Hard shell capsules having improved release coatings - Patents.com

Abstract

The present invention relates to a method for preparing a polymer-coated hard shell capsule, the hard shell capsule comprising a body and a cap, in a closed state, the cap overlapping the body either in a pre-locked state or in a final locked state, providing the hard shell capsule in a pre-locked state and coating it with a coating solution, suspension or dispersion comprising or consisting of a) at least one polymer; b) at least one glidant; c) at least one emulsifier; d) optionally at least one plasticizer; e) optionally at least one biologically active ingredient; and f) optionally at least one additive different from a) to e) to obtain a coated, preferably pre-locked hard shell capsule coated only on the outer surface, the coating solution, suspension or dispersion having a surface tension of at most 38 mN / m. Furthermore, the present invention relates to the polymer-coated hard shell capsule obtained from the method according to the present invention and to the use of the polymer-coated hard shell capsule for immediate, delayed or sustained release.

Description

[Technical field]

[0001] The present invention provides a method for preparing a polymer-coated hard shell capsule, comprising: The hard shell capsule comprises a body and a cap; In the closed state, the cap overlaps the body in either the pre-locked state or the final locked state; Providing the hard shell capsule in a pre-locked state; a) at least one polymer; b) at least one glidant; c) at least one emulsifier; d) optionally at least one plasticizer; e) optionally at least one biologically active ingredient; and f) optionally at least one additive different from a) to e); to obtain coated, preferably only on the outer surface, pre-locked hard shell capsules, wherein the coating solution, suspension or dispersion has a surface tension of at most 38 mN / m.

[0002] Furthermore, the present invention relates to the polymer coated hard shell capsules obtainable from the process according to the present invention and the use of the polymer coated hard shell capsules for immediate, delayed or sustained release.

[0003] background Polymer-coated hard shell capsules in the field of pharmaceutical or nutraceutical products are known. They are disclosed, for example, in WO 2019 / 096833, WO 2020 / 229178, and WO 2020 / 229192. However, in these applications, the coating process was only carried out in a laboratory-scale setup of less than 9,000 capsules.

[0004] Although these examples work well in these laboratory scale setups, the coatings disclosed are not suitable for industrial scale manufacturing processes. In particular, the inventors of the present invention have surprisingly found that during scale-up of the empty hard capsule coating process, certain formulations as described in the prior art literature exhibit an increased tendency to bridging. Bridging tendency means that the pre-locked coated empty capsules exhibited a polymer bridge between the capsule body and the capsule cap. This polymer bridge makes these capsules unsuitable for industrial manufacturing processes. In downstream processes, such as manual, semi-automatic, or automatic capsule filling processes, it is important that the capsules can be opened and that, if opened, they are not damaged.

[0005] In this regard, it has surprisingly been found by the inventors that the addition of at least one flow promoter and at least one emulsifier and the use of a coating solution, suspension or dispersion with a surface tension of up to 38 mN / m is able to prevent polymer bridging in the final coating prepared on pilot or production scale. It is therefore an object of the present invention to provide a coating solution, suspension or dispersion with a surface tension of up to 38 mN / m that is able to prevent polymer bridging.

[0006] This was particularly unexpected because surface active substances such as emulsifiers typically lower the glass transition temperature of a polymer, which typically results in an increased tendency for sticking.

[0007] Summary of the Invention In a first aspect, the present invention provides a method for preparing a polymer-coated hard shell capsule, comprising the steps of: The hard shell capsule comprises a body and a cap; In the closed state, the cap overlaps the body in either the pre-locked state or the final locked state; Providing the hard shell capsule in a pre-locked state; a) at least one polymer; b) at least one glidant; c) at least one emulsifier; d) optionally at least one plasticizer; e) optionally at least one biologically active ingredient; and f) optionally at least one additive different from a) to e); to obtain a coated, preferably pre-locked hard shell capsule coated only on the outer surface, The coating solution, suspension or dispersion has a surface tension of at most 38 mN / m. It concerns the method.

[0008] In a second aspect, the present invention relates to a polymer-coated hard shell capsule obtainable from the process according to the present invention.

[0009] In a third aspect, the present invention relates to the use of a polymer-coated hard shell capsule according to the present invention for immediate, delayed or sustained release.

[0010] Detailed Description of the Invention Hard Shell Capsule Hard shell capsules for pharmaceuticals or dietary supplements are well known to those skilled in the art. Hard shell capsules are two-piece enclosed capsules consisting of two capsule halves called body and cap. The capsule body and cap materials are usually made of hard, sometimes brittle materials. Hard shell capsules include a body and a cap. The body and cap are usually cylindrical with one open end, with a rounded hemispherical end closed at the opposite end. The shape and size of the cap and the body are such that the body can be telescopically pushed into the open end of the cap with its open end.

[0011] The body and cap include potential overlapping matching areas (overlap areas) on the outside of the body and inside of the cap that partially overlap when the capsule is closed in the pre-locked state and fully overlap in the final-locked state. When the cap is partially slid over the overlapping matching area of ​​the body, the capsule is in the pre-locked state. When the cap is fully slid over the overlapping matching area of ​​the body, the capsule is in the final-locked state. Maintenance of the pre-locked or final-locked state is typically assisted by snap-in locking features on the body and cap, such as matching peripheral notches or dimples, preferably elongated dimples.

[0012] Typically, the body is longer than the cap. To close or lock the capsule, the outer overlap region of the body may be covered by the cap. In the closed state, the cap covers the outer overlap region of the body in either the pre-locked state or the final locked state. In the final locked state, the cap completely covers the outer overlap region of the body, and in the pre-locked state, the cap only partially overlaps the outer overlap region of the body. The cap can be slid over the body and fixed in one of two different positions, where the capsule is typically closed in either the pre-locked state or the final locked state.

[0013] Hard shell capsules are commercially available in different sizes. They are usually delivered as empty containers with the body and cap already in the pre-locked state, or as separate capsule halves, bodies, and caps, if necessary. The pre-locked hard shell capsules can be fed to a capsule filling machine that opens, fills, and closes the capsule to the final lock state. Typically, hard shell capsules are filled with dry materials, such as powders or granules, or viscous liquids, including biologically active ingredients.

[0014] The cap and the body are provided with closure means advantageous for preliminary (temporary) and / or final locking of the capsule. Thus, a protruding point may be provided on the inner wall of the cap, and a slightly larger recessed point on the outer wall of the body arranged so that the protruding part engages in the recess when the capsule is closed. Alternatively, the protruding part may be formed on the outer wall of the body and the recess on the inner wall of the cap. An arrangement may also be provided in which the protruding part or the recess is arranged in a ring or spiral around the wall. Instead of a point-like arrangement of the protruding part and the recessed part, they may surround the wall of the cap or the body in an annular arrangement, but advantageously provided with recesses and openings that allow the exchange of gas into and out of the capsule interior. One or more protruding parts may be provided in an annular arrangement around the inner wall of the cap and the outer wall of the body, such that in the final locking position of the capsule, the protruding part on the cap is adjacent to the protruding part on the body. Optionally, the protruding part is formed on the outside of the body near the open end, and the recess is formed in the cap near the open end, so that the protruding part on the body latches into the recess in the cap in the final locking position of the capsule. The protrusion may be such that the cap can be opened in pre-lock at any time without damage to the capsule, or such that once the cap is closed it cannot be opened again without destroying it. Capsules with one or more such latching mechanisms (latches) (e.g. two circumferential grooves) are preferred. More preferred are capsules with at least two such latching means that fasten the two capsule parts to different degrees. In this type of part, a first latching (dimple or circumferential notch) means can be formed in the capsule cap and capsule body near the opening, and a second latching (circumferential notch) can be shifted slightly further towards the closed end of the capsule parts. The first latching means fastens the two capsule parts to a lesser extent than the second latching means. This variant has the advantage that the capsule cap and capsule body can be initially connected together in pre-lock using the first latching mechanism after production of the empty capsule.The two capsule halves are then separated again to fill the capsule. After filling, the two capsule halves are pressed together until a second set of latches secures the capsule halves in their final locked position.

[0015] Preferably, the body and cap of the hard shell capsule each include a peripheral notch and / or dimple in the area where the cap can slide over the body. The peripheral notch of the body and the dimple of the cap match each other to provide a snap-in or snap-in-place mechanism. The dimples may be circular or elongated in the longitudinal direction (oval). The peripheral notch of the body and the peripheral notch of the cap (substantially matching rings) also match each other to provide a snap-in or snap-in-place mechanism. This allows the capsule to be closed by a snap-in-place mechanism in either a pre-locked or final-locked state.

[0016] Preferably, matching peripheral notches on the body and elongated dimples on the cap are used to secure the body and cap together in the pre-locked condition.Matching peripheral notches on the body and cap are preferably used to secure or lock the body and cap together in the final-locked condition.

[0017] The area where the cap can slide over the body can be referred to as the overlap area of ​​the body and the cap or simply the overlap area. If the cap overlaps the body only partially, perhaps 20-90% or 60-85% of the overlap area, the hard shell capsule is only partially closed (pre-locked). Preferably, if there is a locking mechanism such as matching peripheral notches and / or dimples on the body and the cap, the partially closed capsule can be referred to as pre-locked. If the capsule is polymer-coated in the pre-locked state, the coating will completely cover the outer surface including the part of the overlap area of ​​the body and the cap that is not overlapped by the cap in this pre-locked state. If the capsule is polymer-coated in the pre-locked state and then closed to the final-locked state, the coating of the part of the overlap area of ​​the body and the cap that is not overlapped by the cap in the pre-locked state will then be covered by the cap. The presence of the part of the coating that is then enclosed in the final-locked state between the body and the cap is sufficient to strongly seal the hard shell capsule.

[0018] The hard shell capsule is finally closed or in a finally locked state when the cap overlaps the body over the entire overlap area of ​​the body. Preferably, if there are locking features such as matching peripheral notches and / or dimples on the body and cap, the finally closed capsule can be said to be finally locked.

[0019] Typically, a dimple is preferred for securing the body and cap in a pre-locked state. As a non-binding rule, the matching area of ​​the dimple is smaller than the matching area of ​​the peripheral notch. Thus, a snapped-in dimple can be snapped out again by applying less force than would be required to snap out a snap-in fastening with a matching peripheral notch.

[0020] The dimples on the body and cap are located in the area where the cap can be slid over the body and match up with each other in a pre-locked state by snapping in or snapping into place mechanism. For example, there may be two, four or preferably six notches or dimples located in a circular distribution around the cap.

[0021] Typically, the dimples on the cap and the peripheral notches on the body in the area where the cap can be slid over the body match up to allow the capsule to be closed by a snap-in mechanism in the pre-locked state. In the pre-locked state, the force required to open is relatively low, so that the hard shell capsule can be opened again manually or mechanically without damage. Thus, the "pre-locked state" is sometimes also referred to as the "loosely capped state".

[0022] Typically, peripheral notches or matching locking rings on the body and cap in the area where the cap can be slid over the body match up with one another so that they allow the capsule to be closed by a snap-in mechanism in a final locked state in which the hard shell capsule cannot or hardly can be reopened again manually or mechanically without damage, because the force required to open is relatively high.

[0023] Typically, dimples and peripheral notches are formed in the capsule body or capsule cap such that when the capsule parts provided with these protrusions and recesses are engaged with each other, a uniform gap is formed along the contact surface between the capsule body and the capsule cap placed thereon, ideally between 10 microns and 150 microns, more particularly between 20 microns and 100 microns.

[0024] Preferably, the body of the hard shell capsule includes a tapered rim, which prevents the body and cap rim from colliding and being damaged when the capsule is closed manually or mechanically.

[0025] In contrast to hard shell capsules, soft shell capsules are bonded integral encapsulated capsules. Soft gel capsules are often made from blown soft gelling materials and are usually filled by injection with a liquid containing a biologically active ingredient. The present invention does not relate to bonded soft shell integral encapsulated capsules.

[0026] Hard Shell Capsule Size The closed final locked hard shell capsule may have an overall length in the range of about 5-40 mm. The cap diameter may be in the range of about 1.3-12 mm. The body diameter may be in the range of about 1.2-11 mm. The cap length may be in the range of about 4-20 mm and the body length may be in the range of about 8-30 mm. The fill volume may be between about 0.004-2 ml. The difference between the pre-lock length and the final lock length may be about 1-5 mm.

[0027] The capsules can be divided into standardized sizes, e.g., sizes 000 to 5. A size 000 closed capsule has, e.g., a total length of about 28 mm, with a cap outer diameter of about 9.9 mm and a body outer diameter of about 9.5 mm. The cap length is about 14 mm and the body length is about 22 mm. The fill volume is about 1.4 ml.

[0028] A size 5 closed capsule, for example, has an overall length of about 10 mm, with a cap outer diameter of about 4.8 mm and a body outer diameter of about 4.6 mm. The cap length is about 5.6 mm and the body length is about 9.4 mm. The fill volume is about 0.13 ml.

[0029] A size 0 capsule may exhibit a length of about 23-24 mm in the pre-locked state and a length of about 20.5-21.5 mm in the final locked state, so the difference between the pre-locked length and the final locked length may be about 2-3 mm.

[0030] Coated Hard Shell Capsules The present invention relates to polymer-coated hard shell capsules obtainable by the process as described herein.

[0031] Body and Cap Materials The base material of the body and cap can be selected from hydroxypropylmethylcellulose, starch, gelatin, pullulan, and copolymers of C1-C4 alkyl esters of (meth)acrylic acid and (meth)acrylic acid. Hard shell capsules in which the body and cap comprise or consist of HPMC or gelatin are preferred, with HPMC being most preferred, due to its good adhesion properties to polymeric coatings.

[0032] Polymer or polymer mixture contained in the coating layer The at least one polymer contained in the coating layer is preferably a film-forming polymer and may be selected from the group of anionic polymers, cationic polymers, and neutral polymers, or any mixture thereof.

[0033] Selection of any general or specific polymer feature or embodiment as disclosed herein can be combined without limitation with other general or specific selections of materials or numerical features or embodiments as disclosed herein, such as capsule materials, capsule sizes, coating thicknesses, biologically active ingredients, and other features or embodiments as disclosed.

[0034] The coating layer, which may be a single layer or which may comprise or consist of two or more individual layers, may comprise a total of 10-100% by weight, 20-95% by weight, 30-90% by weight of one or more polymers, preferably (meth)acrylate copolymers.

[0035] The monomer percentages mentioned for each polymer generally add up to 100% by weight.

[0036] Glass transition temperature T gm The coating layer has a glass transition temperature T of 125° C. or less, preferably −10 to 115° C. gm The copolymer may comprise one or more polymers having the formula:

[0037] The coating layer has a glass transition temperature T of 130° C. or less, preferably 127° C. or less, more preferably 50 to 127° C. gm The composition may comprise one or more anionic celluloses, ethyl cellulose, and / or one or more starches containing at least 35% by weight amylose.

[0038] Glass transition temperature T gm is 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 T gm was determined by the half step height method as described in DIN EN ISO 11357-2, section 10.1.2.

[0039] Anionic Polymers - Enteric Coating and Gastric Resistance The described method is particularly useful for providing tightly closed polymer-coated hard shell capsules for pharmaceutical or nutraceutical dosage forms with gastro-resistance and intended rapid release in the small intestine (enteric coating) or large intestine (colonic targeting).

[0040] At least one polymer included in the coating layer may be an anionic polymer selected from the group of anionic (meth)acrylate copolymers, anionic polyvinyl polymers or copolymers, and anionic celluloses.

[0041] The above-mentioned anionic polymers are also called "enteric polymers". In the coating layer, such polymers can provide enteric protection to the capsule. Enteric protection means that when the capsule is in the final closed state and contains a fill containing pharmaceutical or nutraceutical biologically active ingredients, less than 10% of the contained biologically active ingredients are released after 120 minutes in 0.1 HCl at pH 1.2. Most preferably, after 120 minutes in 0.1 HCl at pH 1.2, followed by changing to a buffer medium at pH 6.8, about 80% or more of the contained biologically active ingredients are released after a total time of 165 minutes or 180 minutes.

[0042] Colon targeting means that when the capsule is in final closed state and contains a filler containing pharmaceutical or nutraceutical biologically active ingredients, less than 10% of the biologically active ingredients contained therein are released after 120 minutes in 0.1 HCl at pH 1.2.Preferably, after 120 minutes in 0.1 HCl at pH 1.2, followed by a change to a buffer medium at pH 6.8, about 80% or more of the biologically active ingredients contained therein are released after a total time of 165 minutes.Most preferably, after 120 minutes in 0.1 HCl at pH 1.2, followed by an intermediate change to a buffer medium at pH 6.5 or 6.8 for 60 minutes, followed by a final change to a buffer medium at pH 7.2 or pH 7.4, about 80% or more of the biologically active ingredients contained therein are released after a total time of 225 minutes or 240 minutes.

[0043] The dissolution test was performed according to the United States Pharmacopeia 43 (USP). <711> The test is performed utilizing USP Apparatus II with a paddle speed of 50 or 75 rpm as per chapter. The test media temperature is adjusted to 37 + 0.5°C. Samples are taken at appropriate time points.

[0044] Anionic (Meth)Acrylate Copolymer 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-C12 alkyl esters, preferably C1-C4 alkyl esters of acrylic or methacrylic acid, and 75-5% by weight, preferably 60-5% by weight, in particular 40-60% by weight of (meth)acrylate monomers having anionic groups. The proportions generally mentioned add up to 100% by weight. However, it is further possible for small amounts of vinyl-copolymerizable further monomers, such as hydroxyethyl methacrylate or hydroxyethyl acrylate, in the range of 0-10% by weight, for example 1-5% by weight, to be present without causing any impairment or change of the essential properties. It is preferred that no vinyl-copolymerizable further monomers are present.

[0045] C1-C4 alkyl esters of acrylic or methacrylic acid are in particular methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate and butyl acrylate.

[0046] The (meth)acrylate monomer having an anionic group is, for example, acrylic acid, preferably methacrylic acid.

[0047] Suitable anionic (meth)acrylate copolymers are those polymerized from 40 to 60% by weight of methacrylic acid and 60 to 40% by weight of methyl methacrylate or 60 to 40% by weight of ethyl acrylate (EUDRAGIT® L or EUDRAGIT® L 100 55 type).

[0048] EUDRAGIT® L is a copolymer polymerized from 50% by weight of methyl methacrylate and 50% by weight of methacrylic acid. The pH of onset of release of a particular active ingredient in intestinal fluid or simulated intestinal fluid can be stated to be around a pH value of 6.0.

[0049] EUDRAGIT® L 100-55 is a copolymer polymerized from 50% by weight of methyl methacrylate and 50% by weight of methacrylic acid. EUDRAGIT® L 30 D-55 is a dispersion containing 30% by weight of EUDRAGIT® L 100-55. It can be stated that the pH of onset of release of a particular active ingredient in intestinal fluid or simulated intestinal fluid is about a pH value of 5.5.

[0050] Likewise suitable are anionic (meth)acrylate copolymers (EUDRAGIT® S type) polymerized from 20-40% by weight of methacrylic acid and 80-60% by weight of methyl methacrylate. It can be stated that the pH value of the onset of release of a particular active ingredient in intestinal fluid or simulated intestinal fluid is approximately a pH value of 7.0.

[0051] A suitable (meth)acrylate copolymer is polymerized from 10-30% by weight of methyl methacrylate, 50-70% by weight of methyl acrylate and 5-15% by weight of methacrylic acid (EUDRAGIT® FS type). It can be stated that the pH at the onset of release of a particular active ingredient in intestinal fluid or simulated intestinal fluid is about a pH value of 7.0.

[0052] EUDRAGIT® FS is a copolymer polymerized from 25% by weight methyl methacrylate, 65% by weight methyl acrylate, and 10% by weight methacrylic acid. EUDRAGIT® FS 30 D is a dispersion containing 30% by weight EUDRAGIT® FS.

[0053] 20 to 34% by weight of methacrylic acid and / or acrylic acid; 20 to 69% by weight of methyl acrylate; 0-40% by weight of ethyl acrylate and / or 0 to 10% by weight of a further vinyl copolymerizable monomer; Suitable copolymers are those consisting of However, the glass transition temperature of the copolymer according to ISO 11357-2:2013-05, subsection 3.3.3 is below 60° C. This (meth)acrylate copolymer is particularly suitable for compressing pellets into tablets due to its good elongation at break properties.

[0054] 20 to 33% by weight of methacrylic acid and / or acrylic acid; 5 to 30% by weight of methyl acrylate; 20 to 40% by weight of ethyl acrylate; More than 10% by weight to 30% by weight of butyl methacrylate, and optionally 0 to 10% by weight of a further vinyl copolymerizable monomer; Suitable copolymers are those polymerized from The total proportion of monomers should total 100% by weight. However, the glass transition temperature (midpoint temperature Tmg) of the copolymer according to subsection 3.3.3 of ISO 11357-2:2013-05 is 55 to 70°C.

[0055] The copolymers preferably consist of 90, 95 or 99 to 100% by weight of the monomers methacrylic acid, methyl acrylate, ethyl acrylate and butyl methacrylate, within the ranges of amounts indicated above. However, this does not necessarily lead to a reduction in the essential properties, and small amounts in the range of 0 to 10% by weight, for example 1 to 5% by weight, of further vinyl copolymerizable monomers, such as methyl methacrylate, butyl acrylate, hydroxyethyl methacrylate, vinylpyrrolidone, vinylmalonic acid, styrene, vinyl alcohol, vinyl acetate and / or derivatives thereof, can also be present.

[0056] Further suitable anionic (meth)acrylate copolymers may be so-called core / shell polymers as described in WO 2012 / 171575 or WO 2012 / 171576. A suitable core-shell polymer is a copolymer from a two-stage emulsion polymerization process having a 75% core comprising polymerized units of 30% ethyl acrylate and 70% methyl methacrylate by weight, and a 25% shell polymerized from 50% ethyl acrylate and 50% methacrylic acid by weight.

[0057] A suitable core-shell polymer may be a copolymer from a two-stage emulsion polymerization process having 70-80 wt. % core containing 65-75 wt. % ethyl acrylate and 25-35 wt. % methyl methacrylate polymerized units, and 20-30 wt. % shell containing 45-55 wt. % ethyl acrylate and 45-55 wt. % methacrylic acid polymerized units.

[0058] Anionic Cellulose The anionic cellulose may be selected from carboxymethylethylcellulose and its salts, cellulose acetate phthalate (CAP), cellulose acetate succinate (CAS), cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP, HP50, HP55), hydroxypropylmethylcellulose acetate succinate (HPMCAS-LF, -MF, -HF).

[0059] The hard shell capsule is coated with a coating layer that covers the hard shell capsule in the pre-locked state. The coating layer preferably has a glass transition temperature T gm The coating layer may comprise one or more anionic celluloses, ethyl cellulose, and / or one or more starches containing at least 35% by weight amylose, preferably having a molecular weight of about 1 to 5.8 mg / cm2 (determined by differential scanning calorimetry (DSC) according to ISO 11357-2:2013-05). 2 , more preferably 2 to 5 mg / cm 2is present in an amount of

[0060] The coating layer, which may be a single layer or which may comprise or consist of two or more individual layers, may comprise a total of 10-100%, 20-95%, 30-90% by weight of one or more anionic celluloses, ethyl cellulose, and / or one or more starches containing at least 35% by weight of amylose.

[0061] Glass transition temperature T of hydroxypropyl methylcellulose phthalate gm is about 132 to 138°C (HP-55 type is about 133°C, and HP-50 type is about 137°C).

[0062] Glass transition temperature T of hydroxypropyl methylcellulose acetate succinate (HPMCAS) gm is about 120°C (AquaSolve™ L HPMCAS is 119°C, AquaSolve™ M HPMCAS is 120°C, and AquaSolve™ H HPMCAS is 122°C).

[0063] Ethyl cellulose Ethylcellulose is a derivative of cellulose in which some of the hydroxyl groups of the repeating glucose units are converted to ethyl ether groups. Ethylcellulose can be used as a delayed release coating material for capsules as disclosed. The glass transition temperature T gm may be in the range of about 128-130° C. (Hui Ling Lai et al. Int. J. Pharmaceuticals 386 (2010) 178-184).

[0064] Starch containing at least 35% by weight amylose Starches containing at least 35% amylose by weight are commercially available as corn or maize derived starches.

[0065] Starches containing at least 35% by weight of amylose are known, for example, from EP 1296658. Chemically modified (acetylated) starches of this type with a high amylose content are obtained by a pregelatinization process. These starches show high mechanical resistance for the production of capsules and coatings for solid formulations used for various applications in the pharmaceutical or nutraceutical fields.

[0066] The glass transition temperature T of starch containing at least 35% by weight of amylose gm may be in the range of about 52-60° C. (Peng Liu et al., J. Cereal Science (2010) 388-391).

[0067] Anionic Vinyl Copolymer The anionic vinyl copolymer may be selected from unsaturated carboxylic acids other than acrylic or methacrylic acid, as exemplified by polyvinyl acetate phthalate or copolymers of vinyl acetate and crotonic acid (preferably in a 9:1 ratio).

[0068] Cationic Polymers - Moisture Protection The described method is particularly useful for providing polymer-coated hard shell capsules, and pharmaceutical or nutraceutical dosage forms based on these types of capsules, with improved moisture protection properties, such as reduced moisture absorption during storage. For this purpose, a coating with a cationic polymer, preferably a cationic (meth)acrylate copolymer, is presented.

[0069] Suitable cationic (meth)acrylate copolymers for inclusion in the coating layer can be polymerized from monomers including C1-C4 alkyl esters of acrylic or methacrylic acid and alkyl esters of acrylic or methacrylic acid having tertiary or quaternary ammonium groups on the alkyl group. Cationic water-soluble (meth)acrylate copolymers can be partially or fully polymerized from alkyl acrylates and / or alkyl methacrylates having tertiary amino groups on the alkyl radical. Coatings including these types of polymers can have the advantage of providing moisture protection to the hard shell capsule. Moisture protection is to be understood as reduced moisture or water absorption during storage of the readily filled and final locked capsules.

[0070] Suitable cationic (meth)acrylate copolymers can be polymerized from 30-80% by weight of C1-C4 alkyl esters of acrylic or methacrylic acid and 70-20% by weight of alkyl (meth)acrylate monomers bearing a tertiary amino group on the alkyl radical.

[0071] A preferred cationic (meth)acrylate copolymer can be polymerized from 20-30% by weight methyl methacrylate, 20-30% by weight butyl methacrylate, and 60-40% by weight dimethylaminoethyl methacrylate (EUDRAGIT® E-type polymer).

[0072] A particularly suitable commercially available (meth)acrylate copolymer having tertiary amino groups is polymerized from 25% by weight methyl methacrylate, 25% by weight butyl methacrylate, and 50% by weight dimethylaminoethyl methacrylate (EUDRAGIT® E 100 or EUDRAGIT® E PO (powder form)). EUDRAGIT® E 100 and EUDRAGIT® E PO are water-soluble at pH values ​​below about 5.0 and are therefore also soluble in gastric secretions.

[0073] Suitable (meth)acrylate copolymers may be composed of 85-98% by weight of free radically polymerized C1-C4 alkyl esters of acrylic or methacrylic acid and 15-2% by weight of a (meth)acrylate monomer having a quaternary amino group on the alkyl radical.

[0074] Preferred C1-C4 alkyl esters of acrylic or methacrylic acid are methyl acrylate, ethyl acrylate, butyl acrylate, butyl methacrylate, and methyl methacrylate.

[0075] Further suitable cationic (meth)acrylate polymers may contain polymerized monomer units of 2-trimethylammonium ethyl methacrylate chloride or trimethylammonium propyl methacrylate chloride.

[0076] A suitable copolymer can be polymerized from 50-70% by weight of methyl methacrylate, 20-40% by weight of ethyl acrylate, and 7-2% by weight of 2-trimethylammonium ethyl methacrylate chloride.

[0077] A particularly suitable copolymer is polymerized from 65% by weight methyl methacrylate, 30% by weight ethyl acrylate, and 5% by weight 2-trimethylammonium ethyl methacrylate chloride (EUDRAGIT® RS).

[0078] Further suitable (meth)acrylate copolymers can be polymerized from 85% to less than 93% by weight of C1-C4 alkyl esters of acrylic or methacrylic acid and from more than 7% to 15% by weight of (meth)acrylate monomers having a quaternary amino group on the alkyl radical. Such (meth)acrylate monomers are commercially available and have been used for a long time in release retarding coatings.

[0079] A particularly suitable copolymer is polymerized from 60% by weight methyl methacrylate, 30% by weight ethyl acrylate, and 10% by weight 2-trimethylammonium ethyl methacrylate chloride (EUDRAGIT® RL).

[0080] Neutral Polymer A neutral polymer is defined as a polymer polymerized from neutral monomers and less than 5% by weight, preferably less than 2% by weight, or most preferably 0% by weight, of monomers carrying ionic groups.

[0081] Suitable neutral polymers for coating the hard shell capsules are methacrylate copolymers, preferably copolymers of ethyl acrylate and methyl methacrylate, such as EUDRAGIT® NE or EUDRAGIT® NM, neutral celluloses, such as the methyl, ethyl or propyl ethers of cellulose, e.g., hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl acetate, or polyvinyl alcohol.

[0082] Neutral methacrylate copolymers are often useful in mixtures with anionic (meth)acrylate copolymers.

[0083] The neutral methacrylate copolymers are polymerized from (meth)acrylate monomers which have neutral radicals, in particular C1-C4 alkyl radicals, to an extent of at least 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, more preferably to an extent of 100% by weight.

[0084] Suitable (meth)acrylate monomers with neutral radicals are, for example, methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate, butyl acrylate. Methyl methacrylate, ethyl acrylate and methyl acrylate are preferred.

[0085] Methacrylate monomers having anionic radicals, such as acrylic acid and / or methacrylic acid, may be present in small amounts of less than 5% by weight, preferably 2% by weight or less, more preferably 1% by weight or less, or 0.05 to 1% by weight.

[0086] A suitable example is a neutral or substantially neutral (meth)acrylate copolymer polymerized from 20-40% by weight of ethyl acrylate, 60-80% by weight of methyl methacrylate, and 0% to less than 5% by weight, preferably 0-2% or 0.05-1% by weight, of methacrylic acid or acrylic acid.

[0087] A suitable example is a neutral or substantially neutral (meth)acrylate copolymer polymerized from 20-40% by weight of methyl methacrylate, 60-80% by weight of ethyl acrylate, and 0% to less than 5% by weight, preferably 0-2% or 0.05-1% by weight of methacrylic acid or acrylic acid (EUDRAGIT® NE or EUDRAGIT® NM type).

[0088] EUDRAGIT® NE and EUDRAGIT® NM are copolymers containing free radically polymerized units of 28-32 weight percent methyl methacrylate and 68-72 weight percent ethyl acrylate.

[0089] Preference is given to neutral or essentially neutral methyl acrylate copolymers prepared as dispersions using 1 to 10% by weight of a non-ionic emulsifier having an HLB value of 15.2 to 17.3 according to WO 01 / 68767, the latter offering the advantage of no phase separation due to the formation of crystalline structures by the emulsifier (EUDRAGIT® NM type).

[0090] However, according to EP 1 571 164 A1, the corresponding substantially neutral (meth)acrylate copolymers having small proportions of monoolefinically unsaturated C3-C8 carboxylic acids, from 0.05 to 1% by weight, can also be prepared by emulsion polymerization in the presence of relatively small amounts, for example 0.001 to 1% by weight, of anionic emulsifiers.

[0091] Natural Polymers Particularly in dietary supplement dosage forms, so-called "natural polymer" coatings are preferred by many customers. Natural polymers are based on natural, vegetable, microbial or animal sources, but may also be chemically processed. Natural polymers for coatings can be selected from starch, alginates or salts of alginates, preferably sodium alginate, pectin, shellac, zein, carboxymethylzein, modified starches such as EUDRAGUARD® Natural, marine sponge collagen, chitosan, gellan gum, and other polymers. Suitable polymer mixtures may include: Ethylcellulose and pectin, modified starch (EUDRAGUARD® Natural) and alginate and / or pectin, shellac and alginate and / or pectin, shellac and inulin, whey proteins and gums (such as guar gum or tragacanth gum), zein, sodium alginate and chitosan.

[0092] Glidants Glidants usually have lipophilic properties. They prevent the film-forming polymer from agglomerating during film formation.

[0093] The at least one glidant is preferably selected from silica, ground silica, fumed silica, calcium kaolin 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 glycerol monostearate, or mixtures thereof, more preferably glycerol monostearate and talc, or mixtures thereof, such as glycerol monostearate and talc, or mixtures thereof.

[0094] Typical proportions for the use of flow promoters in the coatings of the present invention range from 0.5 to 100% by weight, preferably 3 to 75% by weight, more preferably 5 to 50% by weight, and most preferably 5 to 30% by weight, based on the total weight of the at least one polymer.

[0095] emulsifier Generally, all known emulsifiers are suitable. Non-ionic emulsifiers are preferred, especially those with an HLB greater than 10. HBL values ​​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.

[0096] The at least one emulsifier is preferably selected from polyglycosides, alcohols, sugars and sugar derivatives, polyethers, amines, polyethylene derivatives, alkyl sulfates (e.g., sodium dodecyl sulfate), alkyl ether sulfates, dioctyl sodium sulfosuccinate, polysorbates (e.g., polyoxyethylene(20)sorbitan monooleate), nonylphenol ethoxylates (nonoxynol-9), and mixtures thereof.

[0097] The at least one emulsifier is preferably an alkyl polyglycoside, decyl glucoside, decyl polyglucose, lauryl glucoside, octyl glucoside, N-octyl beta-D-thioglucopyranoside, cetostearyl alcohol, cetyl alcohol, stearyl alcohol, polyoxyethylene cetostearyl alcohol, cetylstearyl alcohol, oleyl alcohol, polyglyceryl-6 dioleate, glyceryl stearate citrate, polyglyceryl-3 caprate, polyglyceryl-3 diisostearate, glyceryl isostearate, polyglyceryl-4 isostearate, glyceryl monolinoleate, dicaprylyl carbonate, alcohol polyglycol ethers, polyethylene glycol ethers of cetearyl alcohol (n=20), stearyl ethers of glyceryl monostearate, polyglyceryl-3 diisos ...3 diisostearate, polyglyceryl-4 isostearate, glyceryl monolinoleate, dicaprylyl carbonate, polyglycol ethers of glyceryl monostearate, polyglyceryl-3 diisostearate, polyglyceryl-4 diisostearate, polyglyceryl-4 diisostearate, polyglyceryl monostearate, polyglyceryl monostearate, polyglyceryl monostearate, polyglyceryl monostearate, polyglyceryl monostearate, polyglyceryl monostearate, polyglyceryl monostearate, polyglyceryl monostearate, polyglyceryl monostearate, polyglyceryl monostearate, polyglyceryl monostearate, polyglyc Polyethylene glycol-6 phosphate, glycol stearate, polyethylene glycol-32 stearate, polyethylene glycol-20 stearate, fatty alcohol polyglycol ethers, polyethylene glycol-4 laurate, polyethylene glycol isocetyl ether (n=20), mono- and diesters of polyethylene glycol-32 (Mw1500g / mol) with 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, BRIJPolyoxyethylene fatty ethers derived from stearyl alcohol such as S2, polyoxyethylene oxypropylene stearate, macrogol stearyl ether (20), diethylaminoethyl stearate, polyethylene glycol stearate, sucrose distearate, sucrose tristearate, sorbitan monostearate, sorbitan tristearate, mannide monooleate, octaglycerol monooleate, sorbitan dioleate, polylysine oleate, polysorbate 20 and polyoxyethylene (20) polysorbates such as sorbitan monooleate (polysorbate 80), sorbitan, sorbitan monolaurate, sucrose cocoate, glycereth-2 cocoate, ethylhexyl cocoate, polypropylene glycol-3 benzyl ether myristate, sodium myristate, sodium gold thiomalate, polyethylene glycol-8 laurate, polyethylene-4 dilaurate, alpha-hexadecyl-omega-hybrid esters ... From hydroxypoly(oxyethylene), cocamide diethanolamine, N-(2-hydroxyethyl)dodecanamide, octylphenoxypolyethoxyethanol, maltoside, 2,3-dihydroxypropyl dodecanoate, 3-[(3R,6R,9R,12R,15S,22S,25S,30aS)-6,9,15,22-tetrakis(2-amino-2-oxoethyl)-3-(4-hydroxybenzyl)-12-(hydroxymethyl)-18-(11-methyltridecyl) )-1,4,7,10,13,16,20,23,26-nonaoxotriacontahydropyrrolo[1,2-g][1,4,7,10,13,16,19,22,25]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 monocaprate, Type I (CapryolPGMC), Polyethoxylated Tallowamine, Polyglycerol, Polyoxyl 40 Hydrogenated Castor Oil, Surfactin, 2-[4-(2,4,4-Trimethylpentan-2-yl)phenoxy]ethanol, Carbomer, Sodium Carbomer, Calcium Carboxymethylcellulose, Carrageenan, Cholesterol, Deoxycholic Acid, Phospholipids such as Egg Phospholipids, Gellan Gum, Lanolin, Capric Acid, Waxes such as Polawax NF, Polawax A31 or Ceral PW, Ester Gum, Deacetyl Phosphate, Soy Lecithin, Sphingomyelin, Sodium Phosphate, Sodium Lauroyl Lactylate, Lanolin, Oxirane Methyl Polymer with Oxirane Monobutyl Ether, 1,2-Diercoyl Phosphatidylcholine, Dimethicone Endblocked with an Average of 14 Moles of Propylene Oxide, Lauryl Methicone Copolyol, Lauroglycol 90, Amphocerine The preferred surfactants are selected from white mineral oils such as KS, dispersions of acrylamide / sodium acryloyldimethyl taurate copolymer in isohexadecane, and sodium polyacrylate, or mixtures thereof. Macrogol stearyl ether (20) and polysorbate 80 are preferred.

[0098] Coating Layer The hard shell capsule is coated with a coating layer comprising at least one polymer, at least one glidant, at least one emulsifier, and optionally at least one plasticizer, optionally at least one biologically active ingredient, and optionally at least one additive, different from the aforementioned components.

[0099] The coating layer may comprise at least one polymer in an amount of 10% by weight or more, 20% by weight or more, 30% by weight or more, 40% by weight or more, 50% by weight or more, 60% by weight or more, 70% by weight or more, 80% by weight or more, 90% by weight or more, or 95% by weight or more. The coating layer may comprise at least one polymer in an amount of 10-100% by weight, 10-90% by weight, 12-80% by weight, 15-80% by weight, 18-80% by weight, 20-80% by weight, or 40-80% by weight.

[0100] Amount and thickness of coating layer For hard shell capsules, the amount of coating layer should not be too high. If too much coating layer is applied, this may make it difficult to later process the polymer-coated prelocked hard shell capsule in the capsule filling machine. 2 Less than, for example, 1-8 mg / cm 2 , or 1-7 mg / cm 2 , or 1-7 mg / cm 2 , or 1-6 mg / cm 2 , or 1-5 mg / cm 2 , or 1-4 mg / cm 2 4mg / cm2, there is usually no problem in using a standard capsule filling machine without deformation. 2 ~Maximum about 8mg / cm 2 In the range of about 1 to about 8 mg / cm, the capsule filling machine can still be used, but the shape of the body and cap should be adjusted to be slightly wider. Such adjustments can be easily performed by any mechanical engineer. Thus, the capsule filling machine can be used in the range of about 1 to about 8 mg / cm. 2 The coating layer amount can be advantageously used within the above range.

[0101] For size #0 hard shell capsules, the amount of coating layer should not be too high. If too much coating layer is applied, this may make it difficult to later process the polymer-coated prelocked hard shell capsule in the capsule filling machine. 2 Less than 1-4mg / cm 2 4mg / cm2, there is usually no problem in using a standard capsule filling machine without deformation. 2 ~Maximum about 8mg / cm 2In the range of about 1 to about 8 mg / cm, the capsule filling machine can still be used, but the shape of the body and cap should be adjusted to be slightly wider. Such adjustments can be easily performed by any mechanical engineer. Thus, the capsule filling machine can be used in the range of about 1 to about 8 mg / cm. 2 The coating layer amount can be advantageously used within the above range.

[0102] For size #1 hard shell capsules, the amount of coating layer should not be too high. If too much coating layer is applied, this may make it difficult to later process the polymer-coated prelocked hard shell capsule in the capsule filling machine. 2 Less than 1-3.5mg / cm 2 If the density is less than 3.5mg / cm, there is usually no problem in using a standard capsule filling machine without deformation. 2 ~Maximum about 8mg / cm 2 In the range of about 1 to about 8 mg / cm, the capsule filling machine can still be used, but the shape of the body and cap should be adjusted to be slightly wider. Such adjustments can be easily performed by any mechanical engineer. Thus, the capsule filling machine can be used in the range of about 1 to about 8 mg / cm. 2 The coating layer amount can be advantageously used within the above range.

[0103] For size #3 hard shell capsules, the amount of coating layer should not be too high. If too much coating layer is applied, this may make it difficult to later process the polymer-coated prelocked hard shell capsule in the capsule filling machine. 2 Less than 1-2.5mg / cm 2 If the density is less than 2.5mg / cm, there is usually no problem in using a standard capsule filling machine without deformation. 2 ~Maximum about 6mg / cm 2In the range of about 1 to about 6 mg / cm, the capsule filling machine can still be used, but the shape of the body and cap should be adjusted to be slightly wider. Such adjustments can be easily performed by any mechanical engineer. Thus, the capsule filling machine can be used in the range of about 1 to about 6 mg / cm. 2 The coating layer amount can be advantageously used within the above range.

[0104] 8 mg / cm 2 Over and up to approx. 20mg / cm 2 In the case of a polymer-coated hard shell capsule, careful opening, filling, and closing to a pre-locked state may still be possible without causing damage to the polymer coating. If the coating layer is thicker than the gap between the uncoated body and the cap, the coated pre-locked capsule cannot be closed without damaging the applied coating, since the cap can hardly slide over the body to the final locked state any more. The upper limit for manual closing of a coated pre-locked hard shell capsule to the final locked state without causing damage is up to about 20 mg / cm. 2 The coating layer may be in an amount of 20 mg / cm 2 Ultra-precise and careful manual closure of the capsule may no longer be possible without causing damage.

[0105] If too much coating layer is applied, there will also be too much coating layer conglomeration at the rim of the cap where the gap between the body and the cap is in the pre-locked state. This can lead to cracks in the coating layer after drying when the coated pre-locked hard shell capsule is opened manually or in a machine. The cracks can lead to capsule leakage later. Finally, if the coating is too thick, it can be difficult or impossible to close the opened coated hard shell capsule to the final lock state because the coating layer is thicker than the gap in the overlap area between the body and the cap.

[0106] As a rough rule, the coating layer on a hard shell capsule should be between 0.7 and 20 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 (=total weight gain).

[0107] As a rough rule, the coating layer on the hard shell capsule may have an average thickness of about 5 to 100 μm, 10 to 50 μm, 15 to 75 μm.

[0108] As a rough rule, the coating layer on the hard shell capsule may be applied in an amount of 5-50%, preferably 8-40%, by dry weight based on the weight of the prelocked capsule.

[0109] Using this guideline, a person skilled in the art would be able to adjust the amount of coating layer within the range between too little and too much.

[0110] biologically active ingredients The biologically active ingredient is preferably a pharmaceutical active ingredient and / or a nutraceutical active ingredient and / or a cosmetic active ingredient.Although a certain biologically active ingredient may be contained in each coating layer, it is preferred that the biologically active ingredient is contained in the filler.In particular, when the biologically active ingredient is liposome, lipid nanoparticle or nucleic acid, the biologically active ingredient is contained only in the filler.

[0111] Pharmaceutical or dietary supplement active ingredients The present invention is preferably useful in immediate, delayed or sustained release compounded pharmaceutical or nutraceutical dosage forms having a loading of pharmaceutical or nutraceutical active ingredients.

[0112] Suitable therapeutic and chemical classes of pharmaceutical active ingredients whose components can be used as fill for the described polymer coated hard shell capsules are, for example, analgesics, antibiotics or anti-infectives, antibodies, antiepileptics, antigens from plants, antirheumatics, benzimidazole derivatives, beta-blockers, cardiovascular drugs, chemotherapeutic drugs, central nervous system drugs, digitalis glycosides, gastrointestinal drugs, e.g. proton pump inhibitors, enzymes, hormones, liquid or solid natural extracts, oligonucleotides, peptides, hormones, proteins, therapeutic bacteria, peptides, protein (metal) salts, i.e. aspartates, chlorides, urological drugs, lipid nanoparticles, liposomes, polymer nanoparticles, vaccines.

[0113] In a preferred embodiment, the pharma- ceutical active ingredient is a nucleic acid, and more preferably, the nucleic acid agent may be DNA, RNA, or a combination thereof. In some embodiments, the nucleic acid agent may be an oligonucleotide and / or a polynucleotide. In some embodiments, the nucleic acid agent may be an oligonucleotide and / or a modified oligonucleotide (including but not limited to, modified by phosphorylation); an antisense oligonucleotide and / or a modified antisense oligonucleotide (including but not limited to, modified by phosphorylation). In some embodiments, the nucleic acid agent may include cDNA and / or genomic DNA. In some embodiments, the nucleic acid agent may include non-human DNA and / or RNA (e.g., viral, bacterial, or fungal nucleic acid sequences). In some embodiments, the nucleic acid agent may be a plasmid, a cosmid, a gene fragment, an artificial and / or natural chromosome (e.g., yeast artificial chromosome), and / or a portion thereof. In some embodiments, the nucleic acid agent may be a functional RNA (e.g., mRNA, tRNA, rRNA, and / or ribozyme). In some embodiments, the nucleic acid agent may be an RNAi inducer, a small interfering RNA (siRNA), a short hairpin RNA (shRNA), and / or a microRNA (miRNA). In some embodiments, the nucleic acid agent may be a peptide nucleic acid (PNA). In some embodiments, the nucleic acid agent may be a polynucleotide that includes synthetic analogs of nucleic acids that may be modified or unmodified. In some embodiments, the nucleic acid agent may include various structural forms of DNA, including single-stranded DNA, double-stranded DNA, supercoiled DNA, and / or triplex DNA; Z-DNA; and / or combinations thereof. Further suitable nucleic acids are disclosed, for example, in WO2012103035, which is incorporated by reference.

[0114] Further examples of drugs that can be used as fill for the described polymer-coated hard shell capsules are, for example, acamprosate, aescin, amylase, acetylsalicylic acid, adrenaline, 5-aminosalicylic acid, aureomycin, bacitracin, balsalazine, beta-carotene, bicalutamide, bisacodyl, bromelain, bromelain, budesonide, calcitonin, carbamacipine, carboplatin, cephalosporins, cetrorelix, clarithromycin, chloromycetin, cimetidine, cisapride, cladribine, clorazepate, cromalin, 1-deaminocysteine-8-D-arginine-vasopressin, deramsic, cephalosporins ... Cran, detirelix, dexlansoprazole, diclofenac, didanosine, digitoxin and other digitalis glycosides, dihydrostreptomycin, dimethicone, divalproex, drospirenone, duloxetine, enzymes, erythromycin, esomeprazole, estrogen, etoposide, famotidine, fluoride, garlic oil, glucagon, granulocyte colony-stimulating factor (G-CSF), heparin, hydrocortisone, human growth hormone (hGH), ibuprofen, ilaprazole, insulin, interferon, interleukin, intron A, ketoprofen, lansoprazole, leuprolidacetat lipase lipase), lipoic acid, lithium, quinine, memantine, mesalazine, methenamine, miramerin, minerals, minoprazole, naproxen, natamycin, nitrofuranthion, novobiocin, olsalazine, omeprazole, orotate, pancreatin, pantoprazole, parathyroid hormone, paroxetine, penicillin, perprazole, pindolol, polymyxin, potassium, pravastatin, prednisone, preglumetasi amprogabide, prosomatostatin, protease, quinapril, rabeprazole, ranitidine, ranolazine, reboxetine, rutoside, somatostatin streptomycin, subtilin, sulfasalazine, sulfanilamide, tamsulosin, tenatoprazole, trypsin, valproic acid, vasopressin, vitamins, zinc, including their salts, derivatives, polymorphs, isomorphs, or any type of mixture or combination thereof.

[0115] It is clear to those skilled in the art that there is a wide overlap between the terms pharmaceutical and nutraceutical active ingredients, excipients and compositions, or pharmaceutical or nutraceutical dosage forms.Many substances that are listed as functional food nutraceuticals can also be used as pharmaceutical active ingredients.Depending on the specific application and the local government laws and classifications, the same substance may be listed as pharmaceutical or nutraceutical active ingredients, or pharmaceutical or nutraceutical compositions, or even both.

[0116] Dietary supplements are well known to those skilled in the art. Dietary supplements are often defined as food extracts that claim to have medical benefits for human health. Thus, dietary supplement active ingredients may also exhibit pharmaceutical activity: examples of dietary supplement active ingredients may be resveratrol from grape products as an antioxidant, soluble dietary fiber products such as psyllium seed husks to reduce hypercholesterolemia, broccoli (sulfanes) as a cancer preventive agent, and soybeans or clover (isoflavonoids) to improve arterial health. Thus, it is clear that many substances listed as dietary supplements can also be used as pharmaceutical active ingredients.

[0117] Exemplary dietary supplements or dietary supplement active ingredients that can be used as fills for the described polymer-coated hard shell capsules may include probiotics and prebiotics. Probiotics are live microorganisms that are believed to aid in human or animal health when consumed. Prebiotics are dietary supplements or dietary supplement active ingredients that induce or promote the growth or activity of beneficial microorganisms in the human or animal intestine.

[0118] Examples of dietary supplements are resveratrol from grape products, omega-3 fatty acids or proanthocyanins from blueberries as antioxidants, soluble dietary fiber products such as psyllium seed husks to reduce hypercholesterolemia, broccoli (sulfanes) as cancer preventatives, and soy or clover (isoflavonoids) to improve arterial health. Other examples of dietary supplements are flavonoids, antioxidants, alpha-linoleic acid from flaxseed, beta-carotene from marigold petals, or anthocyanins from berries. The term nutraceuticals or nutraceuticals is sometimes used as a synonym for dietary supplements.

[0119] Preferred biologically active ingredients are metoprolol, mesalamine, and omeprazole.

[0120] Additives 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 biologically active ingredients contained in coated hard shell capsules and / or with the polymeric coating of hard shell capsules as disclosed and claimed herein. All excipients used should be toxicologically safe and should be used in pharmaceutical or dietary supplement formulations without posing a risk to the patient or consumer.

[0121] The dosage form may comprise an excipient, preferably a pharma- or nutraceutical acceptable excipient, selected from the group of antioxidants, glazes, binders, flavorings, flow aids, fragrances, permeation enhancers, pigments, plasticizers, pore formers or stabilizers, or combinations thereof. The pharma- or nutraceutical acceptable excipient may be included in the core and / or coating layer comprising the polymer as disclosed. The pharma- or nutraceutical acceptable excipient is an excipient that can be used in applications in the pharmaceutical or nutraceutical fields.

[0122] The coating layer may contain up to 90% by weight, up to 80% by weight, up to 70% by weight, up to 50% by weight, up to 60% by weight, up to 50% by weight, up to 40% by weight, up to 30% by weight, up to 20% by weight, up to 10% by weight, up to 5% by weight, up to 3% by weight, up to 1% by weight of additives or pharmaceutical or nutraceutical acceptable excipients, or none (0%).

[0123] Plasticizer The polymer coating of the hard shell capsule may contain one or more plasticizers. Depending on the amount added, plasticizers lower the glass transition temperature through physical interactions with the polymer and promote film formation. Suitable substances usually have a molecular weight between 100 and 20,000 g / mol and contain one or more hydrophilic groups in the molecule, such as hydroxyl, ester, or amino groups.

[0124] Examples of suitable plasticizers are alkyl citrates, alkyl phthalates, alkyl sebacates, diethyl sebacate, dibutyl sebacate, polyethylene glycol, and polypropylene glycol.Preferred plasticizers are triethyl citrate (TEC), acetyl triethyl citrate (ATEC), diethyl sebacate, dibutyl sebacate (DBS), polyethylene glycol, and polypropylene glycol, or mixtures thereof.

[0125] The addition of plasticizers to the formulation can be carried out in a known manner directly, in an aqueous solution, or after thermal pretreatment of the mixture. It is also possible to use a mixture of plasticizers. The polymer coating of the hard shell capsule may contain one or more plasticizers, preferably up to 60% by weight, up to 30% by weight, up to 25% by weight, up to 20% by weight, up to 15% by weight, up to 10% by weight, up to 5% by weight, less than 5% by weight, or no plasticizers at all (0%), calculated based on at least one polymer.

[0126] Filler Standard fillers are usually added to the formulations of the present invention during processing into coatings and binders. The amount of introduction and use of standard fillers in or on top of pharmaceutical coatings are well known to those skilled in the art. Examples of standard fillers are release agents, pigments, stabilizers, antioxidants, pore formers, permeation enhancers, gloss agents, fragrances, or flavoring agents. They are used as processing aids, intended to ensure a reliable and reproducible preparation process and good long-term storage stability, or they achieve additional advantageous properties in pharmaceutical forms. They are added to polymer formulations before processing and can affect the permeability of the coating. This property can be used as an additional control parameter, if necessary.

[0127] Pigments Pigments are rarely added in soluble form. Generally, pigments such as aluminum oxide or iron oxide pigments are used in dispersed form. Titanium dioxide is used as a whitening pigment. Standard percentages for the use of pigments are 10-200% by weight, 20-200% by weight, based on the total weight of the at least one polymer in the coating layer. Percentages up to 200% by weight based on the total weight of the at least one polymer can be easily processed.

[0128] In a particularly advantageous embodiment, the pigments are used directly in concentrated form as an additional outer layer, the so-called topcoat. Application is carried out in the form of a powder or by spraying from an aqueous suspension with a solids content of 5-35% (w / w). The required concentration is lower than in the case of incorporation into a polymer layer and corresponds to 0.1-2% by weight, based on the weight of the pharmaceutical form.

[0129] Optional Topcoat and Subcoat Optionally, the hard shell capsule can be further coated with a subcoat or a topcoat, or both.

[0130] The subcoat may be located between the capsule and the coating layer and comprises at least one polymer as disclosed. The subcoat does not essentially affect the active ingredient release characteristics, but may, for example, improve the adhesion of the polymer coating layer. The subcoat is preferably essentially water-soluble, for example, it may consist of a material such as HPMC as a film former. The average thickness of the subcoat layer is usually very thin, for example, less than 15 μm, preferably less than 10 μm (0.1-1.0 mg / cm 2 ) A subcoat or topcoat does not necessarily have to be applied onto the pre-locked hard shell capsule.

[0131] The topcoat can be located on the coating layer and comprises at least one polymer as disclosed. The topcoat is also preferably water-soluble or essentially water-soluble. The topcoat may have the function of coloring the pharmaceutical or nutraceutical form or protecting it from environmental influences such as moisture during storage. The topcoat may be composed of a binder, e.g., a water-soluble polymer such as polysaccharide or HPMC, or a sugar compound such as sucrose. The topcoat may further contain significant amounts of pharmaceutical or nutraceutical acceptable excipients such as pigments, plasticizers, emulsifiers, or glidants. The topcoat does not essentially affect the release properties. The topcoat can be applied on top of the pharmaceutical or nutraceutical dosage form, including the final locked polymer-coated hard shell capsule as described herein. The average thickness of the topcoat layer is usually very thin, e.g., 15 μm or less, preferably 10 μm or less (0.1-1.0 mg / cm 2 ).

[0132] Method for preparing coated hard shell capsules A method is described for preparing a polymer-coated hard shell capsule suitable as a container for a biologically active ingredient, the hard shell capsule comprising a body and a cap, in a closed state, the cap overlaying the body in either a pre-locked state or a final-locked state, the hard shell capsule being provided in a pre-locked state and spray-coated with a coating solution, suspension or dispersion according to the present invention to produce a coating layer covering the outer surface of the hard shell capsule in the pre-locked state.

[0133] In a further process step, the pre-locked hard shell capsule may be provided with a fill comprising at least one biologically active ingredient and closed to a final locked state.

[0134] In such a further process step, the polymer coated hard shell capsule in the pre-locked state can be opened, filled with a fill comprising a biologically active ingredient, and closed in a final locked state. This further process step is preferably carried out by feeding the coated hard shell capsule in the pre-locked state to a capsule filling machine which performs opening, filling with a fill comprising at least one biologically active ingredient, and closing of the polymer coated hard shell capsule in a final locked state.

[0135] This further process step results in a final locked polymer coated hard shell capsule that is a container for at least one biologically active ingredient. The final locked polymer coated hard shell capsule that is a container for at least one biologically active ingredient is a pharmaceutical or nutraceutical dosage form.

[0136] The dosage form preferably comprises a polymer-coated hard shell capsule in a final locked state containing a fill comprising at least one biologically active ingredient, the polymer-coated hard shell capsule comprising a coating layer according to the present invention, the coating layer covering the outer surface region of the capsule in the pre-locked state but not covering the overlap region where the cap covers the body in the pre-locked state.

[0137] The coating suspension, which includes at least one polymer, at least one flow promoter, and at least one emulsifier, may contain an organic solvent, such as acetone, isopropanol, or ethanol. The concentration of the dry weight material in the organic solvent may be about 5-50% by weight of the polymer. A suitable spray concentration may be about 5-25% by dry weight.

[0138] The coating suspension may be a dispersion of at least one polymer, at least one flow promoter, and at least one emulsifier in an aqueous medium, for example, in water or a mixture of 80% or more by weight water and 20% or less by weight water-soluble solvent, such as acetone or isopropanol. A suitable concentration of dry weight materials in the aqueous medium may be about 5-50% by weight. A suitable spray concentration may be about 5-25% by dry weight.

[0139] Spray coating is preferably carried out in a drum coater or fluidized bed coating equipment by spraying the coating solution or dispersion onto the prelocked capsules.

[0140] The surface tension of the coating solution, suspension or dispersion is preferably determined according to the measurements as described in Example 1.

[0141] In another preferred embodiment the coating solution, suspension or dispersion has a surface tension in the range of 5-38 mN / m, or 5-36 mN / m, or 5-33 mN / m, more preferably the coating solution, suspension or dispersion has a surface tension in the range of 20-36 mN / m, or 20-38 mN / m, or 20-33 mN / m, most preferably the coating solution, suspension or dispersion has a surface tension in the range of 25-33 mN / m, or 25-38 mN / m, or 25-36 mN / m, in each case measured according to DIN EN 14370:2004.

[0142] Method for preparing a fill for a dosage form Suitable methods for preparing the filling for pharmaceutical or nutraceutical dosage forms are well known to those skilled in the art.Suitable methods for preparing the filling for pharmaceutical or nutraceutical dosage forms as disclosed herein can be by compression of dry granules, wet granules or sintered granules, which is direct compression, by extrusion and then rounding, by wet or dry granulation, by direct pelletization, or by binding powder on active ingredient-free beads or neutral cores or active ingredient-containing particles or pellets to form the core containing biologically active ingredients in the form of pellets, and optionally by applying a coating layer in the form of aqueous dispersion or organic solution by spray process or fluidized bed spray granulation.

[0143] Capsule Filling Machine The polymer coated hard shell capsules are provided in a pre-locked condition to a capsule filling machine which performs the steps of separating the body and cap, filling the body with a fill, and reconnecting the body and cap in a final locked condition.

[0144] The capsule filling machine used may be a capsule filling machine, preferably a fully automatic capsule filling machine, capable of producing filled and closed capsules at a production rate of 1000 or more filled and final closed capsules per hour. Capsule filling machines, preferably fully automatic capsule filling machines, are well known in the art and are commercially available from several companies. A suitable capsule filling machine as used in the examples may be, for example, ACG, model AFT Lab.

[0145] The capsule filling machine used is preferably capable of operating at a rate of output of at least 1,000, preferably at least 10,000, at least 100,000, from 10,000 up to 500,000 filled and final closed capsules per hour.

[0146] General Operation of Capsule Filling Machine Prior to the capsule filling process, the capsule filling machine is supplied with a sufficient number or quantity of pre-coated hard shell capsules in a pre-locked state. The capsule filling machine is also supplied with a sufficient amount of fill to be filled during the operation.

[0147] The pre-locked hard shell capsules are allowed to fall by gravity into a feed tube or chute. The capsules can be uniformly aligned by mechanically measuring the diameter difference between the cap and body. The hard shell capsules are then fed, usually in the proper orientation, into a two-compartment housing or bushing.

[0148] The diameter of the upper bushing or housing is usually larger than that of the capsule body bushing, so that the capsule cap can be held in the upper bushing while the body is pulled into the lower bushing by vacuum. When the capsule is opened / body and cap are separated, the upper and lower housings or bushings are separated to position the capsule body for filling.

[0149] The opened capsule body is then filled with the fill. Different types of filling mechanisms can be applied for different fills, such as granules, powders, pellets, or small tablets. Capsule filling machines generally use different mechanisms to handle different dosage ingredients and different numbers of filling stations. The dosing system is usually based on the volume or amount of the fill, which is governed by the capsule size and the capacity of the capsule body. The empty capsule manufacturer usually provides a reference table showing the volume capacity of the manufacturer's capsule body and the maximum fill weight for different capsule sizes, based on the density of the fill material. After filling, the body and cap are reconnected by the machine in a final locked state or position.

[0150] Use / How to Use / Method Steps A method for preparing a suitable polymer-coated hard shell capsule as described herein includes a method of using a hard shell capsule comprising a body and a cap to prepare a polymer-coated hard shell capsule suitable as a container for a pharmaceutical or nutraceutical biologically active ingredient, wherein in a closed state, the cap overlaps the body in either a pre-locked state or a final-locked state; a) providing a hard shell capsule in a pre-locked state; b) spray-coating a coating solution, suspension or dispersion containing a polymer or a mixture of polymers to produce a coating layer covering the outer surface of the pre-locked hard shell capsule; The above-mentioned method can be understood as a method of use, including the above-mentioned.

[0151] Spray coating can be preferably applied by using drum coater equipment or fluidized bed coating equipment. A suitable product temperature during the spray coating process may range from about 15 to 40°C, preferably from about 20 to 35°C. A suitable spray rate may range from about 0.3 to 17.0, preferably from 0.5 to 14 [g / min / kg]. After spray coating, a drying step is included.

[0152] The pre-locked polymer coated hard shell capsule can be opened in step c), filled with a fill containing a pharmaceutical or nutraceutical biologically active ingredient in step d), and then closed in step e) to a final lock state.

[0153] Steps c) to e) can be performed manually or, preferably, assisted by suitable equipment such as a capsule filling machine. Preferably, the coated hard shell capsules in a pre-locked state are fed to a capsule filling machine which performs the opening step c), the filling with the pharmaceutical or nutraceutical biologically active ingredient in step d), and the closing of the capsule to a final locked state in step e).

[0154] All those general or specific feature and embodiment selections as disclosed herein can be combined without limitation with other general or specific selections of materials or numerical features and embodiments as disclosed herein, such as polymers, capsule materials, capsule sizes, coating thicknesses, biologically active ingredients, and other embodiments as disclosed.

[0155] Pharmaceutical or dietary supplement dosage forms A pharmaceutical or nutraceutical dosage form is disclosed that includes a polymer-coated hard shell capsule in a final locked state containing a fill including a pharmaceutical or nutraceutical biologically active ingredient, the polymer-coated hard shell capsule including a coating layer including a polymer or a mixture of polymers, the coating layer covering the outer surface area of ​​the capsule in a pre-locked state. Because the outer surface area of ​​the capsule in the pre-locked state is greater than the outer surface area of ​​the capsule in the final locked state, a portion of the polymer coating layer is hidden or surrounded between the body and the cap of the hard shell capsule, thereby providing an efficient seal.

[0156] item In particular, the present invention relates to: 1. A method for preparing a polymer-coated hard shell capsule suitable as a container for a pharmaceutical or nutraceutical biologically active ingredient, comprising: The hard shell capsule comprises a body and a cap; In the closed state, the cap overlaps the body in either the pre-locked state or the final locked state; Providing the hard shell capsule in a pre-locked state; a) at least one polymer, preferably at least one (meth)acrylate copolymer, anionic cellulose, ethyl cellulose, or starch containing at least 35% by weight of amylose; b) at least one glidant; c) at least one emulsifier; d) optionally at least one plasticizer; e) optionally at least one biologically active ingredient, preferably at least one pharmaceutical, nutraceutical, or cosmetic ingredient; and f) optionally at least one additive different from a) to e); to obtain a coated, preferably pre-locked hard shell capsule coated only on the outer surface, the coating solution, suspension or dispersion has a surface tension of at most 38 mN / m, preferably at most 36 mN / m, more preferably at most 33 mN / m; method.

[0157] 2. The method according to item 1, wherein the base material of the body and the cap is selected from hydroxypropyl methylcellulose, starch, gelatin, pullulan, and copolymers of C1-C4 alkyl esters of (meth)acrylic acid and (meth)acrylic acid, preferably hydroxypropyl methylcellulose.

[0158] 3. The at least one polymer is selected from at least one (meth)acrylate copolymer, preferably having a glass transition temperature T gm 3. The method according to item 1 or 2, comprising the steps of:

[0159] 4. At least one polymer is i) a core-shell polymer which is a copolymer obtained by a two-stage emulsion polymerization process, having 70-80% by weight of a core comprising 65-75% by weight of polymerized units of ethyl acrylate and 25-35% by weight of methyl methacrylate, and 20-30% by weight of a shell comprising 45-55% by weight of ethyl acrylate and 45-55% by weight of polymerized units of methacrylic acid; or ii) an anionic polymer 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 iii) cationic (meth)acrylate copolymers obtained by polymerizing a C1-C4 alkyl ester of acrylic acid or methacrylic acid with an alkyl ester of acrylic acid or methacrylic acid having a tertiary or quaternary ammonium group in the alkyl group; or iv) (meth)acrylate copolymers obtained by polymerizing methacrylic acid and ethyl acrylate, or by polymerizing methacrylic acid and methyl methacrylate, or by polymerizing ethyl acrylate and methyl methacrylate, or by polymerizing methacrylic acid, methyl acrylate and methyl methacrylate; or v) (meth)acrylate copolymers obtained by polymerizing 40 to 60% by weight of methacrylic acid and 60 to 40% by weight of ethyl acrylate; or vi) (meth)acrylate copolymers obtained by polymerizing 60 to 80% by weight of ethyl acrylate and 40 to 20% by weight of methyl methacrylate; or vii) (Meth)acrylate copolymers obtained by polymerizing 5 to 15% by weight of methacrylic acid, 60 to 70% by weight of methyl acrylate, and 20 to 30% by weight of methyl methacrylate; or mixtures thereof. 3. The method according to item 1 or 2, wherein

[0160] 5. At least one polymer is i) a mixture, in a weight ratio of 10:1 to 1:10, of a (meth)acrylate copolymer obtained by copolymerizing 40 to 60% by weight of methacrylic acid and 60 to 40% by weight of ethyl acrylate, and a (meth)acrylate copolymer obtained by polymerizing 60 to 80% by weight of ethyl acrylate and 40 to 20% by weight of methyl methacrylate; or ii) mixtures of (meth)acrylate copolymers obtained by copolymerizing 5-15% by weight of methacrylic acid, 60-70% by weight of methyl acrylate and 20-30% by weight of methyl methacrylate in a weight ratio of 1:1 to 5:1 with (meth)acrylate copolymers obtained by copolymerizing 40-60% by weight of methacrylic acid and 60-40% by weight of ethyl acrylate. 3. The method according to item 1 or 2, wherein

[0161] 6. The method according to item 1 or 2, wherein the at least one polymer is selected from at least one anionic cellulose, ethyl cellulose, or starch containing at least 35% by weight of amylose.

[0162] 7. The method according to item 1 or 2, wherein the at least one polymer is selected from starch, alginate or a salt of alginate, sodium alginate, pectin, shellac, zein, carboxymethylzein, modified starch, marine sponge collagen, chitosan, gellan gum, ethylcellulose and pectin, modified starch and alginate and / or pectin, shellac and alginate and / or pectin, shellac and inulin, whey protein and gum, zein, sodium alginate and chitosan, or mixtures thereof.

[0163] 8. At least one glidant is i) at least one polymer a) is present in an amount of 3 to 75% by weight, based on the total weight of the polymer a), and / or ii) selected from silica, ground silica, fumed silica, kaolin calcium silicate, magnesium silicate, colloidal silicon dioxide, talc, stearates, sodium stearyl fumarate, starch, stearic acid, or mixtures thereof, preferably selected from talc, magnesium stearate, colloidal silicon dioxide, and glycerol monostearate, or mixtures thereof, more preferably selected from glycerol monostearate and talc; 8. The method according to any one of items 1 to 7.

[0164] 9. At least one emulsifier is i) at least one polymer a) is present in an amount of 1.5 to 40% by weight, based on the total weight of the polymer a), and / or ii) a non-ionic emulsifier, preferably a non-ionic emulsifier having an HLB greater than 10; 9. The method according to any one of items 1 to 8.

[0165] 10. At least one plasticizer is i) at least one polymer a) is present in an amount of 2 to 40% by weight, based on the total weight of the polymer a), and / or ii) alkyl citrates, alkyl phthalates, alkyl sebacates, polyethylene glycols, polypropylene glycols, or mixtures thereof, preferably selected from diethyl sebacate, triethyl citrate (TEC), acetyl triethyl citrate (ATEC), diethyl sebacate, dibutyl sebacate (DBS), polyethylene glycols, or mixtures thereof; 10. The method according to any one of items 1 to 9.

[0166] 11. The method according to any one of items 1 to 10, wherein the at least one additive is present in an amount of up to 400 wt.-%, preferably up to 200 wt.-%, more preferably up to 100 wt.-%, or up to 50 wt.-%, or up to 30 wt.-%, or up to 15 wt.-%, or up to 5 wt.-%, or up to 3 wt.-%, or up to 1 wt.-%, based on the total weight of the at least one polymer a), and is preferably selected from antioxidants, gloss agents, flavorings, flow aids, fragrances, penetration enhancers, pigments, polymers different from a), pore formers or stabilizers, or combinations thereof.

[0167] 12. The method of any one of items 1 to 11, wherein the body and the cap include a peripheral notch or dimple in the area where the cap overlaps the body that allows the capsule to be closed by a snap-in mechanism into place in either a pre-locked or final locked state.

[0168] 13. The method of any one of items 1 to 12, wherein the body includes a tapered rim.

[0169] 14. The coating layer is approximately 0.7 to 20 mg / cm 2 , preferably 2 to 10 mg / cm 2 , 4-8mg / cm 2 , 1.0-8mg / cm 2 , 1.5-5.5mg / cm 2 , or 1.5-4 mg / cm 2 14. The method according to any one of items 1 to 13, wherein

[0170] 15. The method according to any one of items 1 to 14, wherein the polymer-coated hard shell capsule in a pre-locked state is opened, filled with a fill containing a pharmaceutical or nutraceutical biologically active ingredient, and closed in a final-locked state.

[0171] 16. The method according to any one of items 1 to 15, wherein the polymer-coated hard shell capsules in a pre-locked state are fed to a capsule filling machine which performs opening, filling with a fill material comprising a pharmaceutical or nutraceutical biologically active ingredient, and closing to a final locked state.

[0172] 17. A polymer-coated hard shell capsule obtainable by the process according to any one of items 1 to 16.

[0173] 18. Use of a polymer coated hard shell capsule according to item 17 for immediate, delayed or sustained release, preferably delayed release, more preferably immediate, delayed or sustained release for intestinal delivery. EXAMPLES

[0174] Preparation of the Composition Example 1: Measuring the surface tension of a coating suspension In Example 1, the surface tension is measured for several coating suspensions, which are indicated in the respective tables (Tables 1 to 3) with "Invention" if the coating suspension is according to the invention, and with "Comparative" if the coating suspension is not according to the invention.

[0175] Principle of the test method (according to DIN EN 14370:2004) The free surface enthalpy per unit surface area is called surface tension. It is expressed in mN / m. These methods are based on measuring the maximum force that must be applied perpendicular to a plate in contact with the surface of the liquid to separate it from the surface. The method is applicable to aqueous solutions of most substances, regardless of their degree of purity.

[0176] The plate is suspended vertically from metal pins and wire mounting brackets, which establish connections to the force measurement system. The measurement vessel holding the test solution is a temperature-controlled glass vessel. It is designed so that the temperature of the test solution and the gas phase above its surface remains constant during the measurement, preventing sample evaporation.

[0177] Device: Tension meter: Kruess Processor Tensiometer K12(Kruess) Parameters: Temperature: 30℃ Heating time: 15 minutes

[0178] [Table 1]

[0179] [Table 2]

[0180] [Table 3]

[0181] Example 2: (Comparative) Enteric Coating of Prelocked Capsules in a Drum Coater The functional coat and top coat formulations were pre-locked at 594.5 mm. 2 and a batch size of 400,000 capsules (K-caps size 0).

[0182] Functional Coatings: EUDRAGIT® L 30 D-55 was provided as a 30 wt% aqueous polymer dispersion and was diluted with the calculated amount of water. The dispersion was gently stirred while the triethyl citrate was added. After 10 minutes, EUDRAGIT® NM 30D was slowly added under continuous stirring. The final coating suspension was sieved through a 400 μm sieve and stirred during the coating process. The capsules were coated in a pre-locked state utilizing a drum coater.

[0183] [Table 4]

[0184] Top Coating The METHOCEL™ was thoroughly dispersed in the water with gentle agitation to prevent clumping. The spray suspension was gently agitated during the coating process.

[0185] [Table 5]

[0186] Capsule Coating Process The capsules are coated in a fully perforated side-bend pan coating system Bohle BFC 400. The relevant process parameters are listed in Table 6.

[0187] [Table 6]

[0188] Bridging Tests: Capsules were tested for bridging between the body and the cap. The test was performed by holding the body and gently twisting the cap of the capsule. If the cap could not be twisted without damaging the capsule, hearing or feeling a crack, and if the cap could not be twisted at all, the capsule was broken and bridging was determined. 100 capsules were tested. According to the present invention, it is considered acceptable for less than 10% of the capsules in a batch to exhibit bridging.

[0189] result: 22.7% of the batches showed bridging at the end of the functional coating and 17.3–26.3% ( n = 5) at the end of the top coating process.

[0190] Example 3: (Comparative) Enteric Coating of Prelocked Capsules in a Drum Coater The functional coat and top coat formulations were pre-locked at 594.5 mm. 2 and a batch size of 200,000 capsules (K-caps size 0).

[0191] Functional Coatings: EUDRAGIT® L 30 D-55 was provided as a 30 wt% aqueous polymer dispersion and was diluted with the calculated amount of water. The dispersion was gently stirred while the triethyl citrate was added. After 10 minutes, EUDRAGIT® NM 30D was slowly added under continuous stirring. The final coating suspension was sieved through a 400 μm sieve and stirred during the coating process. The capsules were coated in a pre-locked state utilizing a drum coater.

[0192] [Table 7]

[0193] Top Coating The METHOCEL™ E3 product is a carbohydrate polymer that dissolves in cold water by swelling and subsequent hydration. The METHOCEL™ E3 was thoroughly dispersed in water with gentle agitation to prevent clumping. The spray suspension was gently agitated during the coating process.

[0194] [Table 8]

[0195] Capsule Coating Process The capsules are coated in a fully perforated side-bent pan coating system, Bohle BFC 200. The relevant process parameters are listed in Table 9.

[0196] [Table 9]

[0197] Bridging Tests: Capsules were tested for bridging between the body and the cap. The test was performed by holding the body and gently twisting the cap of the capsule. If the cap could not be twisted without damaging the capsule, hearing or feeling a crack, and if the cap could not be twisted at all, the capsule was broken and bridging was determined. 100 capsules were tested. According to the present invention, it is considered acceptable for less than 10% of the capsules in a batch to exhibit bridging.

[0198] result: After application of the functional coating and top coating process, more than 50% (n=5) of the batches showed bridging.

[0199] Example 4: (Comparative) Enteric Coating of Prelocked Capsules in a Drum Coater The functional coat compound is 594.5 mm in the pre-locked state. 2and a batch size of 30,000 capsules (K-caps size 0).

[0200] Functional Coatings EUDRAGIT® L 30 D-55 was provided as a 30 wt% aqueous polymer dispersion and was diluted with the calculated amount of water. The dispersion was gently stirred while the triethyl citrate was added. After 10 minutes, EUDRAGIT® NM 30D was slowly added under continuous stirring. The final coating suspension was sieved through a 400 μm sieve and stirred during the coating process. The capsules were coated in a pre-locked state utilizing a drum coater.

[0201] [Table 10]

[0202] Capsule Coating Process The capsules are coated in a fully perforated side-vent pan coating system, Glatt GMPC 2. The relevant process parameters are listed in Table 11.

[0203] [Table 11]

[0204] Bridging Tests: Capsules were tested for bridging between the body and the cap. The test was performed by holding the body and gently twisting the cap of the capsule. If the cap could not be twisted without damaging the capsule, hearing or feeling a crack, and if the cap could not be twisted at all, the capsule was broken and bridging was determined. 100 capsules were tested. According to the present invention, it is considered acceptable for less than 10% of the capsules in a batch to exhibit bridging.

[0205] result: This example results in 15 out of 100 requiring significant force to separate the cap and body of the capsule.

[0206] Example 5: (Invention) Enteric Coating of Prelocked Capsules in a Drum Coater The functional coat and top coat formulations were pre-locked at 594.5 mm. 2 and a batch size of 40,000 capsules (K-caps size 0).

[0207] Functional Coatings In the preparation of the GMS emulsion, 40% of the water was heated up to 70-80°C. The polysorbate 80 solution, triethyl citrate, and GMS were homogenized in the heated water for 10 minutes using a homogenizer (e.g., Ultra Turrax). The solid content was about 15%. The remaining 60% of the water was stirred into the hot GMS emulsion by using a conventional stirrer and cooled to room temperature with continuous stirring. The excipient suspension was then slowly poured into the EUDRAGIT® L 30 D-55 dispersion with gentle stirring with a conventional stirrer. After 10 minutes of gentle stirring, EUDRAGIT® NM 30 D was slowly added under continuous stirring and stirred for another 15 minutes. The final coating suspension was sieved through a 300 μm sieve and stirred during the coating process. The capsules were coated in a pre-locked state utilizing a drum coater.

[0208] [Table 12]

[0209] Top Coating METHOCEL™ VLV was completely dispersed in water with gentle stirring to prevent clumping. 40% of the water was heated up to 70-80°C. Polysorbate 80 solution, triethyl citrate, and GMS were homogenized in the heated water for 10 minutes using a homogenizer (e.g., Ultra Turrax). The solid content should be about 15%. The remaining 60% of the water was stirred into the hot GMS emulsion by using a conventional stirrer and cooled to room temperature with continuous stirring. Slowly pour the suspension into the METHOCEL™ VLV solution with gentle stirring with a conventional stirrer. Pass the spray suspension through a 0.3 mm sieve. The excipient suspension was added to the polymer dispersion. The spray suspension was gently stirred during the coating process.

[0210] [Table 13]

[0211] Capsule Coating Process The capsules are coated in a fully perforated side-bent pan coating system Bohle BFC 40. The relevant process parameters are listed in the table.

[0212] The equipment parameters were kept the same for the functional and top coatings.

[0213] [Table 14]

[0214] Bridging Tests: Capsules were tested for bridging between the body and the cap. The test was performed by holding the body and gently twisting the cap of the capsule. If the cap could not be twisted without damaging the capsule, hearing or feeling a crack, and if the cap could not be twisted at all, the capsule was broken and bridging was determined. 100 capsules were tested. According to the present invention, it is considered acceptable for less than 10% of the capsules in a batch to exhibit bridging.

[0215] result: This example results in 2 out of 100 requiring a large amount of force to separate the cap and body of the capsule.

[0216] Disintegration test (according to a modified method based on the European Pharmacopoeia 2.9.1 test B for gastro-resistant capsules) - unfilled capsules Method: 0.1N HCl for 2 hours followed by a complete change to a buffer system pH 6.8. Equipment: PTZ Auto 4 EZ Pharma Test Detection methods: visual and electrical impedance Temperature: 37.0℃ Medium I: 700 ml of 0.1N HCL according to the European Pharmacopoeia Medium II: 700 mL of phosphate buffer, pH 6.8 according to the European Pharmacopoeia Sample: n=6 [Table 15]

[0217] Dissolution test (according to the European Pharmacopoeia (2.9.3) Apparatus II) Capsules are manually filled: Polymer coated pre-locked capsules were manually filled with 500 mg of a 4:6 caffeine / lactose mixture, closed to a final lock state, and tested in a dissolution test.

[0218] method: Equipment: ERWEKA DT 700 paddle equipment (USPII) Detection method: Online UV Temperature: 37.5℃ Medium I: 700 ml of 0.1 N HCL adjusted to pH 1.2 (by using 2 N NaOH and 2 N HCl) Medium II: After 2 hours, add 214 ml of 0.2N Na 3 PO 4 Solutions are added to increase the pH to 6.8 (pH is fine-tuned by using 2N NaOH and 2N HCl). Paddle speed: 75 rpm [Table 16]

[0219] Example 6: (Invention) Enteric Coating of Prelocked Capsules in a Drum Coater The functional coat and top coat formulations were measured at 545.8 mm in pre-locked condition. 2 and a batch size of 30,000 capsules (V-caps plus size 0).

[0220] Functional Coatings In the preparation of the GMS emulsion, 40% of the water was heated up to 70-80°C. The polysorbate 80 solution, triethyl citrate, and GMS were homogenized in the heated water for 10 minutes using a homogenizer (e.g., Ultra Turrax). The solid content was about 15%. The remaining 60% of the water was stirred into the hot GMS emulsion by using a conventional stirrer and cooled to room temperature with continuous stirring. The excipient suspension was then slowly poured into the EUDRAGIT® L 30 D-55 dispersion under gentle stirring with a conventional stirrer. After 10 minutes of gentle stirring, EUDRAGIT® NM 30 D was slowly added under continuous stirring and stirred for another 15 minutes. The final coating suspension was sieved through a 400 μm sieve and stirred during the coating process.

[0221] [Table 17]

[0222] Capsule Coating Process The capsules are coated in a fully perforated side-bent pan coating system Bohle BFC 40. The relevant process parameters are listed in the table.

[0223] [Table 18]

[0224] Bridging Tests: Capsules were tested for bridging between the body and the cap. The test was performed by holding the body and gently twisting the cap of the capsule. If the cap could not be twisted without damaging the capsule, hearing or feeling a crack, and if the cap could not be twisted at all, the capsule was broken and bridging was determined. 100 capsules were tested. According to the present invention, it is considered acceptable for less than 10% of the capsules in a batch to exhibit bridging.

[0225] result: This example results in 2 out of 100 requiring a large amount of force to separate the cap and body of the capsule.

[0226] Example 7: (Invention) Enteric Coating of Prelocked Capsules in a Drum Coater The functional coat and top coat formulations were pre-locked at 594.5 mm. 2 and a batch size of 30,000 capsules (K-caps size 0).

[0227] Functional Coatings In the preparation of the GMS emulsion, 40% of the water was heated up to 70-80°C. The polysorbate 80 solution, triethyl citrate, and GMS were homogenized in the heated water for 10 minutes using a homogenizer (e.g., Ultra Turrax). The solid content was about 15%. The remaining 60% of the water was stirred into the hot GMS emulsion by using a conventional stirrer and cooled to room temperature with continuous stirring. The excipient suspension was then slowly poured into the EUDRAGIT® L 30 D-55 dispersion under gentle stirring with a conventional stirrer. After 10 minutes of gentle stirring, EUDRAGIT® NM 30 D was slowly added under continuous stirring and stirred for another 15 minutes. The final coating suspension was sieved through a 400 μm sieve and stirred during the coating process.

[0228] [Table 19]

[0229] Capsule Coating Process The capsules are coated in a fully perforated side-bent pan coating system Glatt GMPC 2. The relevant process parameters are listed in the table.

[0230] [Table 20]

[0231] Bridging Tests: Capsules were tested for bridging between the body and the cap. The test was performed by holding the body and gently twisting the cap of the capsule. If the cap could not be twisted without damaging the capsule, hearing or feeling a crack, and if the cap could not be twisted at all, the capsule was broken and bridging was determined. 100 capsules were tested. According to the present invention, it is considered acceptable for less than 10% of the capsules in a batch to exhibit bridging.

[0232] result: This example results in 1 in 100 requiring significant force to separate the cap and body of the capsule.

[0233] Example 8: (Invention) Enteric Coating of Prelocked Capsules in a Drum Coater The functional coat and top coat formulations were measured at 545.8 mm in pre-locked condition. 2 and a batch size of 200,000 capsules (Vcaps plus size 0).

[0234] Functional Coatings In the preparation of the GMS emulsion, 40% of the water was heated up to 70-80°C. The polysorbate 80 solution, triethyl citrate, and GMS were homogenized in the heated water for 10 minutes using a homogenizer (e.g., Ultra Turrax). The solid content was about 15%. The remaining 60% of the water was stirred into the hot GMS emulsion by using a conventional stirrer and cooled to room temperature with continuous stirring. The excipient suspension was then slowly poured into the EUDRAGIT® L 30 D-55 dispersion with gentle stirring with a conventional stirrer. After 10 minutes of gentle stirring, EUDRAGIT® NM 30 D was slowly added under continuous stirring and stirred for another 15 minutes. The final coating suspension was sieved through a 300 μm sieve and stirred during the coating process. The capsules were coated in a pre-locked state utilizing a drum coater.

[0235] [Table 21]

[0236] Top Coating METHOCEL™ VLV was completely dispersed in water with gentle stirring to prevent clumping. 40% of the water was heated up to 70-80°C. Polysorbate 80 solution, triethyl citrate, and GMS were homogenized in the heated water for 10 minutes using a homogenizer (e.g., Ultra Turrax). The solid content should be about 15%. The remaining 60% of the water was stirred into the hot GMS emulsion by using a conventional stirrer and cooled to room temperature with continuous stirring. Slowly pour the suspension into the METHOCEL™ VLV solution with gentle stirring with a conventional stirrer. Pass the spray suspension through a 0.3 mm sieve. The excipient suspension was added to the polymer dispersion. The spray suspension was gently stirred during the coating process.

[0237] [Table 22]

[0238] Capsule Coating Process The capsules are coated in a fully perforated side-bend pan coating system Bohle BFC 200. The relevant process parameters are listed in the table.

[0239] The equipment parameters were kept the same for the functional and top coatings.

[0240] [Table 23]

[0241] Bridging Tests: The capsules were tested for bridging between the body and the cap. The test was performed by holding the body and gently twisting the cap of the capsule. If the cap could not be twisted without damaging the capsule, hearing or feeling a crack, and if the cap could not be twisted at all, the capsule was broken and bridging was determined. 100 capsules were tested.

[0242] result: 4% of batches exhibited bridging at the end of the functional coating and 7–9% (n=3) at the end of the top coating process.

[0243] Disintegration test (following a modified method based on the European Pharmacopoeia 2.9.1 test B for gastro-resistant capsules) Sample preparation: Fill samples with 500 mg of lactose / caffeine (containing either 20 mg or 200 mg of caffeine) blend and record the capsule length (target 21.7 + 0.3 mm). Method: 2 hours in 0.1N HCl, followed by 30 minutes in phosphate buffer pH 5.5, followed by 1 hour in phosphate buffer pH 6.8. Detection methods: visual and electrical impedance Temperature: 37.0℃ Medium I: 700 ml of 0.1 N HCl according to the European Pharmacopoeia without discs Medium II: 700 mL of phosphate buffer pH 5.5 without discs Medium III: 700 mL of phosphate buffer pH 6.8 without discs Sample: n=6 Composition of phosphate buffer pH 5.5 (medium II): 2100 ml 0.1N HCl + 534 g 0.2M NaOH, adjusted to pH 5.50 (±0.05) with 2N HCl or 2N NaOH 3 PO 4 aqueous solution Composition of phosphate buffer pH 6.8 (medium III): 2100 ml 0.1N HCl + 684 g 0.2M NaOH, adjusted to pH 6.80 (±0.05) with 2N HCl or 2N NaOH 3 PO 4 aqueous solution [Table 24]

[0244] Example 9: (Invention) Enteric Coating of Prelocked Capsules in a Drum Coater The functional coat and top coat formulations were measured at 545.8 mm in pre-locked condition. 2 and a batch size of 40,000 capsules (Vcaps plus size 0).

[0245] Functional Coatings In the preparation of the GMS emulsion, 40% of the water was heated up to 70-80°C. The polysorbate 80 solution, triethyl citrate, and GMS were homogenized in the heated water for 10 minutes using a homogenizer (e.g., Ultra Turrax). The solid content was about 15%. The remaining 60% of the water was stirred into the hot GMS emulsion by using a conventional stirrer and cooled to room temperature with continuous stirring. The excipient suspension was then slowly poured into the EUDRAGIT® L 30 D-55 dispersion with gentle stirring with a conventional stirrer. After 10 minutes of gentle stirring, EUDRAGIT® NM 30 D was slowly added under continuous stirring and stirred for another 15 minutes. The final coating suspension was sieved through a 300 μm sieve and stirred during the coating process. The capsules were coated in a pre-locked state utilizing a drum coater.

[0246] [Table 25]

[0247] Top Coating METHOCEL™ VLV was completely dispersed in water with gentle stirring to prevent clumping. 40% of the water was heated up to 70-80°C. Polysorbate 80 solution, triethyl citrate, and GMS were homogenized in the heated water for 10 minutes using a homogenizer (e.g., Ultra Turrax). The solid content should be about 15%. The remaining 60% of the water was stirred into the hot GMS emulsion by using a conventional stirrer and cooled to room temperature with continuous stirring. Slowly pour the suspension into the METHOCEL™ VLV solution with gentle stirring with a conventional stirrer. Pass the spray suspension through a 0.3 mm sieve. The excipient suspension was added to the polymer dispersion. The spray suspension was gently stirred during the coating process.

[0248] [Table 26]

[0249] Capsule Coating Process The capsules are coated in a fully perforated side-bent pan coating system Bohle BFC 40. The relevant process parameters are listed in the table.

[0250] The equipment parameters were kept the same for the functional and top coatings.

[0251] [Table 27]

[0252] Bridging Tests: Capsules were tested for bridging between the body and the cap. The test was performed by holding the body and gently twisting the cap of the capsule. If the cap could not be twisted without damaging the capsule, hearing or feeling a crack, and if the cap could not be twisted at all, the capsule was broken and bridging was determined. 100 capsules were tested. According to the present invention, it is considered acceptable for less than 10% of the capsules in a batch to exhibit bridging.

[0253] result: 3% of the batches exhibited bridging at the end of the functional coating and 3% (n=3) at the end of the top coating process.

[0254] Disintegration test (following a modified method based on the European Pharmacopoeia 2.9.1 test B for gastro-resistant capsules) Sample preparation: Fill samples with 500 mg of lactose / caffeine (containing either 20 mg or 200 mg of caffeine) blend and record the capsule length (target 21.7 + 0.3 mm). Method: 2 hours in 0.1N HCl, followed by 30 minutes in phosphate buffer pH 5.5, followed by 1 hour in phosphate buffer pH 6.8. Detection methods: visual and electrical impedance Temperature: 37.0℃ Medium I: 700 ml of 0.1 N HCl according to the European Pharmacopoeia without discs Medium II: 700 mL of phosphate buffer pH 5.5 without discs Medium III: 700 mL of phosphate buffer pH 6.8 without discs Sample: n=6 Composition of phosphate buffer pH 5.5 (medium II): 2100 ml 0.1N HCl + 534 g 0.2M NaOH, adjusted to pH 5.50 (±0.05) with 2N HCl or 2N NaOH 3 PO 4 aqueous solution Composition of phosphate buffer pH 6.8 (medium III): 2100 ml 0.1N HCl + 684 g 0.2M NaOH, adjusted to pH 6.80 (±0.05) with 2N HCl or 2N NaOH 3 PO 4 aqueous solution [Table 28]

[0255] Dissolution test (according to the European Pharmacopoeia (2.9.3) Apparatus II) Capsules are manually filled: Polymer coated pre-locked capsules were manually filled with 500 mg of a 4:6 caffeine / lactose mixture, closed to a final lock state, and tested in a dissolution test.

[0256] method: Equipment: ERWEKA DT 700 paddle equipment (USPII) Detection method: Online UV Temperature: 37.5℃ Medium I: 700 ml of 0.1 N HCl according to the European Pharmacopoeia without discs Medium II: 700 mL of phosphate buffer pH 5.5 without discs Medium III: 700 mL of phosphate buffer pH 6.8 without discs Sample: n=6 Paddle speed: 75 rpm Composition of phosphate buffer pH 5.5 (medium II): 2100 ml 0.1N HCl + 534 g 0.2M NaOH, adjusted to pH 5.50 (±0.05) with 2N HCl or 2N NaOH 3 PO 4 aqueous solution Composition of phosphate buffer pH 6.8 (medium III): 2100 ml 0.1N HCl + 684 g 0.2M NaOH, adjusted to pH 6.80 (±0.05) with 2N HCl or 2N NaOH 3 PO 4 aqueous solution [Table 29]

[0257] Example 10 (comparison) according to WO 2020 / 229178: Enteric coating of standard EUDRAGIT® L 30D-55 coating with glycerol monostearate (GMS) on prelocked capsules, followed by topcoat of HPMC in a drum coater and automated capsule filling. The GMS emulsion was prepared by adding polysorbate 80 (33% solution), triethyl citrate, and GMS in hot water (70-80°C) with a high shear homogenizer for 10 minutes. The prepared GMS emulsion was cooled at room temperature and then added to the EUDRAGIT® polymer dispersion under overhead stirring. The spray suspension was gently stirred during the coating process. The capsules were coated in a prelocked state utilizing a drum coater. Topcoat: HPMC was dissolved in water with stirring and sprayed onto the coated capsules utilizing a drum coater.

[0258] [Table 30]

Claims

1. A method for preparing a polymer-coated hard shell capsule suitable as a container for a biologically active ingredient of a pharmaceutical or dietary supplement, wherein the hard shell capsule includes a body and a cap, in the closed state, the cap overlaps the body in either a preliminary locking state or a final locking state, providing the hard shell capsule in the preliminary locking state, a) at least one polymer; b) at least one flow promoter; c) at least one emulsifier; d) optionally at least one plasticizer; e) optionally at least one biologically active ingredient; and f) optionally at least one additive different from a) to e); coating with a coating solution, suspension or dispersion comprising or consisting of these to obtain the coated hard shell capsule in the preliminary locking state, wherein the coating solution, suspension or dispersion has a surface tension of at most 38 mN / m as measured according to DIN EN 14370:2004, method.

2. The method according to claim 1, wherein the base materials of the body and the cap are selected from hydroxypropyl methylcellulose, starch, gelatin, pullulan, and copolymers of C1-C4 alkyl esters of (meth)acrylic acid and (meth)acrylic acid.

3. The method according to claim 1 or 2, wherein the at least one polymer is selected from at least one (meth)acrylate copolymer.

4. The method according to claim 1 or 2, wherein the at least one polymer is selected from at least one anionic cellulose, ethyl cellulose, or starch containing at least 35% by weight amylose.

5. The at least one polymer is I. A core-shell polymer which is a copolymer obtained by a two-stage emulsion polymerization process having a core containing 70-80% by weight of polymerization units of 65-75% by weight of ethyl acrylate and 25-35% by weight of methyl methacrylate and a shell containing 20-30% by weight of polymerization units of 45-55% by weight of ethyl acrylate and 45-55% by weight of methacrylic acid; or II. An anionic polymer obtained by polymerizing 25 to 95% by weight of a C1-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 III. A cationic (meth)acrylate copolymer obtained by polymerizing a C1-C4 alkyl ester of acrylic acid or methacrylic acid and an alkyl ester of acrylic acid or methacrylic acid having a tertiary or quaternary ammonium group in the alkyl group; or iv) A (meth)acrylate copolymer obtained by polymerizing methacrylic acid and ethyl acrylate, or methacrylic acid and methyl methacrylate, or ethyl acrylate and methyl methacrylate, or methacrylic acid, methyl acrylate and methyl methacrylate; or v) A (meth)acrylate copolymer obtained by polymerizing 40 to 60% by weight of methacrylic acid and 60 to 40% by weight of ethyl acrylate; or vi) A (meth)acrylate copolymer obtained by polymerizing 60 to 80% by weight of ethyl acrylate and 40 to 20% by weight of methyl methacrylate; or vii) A (meth)acrylate copolymer obtained by polymerizing 5 to 15% by weight of methacrylic acid, 60 to 70% by weight of methyl acrylate and 20 to 30% by weight of methyl methacrylate; or a mixture thereof is the method according to claim 1 or 2.

6. wherein the at least one polymer is i) A mixture of a (meth)acrylate copolymer obtained by copolymerizing 40 to 60% by weight of methacrylic acid and 60 to 40% by weight of ethyl acrylate in a weight ratio of 10:1 to 1:10, and a (meth)acrylate copolymer obtained by polymerizing 60 to 80% by weight of ethyl acrylate and 40 to 20% by weight of methyl methacrylate; or ii) A mixture of a (meth)acrylate copolymer obtained by copolymerizing 5 to 15% by weight of methacrylic acid, 60 to 70% by weight of methyl acrylate and 20 to 30% by weight of methyl methacrylate at a weight ratio of 1:1 to 5:1, and a (meth)acrylate copolymer obtained by copolymerizing 40 to 60% by weight of methacrylic acid and 60 to 40% by weight of ethyl acrylate The method according to claim 1 or 2, which is as described above.

7. The at least one flow promoter is i) Present in an amount of 3 to 75% by weight based on the total weight of the at least one polymer a), and / or ii) Selected from silica, pulverized silica, fumed silica, calcium kaolin silicate, magnesium silicate, colloidal silicon dioxide, talc, stearates, sodium stearyl fumarate, starch, stearic acid, and glycerol monostearate, or a mixture thereof The method according to claim 1 or 2.

8. The at least one emulsifier is i) Present in an amount of 1.5 to 40% by weight based on the total weight of the at least one polymer a), and / or ii) A non-ionic emulsifier The method according to claim 1 or 2.

9. The at least one plasticizer is i) Present in an amount of 2 to 40% by weight based on the total weight of the at least one polymer a), and / or ii) Selected from alkyl citrates, alkyl phthalates, and alkyl sebacates, polyethylene glycol, propylene glycol, or a combination thereof The method according to claim 1 or 2.

10. The method according to claim 1 or 2, wherein at least one additive is included in an amount of up to 400% by weight based on the total weight of the at least one polymer a).

11. The method according to claim 1 or 2, wherein the body and the cap include peripheral notches or dimples in the region where the cap overlaps the body, enabling the capsule to be closed by a snap-in mechanism at a predetermined position in either the preliminary locked state or the final locked state.

12. The method according to claim 1 or 2, wherein the body includes a tapered rim.

13. Apply the coating layer in an amount of 0.7 to 20 mg / cm ２ The method according to claim 1 or 2.

14. A polymer-coated hard shell capsule obtained from the method according to claim 1 or 2.

15. Use of the polymer-coated hard shell capsules according to claim 14 for immediate release, delayed release, or sustained release.