Prefunctionalized hard shell capsules for enhanced drug release at pH values ​​between 5 and 5.5

Abstract

The present invention relates to a method for preparing a polymer-coated hard shell capsule, which comprises at least an intermediate coating layer, and an enteric coating layer, and optionally a top coating layer, and is suitable as a container for a biologically active ingredient of a medicine or a functional food, the hard shell capsule comprising a body and a cap, in a closed state, the cap overlaps with the body, either in a pre-locked state or in a final-locked state, the hard shell capsule being provided in a pre-locked state, comprising a first coating layer comprising or consisting of: a1) at least one polymer; b1) at least one alkaline agent; c1) optionally at least one lubricant; and d1) optionally at least one additive different from a1) to c1); with a coating solution, suspension, or dispersion to obtain an intermediate coating layer of the pre-locked hard shell capsule; and thereafter with a second coating solution, suspension, or dispersion different from the first coating solution, suspension, or dispersion, comprising or consisting of: a2) at least two polymers; b2) optionally at least one lubricant; c2) optionally at least one emulsifier; d2) optionally at least one plasticizer; e2) optionally at least one biologically active ingredient; and f2) optionally at least one additive different from a2) to e2), wherein the first polymer has a T of 35° C. or higher. gm and the second polymer is an anionic polymer having a T gm The total coating amount of the coating layer is 2.0 mg / cm 2 ~10mg / cm 2 Further, the present invention relates to a polymer coated hard shell capsule obtainable from the process according to the present invention and the use of the polymer coated hard shell capsule which provides less than 10% drug release over 120 minutes in 0.1 N hydrochloric acid, followed by at least 80% drug release within another 150 minutes at a pH value of 5.

Description

[Technical field]

[0001] The present invention relates to a method for preparing a polymer-coated hard shell capsule, which comprises at least an intermediate coating layer, and an enteric coating layer, and optionally a top coating layer, and is suitable as a container for a biologically active ingredient of a pharmaceutical or functional food, the hard shell capsule comprising a body and a cap, in a closed state, the cap overlaps with the body, either in a pre-locked state or in a final-locked state, the hard shell capsule being provided in a pre-locked state, a1) at least one polymer; b1) at least one alkaline agent; c1) optionally at least one lubricant; and d1) optionally at least one additive different from a1) to c1); to obtain a pre-locked hard shell capsule intermediate coating layer; and thereafter a2) at least two polymers; b2) optionally at least one lubricant; c2) optionally at least one emulsifier; d2) optionally at least one plasticizer; e2) optionally at least one biologically active ingredient; and f2) optionally at least one additive different from a2) to e2); to obtain an enteric coating layer of the pre-locked hard shell capsule, wherein the second coating solution, suspension, or dispersion is different from the first coating solution, suspension, or dispersion, and the second coating solution, suspension, or dispersion comprises or consists of: The first polymer has a T gm an anionic polymer having the formula: The second polymer has a T gm is a polymer having the formula: The total coating amount of the coating layer is 2.0 mg / cm 2~10mg / cm 2 That is, Further, the present invention relates to a polymer coated hard shell capsule obtainable from the method according to the present invention and its use to provide less than 10% drug release in 0.1 N hydrochloric acid over 120 minutes, followed by at least 80% drug release within another 150 minutes at a pH value of 5.

[0002] background A favorable location in the gastrointestinal tract for the release and absorption of biologically active ingredients is the duodenum. It is conceivable that biologically active ingredients can be provided as pellets or in capsules with a specific coating of one or more coating layers to achieve a targeted release, but this must be adapted to the requirements of the target, the pellet or capsule, and the biologically active ingredient.

[0003] Release of biologically active ingredients in the duodenum is important, for example, for the treatment of duodenal ulcers, but systemic drug absorption is also important, for example because the composition of the mucus layer changes and it becomes thicker (see below), and therefore early release in the duodenum is beneficial for the rapid absorption of drugs with poor bioavailability.

[0004] It was an object of the present invention to provide a system for pre-coated capsules which exhibits a targeted release in the duodenum, ie at a pH value of about 5, and which is preferably suitable for automatic capsule filling.

[0005] In the prior art coating systems, coating systems suitable for release at a pH value of about 5 are described, for example, in WO 2021 / 115648. The publication discloses that the proposed coating system is generally useful for capsules. However, examples and detailed disclosures are presented only for pellets. Looking at the publication, it can be seen that the coatings used in the examples and explicitly disclosed are not suitable for use with pre-coated capsules, and therefore the publication teaches otherwise than the present invention.

[0006] Surprisingly, the inventors of the present invention have found that in order to solve the above problems, a specific intermediate coating layer and an enteric coating layer are required for the pre-coated capsule.

[0007] Summary of the Invention In a first aspect, the present invention provides a method for preparing a polymer-coated hard shell capsule, comprising at least an intermediate coating layer, and an enteric coating layer, and optionally a top coating layer, suitable as a container for a biologically active ingredient of a pharmaceutical or functional food, the hard shell capsule comprising a body and a cap, in a closed state, the cap overlaps with the body, either in a pre-locked state or in a final-locked state, the hard shell capsule being provided in a pre-locked state, a1) at least one polymer; b1) at least one alkaline agent; c1) optionally at least one lubricant; and d1) optionally at least one additive different from a1) to c1); to obtain a pre-locked hard shell capsule intermediate coating layer; and thereafter a2) at least two polymers; b2) optionally at least one lubricant; c2) optionally at least one emulsifier; d2) optionally at least one plasticizer; e2) optionally at least one biologically active ingredient; and f2) optionally at least one additive different from a2) to e2); to obtain an enteric coating layer of the pre-locked hard shell capsule, The first polymer has a T of 35° C. or higher, preferably 35° C. to 155° C., more preferably 80° C. to 145° C., and most preferably 90° C. to 125° C. gm an anionic polymer having the formula: The second polymer has a T gm is a polymer having the formula: The total coating amount of the coating layer is 2.0 mg / cm 2 ~10mg / cm 2 That is, 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 sustained release, i.e. to provide less than 10% drug release over 120 minutes in 0.1 N hydrochloric acid, followed by at least 80% drug release within a further 150 minutes at a pH value of 5.

[0010] Detailed Description of the Invention Hard Shell Capsule Hard shell capsules for pharmaceutical or nutraceutical purposes are well known to those skilled in the art. Hard shell capsules are two-piece encapsulated capsules that include two capsule halves called the body and the 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 the cap are usually cylindrical with an open end and rounded hemispherical with a closed end on the opposite end. The shape and size of the cap and the body are such that the open end of the body can be pushed into the open end of the cap in a nested manner.

[0011] The body and cap include potentially overlapping matching regions (overlap regions) 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. The capsule is in the pre-locked state when the cap is partially slid over the overlapping matching region of the body. The capsule is in the final-locked state when the cap is fully slid over the overlapping matching region of the body. Maintenance of the pre-locked or final-locked state is typically supported by a snap-in locking mechanism on the body and cap, such as a matching surrounding notch or dimple, preferably an elongated dimple.

[0012] Typically, the body is longer than the cap. The outer overlapping area of ​​the body can be covered by the cap to close or lock the capsule. In the closed state, the cap covers the outer overlapping area 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 overlapping area of ​​the body, and in the pre-locked state, the cap only partially overlaps the outer overlapping area of ​​the body. The cap can be slid over the body to be fixed in one of two different positions that typically result in the capsule being closed in either the pre-locked state or the final-locked state.

[0013] Hard shell capsules are commercially available in a variety of sizes. They are usually delivered as empty containers with the body and cap already arranged in a pre-locked state, or sometimes as separate capsule halves, i.e. body and cap. The pre-locked hard shell capsules can be fed to a capsule filling machine, which opens, fills and closes the capsule to a final lock state. Typically, hard shell capsules are filled with dry materials, such as powders, or granules, or pellets, or mini-tablets, or sub-micron particles, or viscous liquids containing biologically active ingredients.

[0014] The cap and the body are provided with closure means which are advantageous for the (temporary) pre-locking and / or final locking of the capsule. Thus, the cap may have a raised point on its inner wall and a somewhat larger recessed point on its outer wall, arranged so that the raised point fits into the recessed point when the capsule is closed. Alternatively, a raised portion may be formed on the outer wall of the body and a recess on the inner wall of the cap. An arrangement is also possible in which the raised portion or recessed portion is arranged in a ring or spiral around the wall. Instead of a point-like arrangement of raised portions and recessed portions, a ring-like arrangement is also possible in which the raised portions and recessed portions extend over the entire circumference of the cap or body wall, but advantageously with recesses and openings allowing the exchange of gases into and out of the capsule interior. One or more raised portions may be arranged in a ring-like arrangement around the inner wall of the cap and around the outer wall of the body, so that in the final locked position of the capsule, a raised portion on the cap is adjacent to a raised portion on the body. The ridge may be formed near the open end of the outer body and the recess may be formed near the open end of the cap so that in the final locked position of the capsule, the ridge on the body latches into the recess on the cap. The ridge may allow the cap to be opened at any time in a pre-locked state without damaging the capsule or, once closed, to prevent the capsule from being reopened without being destroyed. Capsules having one or more such latching mechanisms (latches) (e.g. two grooves extending all around) are preferred. More preferred are capsules having at least two such latching means that secure the two capsule parts to different degrees. In this part, a first latching (dimple or notch extending all around) means may be formed near the opening of the capsule cap and capsule body, and a second latching (notch extending all around) may be shifted slightly further towards the closed end of the capsule part. The first latching means secures the two capsule parts with less strength than the second latching means.This variant has the advantage that after production of the empty capsule, the capsule cap and the capsule body can first be pre-locked together by means of the first latching mechanism. To fill the capsule, the two capsule parts are separated again. After filling, the two capsule parts are pressed together until the second set of latches secures the capsule parts firmly in the final locked state.

[0015] The body and cap of the hard shell capsule preferably each include a circumferentially extending notch and / or dimple in the area where the cap can be slid over the body. The circumferentially extending notch of the body and the dimple of the cap fit together to provide a snap-in or snap-fit ​​mechanism. The dimples may be circular or longitudinally elongated (oval). The circumferentially extending notch of the body and the circumferentially extending notch of the cap (closely fitting annulus) fit together to provide a snap-in or snap-fit ​​mechanism. This allows the capsule to be closed by a snap-fit ​​mechanism in either a pre-locked or final locked state.

[0016] Matching notches extending around the entire circumference of the body and elongated dimples on the cap are preferably used to secure the body and cap together in the pre-locked state. Matching notches extending around the entire circumference of the body and cap are preferably used to secure or lock the body and cap together in the final-locked state.

[0017] The area where the cap can slide over the body may be referred to as the overlapping area of ​​the body and the cap, or simply the overlapping area. If the cap overlaps with the body only partially, perhaps by 20%-90%, or even 60%-85% of the overlapping area, the hard shell capsule is only partially closed (pre-locked). In the presence of locking mechanisms, preferably matching, circumferentially extending notches and / or dimples in the body and cap, a partially closed capsule may be referred to as pre-locked. If the capsule is polymer-coated in the pre-locked state, the coating completely covers the exterior surface, including the portion of the overlapping area of ​​the body and the cap that is not covered 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 portion of the overlapping area of ​​the body and the cap that was not covered by the cap in the pre-locked state is then covered by the cap. The presence of the portion of the coating that is enclosed between the body and the cap in the final-locked state is then sufficient to seal the hard shell capsule.

[0018] The hard shell capsule is finally closed or finally locked when the cap covers the body and all overlapping areas of the body, preferably in the presence of locking mechanisms such as matching, circumferentially extending notches and / or dimples in the body and cap, and the finally closed capsule may be said to be finally locked.

[0019] Typically, a dimple is preferred for fixing the body and cap in the pre-locked state. As a non-binding rule, the matching area of ​​the dimple is smaller than the matching area of ​​a circumferentially extending notch. A dimple thus snapped in can be snapped out again by applying a force less than that required to snap out a fixation snapped in by matching a circumferentially extending notch.

[0020] The dimples of the body and cap are located in the area where the cap can slide over the body and fit together in a pre-locked state by a snap-in or snap-fit ​​mechanism. There can be, for example, 2, 4 or preferably 6 notches or dimples arranged in a circular distribution around the cap.

[0021] Typically, the dimples of the cap and the notches extending all around the body fit together in the area where the cap can slide over the body, so that they allow the capsule to be closed in a pre-locked state by a snap-fit ​​mechanism. In the pre-locked state, the hard shell capsule can be opened again without damage, either manually or mechanically, since the force required to open it is relatively small. Thus, the "pre-locked state" is sometimes also called "loosely capped".

[0022] Typically, notches extending all the way around the body and cap, or matching locking rings, fit together in the area where the cap can slide over the body, so that they allow the capsule to close in a final locked state by a snap-fit ​​mechanism, in which the hard shell capsule cannot or hardly can be reopened again without damage, either manually or mechanically, because the force required to open it is relatively large.

[0023] Typically, dimples and circumferentially extending notches are formed in the capsule body or the capsule cap such that when the capsule parts provided with these ridges and recesses are fitted together, an ideally defined uniform gap of 10 microns to 150 microns, more specifically 20 microns to 100 microns, is formed along the contact surface between the capsule body and the capsule cap placed thereon.

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

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

[0026] Hard Shell Capsule Size The total length of the closed and final locked hard shell capsule can range from about 5mm to 40mm. The diameter of the cap can range from about 1.3mm to 12mm. The diameter of the body can range from about 1.2mm to 11mm. The length of the cap can range from about 4mm to 20mm and the length of the body can range from 8mm to 30mm. The fill volume can be from about 0.004mL to 2mL. The difference between the length of the pre-locked state and the length of the final locked state can be from about 1mm to 5mm.

[0027] The capsules can be divided into standardized sizes, e.g., sizes 000 to 5. A closed capsule of size 000 has, for example, a total length of about 28 mm, an outer diameter of the cap of about 9.9 mm, and an outer diameter of the body of about 9.5 mm. The length of the cap is about 14 mm, and the length of the body of 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 an outer diameter of the cap of about 4.8 mm and an outer diameter of the body of about 4.6 mm. The length of the cap is about 5.6 mm and the length of the body is about 9.4 mm. The fill volume is about 0.13 mL.

[0029] A size 9 closed capsule, for example, has an overall length of about 8.4 mm and an outer diameter of the cap of about 2.7 mm. The fill volume is about 0.025 mL.

[0030] A size 0 capsule may exhibit a length of approximately 23 mm to 24 mm in the pre-locked state and a length of approximately 20.5 mm to 21.5 mm in the final locked state, so the difference in length between the pre-locked state and the final locked state may be approximately 2 mm to 3 mm.

[0031] Coated Hard Shell Capsules The present invention relates to polymer-coated hard shell capsules obtainable by the process described herein.

[0032] The described method is particularly useful for providing sealed polymer-coated hard shell capsules for pharmaceutical or nutraceutical dosage forms, with gastro-resistance and intended rapid release in the duodenum.

[0033] Body and Cap Materials The substrate 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.

[0034] Polymer or polymer blend contained in intermediate layer or enteric coating layer The following polymers are disclosed that are suitable for use as the at least one polymer in the intermediate layer or as one of the at least two polymers in the enteric coating layer. The at least one polymer in the intermediate coating layer can be any of the polymers listed below. The enteric coating layer requires a first polymer, which is stable to a T above 35°C, preferably between 35°C and 155°C, more preferably between 80°C and 145°C, and most preferably between 90°C and 125°C. gm and the second polymer has a T of 30° C. or less, preferably 20° C. or less, more preferably −10° C. to 20° C. gm Suitable anionic and neutral polymers are similarly described below. When applied to all polymers of both coating layers, expressions such as "polymer of / contained in a coating layer" are used.

[0035] The polymer contained in the coating layer is preferably a film-forming polymer.

[0036] The at least one polymer of the intermediate coating layer can be selected from the group of anionic polymers, cationic polymers, and neutral polymers, or any mixture thereof.

[0037] Selection of any general or specific polymer feature or embodiment disclosed herein can be combined with other general or specific selections, such as, without limitation, any material or numerical feature or embodiment disclosed herein, such as capsule material, capsule size, coating thickness, biologically active component, and any other feature or embodiment disclosed.

[0038] The coating layer may be a single layer or may comprise or consist of two or more individual layers, which may comprise in total 10% to 100% by weight, 20% to 95% by weight, 30% to 90% by weight of one or more polymers, preferably (meth)acrylate copolymers.

[0039] The monomer percentages mentioned for each polymer generally total 100% by weight.

[0040] The intermediate coating layer and the enteric coating layer are different from each other.

[0041] In a preferred embodiment, the further coating layer comprises a top coating layer.The top coating layer comprises at least one cationic polymer, or at least one neutral polymer, or any mixture thereof.In a preferred embodiment, the top coating layer is selected from at least one natural polymer or starch, preferably those described below, or hydroxypropylmethylcellulose, and most preferably hydroxypropylmethylcellulose.

[0042] Glass transition temperature T gm The glass transition temperature T gm is preferably measured by differential scanning calorimetry (DSC) according to ISO 11357-2:2013-05. The measurement is carried out at a heating rate of 20 K / min. The glass transition temperature T gm can also be determined by the half-step height method, as described in section 10.1.2 of DIN EN ISO 11357-2.

[0043] Anionic Polymers 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.

[0044] Anionic (Meth)Acrylate Copolymer The anionic (meth)acrylate copolymer preferably comprises 25% to 95% by weight, preferably 40% to 95% by weight, in particular 60% to 40% by weight of free-radically polymerized C1-C12 alkyl esters, preferably C1-C4 alkyl esters of acrylic acid or methacrylic acid, and 75% to 5% by weight, preferably 60% to 5% by weight, in particular 40% to 60% by weight of (meth)acrylate monomers having anionic groups. In general, the above proportions total 100% by weight. However, in addition to this, it is also possible to have small amounts of further monomers capable of vinylic copolymerization in the range of 0% to 10% by weight, for example 1% to 5% by weight, present without leading to a deterioration or modification of the essential properties, such as hydroxyethyl methacrylate or hydroxyethyl acrylate. It is preferred that no further further monomers capable of vinylic copolymerization 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. (Meth)acrylate monomers having an anionic group are, for example, acrylic acid, preferably methacrylic acid.

[0046] 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).

[0047] EUDRAGIT® L is a copolymer polymerized from 50% by weight of methyl methacrylate and 50% by weight of methacrylic acid. It can be said that the pH at which the release of certain active ingredients in intestinal or simulated intestinal fluid begins is about a pH value of 6.0.gm exceeds 125°C.

[0048] EUDRAGIT® L 100-55 is a copolymer polymerized from 50% by weight ethyl acrylate and 50% by weight methacrylic acid. EUDRAGIT® L 30 D-55 is a dispersion containing 30% by weight EUDRAGIT® L 100-55.

[0049] Likewise suitable are anionic (meth)acrylate copolymers polymerized from 20% to 40% by weight of methacrylic acid and 80% to 60% by weight of methyl methacrylate (EUDRAGIT® S type).The pH value at which the release of certain active ingredients in intestinal or simulated intestinal fluid begins can be stated to be around a pH value of 7.0.

[0050] A suitable (meth)acrylate copolymer is polymerized from 10% to 30% by weight of methyl methacrylate, 50% to 70% by weight of methyl acrylate, and 5% to 15% by weight of methacrylic acid (EUDRAGIT® FS type).

[0051] 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.

[0052] Suitable copolymers are 20% to 34% by weight of methacrylic acid and / or acrylic acid, 20% to 69% by weight of methyl acrylate, and 0% to 40% by weight of ethyl acrylate and / or optionally 0% to 10% by weight of further vinylically copolymerizable monomers provided that the glass transition temperature of the copolymer according to ISO 11357-2:2013-05, subsection 3.3.3, is not more than 60°C.

[0053] Suitable copolymers are 20 to 33% by weight of methacrylic acid and / or acrylic acid, 5% to 30% by weight of methyl acrylate, and 20% to 40% by weight of ethyl acrylate, and More than 10% to 30% by weight of butyl methacrylate, and optionally 0% to 10% by weight of further vinylically copolymerizable monomers where the proportion of monomers totals 100% by weight, and where the glass transition temperature of the copolymer according to ISO 11357-2:2013-05, subsection 3.3.3 (midpoint temperature, Tm,g) is between 55°C and 70°C.

[0054] The copolymers preferably consist of 90%, 95% or 99% to 100% by weight of the monomers, i.e. methacrylic acid, methyl acrylate, ethyl acrylate and butyl methacrylate in the amounts in the ranges indicated above. However, further monomers capable of vinylic copolymerization, such as methyl methacrylate, butyl acrylate, hydroxyethyl methacrylate, vinylpyrrolidone, vinyl-malonic acid, styrene, vinyl alcohol, vinyl acetate and / or their derivatives, can additionally be present in small amounts in the range of 0% to 10% by weight, for example in the range of 1% to 5% by weight, without necessarily leading to a deterioration of the essential properties.

[0055] 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 may be a copolymer from a two-stage emulsion polymerization process having 75% by weight of a core comprising 30% by weight of polymerized units of ethyl acrylate and 70% by weight of methyl methacrylate and 25% by weight of a shell comprising 50% by weight of ethyl acrylate and 50% by weight of methacrylic acid.

[0056] A suitable core-shell polymer may be a copolymer obtained by a two-stage emulsion polymerization process, having 70% to 80% by weight of a core containing 65% to 75% by weight of polymerized units of ethyl acrylate and 25% to 35% by weight of methyl methacrylate, and 20% to 30% by weight of a shell containing 45% to 55% by weight of ethyl acrylate and 45% to 55% by weight of polymerized units of methacrylic acid.

[0057] 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).

[0058] The coating layer preferably has a glass transition temperature T gm (measured by Differential Scanning Calorimetry (DSC) according to ISO 11357-2:2013-05)) and the coating layer preferably has a molecular weight of about 1 mg / cm 2 ~5.8mg / cm 2More preferably, in an amount of 2 mg / cm 2 ~5mg / cm 2 is present in an amount of

[0059] The coating layer may comprise a total of 10% to 100%, 20% to 95%, 30% to 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.

[0060] Glass transition temperature T of hydroxypropyl methylcellulose phthalate gm is approximately 132°C to 138°C (HP-55 type: approximately 133°C, HP-50 type: approximately 137°C).

[0061] Glass transition temperature T of hydroxypropyl methylcellulose acetate succinate (HPMCAS) gm is about 120°C (AquaSolve™ L HPMCAS: 119°C, AquaSolve™ M HPMCAS: 120°C, AquaSolve™ H HPMCAS: 122°C).

[0062] Anionic Vinyl Copolymer The anionic vinyl copolymer may be selected from unsaturated carboxylic acids other than acrylic or methacrylic acid and is exemplified by polyvinyl acetate phthalate, or a copolymer of vinyl acetate and crotonic acid, preferably in a 9:1 ratio.

[0063] Cationic Polymer Suitable cationic (meth)acrylate copolymers contained 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 with tertiary or quaternary ammonium groups in the alkyl group. Water-soluble cationic (meth)acrylate copolymers can be partially or fully polymerized from alkyl acrylates and / or alkyl methacrylates with tertiary amino groups in the alkyl group. Coatings including these types of polymers can have the advantage of providing moisture protection to the hard shell capsule. Moisture protection should be understood to mean that the uptake of moisture or water is reduced during storage of the filled and finally locked capsules ready for use.

[0064] Suitable cationic (meth)acrylate copolymers can be polymerized from 30% to 80% by weight of C1-C4-alkyl esters of acrylic or methacrylic acid and 70% to 20% by weight of alkyl (meth)acrylate monomers having a tertiary amino group in the alkyl group.

[0065] 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).

[0066] A particularly suitable commercially available (meth)acrylate copolymer having tertiary amino groups is polymerized from 25% by weight of methyl methacrylate, 25% by weight of butyl methacrylate, and 50% by weight of dimethylaminoethyl methacrylate (EUDRAGIT® E 100 or EUDRAGIT® E PO (powder form)). EUDRAGIT® E 100 and EUDRAGIT® E PO are water-soluble at pH values ​​below about 5.0 and are therefore also soluble in gastric juices.

[0067] A suitable (meth)acrylate copolymer may be composed of 85% to 98% by weight of a free-radically polymerized C1-C4 alkyl ester of acrylic or methacrylic acid and 15% to 2% by weight of a (meth)acrylate monomer having a quaternary amino group in the alkyl group.

[0068] Preferred C1-C4-alkyl esters of acrylic or methacrylic acid are methyl acrylate, ethyl acrylate, butyl acrylate, butyl methacrylate, and methyl methacrylate.

[0069] Further suitable cationic (meth)acrylate polymers may include polymerized monomer units of 2-trimethylammonium ethyl methacrylate chloride, or trimethylammonium propyl methacrylate chloride.

[0070] A suitable copolymer can be polymerized from 50% to 70% by weight of methyl methacrylate, 20% to 40% by weight of ethyl acrylate, and 7% to 2% by weight of 2-trimethylammonium ethyl methacrylate chloride.

[0071] 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).

[0072] 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 7% to 15% by weight of (meth)acrylate monomers having quaternary amino groups in the alkyl group. Such (meth)acrylate monomers are commercially available and have been used in sustained release coatings for a long time.

[0073] 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).

[0074] 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, of monomers having ionic groups, or most preferably a polymer polymerized without any monomers containing ionic groups.

[0075] 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, such as hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl acetate, or polyvinyl alcohol.

[0076] Often, neutral methacrylate copolymers are useful in mixtures with anionic (meth)acrylate copolymers.

[0077] The neutral methacrylate copolymers are polymerized 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, of (meth)acrylate monomers having neutral groups, in particular C1-C4 alkyl groups.

[0078] Suitable (meth)acrylate monomers with neutral groups are, for example, methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate, butyl acrylate. Methyl methacrylate, ethyl acrylate and methyl acrylate are preferred.

[0079] Methacrylate monomers having anionic groups, such as acrylic acid and / or methacrylic acid, may be present in small amounts, less than 5% by weight, preferably 2% or less, more preferably 1% or less, or even 0.05% to 1% by weight.

[0080] A suitable example is a neutral or substantially neutral (meth)acrylate copolymer polymerized from 20% to 40% by weight of ethyl acrylate, 60% to 80% by weight of methyl methacrylate, and 0% to less than 5% by weight, preferably 0% to 2% by weight, or 0.05% to 1% by weight, of methacrylic acid or acrylic acid.

[0081] A suitable example is a neutral or substantially neutral (meth)acrylate copolymer (EUDRAGIT® NE or EUDRAGIT® NM type) polymerized from 20% to 40% by weight methyl methacrylate, 60% to 80% by weight ethyl acrylate, and 0% to less than 5% by weight, preferably 0% to 2% or 0.05% to 1% by weight, of methacrylic acid or acrylic acid.

[0082] EUDRAGIT® NE and EUDRAGIT® NM are copolymers containing free radically polymerized units of 28% to 32% by weight methyl methacrylate and 68% to 72% by weight ethyl acrylate.

[0083] Preference is given to neutral or substantially neutral methyl acrylate copolymers prepared as dispersions with 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 associated with the formation of crystalline structures by the emulsifier (EUDRAGIT® NM type).

[0084] However, according to EP 1 571 164 A1, corresponding substantially neutral (meth)acrylate copolymers having small proportions of monoolefinically unsaturated C3-C8 carboxylic acids, of 0.05% to 1% by weight, can also be prepared by emulsion polymerization in the presence of relatively small amounts, for example 0.001% to 1% by weight, of anionic emulsifiers.

[0085] Natural Polymers Particularly for functional food dosage forms, so-called "natural polymer" coatings are preferred by many customers. Natural polymers are based on natural, vegetable, microbial or animal sources, but in some cases are further chemically processed. Natural polymers for coatings can be selected from starch, alginates or alginate salts, preferably sodium alginate, pectin, shellac, zein, carboxymethylzein, modified starches such as EUDRAGUARD® Natural, marine marine collagen, chitosan, gellan gum, and other polymers. Suitable polymer mixtures can include ethylcellulose and pectin, modified starch (EUDRAGUARD® Natural) and alginate and / or pectin, shellac and alginate and / or pectin, shellac and inulin, whey protein and gum (such as guar gum or tragacanth gum), zein and polyethylene glycol, sodium alginate and chitosan.

[0086] Ethyl cellulose is a derivative of cellulose in which some of the hydroxyl groups of the glucose repeating units are converted to ethyl ether groups. Ethyl cellulose can be used as a sustained release coating material for the disclosed capsules. The glass transition temperature T gm can be in the range of about 128-130° C. (Hui Ling Lai, et al., Int. JP pharmaceuticals 386 (2010) 178-184).

[0087] Further ingredients that may be present in the enteric coating or top coating are described below.

[0088] Unless otherwise specified, the components are generally suitable for use in both coating layers, and unless otherwise specified, the amount of each component is given with reference to the total weight of the at least one polymer included in each coating layer.

[0089] Lubricants The lubricant is usually lipophilic and prevents the core from agglomerating during the formation of the film-forming polymer.

[0090] The at least one lubricant is preferably selected from silica, ground silica, fumed silica, calcium kaolin silicate, magnesium silicate, colloidal silicon dioxide, talc, calcium stearate, magnesium stearate, zinc stearate, sodium stearyl fumarate, starch, stearates such as stearic acid, preferably talc, magnesium stearate, colloidal silicon dioxide, and glycerol monostearate, or mixtures thereof, more preferably glycerol monostearate and talc, or mixtures thereof, as are commercially available, for example, under the trade name RXCIPIENTS® GL100 or RXCIPIENTS® GL200.

[0091] The typical proportion of the lubricant used in the coating layer ranges from 0.5% to 100% by weight, preferably from 3% to 75% by weight, more preferably from 5% to 50% by weight, and most preferably from 5% to 30% by weight, based on the total weight of the at least one polymer.

[0092] emulsifier Generally, all known emulsifiers are suitable. Non-ionic emulsifiers are preferred, especially those with an HLB greater than 10, or greater than 12. The HLB value can be determined according to Griffin, William C. (1954), “Calculation of HLB Values ​​of Non-Ionic Surfactants” (PDF), Journal of the Society of Cosmetic Chemists, 5 (4): 249-56.

[0093] 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, sodium dioctyl sulfosuccinate, polysorbates (e.g., polyoxyethylene (20) sorbitan monooleate), nonylphenol ethoxylates (nonoxynol-9) and mixtures thereof.

[0094] 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), sucrose, glyceryl stearate, poly ... Polyethylene glycol-6 stearate, glycol stearate, polyethylene glycol-32 stearate, polyethylene glycol-20 stearate, fatty alcohol polyglycol ethers, polyethylene glycol-4 laurate, polyethylene glycol isocetyl ether (n=20), polyethylene glycol-32 (Mw1500g / mol), mono- and diesters of lauric acid (C12), nonaethylene glycol, polyethylene glycol nonylphenyl ether, octaethylene glycol monododecyl ether, pentaethylene glycol monododecyl ether, polyethylene glycol macrocetyl ether, polyethylene glycol esters of palmitic acid (C16) or stearic acid (C18) or caprylic acid, BRIJ Polyoxyethylene 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, polyricinoleic acid, polysorbates such as sorbate 20 and polyoxyethylene (20) sorbitan monooleate (polysorbate 80), sorbitan, sorbitan monolaurate,Sucrose Cocoate, Glycereth-2 Cocoate, Ethylhexyl Cocoate, Polypropylene Glycol-3 Benzyl Ether Myristate, Sodium Myristate, Sodium Gold Thiomalate, Polyethylene Glycol-8 Laurate, Polyethylene-4 Dilaurate, α-Hexadecyl-ω-Hydroxypolyol (oxyethylene), Cocamide Diethanolamine, N-(2-Hydroxyethyl)dodecanamide, Octylphenoxypolyether Toxicethanol, 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-68), and poloxamer 407, propylene glycol monocaprylate, Licorice, Capryol PGMC (Type I), 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, Cetyl Phosphate DEA, Soy Lecithin, Sphingomyelin, Sodium Phosphate, Sodium Lauroyl Lactylate, Lanolin, Oxirane Methyl Polymer with Oxirane Monobutyl Ether, 1,2-Diercoyl Phosphatitylcholine, Dimethicone endcapped with an average of 14 moles of Propylene Oxide,Lauryl methicone copolyol, lauroglycol 90, white mineral oil such as Amphocerine KS, dispersion of acrylamide / sodium acryloyldimethyltaurate copolymer in isohexadecane, and sodium polyacrylate or mixtures thereof. Macrogol stearyl ether (20) and polysorbate 80 are preferred.

[0095] In one embodiment, less than 3% by weight, preferably 1.5% by weight, of at least one emulsifier is present, or substantially no or no emulsifier, based on the total weight of the at least one polymer.

[0096] Enteric Coating or Top Coating Layer The enteric coating layer or top coating layer can comprise 10% or more, 20% or more, 30% or more, 40% or more, 50% or more, 60% or more, 70% or more, 80% or more, 90% or more, or 95% or more by weight of polymer. The coating layer can comprise 10%-100%, 10%-90%, 12%-80%, 15%-80%, 18%-80%, 20%-80%, or 40%-80% by weight of polymer.

[0097] The topcoat layer is located on the enteric coating layer and comprises at least one polymer as described above. The topcoat is also preferably water-soluble or substantially water-soluble. The topcoat can have the function of coloring the pharmaceutical or nutraceutical dosage form or protecting it from environmental influences, such as moisture during storage.

[0098] Intermediate Coating Layer The intermediate coating layer is located on or above the capsule and comprises at least one polymer and at least one alkaline agent.

[0099] The intermediate coating layer may contain 5% to 90% by weight, preferably 10% to 70% by weight, more preferably 30% to 50% by weight of at least one polymer, based on the total weight of the intermediate coating layer. The at least one polymer is preferably selected from hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxyethyl methylcellulose (HEMC), ethyl cellulose (EC), methyl cellulose (MC), cellulose esters, cellulose such as cellulose glycolic acid, polyethylene glycol, polyethylene oxide, polyvinylpyrrolidone, polyvinyl acetate, polyvinyl alcohol or mixtures thereof, preferably hydroxypropyl methylcellulose.

[0100] The intermediate coating layer may contain 10% to 75% by weight, preferably 10% to 50% by weight, of the alkaline agent based on the total weight of the coating layer.

[0101] The alkaline agent may be an alkali metal salt or an alkaline earth metal salt. The alkaline agent may be selected from calcium oxide, calcium carbonate, magnesium carbonate, magnesium oxide, sodium carbonate, sodium bicarbonate, and sodium hydroxide, or any mixture thereof. The preferred alkaline agent is magnesium oxide and / or magnesium carbonate.

[0102] The intermediate coating layer preferably comprises at least one lubricant in an amount of 2% to 50% by weight, more preferably 5% to 25% by weight, based on the total weight of the intermediate coating layer. Suitable lubricants are the same as those described for the enteric coating layer herein. Preferably, the at least one lubricant is glycerol.

[0103] The intermediate layer may contain 1% to 95% by weight, preferably 10% to 50% by weight, based on the total weight of the intermediate layer, of at least one additive, such as a polymer binder, a plasticizer, or an anti-blocking agent, or a combination thereof. Suitable additives are the same as those described for the enteric coating layer.

[0104] The intermediate layer is preferably disposed directly on the capsule.

[0105] Amount and thickness of enteric and intermediate coating layers The total coating amount is 2.0mg / cm to ensure the processability and to prevent leakage into the final capsule in industrial filling machines. 2 ~10mg / cm 2 It was found that this was not necessary.

[0106] For size #0 hard shell capsules, the amount of coating layer should not be too high. If too much coating layer is applied, it may be difficult to subsequently process the prelocked polymer coated hard shell capsules in the capsule filling machine. A coating layer amount of 5 mg / cm 2 Less than 2 mg / cm 2 ~4mg / cm 2 In the case of 4 mg / cm, there is usually no problem if standard capsule filling machines are used without modification. 2 ~about 8mg / cm 2 In the range of 1000 to 2000 mm, 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 made by a mechanical engineer. Therefore, the capsule filling machine can be used only when the amount of the coating layer is about 3 mg / cm2. 2 ~about 8mg / cm 2 can be advantageously used within the range.

[0107] For size #1 hard shell capsules, the amount of coating layer should not be too high. If too much coating layer is applied, it may be difficult to subsequently process the prelocked polymer coated hard shell capsules in the capsule filling machine. A coating layer amount of 4 mg / cm 2 Less than 2-3.5mg / cm 2 In the case of 3.5 mg / cm, there are usually no problems in using standard capsule filling machines without modification. 2 ~about 8mg / cm 2 In the range of 1000 to 2000 mm, 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 made by a mechanical engineer. Therefore, the capsule filling machine can be used only when the amount of the coating layer is about 3 mg / cm2. 2 ~about 8mg / cm 2 can be advantageously used within the range.

[0108] For size #3 hard shell capsules, the amount of coating layer should not be too high. If too much coating layer is applied, it may be difficult to subsequently process the prelocked polymer coated hard shell capsules in the capsule filling machine. 2 ~about 6mg / cm 2 In the range of 1000 to 2000 mm, 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 made by a mechanical engineer. Therefore, the capsule filling machine can be used only when the amount of the coating layer is about 3 mg / cm2. 2 ~about 6mg / cm 2 can be advantageously used within the range.

[0109] If too much coating layer is applied, excess coating layer will also collect at the edge of the cap where the gap between the body and the cap is in pre-locked state. This may occur after drying in cracks in the coating layer when the pre-locked polymer-coated hard shell capsule is opened manually or mechanically. The cracks may lead to subsequent leakage from the capsule. Finally, if the coating is too thick, it may be difficult or impossible to close the opened coated hard shell capsule to the final lock state, since the coating layer is thicker than the gap in the overlapping area between the body and the cap.

[0110] As a rough rule of thumb, the coating layer on a hard shell capsule should be 0.7 mg / cm 2 ~20mg / cm 2 , 1.0 mg / cm 2 ~18mg / cm 2 , 2 mg / cm 2 ~10mg / cm 2 , 4 mg / cm 2 ~8mg / cm 2 , 1.0 mg / cm 2 ~8mg / cm 2 , 1.5 mg / cm 2 ~5.5mg / cm 2 , 1.5 mg / cm 2 ~4mg / cm 2 (=total weight gain).

[0111] As a rough rule, the coating layer on the hard shell capsule may have an average thickness of about 5 μm to 100 μm, 10 μm to 50 μm, 15 μm to 75 μm.

[0112] As a rough rule, the coating layer on the hard shell capsule may be applied in an amount of 5% to 50% by dry weight, preferably 8% to 40% by dry weight, based on the weight of the prelocked capsule.

[0113] Following this guidance, one skilled in the art would be able to adjust the amount of coating layer to a range between too little and too much.

[0114] Biologically Active Ingredients The biologically active ingredient is preferably a pharmaceutical active ingredient and / or a functional food active ingredient and / or a cosmetic active ingredient.Even if a given biologically active ingredient may be contained in each coating layer, it is preferred that the biologically active ingredient is contained in the filling.In particular, when the biologically active ingredient is contained in liposomes, lipid nanoparticles or nucleic acids, the biologically active ingredient is only contained in the filling.

[0115] Active pharmaceutical ingredients or functional food ingredients The present invention is particularly useful for sustained release formulated pharmaceutical or functional food dosage forms loaded with pharmaceutical or functional food active ingredients.

[0116] Suitable therapeutic and chemical classes of pharmaceutical active ingredients that can be used as fillers in the polymer-coated hard shell capsules described herein are, for example, analgesics, antibiotics or anti-infectives, antibodies, antiepileptics, plant-derived antigens, antirheumatics, benzimidazole derivatives, beta blockers, cardiovascular drugs, chemotherapeutic drugs, CNS drugs, digitalis glycosides, gastrointestinal drugs, such as proton pump inhibitors, enzymes, hormones, liquid or solid natural extracts, oligonucleotides, peptides, hormones, proteins, therapeutic bacteria, peptides, protein (metal) salts, i.e. aspartates, chlorides, urological drugs, lipid nanoparticles, liposomes, polymeric nanoparticles, vaccines. Preferred embodiments include at least one liposome or lipid nanoparticle, each of which contains at least one polynucleotide.

[0117] In a preferred embodiment, the pharma- ceutical active ingredient is a lipid nanoparticle or liposome containing a polynucleotide or a nucleic acid, respectively, 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 nucleic acid sequences, bacterial nucleic acid sequences, or fungal nucleic acid sequences). In some embodiments, the nucleic acid agent may be a plasmid, a cosmid, a gene fragment, an artificial chromosome and / or a natural chromosome (e.g., yeast artificial chromosome), and / or a part 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-inducing agent, 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, including synthetic analogs of nucleic acids, which may or may not be modified. In some embodiments, the nucleic acid agent may include various structural forms of DNA, including single-stranded DNA, double-stranded DNA, DNA supercoils, and / or DNA triplexes; Z-DNA, and / or combinations thereof. Further suitable nucleic acids are disclosed, for example, in WO 2012 / 103035, which are incorporated by reference.

[0118] Further examples of drugs that can be used as fill materials for the polymer coated hard shell capsules described herein include, for example, acamprosate, aescin, amylase, acetylsalicylic acid, adrenaline, 5-aminosalicylic acid, auremycin, bacitracin, balsalazine, beta carotene, bicarotamide, bisacodyl, bromelain, budesonide, calcitonin, carbamacipine, carboplatin, cephalosporins, cetrorelix, clarithromycin, chloromycin, cimetidine, cisapride, cladribine, clorazepate, cromolyn, 1-deaminocysteine, 1-aminosalicylic acid ... In-8-D-arginine-vasopressin, deramciclane, 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, leuprolide acetate, lipase, lipoic acid, lithium, quinine, memantine, mesalazine, methenamine, miramerin, minerals, minoprazole, naproxen, natamycin, nitrofurantoin, novobiocin, olsalazine, omeprazole, orotate, pancreatin, pantoprazole, parathyroid hormone, paroxetine, penicillin, perprazole, pindolol, polymyxin, potassium, pravastatin, prednisone, prednisone Glumetacin progabide, 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 and isomorphs, acetaminophen, codeine, griseofulvin, isosorbide-5 mononitrate, lumiracoxib,Metoprolol, minoxidil, nefazodone, phenytoin, remogliflozin etabonate, rivastigmine, theophylline, colchicine, darunavir, nifedipine, valacyclovir, mizoribine, ribavirin, antipyrine, glipidine, phenytoin, selegiline, theopirin, cilostazol, cimetidine, darunavir, digoxin, famotidine, fexofenadine, forskolin, indina vir, nevirapine, quinidine, ranitidine, tacrolimus, talinolol, verapamil, benazepril, cefadroxil, cephalexin, atenolol, ciproxacin, fluvastatin, metformin, levodopa, gabardine, pseudoephedrine, ropivacaine, sotalol, azacitidine, and decitabine, or mixtures or combinations thereof, preferably with acetaminophen, codeine, griseo Fulvin, isosorbide-5 mononitrate, lumiracoxib, metoprolol, minoxidil, nefazodone, phenytoin, remogliflozin etabonate, rivastigmine, theophylline, colchicine, darunavir, nifedipine, valacyclovir, mizoribine, ribavirin, antipyrine, glipidine, phenytoin, selegiline, theopirin, cilostazol, cimetidine, darunavir, digoxin, famotidine, fulvin Exofenadine, forskolin, indinavir, nevirapine, quinidine, ranitidine, tacrolimus, talinolol, verapamil, benazepril, cefadroxil, cephalexin, atenolol, ciproxacin, fluvastatin, metformin, levodopa, gapabentine, pseudoephedrine, ropivacaine, sotalol, azacitidine, and decitabine, or mixtures or combinations thereof.

[0119] It is clear to those skilled in the art that the terms active ingredient, excipient and composition of pharmaceuticals and functional foods overlap widely with pharmaceutical dosage forms or functional food dosage forms, respectively. Many substances listed as functional foods can also be used as active ingredients of pharmaceuticals. Depending on the specific application and local government laws and classifications, the same substance can be listed as active ingredient of pharmaceuticals or functional foods, pharmaceutical composition or functional food composition, or both, respectively.

[0120] Functional foods are well known to those skilled in the art. In many cases, functional foods are defined as food extracts that are claimed to have medical effects on human health. Thus, the active ingredients of functional foods may also exhibit pharmaceutical efficacy: examples of functional food active ingredients can be resveratrol from grape products as an antioxidant, soluble dietary fiber products such as psyllium seed husks to reduce hypercholesterolemia, broccoli (sulfane) as a cancer preventive agent, and soybean or clover (isoflavonoids) to improve arterial health. Thus, it is clear that many substances listed as functional foods can also be used as pharmaceutical active ingredients.

[0121] Representative functional foods or functional food active ingredients that can be used as the fill of the polymer-coated hard shell capsules described herein can also include probiotics and prebiotics. Probiotics are live microorganisms that are believed to support human or animal health when consumed. Prebiotics are functional foods or functional food active ingredients that induce or promote the growth or activity of beneficial microorganisms in the human or animal intestine.

[0122] Examples of functional foods 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 functional foods are flavonoids, antioxidants, alpha-linolenic acid from flaxseed, beta-carotene from marigold petals or anthocyanins from berries. Sometimes the terms neutraceutical or nutriceutical are used as synonyms for functional foods (nutraceutical).

[0123] Preferred biologically active ingredients are azacitidine, decitabine, metoprolol, mesalamine, and omeprazole.

[0124] Additives The additive according to the present invention is preferably an excipient. Excipients are well known to those skilled in the art and are often combined with the biologically active ingredients contained in the coated hard shell capsule and / or the polymeric coating layer of the hard shell capsule disclosed and claimed herein. All excipients used must be toxicologically safe and must be used in the drug or functional food without risk to the patient or consumer.

[0125] The dosage form may include an excipient, preferably a medicament or nutraceutical acceptable excipient selected from the group of antioxidants, brighteners, binders, flavorings, flow aids, fragrances, permeation enhancers, pigments, pore formers, stabilizers, or combinations thereof. The medicament or nutraceutical acceptable excipient may be included in the core and / or coating layer comprising the disclosed polymer. The medicament or nutraceutical acceptable excipient is an excipient that can be used for applications in the pharmaceutical or nutraceutical fields.

[0126] The intermediate coating layer, the enteric coating layer, or the top 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, or no additives (0%), which are preferably pharmaceutical or functional food acceptable excipients, based on the total weight of the at least one polymer.

[0127] Plasticizer The polymer coating of the hard shell capsule may contain one or more plasticizers, which, through physical interaction with the polymer, achieve a lowering of the glass transition temperature and promote film formation, depending on the amount added. Suitable substances usually have a molecular weight of 90 g / mol to 20,000 g / mol and contain one or more hydrophilic groups in the molecule, such as hydroxyl, ester or amino groups.

[0128] 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.

[0129] The addition of the plasticizer to the formulation can be done by known methods, either directly in aqueous solution or after thermal pretreatment of the mixture. A mixture of plasticizers may be used. The polymer coating of the hard shell capsule can contain one or more plasticizers, preferably 60% or less by weight, 30% or less by weight, 25% or less by weight, 20% or less by weight, 15% or less by weight, 10% or less by weight, 5% or less by weight, or less than 5% by weight, or no plasticizer (0%), calculated on the basis of at least one polymer.

[0130] Filler Standard fillers are usually added to the formulations of the present invention during processing into coatings and binders. The loading amount and use of standard fillers on pharmaceutical coatings or layers 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. Fillers are used as processing aids, intended to ensure reliable and reproducible manufacturing methods and good long-term storage stability, or fillers achieve further advantageous properties in the pharmaceutical dosage form. Fillers can be added to polymer formulations before processing to affect the permeability of the coating. This property can be used as an additional control parameter, if necessary.

[0131] Pigments Pigments are rarely added in soluble form. As a rule, pigments, such as aluminum oxide or iron oxide pigments, are used in dispersed form. Titanium dioxide is used as a whitening pigment. Standard proportions of pigments used are 10% to 200% by weight, 20% to 200% by weight, based on the total weight of the at least one polymer in the coating layer. Proportions of up to 200% by weight, based on the total weight of the at least one polymer, are easily processable.

[0132] In a particularly advantageous embodiment, the pigment is used in the topcoat. Application is carried out in the form of a powder or by spraying an aqueous suspension with a solids content of 5% to 35% (w / w). The required concentration is lower than that incorporated into the polymer layer, amounting to 0.1% to 2% by weight, based on the weight of the pharmaceutical dosage form.

[0133] Method for preparing coated hard shell capsules A method for preparing a polymer-coated hard shell capsule is described. The hard shell capsule includes a body and a cap, and in a closed state, the cap overlaps the body in either a pre-locked state or a final-locked state; the hard shell capsule is provided in a pre-locked state, and is coated, preferably spray-coated, with a first coating solution, suspension, or dispersion according to the present invention to form an intermediate coating layer, and then, optionally, dried, and is preferably coated, preferably spray-coated, with a coating solution, suspension, or dispersion according to the present invention to form an enteric coating layer, which coats the outer surface of the hard shell capsule in the pre-locked state. Furthermore, a top coating layer can be applied thereafter, after an optional drying step.

[0134] In a further method step the prelocked hard shell capsule can be provided with a fill containing the biologically active ingredients of a pharmaceutical or nutraceutical product and closed to the final locked state.

[0135] In such further process steps, the polymer coated hard shell capsules in the pre-locked state may be opened, filled with a fill comprising at least one biologically active ingredient, and closed to a final locked state. This further processing step is preferably carried out by feeding the coated hard shell capsules in the pre-locked state to a capsule filling machine which opens the polymer coated hard shell capsules, fills them with a fill comprising at least one biologically active ingredient, and closes them to a final locked state.

[0136] This further process step results in a final locked polymer coated hard shell capsule, which is a container for at least one biologically active ingredient. The final locked polymer coated hard shell capsule as a container for at least one biologically active ingredient is preferably a pharmaceutical or nutraceutical dosage form.

[0137] The pharmaceutical or nutraceutical dosage form preferably comprises a final-locked polymer-coated hard shell capsule 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 area of ​​the pre-locked capsule but not the overlapping area where the pre-locked cap covers the body.

[0138] The coating suspension may include an organic solvent, such as acetone, isopropanol, or ethanol. The concentration of the dry weight material in the organic solvent may be about 5% to 50% by weight of polymer. A suitable spray concentration may be about 5% to 25% by weight of the dry weight.

[0139] The coating suspension can be, for example, a dispersion of the polymer in an aqueous medium such as water or a mixture of 80% or more by weight water and 20% or less by weight of a water-soluble solvent, such as acetone or isopropanol. A suitable concentration of the dry weight material in the aqueous medium can be about 5% to 50% by weight. A suitable spray concentration can be about 5% to 25% by weight dry weight.

[0140] Spray coating is preferably carried out in a drum coater or in a fluidized bed coating apparatus by spraying the coating solution or dispersion onto the prelocked capsules.

[0141] Method for preparing a dosage form fill Suitable methods for preparing the filling for pharmaceutical dosage forms or functional food dosage forms are well known to those skilled in the art.Suitable methods for preparing the filling for pharmaceutical dosage forms or functional food dosage forms disclosed herein can be by direct compression, compression of dry, wet or sintered granules, by extrusion and then rounding, by wet or dry granulation, by direct pelleting, or by binding powder onto active ingredient-free beads or neutral cores or active ingredient-containing particles or pellets, and in some cases by applying a coating layer in the form of an aqueous dispersion or organic solution in a spray method, or by fluidized bed spray granulation, forming the core containing biologically active ingredients in the form of small tablets.

[0142] Capsule filling machine The polymer-coated hard shell capsules are fed in a pre-locked state to a capsule filling machine which performs the steps of separating the body and cap, filling the body with a filler, and rejoining the body and cap to a final lock state.

[0143] The capsule filling machine used may be a capsule filling machine, preferably a fully automated capsule filling machine, capable of producing filled and finally closed capsules at a production rate of more than 1,000 capsules per hour. Capsule filling machines, preferably fully automated capsule filling machines, are well known in the art and are commercially available from several companies.

[0144] The capsule filling machine used is preferably capable of operating at a speed to produce 1,000 or more, preferably 10,000 or more, 100,000 or more, and from 10,000 to 500,000 filled and finally closed capsules per hour.

[0145] General Operation of Capsule Filling Machine Prior to the capsule filling process, the capsule filling machine is provided with a sufficient number or quantity of pre-locked pre-coated hard shell capsules. The capsule filling machine is also provided with a sufficient quantity of the fill material to be filled during the run.

[0146] 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 the body. The hard shell capsules are then fed into a two-piece housing, usually in the proper orientation, or into a brushing.

[0147] The diameter of the upper bushing or housing is usually larger than that of the capsule body bushing: thus the capsule cap is held in the upper bushing while the body is pulled into the lower bushing by vacuum. Once the capsule is opened / body and cap are separated, the upper and lower housings or bushings are separated and the capsule body is positioned for filling.

[0148] The open capsule body is then filled with the fill material. Various types of filling mechanisms can be applied for different fill materials such as granules, powders, pellets, or minitablets. Generally, capsule filling machines employ different mechanisms to handle different dosage ingredients as well as different numbers of filling stations. The dosing system is usually based on the volume or amount of the fill material, which is defined by the capsule size and the capacity of the capsule body. Empty capsule manufacturers usually provide a reference table showing the capacity of their 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 rejoined by the machine in a final locked state or position.

[0149] Use / How to use / Method process The process of preparing a polymer-coated hard shell capsule suitable as described herein can be understood as a method of using a hard shell capsule to prepare a polymer-coated hard shell capsule comprising a body and a cap, in a closed state, the cap overlapping the body in a pre-locked or final-locked state, suitable as a container for a biologically active ingredient of a medicine or a functional food, said method comprising: a) providing a hard shell capsule in a pre-locked state; b) spray coating with a first and a second coating solution, suspension, or dispersion containing a polymer or a mixture of polymers to form an intermediate coating layer and an enteric coating layer covering the outer surface of the hard shell capsule in a pre-locked state; Includes.

[0150] Spray coating can be applied preferably using a drum coater or a fluidized bed coating apparatus, more preferably using a drum coater. A suitable product temperature during the spray coating process may range from about 15°C to 40°C, preferably from about 23°C to 30°C. A suitable spray rate may range from about 0.3 to 17.0, preferably from 0.5 to 14 [g / min / kg]. A drying step is included after spray coating.

[0151] The pre-locked polymer-coated hard shell capsule can be opened in step c), filled with a fill containing a biologically active ingredient of a medicine or nutraceutical in step d), and then closed in step e) to a final lock state.

[0152] Steps c) to e) can be performed manually or, preferably, are supported by a suitable device, such as a capsule filling machine. The coated hard shell capsules in the pre-locked state are preferably fed to a capsule filling machine, which performs step c) of opening, step d) of filling with a biologically active ingredient of a pharmaceutical or functional food, and step e) of closing the capsule to the final locking state.

[0153] All of the process choices in its general or specific features and embodiments disclosed herein can be combined, without limitation, with any other general or specific choices, such as the material or numerical features and embodiments disclosed herein, e.g., polymers, capsule materials, capsule sizes, coating thicknesses, biologically active ingredients, and any other embodiments disclosed.

[0154] use The polymer-coated hard shell capsules of the present invention can be used to provide less than 10% drug release over 120 minutes in 0.1 N hydrochloric acid, followed by at least 80% drug release at a pH value of 5 for up to an additional 150 minutes.

[0155] The drug release can be measured according to the following conditions.

[0156] A) Dissolution conditions 1) Solubility parameters Equipment: USP Type I Dissolution media: Acidic stage media for 2 hours, then completely switched to buffer stage media for 2 hours Sampling points: Acid stage medium; 60 min, 120 min Buffer step medium: 10 min, 20 min, 30 min, 45 min, 60 min, 120 min Volume of medium: 750 mL for acidic stage, 1000 mL for buffer stage Speed: 100rpm Temperature: 37℃±0.5℃ Collection amount: 10mL

[0157] 2) Dissolution medium I. Acidic stage medium - 0.1N HCl; Buffer stage medium - pH 5.0 buffer, or II. Acidic stage medium - 0.1N HCl; Buffer stage medium - pH 4.5 buffer, or III. Acidic stage medium - 0.1N HCl; Buffer stage medium - pH 3.0 buffer

[0158] 3) Composition of the buffer stage medium I. Buffer Stage Medium - pH 5.0 Buffer 1 g of potassium dihydrogen phosphate (KH2PO4), 2 g of dipotassium hydrogen phosphate anhydrous (K2HPO4) and 8.5 g of sodium chloride (NaCl) were weighed and transferred to a 1 liter beaker. To this was added 500 mL of water to dissolve the salts and the volume was made up to 1000 mL with water. The pH was adjusted to 5.0 + 0.05 using ortho-phosphoric acid.

[0159] II. Buffer stage medium pH 4.5 buffer 1g of potassium dihydrogen phosphate (KH2PO4), 2g of dipotassium hydrogen phosphate anhydrous (K2HPO4) and 8.5g of sodium chloride (NaCl) were weighed and transferred to a 1 litre beaker. To this was added 500mL of water to dissolve the salts and the volume was brought up to 1000mL with water. The pH was adjusted to 4.5 + 0.05 using ortho-phosphoric acid.

[0160] III. Buffer stage medium - pH3.0 buffer Weigh out 1g of potassium dihydrogen phosphate (KH2PO4), 2g of dipotassium hydrogen phosphate anhydrous (K2HPO4) and 8.5g of sodium chloride (NaCl) into a 1 litre beaker. To this add 500mL of water to dissolve the salts and make up the volume to 1000mL with water. The pH was adjusted to 3.0 + 0.05 using ortho-phosphoric acid.

[0161] 4) Dissolution procedure: Acid stage: Six accurately weighed caffeine capsules were transferred into different dissolution bottles and then the dissolution test was carried out according to the parameters given in the above method (acid stage). After 1 and 2 hours, 10 mL aliquots were taken and analyzed as the acid stage sample solutions.

[0162] Buffer stage : The capsules after the acidic stage were transferred to the buffer stage medium. The dissolution test was continued according to the parameters given in the method above (buffer stage). Aliquots of each interval were filtered through a 0.45 μm nylon membrane syringe filter, the first few mL of filtrate were discarded and analyzed as the buffer stage sample solution using the following chromatographic conditions:

[0163] B) Chromatography conditions Column: Agilent Zorbax Eclipse XDB C 18 column, 150 x 4.6 mm, 5 μm or equivalent Mobile phase: water / ACN (80:20) Wavelength: 273nm Column temperature: 25℃ Injection volume: 10μL Flow rate: 1.5mL / min

[0164] item In particular, the present invention refers to: 1. A method for preparing a polymer-coated hard shell capsule, comprising at least an intermediate coating layer, and an enteric coating layer, and optionally a top coating layer, suitable as a container for a biologically active ingredient of a pharmaceutical or functional food, the hard shell capsule comprising a body and a cap, in a closed state, the cap overlaps with the body in either a pre-locked state or a final-locked state, the hard shell capsule being provided in a pre-locked state; a1) at least one polymer; b1) at least one alkaline agent; c1) optionally at least one lubricant, and d1) optionally at least one additive different from a1) to c1); to obtain a pre-locked hard shell capsule intermediate coating layer; and thereafter a2) at least two polymers; b2) optionally at least one lubricant; c2) optionally at least one emulsifier; d2) optionally at least one plasticizer; e2) optionally at least one biologically active ingredient; and f2) optionally at least one additive different from a2) to e2); to obtain an enteric coating layer of the pre-locked hard shell capsule, wherein the second coating solution, suspension, or dispersion is different from the first coating solution, suspension, or dispersion, and the second coating solution, suspension, or dispersion comprises or consists of: The first polymer has a T gm , preferably 35° C. to 155° C., more preferably 80° C. to 145° C., and most preferably 90° C. to 125° C. gm an anionic polymer having the formula: The second polymer has a T gm , preferably T less than 15°C gm is a polymer having the formula: The total coating amount of the coating layer is 2.0 mg / cm 2 ~10mg / cm 2 , preferably 2.2 mg / cm 2 ~9mg / cm 2 , more preferably 2.5 mg / cm 2 ~8mg / cm 2 and preferably The coating amount of the intermediate coating layer is 150% or less, 100% or less, preferably 80% or less of the coating amount of the enteric coating layer. method.

[0165] 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.

[0166] 3. The process according to item 1 or 2, wherein the at least one polymer a1) and / or the at least two polymers a2) are selected from at least one (meth)acrylate copolymer, hydroxypropyl methylcellulose (HPMC), or hydroxypropyl cellulose (HPC).

[0167] 4. The first polymer a2) is i) a core-shell polymer, which is a copolymer obtained by a two-stage emulsion polymerization process, having 70% to 80% by weight of a core containing 65% to 75% by weight of polymerized units of ethyl acrylate and 25% to 35% by weight of methyl methacrylate, and 20% to 30% by weight of a shell containing 45% to 55% by weight of ethyl acrylate and 45% to 55% by weight of polymerized units of methacrylic acid; or ii) an anionic polymer obtained by polymerizing 25% by weight to 95% by weight of a C1 to C12 alkyl ester of acrylic acid or methacrylic acid and 75% by weight to 5% by weight of a (meth)acrylate monomer having an anionic group; or iii) (meth)acrylate copolymers obtained by polymerizing methacrylic acid and ethyl acrylate, methacrylic acid and methyl methacrylate, ethyl acrylate and methyl methacrylate, or methacrylic acid, methyl acrylate, and methyl methacrylate; or iv) a (meth)acrylate copolymer obtained by polymerizing 40% by weight to 60% by weight of methacrylic acid and 60% by weight to 40% by weight of ethyl acrylate; or v) a (meth)acrylate copolymer obtained by polymerizing 5% by weight to 15% by weight of methacrylic acid, 60% by weight to 70% by weight of methyl acrylate, and 20% by weight to 30% by weight of methyl methacrylate; or A mixture of them 4. The method according to any one of items 1 to 3, wherein

[0168] 5. The second polymer a2) is i) a (meth)acrylate copolymer obtained by polymerizing at least two C1-C4 alkyl acrylate monomers with 0% to less than 5% by weight of methacrylic acid or acrylic acid; or ii) a (meth)acrylate copolymer obtained by polymerizing 20% ​​to 40% by weight of ethyl acrylate, 60% to 80% by weight of methyl methacrylate, and 0% to less than 5% by weight of methacrylic acid or acrylic acid; or iii) A (meth)acrylate copolymer obtained by polymerizing 60% by weight to 80% by weight of ethyl acrylate and 40% by weight to 20% by weight of methyl methacrylate. 5. The method according to any one of items 1 to 4, wherein

[0169] 6. At least two polymers a2) A (meth)acrylate copolymer obtained by copolymerizing 40% by weight to 60% by weight of methacrylic acid and 40% by weight to 60% by weight of ethyl acrylate, and A (meth)acrylate copolymer obtained by polymerizing 60% to 78% by weight of ethyl acrylate, 20% to 38% by weight of methyl methacrylate, and optionally 2% by weight or less, preferably 0.1 to 2% by weight of (meth)acrylic acid. 6. The method according to any one of items 1 to 5, wherein

[0170] 7. At least one polymer a1) is i) cellulose, such as hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), hydroxyethyl methylcellulose (HEMC), ethyl cellulose (EC), methyl cellulose (MC), cellulose esters, cellulose glycolates, polyethylene glycol, polyethylene oxide, polyvinylpyrrolidone, polyvinyl acetate, polyvinyl alcohol, or mixtures thereof, preferably hydroxypropyl methylcellulose; and / or ii) is present in an amount of 5% by weight to 90% by weight, preferably 10% by weight to 70% by weight, and more preferably 30% by weight to 50% by weight, based on the total weight of the intermediate layer; The method according to any one of items 1 to 6.

[0171] 8. At least one alkaline agent in the first coating solution is i) selected from calcium oxide, calcium carbonate, magnesium carbonate, magnesium oxide, sodium carbonate, sodium bicarbonate, and sodium hydroxide, or any mixture thereof, preferably selected from magnesium oxide or magnesium carbonate, more preferably magnesium oxide; and / or ii) present in an amount of 10% by weight to 75% by weight, preferably 15% by weight to 50% by weight, based on the total weight of the intermediate layer; The method according to any one of items 1 to 7.

[0172] 9. The method according to any one of items 1 to 8, wherein in the first coating solution, the at least one polymer and the at least one alkaline agent are present in a weight ratio of 1:1 to 1:0.25.

[0173] 10. At least one lubricant is present in the first and / or second coating solution, suspension, or dispersion, preferably the at least one lubricant is i) present in each coating layer in an amount of from 3% to 75% by weight, based on the total weight of the polymer; and / or ii) selected from silica, ground silica, fumed silica, kaolin calcium silicate, magnesium silicate, colloidal silicon dioxide, glycerol, glycerol monostearate, talc, stearates, sodium stearyl fumarate, starch, stearic acid or mixtures thereof, preferably selected from talc, magnesium stearate, colloidal silicon dioxide, glycerol and glycerol monostearate, or mixtures thereof, more preferably glycerol, glycerol monostearate and talc, most preferably glycerol or glycerol monostearate; The method according to any one of items 1 to 9.

[0174] 11. At least one emulsifier is present in the second coating solution, suspension, or dispersion, preferably the at least one emulsifier is i) present in an amount of less than 3% by weight, preferably less than 1.5% by weight, based on the total weight of the polymer, or absent; or ii) is present in an amount of 1.5% to 40% by weight, based on the total weight of the polymer; and / or iii) a non-ionic emulsifier, preferably a non-ionic emulsifier having an HLB greater than 10, preferably greater than 12; and / or iv) selected from polyglycosides, alcohols, sugars and sugar derivatives, polyethers, amines, polyethylene derivatives, alkyl sulfates (e.g., sodium dodecyl sulfate), alkyl ether sulfates, sodium dioctyl sulfosuccinate, polysorbates (e.g., polyoxyethylene (20) sorbitan monooleate), nonylphenol ethoxylates (nonoxynol-9), and mixtures thereof; The method according to any one of items 1 to 10.

[0175] 12. At least one plasticizer is present in the second coating solution, suspension, or dispersion, preferably the at least one plasticizer is i) present in an amount of 2% to 40% by weight, based on the total weight of the polymer; and / or ii) selected from alkyl citrates, alkyl phthalates, and alkyl sebacates, or mixtures thereof, preferably diethyl sebacate, triethyl citrate (TEC), acetyl triethyl citrate (ATEC), diethyl sebacate, and dibutyl sebacate (DBS), or mixtures thereof, more preferably triethyl citrate (TEC); The method according to any one of items 1 to 11.

[0176] 13. The method according to any one of the preceding claims, wherein up to 400 wt. % of at least one additive, based on the total weight of the at least one polymer, is included in the first and / or second coating solution, suspension, or dispersion, preferably selected from antioxidants, brighteners, flavorings, flow aids, fragrances, penetration enhancers, pigments, pore formers or stabilizers, or combinations thereof.

[0177] 14. The method of any one of items 1 to 13, wherein the body and the cap have a circumferentially extending notch or dimple in the area where the cap overlaps the body, thereby allowing the capsule to be closed in either a pre-locked or final locked state by a snap-fit ​​mechanism.

[0178] 15. The method of any one of items 1 to 14, wherein the body has a tapered rim.

[0179] 16. The method according to any one of items 1 to 15, wherein the polymer-coated hard shell capsule in the pre-locked state is opened, filled with a fill containing a biologically active ingredient of a drug or functional food, and closed to the final locked state.

[0180] 17. The process according to any one of items 1 to 16, wherein the polymer-coated hard shell capsules in the pre-locked state are fed to a capsule filling machine, which opens them, fills them with a fill comprising a biologically active ingredient of a medicine or functional food, and closes them to the final lock state.

[0181] 18. A polymer-coated hard shell capsule obtainable by the process according to any one of items 1 to 17.

[0182] 19. Use of the polymer coated hard shell capsule according to item 18 to provide less than 10% drug release over 120 minutes in 0.1N hydrochloric acid, followed by at least 80% drug release within another 150 minutes at a pH value of 5.

[0183] Working Example Compounds used in the experiment

[0184] [Table 1-1]

[0185] [Table 1-2]

[0186] A. Preparation of the Core: 1. Caffeine Blend: 1.1 Composition of caffeine blends

[0187] [Table 2]

[0188] 1.2 Process for preparing caffeine blend: I. Weigh out the required amounts of all ingredients. II. Caffeine and Microcrystalline Cellulose (MCC) PH101 were sieved through a No. 40 sieve. III. Mix the above ingredients in a double cone blender for 15 minutes at 15 RPM. IV. Prepare the blend for filling into pre-coated or uncoated size “0” / “3” HPMC capsules. V. Fill the blend into pre-coated / post-coated HPMC capsules using a manual capsule filling machine with size "0" / "3" change part.

[0189] B. Core Preparation 2. Sotalol Hydrochloride Pellets: 2.1 Composition of Sotalol Hydrochloride Pellets:

[0190] [Table 3]

[0191] 2.2 Method for preparing sotalol hydrochloride pellets: I. Weigh out the required amounts of all ingredients. II. HPMC [3 cps] was dissolved in water using an overhead stirrer until a clear solution was obtained. III. Sotalol was sieved through a No. 40 (400 μm) sieve and mixed with Aerosil 200 in a poly bag for 2 minutes, and then the resulting blend was added to the solution of step II. IV. The suspension was passed through a No. 40 sieve and used to layer the drug onto the NPS. V. Use a dehumidifier while spraying the drug solution onto the NPS.

[0192] C. Coating: 1. Coating Compositions for Comparative and Inventive Experiments

[0193] [Table 4-1]

[0194] [Table 4-2]

[0195] [Table 5-1]

[0196] [Table 5-2]

[0197] [Table 6]

[0198] 2. Coating process for the invention experiment: 2.1 Sub-coating: 2.1.1 Subcoatings for Experiments C1, I1 to I5: I. Weigh out the required amounts of all ingredients. II. VIVAPHARM® HPMC E3 was dissolved in water with glycerol anhydrous (EMPROVE®) using an overhead stirrer until a clear solution was obtained. III. Magnesium oxide (light) was slowly added to the above solution with stirring and the resulting suspension was then mixed for 30 minutes. IV. The suspension was passed through a No. 40 sieve and used for subcoating.

[0199] [Table 7]

[0200] 2.1.2 Subcoating of Experiment C5: I. Slowly add Klucel™ EF PHARM to half of the water while stirring with a dissolver plate. II. Continue stirring until a clear solution is obtained that does not contain any undissolved particles. III. Add MgO and talc to remaining half of the water while homogenizing with Silverson. IV. This suspension is then added to the polymer solution. V. Throughout the coating process, the suspension was kept stirred with a magnetic stirrer.

[0201] [Table 8]

[0202] 2.2 Enteric Coating: 2.2.1 Enteric coating for experiments C1, C2, C5, C6, and C7: I. Weigh out the required amounts of all ingredients. II.TEC and talc were homogenized in water for 15 minutes and then slowly added to the EUDRAGIT® L 30 D-55 dispersion with stirring and the resulting suspension was mixed for 30 minutes using an overhead stirrer. III. The suspension was passed through a No. 40 sieve and used for enteric coating.

[0203] 2.2.2 Enteric coating for experiments I1-I5: I. Weigh out the required amounts of all ingredients. II. Water is added to the EUDRAGIT® L 30 D-55 while stirring with a conventional stirrer (eg, a propeller stirrer or magnetic stirrer). III. Prepare excipient suspension: 40% of the total water was heated to 70°C-80°C. IV. TWEEN 80-LQ-(CQ) (diluted to a 30% aqueous solution), triethyl citrate, and IMWITOR® 900 K were homogenized in heated water using a homogenizer (e.g., Ultra Turrax) for 10 minutes. V. The remaining 60% of the water was stirred into the heated emulsion using a conventional stirrer and allowed to cool to room temperature with continued stirring. VI. With continued stirring, the excipient suspension is then added to the EUDRAGIT® L 30 D-55 and stirred for an additional 10 minutes. VII. While stirring, slowly add EUDRAGIT NM 30 D to the diluted EUDRAGIT® L 30 D-55. Continue stirring the suspension. VIII. After stirring for 15 minutes, the suspension is passed through a No. 40 sieve. The suspension is stirred throughout the entire coating process. IX. The suspension was passed through a No. 40 sieve and used for enteric coating.

[0204] 2.2.3 Enteric coating for experiment C3: I. Weigh out the required amounts of all ingredients. II. Water is added to the EUDRAGIT® L 30 D-55 while stirring with a conventional stirrer (eg, a propeller stirrer or magnetic stirrer). III. Dissolve sodium hydroxide in a small amount of water and add to the suspension from step II with stirring. IV. Prepare excipient suspension by heating 40% of the total water to 70°C-80°C. V. TWEEN 80-LQ-(CQ) (diluted to a 30% aqueous solution), triethyl citrate, and IMWITOR® 900 K were homogenized in heated water using a homogenizer (e.g., Ultra Turrax) for 10 minutes. VI. The remaining 60% of the water was stirred into the heated emulsion using a conventional stirrer and allowed to cool to room temperature with continued stirring. VII. With continued stirring, the excipient suspension is then added to the EUDRAGIT® L 30 D-55 and stirred for an additional 10 minutes. VIII. While stirring, slowly add EUDRAGIT NM 30 D to the diluted EUDRAGIT® L 30 D-55. Continue stirring the suspension. IX. After stirring for 15 minutes, the suspension is passed through a No. 40 sieve. The suspension is stirred throughout the entire coating process. X. The suspension was passed through a No. 40 sieve and used for enteric coating.

[0205] 2.2.4 Enteric coating of experiment C4: I. Weigh out the required amounts of all ingredients. II. Sodium hydroxide was dissolved in purified water and then slowly added to the EUDRAGIT® L 30 D-55 dispersion with stirring and the resulting suspension was mixed for 30 minutes using an overhead stirrer. III.TEC and talc were homogenized in water for 15 minutes and then slowly added to the EUDRAGIT® L 30 D-55 dispersion with stirring and the resulting suspension mixed for 30 minutes using an overhead stirrer. IV. The suspension was passed through a No. 40 sieve and used for enteric coating.

[0206] 2.2.5 Top coating for experiments C2, C7, and I2-I5: I. Weigh out the required amounts of all ingredients. II. VIVAPHARM® HPMC E3 was dissolved in water while stirring with a conventional stirrer (eg, a propeller stirrer or a magnetic stirrer). III. Prepare excipient suspension: 40% of the total water was heated to 70°C-80°C. IV. TWEEN 80-LQ-(CQ) (diluted to a 30% aqueous solution), triethyl citrate, and IMWITOR® 900 K were homogenized in heated water using a homogenizer (e.g., Ultra Turrax) for 10 minutes. V. The remaining 60% of the water was stirred into the heated emulsion using a conventional stirrer and allowed to cool to room temperature with continued stirring. VI. The excipient suspension is then added to the EUDRAGIT® L 30 D-55 with continued stirring. VII. After stirring for 15 minutes, the suspension is passed through a No. 40 sieve. The suspension is stirred throughout the entire coating process. VIII. The suspension was passed through a No. 40 sieve and used for enteric coating.

[0207] [Table 9]

[0208] Observations during coating for experiment C3: When neutralized EUDRAGIT® L 30 D-55 was used to coat empty capsules, processability issues were observed due to capsules sticking together during coating. Capsule sticking was also observed at very low spray rates and suspensions with lower solids content. Thus, the process could not be completed.

[0209] [Table 10]

[0210] [Table 11]

[0211] D. Summary of Results

[0212] [Table 12]

[0213] [Table 13]

[0214] [Table 14]

[0215] Description of SEM method: The pre-coated and post-coated capsules were examined for coating layer thickness using SEM analysis.

[0216] Device: Manufacturer:Thermo Fisher Scientific Model: FEI Quanta 200, Netherland

[0217] Sample preparation: Samples shall be taken randomly from a batch of coated dosage units, i.e. capsules. The taken samples shall be cut with a sharp edged cutter to obtain cross-sections of the coated capsules at room temperature. The cross-sections of the samples shall be fixed in an upright position on a sample mounting disc and analyzed to measure thickness.

[0218] Equipment setup: Analysis method: The samples are analyzed under a scanning electron microscope in low vacuum mode at a pressure of 65 Pascals and at different magnifications.

[0219] The voltage (HV) was maintained at 20 KV.

[0220] The detector used was a Large Field Detector (LFD).

[0221] [Table 15]

Claims

1. 1. A method for preparing a polymer-coated hard shell capsule suitable as a container for a biologically active ingredient of a pharmaceutical or functional food, the hard shell capsule comprising at least an intermediate coating layer, an enteric coating layer, and optionally a top coating layer, the hard shell capsule comprising a body and a cap, wherein in a closed state, the cap overlaps the body in either a pre-locked state or a final-locked state, the hard shell capsule being provided in the pre-locked state; a1) at least one polymer; b1) at least one alkaline agent; c1) optionally at least one lubricant; and d1) optionally at least one additive different from a1) to c1); to obtain the intermediate coating layer of the pre-locked hard shell capsule; and thereafter a2) at least two polymers; b2) optionally at least one lubricant; c2) optionally at least one emulsifier; d2) optionally at least one plasticizer; e2) optionally at least one biologically active ingredient; and f2) optionally at least one additive different from a2) to e2); to obtain the enteric coating layer of the pre-locked hard shell capsule, wherein the second coating solution, suspension, or dispersion is different from the first coating solution, suspension, or dispersion and comprises or consists of: The first polymer has a T ｇｍ an anionic polymer having The second polymer has a T ｇｍ is a polymer having The total coating amount of the coating layer is 2.0 mg / cm ２ ~10 mg / cm ２ That is, method.

2. 2. The method of claim 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.

3. 2. The method of claim 1, wherein the at least one polymer a1) and / or the at least two polymers a2) are selected from at least one (meth)acrylate copolymer, hydroxypropyl methylcellulose (HPMC), or hydroxypropyl cellulose (HPC).

4. The anionic polymer a2) is i) a core-shell polymer which is a copolymer obtained by a two-stage emulsion polymerization process, having 70% to 80% by weight of a core which comprises polymerized units of 65% to 75% by weight of ethyl acrylate and 25% to 35% by weight of methyl methacrylate, and 20% to 30% by weight of a shell which comprises polymerized units of 45% to 55% by weight of ethyl acrylate and 45% to 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) (meth)acrylate copolymers obtained by polymerizing methacrylic acid and ethyl acrylate, methacrylic acid and methyl methacrylate, ethyl acrylate and methyl methacrylate, or methacrylic acid, methyl acrylate, and methyl methacrylate; or iv) 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 v) 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 of them 2. The method of claim 1, wherein

5. The second polymer a2) is i) a (meth)acrylate copolymer obtained by polymerizing at least two C1-C4 alkyl acrylate monomers with 0% to less than 5% by weight of methacrylic acid or acrylic acid; or ii) a (meth)acrylate copolymer obtained by polymerizing 20% ​​to 40% by weight of ethyl acrylate, 60% to 80% by weight of methyl methacrylate, and 0% to less than 5% by weight of methacrylic acid or acrylic acid; or iii) (Meth)acrylate copolymer obtained by polymerizing 60% to 80% by weight of ethyl acrylate and 40% to 20% by weight of methyl methacrylate.

2. The method of claim 1, wherein

6. The at least two polymers a2) are A (meth)acrylate copolymer obtained by copolymerizing 40% by weight to 60% by weight of methacrylic acid and 40% by weight to 60% by weight of ethyl acrylate, and A (meth)acrylate copolymer obtained by polymerizing 60% to 78% by weight of ethyl acrylate, 20% to 38% by weight of methyl methacrylate, and optionally 2% by weight or less of (meth)acrylic acid.

2. The method of claim 1, wherein

7. The at least one polymer a1) is i) selected from cellulose, cellulose ester, cellulose glycolate, polyethylene glycol, polyethylene oxide, polyvinylpyrrolidone, polyvinyl acetate, polyvinyl alcohol, or mixtures thereof; and / or ii) present in an amount of 5% to 90% by weight, based on the total weight of the intermediate layer; The method of claim 1.

8. The at least one alkaline agent b1) is i) selected from calcium oxide, calcium carbonate, magnesium carbonate, magnesium oxide, sodium carbonate, sodium bicarbonate, and sodium hydroxide, or any mixture thereof; and / or ii) present in an amount of from 10% to 75% by weight, based on the total weight of the intermediate layer; The method of claim 1.

9. The method of claim 1, wherein the at least one polymer and the at least one alkaline agent are present in the first coating solution in a weight ratio of 1:1 to 1:0.

25.

10. The method of claim 1 , wherein at least one lubricant is present in the first and / or second coating solution, suspension, or dispersion.

11. The method of claim 1 , wherein at least one emulsifier is present in the second coating solution, suspension, or dispersion.

12. The method of claim 1 , wherein at least one plasticizer is present in the second coating solution, suspension, or dispersion.

13. 10. The method of claim 1, wherein up to 400 wt. % of the at least one additive, based on the total weight of the at least one polymer, is included in the first and / or second coating solution, suspension, or dispersion.

14. 14. A polymer-coated hard shell capsule obtainable from the process of any one of claims 1 to 13.

15. 15. Use of the polymer-coated hard shell capsule of claim 14 to provide less than 10% drug release over 120 minutes in 0.1 N hydrochloric acid, followed by at least 80% drug release within an additional 150 minutes at a pH value of 5.