to a 1-liter beaker. Add 500mL of water to dissolve the salts and make up the volume to 1000mL with water. Adjust the pH to 4.5+0.05 using orthophosphoric acid.

[0518] III. Buffer Phase Medium - pH 3.0 Buffer

[0519] Weigh 1g of potassium dihydrogen phosphate (KH2PO4), 2g of anhydrous potassium dihydrogen phosphate (K2HPO4) and 8.5g of sodium chloride (NaCl) and transfer to a 1-liter beaker. Add 500mL of water to dissolve the salts and make up the volume to 1000mL with water. Adjust the pH to 3.0+0.05 using orthophosphoric acid.

[0520] 4) Dissolution procedure:

[0521] Acid stage : Six accurately weighed caffeine capsules were transferred to different dissolution tanks and then subjected to dissolution testing according to the parameters given in the above method (acid phase). After 1 hour and 2 hours, 10 mL aliquots were taken and analyzed as acid phase sample solutions.

[0522] Buffer stage : Transfer the capsules after the acid phase to the buffer phase medium. Continue the dissolution test according to the parameters given in the above method (buffer phase). Filter an aliquot of each interval through a 0.45 μm nylon membrane syringe filter (discard the first few milliliters of filtrate) and analyze as the buffer phase sample solution using the following chromatographic conditions.

[0523] B) Chromatographic conditions

[0524] Column: Agilent Zorbax Eclipse XDB C 18 column, 150 x 4.6 mm, 5 μm or equivalent

[0525] Mobile phase: water / ACN (80:20)

[0526] Wavelength: 273nm

[0527] Column temperature: 25°C

[0528] Injection volume: 10 μL

[0529] Flow rate: 1.5mL / min

[0530]

[0531] Example 7: Enteric coating of API tablets in a fluidized bed coater with increased amounts of lactose in the intermediate coating layer (invention)

[0532] Considering 22.14mm 2 The enteric and top coating formulations were calculated based on the surface area of ​​100 g and a batch size of 750 g API tablets (2.5 mm concave diameter).

[0533] Intermediate coating

[0534] While stirring gently HPMC E3 is fully dispersed in water to prevent caking. Homogenize light magnesium oxide, anhydrous glycerol and lactose in water using a homogenizer (e.g. Ultra Turrax) for 10 minutes. The solid content should be about 15%. Slowly pour the excipient suspension into the mixture while stirring gently with a conventional stirrer. HPMCE3 solution. The spray suspension was passed through a 0.3 mm sieve. The spray suspension was gently stirred during the coating process.

[0535] Table 14: Intermediate coating

[0536]

[0537]

[0538] Enteric coating

[0539] Homogenize triethyl citrate and talc in water using a homogenizer (e.g. Ultra Turrax) for 10 minutes. Then slowly pour the excipient suspension into the mixture while stirring gently with a conventional stirrer. L 30D-55 dispersion and stirred for another 15 minutes. The final coating suspension was sieved through a 400 μm sieve and stirred during the coating process.

[0540] Table 15: Enteric Coating

[0541]

[0542] *Amount based on dry polymer substance [%]

[0543] Tablet coating process

[0544] Process parameters for enteric coating of 750 g mini-tablets using the GPCG-2 system

[0545]

[0546]

[0547] Dissolution test (according to USP 43 <711> )

[0548] Dissolution System

[0549] parameter condition Device USP Apparatus I (40 mesh basket) Dissolution bath temperature 37±0.5℃ Paddle speed 75 rpm 0.1N HCl volume 900 mL pH 3.0 HCl volume 900 mL Dissolution sampling points in 0.1N HCl 60 and 120 minutes Dissolution sampling points in pH 3.0 HCl 165 and 180 minutes Infinity, 300 RPM 240 minutes Sampling volume 1.5 mL

[0550] HPLC system parameters

[0551]

[0552] Dissolution medium

[0553] 0.1N hydrochloric acid (pH 1.2)

[0554] 1. Mix 8.5 ml of concentrated hydrochloric acid in 1000 ml of deionized water and mix well.

[0555] 0.001N hydrochloric acid solution (pH 3.0)

[0556] 1. Mix 1.0 ml of concentrated hydrochloric acid in 11.764 liters of deionized water and mix well.

[0557] 2. If necessary, adjust it to pH 3.0 with 2. If necessary, adjust it to pH 3.0 with 0.1N HCl or 0.1N NaOH solution.

[0558] result

[0559]

[0560] Example 8: (Comparative) Enteric coating of API tablets in a fluidized bed coater without a release accelerator in the intermediate coating layer

[0561] Considering 22.14mm 2 The enteric and top coating formulations were calculated based on the surface area of ​​100 g and a batch size of 750 g API tablets (2.5 mm concave diameter).

[0562] Intermediate coating

[0563] While stirring gently HPMC E3 is fully dispersed in water to prevent caking. Anhydrous glycerol and lactose are homogenized in water using a homogenizer (e.g. Ultra Turrax) for 10 minutes. The solid content should be about 15%. While gently stirring with a conventional stirrer, slowly pour the excipient suspension into HPMC E3 solution. The spray suspension was passed through a 0.3 mm sieve. The spray suspension was gently stirred during the coating process.

[0564] Table 16: Intermediate coating

[0565]

[0566] Enteric coating

[0567] Homogenize triethyl citrate and talc in water using a homogenizer (e.g. Ultra Turrax) for 10 minutes. Then slowly pour the excipient suspension into the mixture while stirring gently with a conventional stirrer. L 30D-55 dispersion and stirred for another 15 minutes. The final coating suspension was sieved through a 400 μm sieve and stirred during the coating process.

[0568] Table 17: Enteric Coating

[0569]

[0570] *Amount based on dry polymer substance [%]

[0571] Tablet Coating Process Process parameters for enteric coating of 750 g tablets using the GPCG-2 system

[0572]

[0573] Dissolution test (according to USP 43 <711> )

[0574] Dissolution System

[0575] parameter condition Device USP Apparatus I (40 mesh basket) Dissolution bath temperature 37±0.5℃ Paddle speed 75rpm 0.1N HCl 900mL pH 3.0HCl 900mL Dissolution sampling points in 0.1N HCl 60 and 120 minutes Dissolution sampling point in pH 3.0 HCl 165 and 180 minutes Infinity, 300RPM 240 minutes Sampling volume 1.5mL

[0576] HPLC system parameters

[0577]

[0578] Dissolution medium

[0579] 0.1N hydrochloric acid (pH 1.2)

[0580] 1. Mix 8.5 ml of concentrated hydrochloric acid in 1000 ml of deionized water and mix well.

[0581] 0.001N hydrochloric acid solution (pH 3.0)

[0582] 1. Mix 1.0 ml of concentrated hydrochloric acid in 11.764 liters of deionized water and mix well.

[0583] 2. If necessary, adjust it to pH 3.0 with 2. If necessary, adjust it to pH 3.0 with 0.1N HCl or 0.1N NaOH solution.

[0584] result

[0585]

[0586] Example 9: (Invention) Preparation of caffeine tablets; followed by sealing, intermediate coating and enteric coating of caffeine tablets (enteric coating, EUDRAGIT L30D-55 weight gain 6.25%)

[0587] Tablet Compression: A formulation blend of caffeine, MCC, lactose, Aerosil 200, and croscarmellose sodium was prepared using a Turbula mixer. Magnesium stearate was then added as a lubricant, with a total mixing time of 15 minutes. The blend was compressed using a Korsch Xl tablet press with a 2.5 mm multi-tip tool. A 2.5 mm round tablet weighing 10.0 mg, 1.8 mm thick, and 3.02 KP hardness was prepared using a compression force of about 17 KN.

[0588] Preparation composition:

[0589] Element Function quantity(%) Amount (g) caffeine API 20 200 Lactose Monohydrate Diluent / filler 48.5 485 Croscarmellose Sodium Super disintegrant 5 50 Microcrystalline Cellulose PH-200 Diluent / filler 25 250 Aerosil Glidants 1 10 Magnesium Stearate Lubricants 0.5 5 total 100.00 1000

[0590] Considering 22.3mm 2 The seal coating, intermediate coating and enteric coating formulations were calculated based on the surface area of ​​100 g and batch size of 750 g API tablets (2.5 mm concave diameter).

[0591] Seal coating

[0592] Continue on low to medium speed for 15 minutes until all ingredients are dissolved. HPMC E3 and PEG 600 were added to a container of water and stirred gently to prevent caking. The solid content should be about 7.5. The spray solution was passed through a 40 mesh screen and stirred gently during the coating process.

[0593] Table 18: Seal Coating

[0594]

[0595] Intermediate coating

[0596] While stirring gently HPMC E3 and anhydrous lactose are fully dispersed in 2 / 3 of the water to prevent caking. In the remaining 1 / 3 of the water, PEG 600 and light magnesium oxide are homogenized at 2500 rpm for 10 minutes using a homogenizer (e.g. Ultra Turrax). The solid content should be about 15%. Slowly pour the excipient suspension into the mixture while gently stirring with a conventional stirrer. HPMC E3 solution. Pass the spray suspension through a 40 mesh screen. Gently stir the spray suspension during the coating process.

[0597] Table 19: Intermediate coating

[0598]

[0599] *Amount based on dry polymer substance [%]

[0600] Enteric coating

[0601] Homogenize triethyl citrate and talc in water using a homogenizer (e.g. Ultra Turrax) for 10 minutes. Then slowly pour the excipient suspension into the mixture while stirring gently with a conventional stirrer. L 30D-55 dispersion and stirred for another 15 minutes. The final coating suspension was sieved through a 400 μm sieve and stirred during the coating process.

[0602] Table 20: Enteric Coating

[0603]

[0604]

[0605] *Amount based on dry polymer substance [%]

[0606] Tablet Coating Process Process parameters for enteric coating of 750 g tablets using the GPCG-2 system

[0607]

[0608] Dissolution test (according to USP 43 <711> )

[0609] Dissolution System

[0610]

[0611]

[0612] Dissolution medium

[0613] 0.1N hydrochloric acid (pH 1.2)

[0614] 2. Mix 8.5 ml of concentrated hydrochloric acid in 1000 ml of deionized water and mix well.

[0615] 0.001N hydrochloric acid solution (pH 3.0)

[0616] 3. Mix 1.0 ml of concentrated hydrochloric acid in 11.764 liters of deionized water and mix well.

[0617] 4. If necessary, adjust it to pH 3.0 with 2. If necessary, adjust it to pH 3.0 with 0.1N HCl or 0.1N NaOH solution.

[0618] result

[0619]

[0620] Dissolution medium

[0621] 0.1N hydrochloric acid (pH 1.2)

[0622] 1. Mix 8.5 ml of concentrated hydrochloric acid in 1000 ml of deionized water and mix well.

[0623] Acetate buffer solution (pH 5.0)

[0624] 1. Weigh 5.08 g of sodium acetate trihydrate into 500 mL of deionized water, then add 6.3 mL of 2N glacial acetic acid to make up the volume to 1 L.

[0625] 2. If necessary, adjust it to pH 5.0 with 0.1N HCl or 0.1N NaOH solution.

[0626] result

[0627]

Claims

1. A dosage form, comprising a) a core comprising at least one biologically active ingredient, b) an intermediate coating layer (ICL) on or over the core, the intermediate coating layer comprising i) at least one polymer; ii) at least one alkaline substance; iii) at least one release accelerating agent selected from the group consisting of iron oxide, aluminum oxide, titanium dioxide, dimethyl sulfoxide, zinc oxide, sucrose, maltose, lactose, dextrates, glucose, fructose, dyes, or any mixture thereof; iv) optionally at least one glidant; v) optionally at least one plasticizer; and vi) optionally at least one additive different from i) to v); wherein The at least one release accelerating agent is present in an amount of 0.1-20 wt % based on the weight of the at least one polymer; and c) an enteric coating layer (ECL) on or above the intermediate coating layer, the enteric coating layer comprising i) at least one polymer; ii) optionally at least one glidant; 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).

2. The dosage form according to any one of the preceding claims, wherein the dosage form is a coated hard shell capsule, tablet or minitablet.

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

4. The dosage form according to any one of the preceding claims, wherein the alkaline substance i) is an alkali 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) is magnesium oxide or magnesium carbonate.

5. The dosage form according to any of the preceding claims, wherein the at least one release accelerating agent is Fe2O3, TiO2, lactose, disodium 2-[[4-[ethyl-[(3-sulfonated phenyl)methyl]amino]phenyl]-[4-[ethyl-[(3-sulfonated phenyl)methyl]ammoniumylidene]cyclohexa-2,5-diene-1-ylidene]methyl]benzenesulfonate, or any mixture thereof.

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

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

8. The dosage form according to any one of claims 1 to 5, wherein the at least one polymer in the intermediate coating layer and / or the enteric coating layer, preferably the enteric coating layer, is a mixture of: i) an anionic polymer and a second polymer, the anionic polymer has a Tgm ≥ 35°C, preferably 35-155°C, more preferably 80-145°C, most preferably 90-125°C, and the second polymer is a polymer with a Tgm ≤ 30°C, preferably < 15°C; or ii) (meth)acrylate copolymers obtained by copolymerizing 40 to 60% by weight of methacrylic acid and 60 to 40% by weight of ethyl acrylate and (meth)acrylate copolymers obtained by polymerizing 60 to 80% by weight, preferably 60 to 78% by weight of ethyl acrylate and 40 to 20% by weight, preferably 38 to 20% by weight of methyl methacrylate, preferably in a weight ratio of 20:1 to 1:20 and optionally up to 2% by weight of (meth)acrylic acid; or iii) (meth)acrylate copolymers obtained by copolymerizing 5-15 wt% of methacrylic acid, 60-70 wt% of methyl acrylate and 20-30 wt% of methyl methacrylate, and (meth)acrylate copolymers obtained by copolymerizing 40-60 wt% of methacrylic acid and 60-40 wt% of ethyl acrylate, preferably in a weight ratio of 20:1 to 1:

20.

9. The dosage form according to any one of claims 1 to 5, wherein the 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 weight of amylose, or mixtures thereof.

10. The dosage form according to any one of claims 1 to 5, wherein the at least one polymer in the intermediate coating layer and / or the enteric coating layer, preferably the intermediate 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 esters, cellulose glycolates, polyethylene glycol, polyethylene oxide, polyvinyl pyrrolidone, polyvinyl acetate, polyvinyl alcohol, or mixtures thereof.

11. The dosage form according to any one of claims 1 and 3-10, wherein the core comprises the biologically active ingredient, the biologically active ingredient i) distributed in a matrix structure; or ii) bound in a binder in a coating on the core.

12. The dosage form of any one of claims 1-10, wherein the core comprises the biologically active ingredient in the fill of a hard shell capsule, wherein the core is the hard shell capsule.

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

14. Use of a dosage form according to any one of the preceding claims to provide at least 80% drug release at pH 5 within 60 min.

15. Use of a dosage form according to any one of the preceding claims to provide at least 80% drug release at pH 3 within 60 min.

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