Method for producing coated hard capsules

Abstract

The present invention discloses a process for producing polymer-coated hard capsules suitable for use as containers for pharmaceutical or nutraceutical bioactive ingredients. The hard capsules comprise a body and a cap, and in a closed state, the cap overlaps the body in a pre-locked or final-locked state. The hard capsules are provided in a pre-locked state and are spray-coated with a coating solution, suspension, or dispersion containing a polymer or polymer mixture to produce a coating layer covering the outer surface of the hard capsules in the pre-locked state. [Selection diagram] None

Description

[Technical field]

[0001] The present invention is in the field of methods for producing polymer-coated hard shell capsules. [Background technology]

[0002] US Patent No. 4,138,013 describes a hard capsule having an enteric coating. The hard capsule has a body and a cap portion which are interlocking in a telescopic manner. The body and the cap portion of the capsule are formed by dip molding using a homogeneous film-forming mixture containing a material selected from hydroxypropylmethylcellulose (HPMC), (1) a mixture of hydroxypropylmethylcellulose and an ammonium salt of cellulose acetate phthalate, or (2) a mixture of gelatin and an ammonium salt of a copolymer of (meth)acrylic acid and an alkyl methacrylic acid ester. The capsule itself is already enteric coated without the application of an additional enteric coating layer.

[0003] Huyghebaert et al., European Journal of Pharmaceutical Sciences 21 (2004) 617-623, describe an alternative method for enteric coating capsules made of HPMC, resulting in ready-to-use enteric coated capsule members. In contrast to gelatin capsules, it has been reported that HPMC capsules can be enteric coated relatively easily compared to aqueous formulations. However, to avoid leakage from the capsule and uncontrolled leakage of the contents in the stomach, an additional seal must be applied between the capsule members, for example by applying a gelatin solution manually. Another technique involves applying a water / ethanol mixture between the capsule members and welding the members together at 40-60°C.

[0004] By using aqueous formulations based on (meth)acrylate copolymers or polyvinyl acetate phthalate, plasticizers such as triethyl citrate, and further auxiliaries such as talc (EUDRAGIT® FS30D, EUDRAGIT® L30D-55, Aquoat® AS-HF, or Sureteric®), it is possible to provide HPMC capsules with an enteric membrane from separately coated bodies and caps. With this coating technique, it is possible to dispense with a separate sealing step. In particular, HPMC capsules coated with (meth)acrylate copolymers show particular advantages due to their combined properties.

[0005] WO 2011 / 012369 describes a coating composition for enteric coating a capsule member made of a water-soluble or water-swellable polymeric material.

[0006] US Patent No. 8,590,278 describes a method for fluid-tight sealing of filled drug capsules. The capsule members are filled with a gas that is at a different temperature, pressure, or both than the temperature, pressure, or both outside the capsule. The capsule members are assembled such that a pressure differential is reduced across the capsule body and capsule cap. A leak-tight seal is provided in the gap between the capsule body and capsule cap, the gap being approximately 20-50 microns.

[0007] US Patent Publication No. 20170035699 describes an acid-resistant banding solution for acid-resistant two-piece hard capsules.

[0008] WO 2015 / 177028 describes a modified release capsule, characterized in that it contains a non-liquid fill and is band-sealed under a modified release coating. The modified release coating may be a delayed release coating or a controlled release coating, or it may be an enteric coating. The film-forming agent for the enteric coating may be selected from an anionic (meth)acrylate copolymer or an anionic cellulose. The amount of coating is about 1 cm2 of the surface area of ​​the capsule concerned. 2 The amount may be about 2-12 mg per capsule. Before applying the coating to the immediately filled and closed capsule, a band seal is applied to the gap between the body and cap to prevent leakage.

[0009] WO 2013 / 1710012, WO 2007 / 070052, WO 2011 / 151722, and WO 2017 / 120592 contain examples where active ingredients, including powdered formulations, are filled into hard capsules, closed, and then coated with an enteric (meth)acrylate copolymer. Summary of the Invention

[0010] The present invention relates to a method for producing a polymer-coated hard capsule suitable as a container for a pharmaceutical or nutraceutical bioactive ingredient, said hard capsule comprising a body and a cap, the cap covering the body in both pre-locked and final-locked states in the closed stage, said hard capsule being provided in a pre-locked state and being spray-coated with a coating solution or dispersion comprising a polymer or a mixture of polymers to form a coating layer covering the outer surface of the hard capsule in the pre-locked state.The present invention also relates to a polymer-coated hard capsule obtained by the described method, and to a pharmaceutical or nutraceutical dosage form comprising the polymer-coated hard capsule in the final-locked stage, the fill containing a pharmaceutical or nutraceutical active ingredient.The present invention relates to a polymer-coated hard capsule.

[0011] Huyghebaert et al., European Journal of Pharmaceutical Sciences 21 (2004) 617-623, describes coating the body and cap of a hard capsule separately with a polymer. The body and cap can be filled with the active ingredient and show no leakage in release tests. Also, no additional banding is required. However, this method has the disadvantage that the separately polymer-coated body and cap must then be manually filled and closed. Since the body and cap often have errors, the corresponding body and cap must be manually selected. Furthermore, the original shape of the uncoated body and cap may be adversely affected by the coating process in that the circular shape may be distorted. Thus, the proportion of out-of-specification parts is often increased, and the separately coated caps and bodies do not easily match. Therefore, the matching caps and bodies must be manually selected, which must be repeated many times, and is not a suitable method from the beginning. The need for manual processing limits large-scale industrial application.

[0012] Conventional capsule filling machines are designed to process by opening uncoated capsules in a pre-locked state, filling them with active ingredients or compositions containing active ingredients, and closing them to a final lock state. However, there does not appear to be any conventional equipment capable of processing separately polymer-coated bodies and caps. Thus, there is a need to design and build specially designed equipment. These equipment must also address the problem of increased circular deformation rates of separately coated bodies and caps, requiring a high level of engineering effort.

[0013] Thus, there is a need for a polymer coating process for hard capsules that does not require further banding of the closed capsules and results in tightly closed capsules that do not cause unwanted leakage of the active ingredient. The problem of deformation of the roundness of the body and cap due to the polymer coating process, which can occur when the body and cap are polymer coated separately, needs to be avoided. The process needs to be suitable for conventional capsule filling machines.

[0014] Compared to the separate coating described by Huyghebaert et al., European Journal of Pharmaceutical Sciences 21 (2004) 617-623, the described method has the advantage that the coating process is only one time. There is no spraying of coating material inside the capsule member. Thus, the loss of expensive coating solution or dispersion is significantly less. It was found that the circular shape of the body and cap is not deformed or is almost not deformed when capsules in the prelocked state are used. This change in capsule shape stability may be related to the stabilizing effect of the two capsule members in the overlapping area of ​​the prelocked state. Thus, the prelocked state provides sufficient equipment stability in the coating and drying process of conventional coating equipment such as fluidized bed coaters and drum coaters. Furthermore, since the body and cap of the capsule member provided in the prelocked state are already corresponding, there is no need to select corresponding bodies and caps. As a result of the improvement, the polymer-coated capsules in the prelocked state can be further processed in conventional capsule filling machines. Thus, the pre-locked coated capsules are suitable as part of large scale industrial production of pharmaceutical or nutraceutical dosage forms comprising a final locked polymer coated hard capsule and containing a fill comprising a pharmaceutical or nutraceutical bioactive ingredient, for example by opening the pre-locked coated capsules, filling with the active ingredient or active ingredient-containing composition, and closing to the final lock state.

[0015] Surprisingly, it has been found that the hard capsules coated by the method of the present invention are tightly closed and do not exhibit leakage, even though only a portion of the overlapping area between the body and the cap is sealed by the coating. The described method is particularly useful for providing a hard, final-locked polymer-coated hard capsule for pharmaceutical or nutraceutical dosage forms with gastro-resistance and intended immediate release in the small intestine. The described method is also useful for providing a polymer-coated hard capsule and pharmaceutical or nutraceutical dosage forms based on this type of capsule with improved moisture resistance, particularly to reduce moisture absorption during storage.

[0016] The term polymer or polymer mixture is understood as one polymer or a mixture of two or more polymers, for example a mixture of two or three polymers. The coating layer may comprise or consist of several individual layers, possibly two layers each containing one polymer or a polymer mixture, and the two or more layers may contain the same or different polymers. Preferably, the coating layer comprises or consists of a layer containing only one polymer, preferably one polymer or a mixture of two. One polymer means only one polymer, or only one main polymer to which a very small amount of additional polymer (not more than 5 or 2 or 1% by weight, calculated on the weight of the main polymer) is added that does not essentially affect the function of the main polymer. A very small amount of additional polymer may be added for additive functions, such as improving the adhesion of the coating layer to the capsule material. [Brief description of the drawings]

[0017] [Figure 1a] FIG. 1 includes FIGS. 1a, 1b and 1c, where FIG. 1a shows an example of a capsule with a separate body and cap. [Figure 1b] FIG. 1b shows the body and cap in the pre-locked state. [Figure 1c] FIG. 1c shows the body and cap in the final locked state. [Diagram 2]Figure 2 shows a schematic diagram of the body (left) and cap (right) of a hard capsule of size Vcaps®Plus#1 with relative dimensions in mm. The dimensions are used in Example 2 to calculate the capsule outer surface in the pre-locked state. Body: Length = 16.61 mm, Cylinder (length of cylindrical part) = 13.29 mm, Outer diameter = 6.63 mm. Cap: Length = 9.78 mm, Cylinder (length of cylindrical part) = 6.32 mm, Outer diameter = 6.91 mm. [Diagram 3] Figure 3 refers to Comparative Example C4, in which the body and cap were spray-coated with polymer separately. Figure 3 shows microscopic images of the open-side edges of ten bodies, numbered B1-B10, randomly selected during the spray-coating process. The images were recorded and made black and white for clear reproduction. As shown in images B1-B10, the process of coating the bodies separately causes the originally circular periphery to deform in various ways. [Figure 4] Figure 4 refers to Comparative Example C4, where the body and cap were spray-coated with polymer separately. Figure 4 shows microscopic images of the open-side edges of ten caps, numbered C1-C10, randomly selected during the spray-coating process. The images were recorded and made black and white for clear reproduction. As shown in images C1-C10, the process of coating the caps separately causes various deformations of the originally circular periphery. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] Hard capsule Hard capsules for pharmaceutical or nutraceutical purposes are well known to those skilled in the art. Hard capsules are two-piece sealed capsules with two capsule members called the body and the cap. The materials of the capsule body and cap are often made of hard, sometimes brittle materials. Hard capsules include a body and a cap. Usually, the body and the cap are cylindrical with one open end and rounded hemispherical with the opposite end closed. The shape and size of the cap and the body are such that the open end of the body can be pushed telescopically into the open end of the cap.

[0019] The body and cap have corresponding potential overlapping areas (overlap areas) on the outside of the body and inside of the cap that partially overlap when the capsule is closed in the pre-locking stage and completely overlap in the final locking stage. When the cap is slid some distance over the corresponding overlapping area of ​​the body, the capsule is in the pre-locking stage. When the cap is slid completely to the corresponding overlapping area of ​​the body, the capsule is in the final locking stage. Typically, the pre-locking stage or the final locking stage is maintained by a snap-in locking mechanism on the body and cap, such as corresponding annular notches or recesses, preferably elongated recesses.

[0020] Typically, the body is longer than the cap. To close or snap the capsule, the cap can cover the overlapping area on the outside of the body. In the closed stage, the cap covers the overlapping area on the outside of the body in a pre-locked or final locked state. In the final locked state, the cap covers the entire overlapping area on the outside of the body, and in the pre-locked state, the cap overlaps a portion of the overlapping area on the outside of the body. The cap can be slid over the body and typically locked in one of two different positions, with the capsule closed in the pre-locked or final locked states.

[0021] Hard capsules are commercially available in a variety of sizes. Typically, hard capsules are provided as empty containers with the body and cap already in a pre-locked state, or, if desired, the body and cap are provided as separate capsule parts. The pre-locked hard capsules can be fed into a capsule filling machine, which opens, fills, and closes the capsule to a final lock state. Typically, hard capsules are filled with dry material, e.g., powder or granules containing a bioactive ingredient.

[0022] The cap and the body are supplied closed and equipped with closure means which are advantageous for preliminary (temporary) and / or final locking of the capsule.

[0023] Thus, raised points can be provided on the inner wall of the cap and slightly larger recessed points on the outer wall of the body, arranged so that when the capsule is closed, the raised points fit into the recesses. Alternatively, the raised points can be formed on the outer wall of the body and the recesses on the inner wall of the cap. The raised points or recesses are arranged in a circular or spiral pattern on the wall. Although it is advantageous to have recesses and openings to allow the exchange of gas inside the capsule, instead of a point-like arrangement of raised points and recesses, the wall of the cap or body can be circular.

[0024] One or more ridges may be provided annularly on the inner wall of the cap and on the outer wall of the body such that in the final locked position of the capsule, the ridge on the cap is adjacent to the ridge on the body. The ridge may be formed on the outside of the body near the open end and the recess may be formed near the open end of the cap such that the ridge on the body will engage with the recess in the cap in the final locked position of the capsule. The ridge may be such that the cap can be opened to the pre-locked state at any time without damaging the capsule, or such that once the capsule is closed, it cannot be reopened without being destroyed.

[0025] A capsule having one or more such locking mechanisms (latches), e.g. two annular grooves, is preferred. More preferably, a capsule having at least two such locking means, which fix the two capsule parts to different degrees. In this type of part, a first locking means (recess or annular notch) can be formed near the opening of the capsule cap and capsule body, and a second locking means (annular notch) can be moved slightly towards the closed end of the capsule part. The first locking means is less strong than the second and fixes the two capsule parts. This variant has the advantage that after the empty capsule is produced, the capsule cap and capsule body can first be pre-locked together using the first locking mechanism. To fill the capsule, the two capsule parts are then separated again. After filling, the two capsule parts are engaged until the second latch secures the capsule parts firmly in the final locking stage.

[0026] Preferably, the body and cap of the hard capsule each have an annular notch and / or a recess in the area where the cap can slide over the body. The annular notch in the body and the recess in the cap correspond to each other and provide a snap-in or snap-into-place mechanism. The recess may be circular or longitudinally elongated (elliptical).

[0027] The annular notch in the body and the annular notch in the cap (exactly corresponding rings) also correspond to each other to provide a snap-in or snap-fit ​​mechanism that closes the capsule in a pre-locked or final locked state.

[0028] Corresponding annular notches in the body and elongated recesses in the cap are preferably used to secure the body and cap together in the pre-locked state, and corresponding annular notches in the body and cap are preferably used to secure or lock the body and cap together in the final-locked state.

[0029] The area where the cap can slide over the body can be called the overlap area of ​​the body and the cap, or simply the overlap area. If the cap overlaps the body only partially, possibly by 20-90 or 60-85% of the overlap area, the hard capsule is only partially closed (pre-locked). Preferably, in the presence of locking mechanisms such as corresponding annular notches and / or recesses in the body and the cap, the partially closed capsule can be called pre-locked. When the capsule is polymer-coated in the pre-locking stage, this coating completely covers the outer surface including the part of the overlap area of ​​the body and the cap that is not overlapped by the cap in the pre-locking stage. When the capsule is polymer-coated in the pre-locking stage and then closed to the final locking stage, the coating in the part of the overlap area of ​​the body and the cap that is not overlapped by the cap in the pre-locking stage is then covered by the cap. The presence of this coating in the part enclosed between the body and the cap in the final locking stage is sufficient to tightly seal the hard capsule. This was not an expected measure.

[0030] The hard capsule is finally closed or finally locked when the cap overlaps the entire overlapping area of ​​the body. Preferably, in the presence of a locking mechanism such as corresponding annular notches and / or recesses in the body and cap, the finally closed capsule can be referred to as finally locked.

[0031] Usually, the recess is preferred for fixing the body and the cap in the pre-locked state. As a non-binding rule, the corresponding area of ​​the recess is smaller than the corresponding area of ​​the annular notch. Thus, a snap-in recess can be released again with a force smaller than that required to release the snap-in fixing by the corresponding annular notch.

[0032] The recesses in the body and cap are located in the area where the cap can slide over the body and correspond to each other in a pre-locked state by a snap-in or snap-fit ​​mechanism. For example, there can be two, four, or preferably six notches or recesses located in a circular pattern around the periphery of the cap.

[0033] Typically, the recess in the cap and the annular notch in the body in the area where the cap can slide over the body correspond to each other so that in the pre-locked state, a snap-fit ​​mechanism closes the capsule. In the pre-locked state, the opening force required is relatively small, so that the hard capsule can be reopened by hand or by a machine without damage. Thus, the "pre-locked state" is sometimes expressed as a "loosely fitted state."

[0034] Usually, annular notches or corresponding locking rings on the body and the cap in the area where the cap can slide over the body correspond to each other to close the capsule by a snap-fit ​​mechanism in the pre-locked state, whereas in the final locked state, the force required to open is relatively large, so that the hard capsule cannot or hardly can be reopened manually or by a machine without damage.

[0035] Typically, the recess and annular notch are formed in the capsule body or the capsule cap, and when the capsule members with these protuberances and recesses are brought together, a uniform gap is formed along the contact surface between the capsule body and the overlying capsule cap, ideally between 10 microns and 150 microns, more preferably between 20 microns and 100 microns.

[0036] Preferably, the body of the hard capsule has a tapered periphery which prevents the peripheries of the body and cap from colliding and being damaged when the capsule is closed manually or mechanically.

[0037] In contrast to hard capsules, soft capsules are sealed, one-piece, encapsulated capsules. Softgel capsules are often made from blown softgel materials and are usually filled by injection with a liquid containing a bioactive ingredient. The present invention does not relate to sealed, one-piece, soft, encapsulated capsules.

[0038] Hard capsule size The final locked closed hard capsule has a total length in the range of about 5-40 mm. The cap diameter may be in the range of about 4-12 mm. The body diameter may be in the range of about 2-11 mm. The cap length may be in the range of about 4-20 mm and the body length may be in the range of about 8-30 mm. The fill volume may be between about 0.1-2 ml. The difference between the pre-lock length and the final lock length may be about 1-5 mm.

[0039] Capsules can be divided into standard sizes, for example sizes 000 to 5. A closed size 000 capsule has, for example, a total length of about 28 mm, a cap outer diameter of about 9.9 mm, and a body outer diameter of about 9.5 mm. The cap length is about 14 mm, and the body length is about 22 mm. The fill capacity is about 1.4 ml.

[0040] A closed size 5 capsule, for example, has a total length of about 10 mm, a cap outer diameter of about 4.8 mm, and a body outer diameter of about 4.6 mm. The cap length is about 5.6 mm, and the body length is about 9.4 mm. The fill volume is about 0.13 ml.

[0041] A size 0 capsule exhibits a length of about 23-24 mm in the pre-lock stage and about 20.5-21.5 mm in the final lock stage. Thus, the difference between the pre-lock length and the final lock length may be about 2-3 mm.

[0042] Coated hard capsule The present invention relates to polymer-coated hard capsules obtainable by the process described herein.

[0043] Body and Cap Material The materials 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 capsules whose bodies and caps comprise or consist of HPMC or gelatin are preferred, with HPMC being most preferred due to its excellent adhesion in polymeric coatings.

[0044] Polymer or polymer mixture in the coating layer The polymer or mixture of polymers in the coating layer is preferably a film-forming polymer and may be selected from the group of anionic, cationic and neutral polymers or any mixture thereof.

[0045] Any selection of general or specific polymer features or embodiments disclosed herein can be combined without limitation with any other selection of general or specific materials or numerical features or embodiments disclosed herein, such as capsule materials, capsule sizes, coating thicknesses, bioactive components, and other disclosed features or embodiments.

[0046] Anionic Polymers - Enteric Coatings and Gastric Resistance The described method is particularly useful for providing tightly closed polymer-coated hard capsules for pharmaceutical or nutraceutical dosage forms with gastro-resistance and intended immediate release in the small intestine (enteric coating) or large intestine (colonic targeting).

[0047] The polymer or mixture of polymers 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.

[0048] The anionic polymers are also called “enteric polymers.” In the coating layer, such polymers can provide enteric protection to the capsule.

[0049] By enteric protected is meant that when the capsule is in its final closed state and contains a fill containing a pharmaceutical or nutraceutical bioactive ingredient, less than 10% of the contained bioactive ingredient is released after 120 minutes in 0.1N HCl, pH 1.2, and preferably after 120 minutes in 0.1N HCl, pH 1.2, and then changing to a pH 6.8 buffer, about 80% or more of the bioactive ingredient is released after a total of 165 or 180 minutes.

[0050] Colon targeting means that when the capsule is in the final closed state and contains a fill containing a pharmaceutical or nutraceutical bioactive ingredient, less than 10% of the bioactive ingredient is released after 120 minutes in 0.1N HCl, pH 1.2. Preferably, after 120 minutes in 0.1N HCl, pH 1.2, and then changing to a pH 6.8 buffer, about 80% or more of the bioactive ingredient is released after a total of 165 minutes. Most preferably, after 120 minutes in 0.1N HCl, pH 1.2, and then changing to a pH 6.5 or 6.8 buffer for 60 minutes, and then finally changing to a pH 7.2 or pH 7.4 buffer, about 80% or more of the bioactive ingredient is released after a total of 225 or 240 minutes.

[0051] Dissolution tests were performed using USP Apparatus II at a paddle speed of 75 rpm according to United States Pharmacopoeia 40 (USP). <711> The temperature of the test liquid should be adjusted to 37 + 0.5°C. Samples should be taken at appropriate times.

[0052] Anionic (Meth)Acrylate Copolymer Preferably, the anionic (meth)acrylate copolymer comprises 25-95, preferably 40-95, in particular 60-40% by weight of free-radically polymerized C1-C12 alkyl esters, preferably C1-C4 alkyl esters of acrylic or methacrylic acid, and 75-5, preferably 60-5, in particular 40-60% by weight of (meth)acrylate monomers having anionic groups. The above proportions usually add up to 100% by weight. However, it is also possible to have small amounts of 0-10% by weight, for example 1-5% by weight, of additional monomers capable of vinyl copolymerization, such as, for example, hydroxyethyl methacrylate or hydroxyethyl acrylate, without impairing or altering the essential properties. It is preferred that no additional monomers capable of vinyl copolymerization are present.

[0053] 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.

[0054] The (meth)acrylate monomer having an anionic group is, for example, acrylic acid, preferably methacrylic acid.

[0055] A suitable anionic (meth)acrylate copolymer is one in which 40-60% by weight methacrylic acid is polymerized with 60-40% by weight methyl methacrylate or 60-40% by weight ethyl acrylate (EUDRAGIT® L or EUDRAGIT® L 100-55).

[0056] EUDRAGIT® L is a copolymer of 50% by weight methyl methacrylate and 50% by weight methacrylic acid. In intestinal fluid or simulated intestinal fluid, the pH at which certain active ingredients begin to be released is said to be about pH 6.0.

[0057] EUDRAGIT® L100-55 is a copolymer of 50% by weight ethyl acrylate and 50% by weight methacrylic acid. EUDRAGIT® L30D-55 is a dispersion containing 30% by weight EUDRAGIT® L100-55. In intestinal fluid or simulated intestinal fluid, the pH at which certain active ingredients begin to be released can be said to be around pH 5.5.

[0058] Similarly suitable is an anionic (meth)acrylate copolymer (EUDRAGIT® S) having 20-40% by weight of methacrylic acid and 80-60% by weight of methyl methacrylate polymerized therein. In intestinal fluid or simulated intestinal fluid, the pH at which certain active ingredients begin to be released is approximately pH 7.0.

[0059] A suitable (meth)acrylate copolymer is one in which 10-30% by weight of methyl methacrylate, 50-70% by weight of methyl acrylate, and 5-15% by weight of methacrylic acid are polymerized (EUDRAGIT® FS). In intestinal fluid or simulated intestinal fluid, the pH at which certain active ingredients begin to be released can be around pH 7.0.

[0060] EUDRAGIT® FS is a copolymer of 25% by weight methyl methacrylate, 65% by weight methyl acrylate, and 10% by weight methacrylic acid. EUDRAGIT® FS30D is a dispersion containing 30% by weight EUDRAGIT® FS.

[0061] Suitable copolymers are 20 to 34% by weight of methacrylic acid and / or acrylic acid, 20 to 69% by weight of methyl acrylate; and 0-40% by weight of ethyl acrylate, and / or 0 to 10% by weight of an additional monomer capable of vinyl copolymerization; The glass transition temperature of the copolymer according to ISO 11357-2, 3.3.3 is below 60° C. This (meth)acrylate copolymer is particularly suitable for compressing pellets into tablets due to its excellent elongation at break.

[0062] Suitable copolymers are 20 to 33% by weight of methacrylic acid and / or acrylic acid, 5 to 30% by weight of methyl acrylate, 20 to 40% by weight of ethyl acrylate, More than 10 to 30% by weight of butyl methacrylate, and optionally A copolymer in which 0 to 10% by weight of an additional monomer capable of being copolymerized with vinyl is polymerized; The proportion of monomers is 100% by weight in total. The glass transition temperature (midpoint temperature Tmg) of the copolymer according to ISO 11357-2, 3.3.3, is 55-70° C. Due to the excellent mechanical properties, this type of copolymer is particularly suitable for compressing pellets into tablets.

[0063] The copolymer preferably consists essentially of only the monomers methacrylic acid, methyl acrylate, ethyl acrylate and butyl methacrylate in amounts within the ranges mentioned above, i.e. 90, 95 or 99 to 100% by weight. However, without necessarily impairing the essential properties, it may further contain a small amount of 0 to 10% by weight, e.g. 1 to 5% by weight, of an additional monomer capable of vinyl copolymerization, e.g. methyl methacrylate, butyl acrylate, hydroxyethyl methacrylate, vinyl pyrrolidone, vinyl malonic acid, styrene, vinyl alcohol, vinyl acetate and / or derivatives thereof.

[0064] Further suitable anionic (meth)acrylate copolymers are so-called core / shell polymers, as described in WO 2012 / 171575 or WO 2012 / 171576. A suitable core-shell polymer is a copolymer 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 polymerized units of ethyl acrylate and 50% by weight of methacrylic acid, obtained in a two-stage emulsion polymerization process.

[0065] A suitable core-shell polymer is a copolymer having 70-80% by weight of a core containing 65-75% by weight of polymerized units of ethyl acrylate and 25-35% by weight of methyl methacrylate and 20-30% by weight of a shell containing 45-55% by weight of ethyl acrylate and 45-55% by weight of polymerized units of methacrylic acid, obtained by a two-stage emulsion polymerization process.

[0066] 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).

[0067] 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 (preferred ratio 9:1).

[0068] Cationic polymer - Moisture absorption prevention The above method is particularly useful for providing polymer-coated hard capsules and pharmaceutical or nutraceutical dosage forms based on such capsules with improved moisture resistance, e.g., reducing moisture absorption during storage. For this purpose, a coating with a cationic polymer, preferably a cationic (meth)acrylate copolymer, is proposed.

[0069] Suitable cationic (meth)acrylate copolymers in the coating layer are prepared by polymerizing monomers comprising C1-C4 alkyl esters of acrylic or methacrylic acid with alkyl esters of acrylic or methacrylic acid having a tertiary or quaternary ammonium group in the alkyl group.

[0070] Cationic water-soluble (meth)acrylate copolymers are partially or fully polymerized alkyl acrylates and / or alkyl methacrylates having tertiary amino groups on the alkyl radicals. Coatings containing these polymers have the advantage of providing moisture resistance to hard capsules. Moisture resistance is understood as a reduction in the absorption of moisture or water immediately after filling and during storage of the final locked capsule.

[0071] Suitable cationic (meth)acrylate copolymers are prepared by polymerizing 30-80% by weight of a C1-C4 alkyl ester of acrylic or methacrylic acid with 70-20% by weight of an alkyl (meth)acrylate monomer having a tertiary amino group in the alkyl radical.

[0072] A preferred cationic (meth)acrylate copolymer has 20-30% by weight methyl methacrylate, 20-30% by weight butyl methacrylate, and 60-40% by weight dimethylaminoethyl methacrylate polymerized therein (EUDRAGIT® E polymer).

[0073] A particularly suitable commercially available (meth)acrylate copolymer having tertiary amino groups is 25% by weight methyl methacrylate, 25% by weight butyl methacrylate, and 50% by weight dimethylaminoethyl methacrylate polymerized (EUDRAGIT® E100 or EUDRAGIT® EPO (powder form)). EUDRAGIT® E100 and EUDRAGIT® EPO are water soluble at a pH below about 5.0 and therefore are also gastric juice soluble.

[0074] A suitable (meth)acrylate copolymer may be composed of 85-98% by weight of free radically polymerized C1-C4 alkyl esters of acrylic or methacrylic acid and 15-2% by weight of a (meth)acrylate monomer having a quaternary amino group on the alkyl radical.

[0075] Preferred C1-C4 alkyl esters of acrylic or methacrylic acid are methyl acrylate, ethyl acrylate, butyl acrylate, butyl methacrylate and methyl methacrylate.

[0076] Further suitable cationic (meth)acrylate polymers can contain polymerized monomer units of 2-trimethylammonium-ethyl methacrylate chloride or trimethylammonium-propyl methacrylate chloride.

[0077] A suitable copolymer can be polymerized from 50-70% by weight methyl methacrylate, 20-40% by weight ethyl acrylate and 7-2% by weight 2-trimethylammonium ethyl methacrylate chloride.

[0078] A particularly suitable copolymer is one in which 65% by weight methyl methacrylate, 30% by weight ethyl acrylate, and 5% by weight 2-trimethylammonium ethyl methacrylate chloride are polymerized (EUDRAGIT® RS).

[0079] Further suitable (meth)acrylate copolymers are prepared by polymerizing 85-93% by weight of C1-C4 alkyl esters of acrylic or methacrylic acid with 7-15% by weight of (meth)acrylate monomers having a quaternary amino group on the alkyl radical. Such (meth)acrylate monomers are commercially available and have been used for a long time in sustained release coatings.

[0080] A specifically preferred copolymer is one in which 60% by weight methyl methacrylate, 30% by weight ethyl acrylate, and 10% by weight 2-trimethylammonium ethyl methacrylate chloride are polymerized (EUDRAGIT® RL).

[0081] Neutral Polymer A neutral polymer is defined as a polymer synthesized from neutral monomers and less than 5% by weight, preferably less than 2% by weight, of monomers carrying ionic groups, most preferably none of which are monomers carrying ionic groups.

[0082] Suitable neutral polymers for coating hard capsules are methacrylate copolymers, preferably copolymers of ethyl acrylate and methyl methacrylate such as EUDRAGIT® NE or EUDRAGIT® NM, neutral celluloses such as the methyl, ethyl or propyl ethers of cellulose, e.g. hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl acetate or polyvinyl alcohol.

[0083] Neutral methacrylate copolymers are often useful in mixtures with anionic (meth)acrylate copolymers.

[0084] The neutral methacrylate copolymers are prepared by polymerizing (meth)acrylate monomers having neutral radicals, in particular C1-C4 alkyl radicals, to the extent of at least greater than 95% by weight, in particular at least 98% by weight, preferably at least 99% by weight, in particular at least 99% by weight, more preferably 100% by weight.

[0085] Suitable (meth)acrylate monomers with neutral radicals are, for example, methyl methacrylate, ethyl methacrylate, butyl methacrylate, methyl acrylate, ethyl acrylate, butyl acrylate, preferably methyl methacrylate, ethyl acrylate and methyl acrylate.

[0086] Methacrylate monomers having anionic radicals, such as acrylic acid and / or methacrylic acid, may be present in small amounts, less than 5% by weight, preferably 2% or less by weight, more preferably 1% or less or 0.05-1% by weight.

[0087] Suitable examples include neutral or substantially neutral (meth)acrylate copolymers polymerized with 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 or 0.05 to 1% by weight, of methacrylic acid or acrylic acid.

[0088] A suitable example is a neutral or substantially neutral (meth)acrylate copolymer polymerized with 20-40% by weight of methyl methacrylate, 60-80% by weight of 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 (EUDRAGIT® NE or EUDRAGIT® NM type).

[0089] EUDRAGIT® NE and EUDRAGIT® NM are copolymers containing free radically polymerized units of 28-32 weight percent methyl methacrylate and 68-72 weight percent ethyl acrylate.

[0090] According to WO 01 / 68767, neutral or substantially neutral methyl acrylate copolymers are preferred, prepared as a dispersion using 1-10% by weight of a non-ionic emulsifier with an HLB value of 15.2-17.3. "EUDRAGIT® NM type" has the advantage that there is no phase separation with the formation of crystalline structures due to the emulsifier.

[0091] However, according to EP 1 571 164 A1, the corresponding substantially neutral (meth)acrylate copolymers having a small proportion 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.

[0092] Natural Polymers Particularly for nutritional supplement forms, so-called "natural polymer" coatings are preferred by many users. Natural polymers are based on natural, vegetable, microbial or animal sources, but may also be chemically modified. Natural polymers for coating may be selected from polymers such as starch, alginic acid or alginates, preferably sodium alginate, pectin, shellac, zein, carboxymethylzein, modified starches such as EUDRAGUARD® Natural, sponge collagen, chitosan, gellan gum, etc. Suitable polymer mixtures include: May include ethylcellulose and pectin, modified starch (EUDRAGUARD® Natural) and alginic acid and / or pectin, shellac and alginic acid 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.

[0093] Coating Layer The hard capsules are coated with a coating layer comprising the disclosed polymer or polymer mixture, and optionally excipients, preferably pharma- ceutical or nutraceutical acceptable excipients.

[0094] The 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 100% by weight of a polymer or polymer mixture disclosed herein. The coating layer may comprise 10-100, 10-90, 12-80, 15-70, 18-60, or 20-50% by weight of a polymer disclosed herein.

[0095] The coating layer may optionally comprise up to 10, up to 20, up to 30, up to 40, up to 50, up to 60, up to 70, up to 80, up to 90% by weight of excipients, preferably pharmaceutical and / or nutraceutical excipients (pharmaceutical or nutraceutical acceptable excipients). The coating layer may comprise 0-100, 10-90, 20-88, 30-85, 40-82 or 50-80% by weight of excipients, preferably pharmaceutical and / or nutraceutical excipients. The polymer or polymer mixture and any pharmaceutical and / or nutraceutical excipients may total 100%.

[0096] Amount and thickness of coating layer The amount of coating layer applied (= total weight increase of the coating layer) must be sufficient to fill the capillaries between the overlapping areas on the outside of the body covered by the cap. If too little coating layer is applied, there may be no or too little bridging. When the capsule is closed in the final locking stage, the amount of coating layer between the body and the cap may not be sufficient, which may result in insufficient airtightness and leakage of the capsule.

[0097] For hard capsules, the amount of coating layer should not be too high. If too much coating layer is applied, the polymer-coated pre-locked hard capsules may have difficulty in later processing in the capsule filling machine. The amount of coating layer should be less than 8mg / cm2. 2 Less than 1-8mg / cm 2 or 1-5mg / cm 2 or 1-4 mg / cm 2In this case, there is usually no problem with a standard capsule filling machine that has not been modified. 2 In this case, a capsule filling machine can still be used, but the shape of the body and cap must be adjusted to be slightly wider. Such adjustments can easily be made by a mechanical engineer. Thus, the coating layer amount is about 1 to about 8 mg / cm 2 Within this range, a capsule filling machine may be advantageously used.

[0098] For size #0 hard capsules, the amount of coating layer should not be too high. If too much coating layer is applied, the polymer-coated pre-locked hard capsules may have difficulty in later processing in the capsule filling machine. A coating layer amount of 5mg / cm 2 Less than 1-4mg / cm 2 In this case, there is usually no problem with a standard capsule filling machine that has not been modified. 2 In this case, a capsule filling machine can still be used, but the shape of the body and cap must be adjusted to be slightly wider. Such adjustments can easily be made by a mechanical engineer. Thus, the coating layer amount is about 1 to about 8 mg / cm 2 Within this range, a capsule filling machine can be advantageously used.

[0099] For size #1 hard capsules, the amount of coating layer should not be too high. If too much coating layer is applied, the polymer-coated pre-locked hard capsules may have difficulty in later processing in the capsule filling machine. A coating layer amount of 4mg / cm 2 Less than 1-3.5mg / cm 2 In this case, there is usually no problem with a standard capsule filling machine that has not been modified. 2 In this case, a capsule filling machine can still be used, but the shape of the body and cap must be adjusted to be slightly wider. Such adjustments can easily be made by a mechanical engineer. Thus, the coating layer amount is about 1 to about 8 mg / cm2 Within this range, a capsule filling machine may be advantageously used.

[0100] For size #3 hard capsules, the amount of coating layer should not be too high. If too much coating layer is applied, the polymer-coated pre-locked hard capsules may have difficulty in later processing in the capsule filling machine. A coating layer amount of 3 mg / cm 2 Less than 1-2.5mg / cm 2 In this case, there is usually no problem with a standard capsule filling machine that has not been modified. 2 In this case, a capsule filling machine can still be used, but the shape of the body and cap must be adjusted to be slightly wider. Such adjustments can easily be made by a mechanical engineer. Thus, the coating layer amount is about 1 to about 6 mg / cm 2 Within this range, a capsule filling machine may be advantageously used.

[0101] 8 mg / cm 2 ~about 20mg / cm 2 Up to about 100 mg / cm2 of the polymer-coated hard capsule can be carefully manually opened, filled, and closed to the pre-locked state without damaging the polymer coating. If the coating layer is thicker than the gap between the uncoated body and the cap, the cap can hardly slide past the body to the final locking state any more, and the coated pre-locked capsule cannot be closed without damaging the applied coating. The upper limit for the amount of coating layer that can be used to manually close a coated pre-locked hard capsule to the final locking state without damaging it is up to about 20 mg / cm2. 2 20mg / cm 2 Above this, it may no longer be possible to close the capsule manually without damage, even with great precision and care.

[0102] If too much coating layer is applied, when the gap between the body and the cap is in the pre-locking stage, too much of the coating layer will accumulate around the periphery of the cap. This may cause cracks in the coating layer after drying when the coated pre-locked hard capsule is manually or mechanically opened. These cracks may later cause capsule leakage. Finally, a coating that is too thick, or the coating layer is thicker than the gap between the body and the cap in the overlapping area, may cause problems in that the open coated hard capsule cannot be closed until the final locking stage.

[0103] Roughly speaking, the coating layer on the hard capsule is 0.7-20, 1.0-18, 2-10, 4-8, 1.0-8, 1.5-5.5, 1.5-4 mg / cm 2 (=total weight increase).

[0104] Generally, the coating layer on the hard capsule may have an average thickness of about 5-100, 10-50, 15-75 μm.

[0105] Generally, the coating layer on the hard capsule may be applied in an amount of 5 to 50, preferably 8 to 40, dry weight % based on the weight of the pre-locked capsule.

[0106] Those skilled in the art will be able to adjust for too little and too much coating layer amounts using this guideline.

[0107] Preferred Embodiments A first preferred embodiment comprises: The present invention discloses a method for producing a polymer-coated hard capsule suitable as a container for a pharmaceutical or nutraceutical bioactive ingredient, the hard capsule comprising a body and a cap, the cap overlapping the body in a pre-locked or final locked state in a closed stage, the hard capsule being provided in a pre-locked state and being spray-coated with a coating solution or dispersion comprising a polymer or a mixture of polymers to produce a coating layer covering the outer surface of the hard capsule in the pre-locked state, The coating layer is 60-90, preferably 70-85% by weight of a polymer blend and 10-40, preferably 15-30% by weight of a pharma- ceutically or nutraceutical acceptable excipient, the excipient comprising at least a plasticizer and an emulsifier, preferably glycerol monostearate (GMS), triethyl citrate (TEC) and polyoxyethylene (20)-sorbitan monooleate (polysorbate 80); the polymer blend and the pharma- ceutical or nutraceutical acceptable excipient total 100%, the polymer blend comprising 60-90, preferably 70-85, weight percent (meth)acrylate copolymer of 10-30 weight percent methyl methacrylate, 50-70 weight percent methyl acrylate, and 5-15 weight percent methacrylic acid polymerized (EUDRAGIT® FS) and 10-40, preferably 15-30, weight percent (meth)acrylate copolymer of 40-60 weight percent methacrylic acid, and 60-40 weight percent ethyl acrylate polymerized (EUDRAGIT® L100-55); The amount of the coating layer (total weight increase) is 1 to 8, preferably 1 to 4 mg / cm 2 It is.

[0108] The polymer-coated hard capsule of the first embodiment may be advantageously combined with ingredients such as the pharma- cifically active ingredients mesalamine or caffeine.

[0109] A second preferred embodiment comprises: The present invention discloses a method for producing a polymer-coated hard capsule suitable as a container for a pharmaceutical or nutraceutical bioactive ingredient, the hard capsule comprising a body and a cap, the cap overlapping the body in a pre-locked or final-locked state at the closing stage, the hard capsule being provided in a pre-locked state and being spray-coated with a coating solution or dispersion comprising a polymer or a mixture of polymers to produce a coating layer covering the outer surface of the hard capsule in the pre-locked state, The coating layer is 60 to 85, preferably 70 to 80 wt. % of a polymer; and 15-40, preferably 20-30% by weight of pharma- ceutically or nutraceutical acceptable excipients, the excipients including at least a plasticizer and an emulsifier, preferably glycerol monostearate, triethyl citrate and polysorbate 80; the polymer and pharma- ceutically or nutraceutical acceptable excipients total 100%, the polymer being a polymerized (meth)acrylate copolymer of 40-60% by weight methacrylic acid and 60-40% by weight ethyl acrylate (EUDRAGIT® L100-55); The amount of the coating layer (total weight increase) is 1 to 8, preferably 1 to 4 mg / cm 2 It is.

[0110] The polymer coated hard capsule of the second embodiment can be advantageously combined with contents such as the pharma- ceutical active ingredients metoprolol or omeprazole.

[0111] A third preferred embodiment comprises: The present invention discloses a method for producing a polymer-coated hard capsule suitable as a container for a pharmaceutical or nutraceutical bioactive ingredient, the hard capsule comprising a body and a cap, the cap overlapping the body in a pre-locked or final-locked state at the closing stage, the hard capsule being provided in a pre-locked state and being spray-coated with a coating solution or dispersion comprising a polymer or a mixture of polymers to produce a coating layer covering the outer surface of the hard capsule in the pre-locked state, The coating layer is 60 to 85, preferably 70 to 80 wt. % of a polymer; and 15-40, preferably 20-30% by weight of pharma- ceutically or nutraceutical acceptable excipients, the excipients including at least a plasticizer and an emulsifier, preferably glycerol monostearate, triethyl citrate and polysorbate 80; wherein the polymer and pharma- ceutical or nutraceutical acceptable excipients total 100%, the polymer being a polymerized (meth)acrylate copolymer of 10-30% by weight methyl methacrylate, 50-70% by weight methyl acrylate, and 5-15% by weight methacrylic acid (EUDRAGIT® FS); Here, the amount of the coating layer is 1 to 8, preferably 1 to 4 mg / cm. 2 It is.

[0112] The polymer coated hard capsule of the third embodiment may be advantageously combined with contents such as the pharma- ceutical active ingredients mesalamine or metoprolol.

[0113] bioactive ingredients The biologically active ingredient is preferably a pharma- ceutical active ingredient and / or a nutraceutical active ingredient.

[0114] Pharmaceutical or nutraceutical active ingredients The present invention is preferably useful for making pharmaceutical or nutraceutical dosage forms having immediate release, enteric or sustained release content of pharmaceutical or nutraceutical active ingredients.

[0115] Suitable pharmacological and chemical classes of medicament active ingredients which can be used as the content of the mentioned polymer-coated hard capsules are e.g. analgesics, antibiotics or anti-infectives, antibodies, antiepileptics, plant-derived antigenic drugs, antirheumatic drugs, benzimidazole derivatives, beta-blockers, cardiovascular drugs, chemotherapeutic drugs, central nervous system drugs, digitalis glycosides, gastrointestinal drugs such as proton pump inhibitors, enzymes, hormonal drugs, liquid or solid natural extracts, oligonucleotides, peptide hormone proteins, therapeutic bacteria, peptides, protein (metal) salts, i.e. aspartates, chlorides, orthates, urological drugs, vaccines.

[0116] Further examples of drugs that can be used as the contents of the described polymer-coated hard capsules include, for example, acamprosate, aescin, amylase, acetylsalicylic acid, adrenaline, 5-aminosalicylic acid, aureomycin, bacitracin, balsalazine, beta-carotene, bicalutamide, bisacodyl, bromelain, budesonide, calcitonin, carbamazepine, carboplatin, cephalosporins, cetrorelix, clarithromycin, chloromycetin, cimetidine, cisapride, cladrivir. , clorazepate, cromalin, 1-deaminocysteine-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, kainin, memantine, mesalamine, methenamine, miramerin, minerals, minoprazole, naproxen, natamycin, nitrofurantoin, novobiocin, olsalazine, omeprazole, orotic acid, pancreatin, pantoprazole, parathyroid hormone, paroxetine, penicillin, penicillin Luprazole, pindolol, polymyxin, potassium, pravastatin, prednisone, proglumetacin, 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, isomorphs, or any type of mixture or combination thereof.

[0117] It is clear to those skilled in the art that there is a wide overlap between the terms pharma- ceutical and nutraceutical active ingredients, pharma- ceutical and nutraceutical excipients, pharma- ceutical and nutraceutical compositions, and between pharmaceutical or nutraceutical dosage forms. Many substances listed as nutraceuticals can also be used as pharma- ceutical active ingredients. Depending on the specific application and local government laws and classifications, the same substance may be listed as a pharma- ceutical or nutraceutical active ingredient, a pharma- ceutical or nutraceutical composition, or both, respectively.

[0118] Nutraceuticals are well known to those skilled in the art. Nutraceuticals are often defined as dietary extracts that have medical effects on human health. Thus, nutraceutical active ingredients may also exhibit pharmaceutical activity, and examples of nutraceutical active ingredients include resveratrol from grape products as an antioxidant, soluble dietary fiber products such as psyllium seed husks to reduce hypercholesterolemia, broccoli (sulfanes) as a cancer prevention agent, and soybeans or clover (isoflavonoids) to improve arterial health. Thus, it is clear that many substances listed as nutraceuticals can also be used as pharmaceutical active ingredients.

[0119] Exemplary dietary supplements or nutraceutical active ingredients that can be used as the contents of the described polymer-coated hard capsules can also include probiotics and prebiotics. Probiotics are live microorganisms that are believed to maintain human or animal health when consumed. Prebiotics are dietary supplements or nutraceutical active ingredients that induce or promote the growth or activity of beneficial microorganisms in the intestines of humans or animals.

[0120] Examples of dietary supplements are resveratrol from grape produce, omega-3 fatty acids or proanthocyanins from blueberries as antioxidants, soluble dietary fiber products such as psyllium seed husks to lower hypercholesterolemia, broccoli (sulfanes) as cancer preventatives, and soy or clover (isoflavonoids) to improve arterial health. Other examples of dietary supplements are flavonoids, antioxidants, alpha-linoleic acid from flaxseed, beta-carotene from marigold petals, or anthocyanins from berries. The terms neutraceutical and nutriceutical are sometimes used as synonyms of nutraceutical.

[0121] Preferred bioactive ingredients are metoprolol, mesalamine and omeprazole.

[0122] Excipients Excipients are well known to those skilled in the art and are often made with the bioactive ingredients contained in the coated hard capsule and / or the polymeric coating of the hard capsule as disclosed and claimed herein. All excipients used must be toxicologically safe and may be used in pharmaceutical or dietary supplement products without posing a risk to the patient or consumer.

[0123] The dosage form may comprise an excipient selected from the group of antioxidants, glazing agents, binders, flavorings, flow aids, fragrances, glidants, permeation enhancers, dyes, plasticizers, emulsifiers, pore formers or stabilizers, or combinations thereof, and preferably comprises a pharma- ceutically or nutraceutical acceptable excipient. The pharma- ceutically or nutraceutical acceptable excipient may be included in the core and / or coating layer comprising the disclosed polymer. A pharma- ceutically or nutraceutical acceptable excipient is an excipient that is approved for use in pharmaceutical or nutraceutical applications.

[0124] The coating layer may contain up to 90, up to 80, up to 70, up to 50, up to 60, up to 50, up to 40, up to 30, up to 20, up to 10% by weight of excipients, respectively pharma- ceutically or nutraceutical acceptable excipients, or no excipients at all (0%). Preferably, no additional (excipient) polymers are present in the coating layer, except for the polymer or polymer mixture of the coating layer.

[0125] Plasticizer The polymer coating of the hard capsule may contain one or more plasticizers, which, depending on the amount added, lower the glass transition temperature by physical interaction with the polymer and promote film formation. Suitable materials usually have a molecular weight of 100 to 20,000 and contain one or more hydrophilic groups in the molecule, such as hydroxyl, ester or amino groups.

[0126] Examples of suitable plasticizers are alkyl citrates, glycerol esters, alkyl phthalates, alkyl sebacates, sucrose esters, sorbitan esters, diethyl sebacate, dibutyl sebacate, propylene glycol and polyethylene glycol 200-12,000. Preferred plasticizers are triethyl citrate (TEC), acetyl triethyl citrate (ATEC), diethyl sebacate and dibutyl sebacate (DBS). Further esters that are normally liquid at room temperature, such as citrates, phthalates, sebacates or castor oil, are included. Esters of citric acid and sebacic acid are preferably used. Glycerol monostearate (GMS) has plasticizing properties. Glycerol monostearate (GMS) also has some properties of a glidant and may be designed as a glidant, but in this disclosure it is meant as a plasticizer.

[0127] The plasticizer can be added directly to the aqueous solution or added to the formulation after preliminary heat treatment of the mixture in a known manner. Mixtures of plasticizers can also be utilized. However, since the polymers disclosed herein exhibit a minimum film-forming temperature (MFFT) of 35° C. or less, they can be applied as a polymer coating, for example an aqueous polymer dispersion, without the addition of plasticizers. The polymer coating of the hard capsule can preferably contain up to 60, up to 30, up to 25, up to 20, up to 15, up to 10, up to 5, less than 5% by weight of one or more plasticizers, calculated on the polymer or polymer mixture, or can be completely free of plasticizers (0%). Most preferably, the coating layer contains 20-30% by weight of a mixture of glycerol monostearate (GMS) and triethyl citrate, calculated on the polymer or polymer mixture.

[0128] filling Standard fillers are usually added to the formulations of the present invention during the processing step for coatings and binders. The amounts introduced and the use of standard fillers in pharmaceutical coatings or surfaces are well known to those skilled in the art. Examples of standard fillers are release agents, dyes, stabilizers, antioxidants, pore formers, permeation enhancers, gloss agents, fragrances or flavorings. They are used as process adjuvants and are intended to ensure reliable and reproducible manufacturing methods and good long-term storage stability or to achieve further advantageous properties in the pharmaceutical dosage form. They are added to the polymer formulation before processing and can affect the permeability of the coating. This property can be used as an additional control parameter if necessary.

[0129] Flow promoter (mold release agent): Glidants or release agents are usually lipophilic and are usually added to the spray suspension. They prevent the core from agglomerating during film formation. Suitable glidants are talc, Mg or Ca stearates, powdered silica, kaolin or non-ionic emulsifiers with HLB values ​​of 2-8. The typical proportions of release agents and binders used in the coating of the present invention range from 0.5 to 100% by weight relative to the polymer.

[0130] In a particularly advantageous embodiment, the glidant or release agent is added to the outer layer in concentrated form, either in powder form or by spraying from an aqueous suspension having a solids content of 5-30% (weight / weight (w / w)). The required concentration is lower than that required for incorporation into the polymer layer, in amounts of 0.1-2% by weight relative to the weight of the pharmaceutical form.

[0131] The coating layer of the dosage form may for example comprise 20-80, preferably 30-70 wt.% of the disclosed inventive polymer and 20-80, 30-70 wt.% of talc. The inventive polymer and talc may total up to 100 wt.%.

[0132] pigment Very rarely, pigments are added in soluble form. Generally, pigments such as aluminum oxide or iron oxide pigments are used in dispersed form. Titanium dioxide is used as a white pigment. Standard pigment use rates are 10-200, 20-200% by weight based on the polymer or polymer mixture in the coating layer. A rate of up to 200% by weight calculated on the polymer or polymer mixture allows for easy processing.

[0133] In a particularly advantageous embodiment, the dyes are used as such in concentrated form as an additional outer layer, the so-called topcoat, either in powder form or by spraying from an aqueous suspension with a solids content of 5-35% (w / w). The required concentration is lower than that required for incorporation into the polymer layer, amounting to 0.1-2% by weight relative to the weight of the pharmaceutical form.

[0134] Optional topcoat and subcoat Optionally, the hard capsule may be further coated with a subcoat or a topcoat or both.

[0135] A subcoat can be disposed between the capsule and the coating layer, comprising the disclosed polymer or polymer mixture. The subcoat essentially has no effect on the release characteristics of the active ingredient, but can, for example, improve the adhesion of the polymer coating layer. The subcoat is preferably essentially water-soluble and may, for example, consist of a material such as HPMC as a film former. The average thickness of the subcoat layer is usually very thin, for example, less than 15 μm, preferably less than 10 μm (0.1-0.6 mg / cm). 2 A subcoat or topcoat does not necessarily have to be applied to the pre-locked hard capsule.

[0136] A topcoat can be disposed on the coating layer comprising the disclosed polymer or polymer mixture. The topcoat is preferably water-soluble or essentially water-soluble. The topcoat may have the function of coloring the pharmaceutical or nutraceutical dosage form or protecting it from environmental influences, e.g. moisture during storage. The topcoat may consist of a binder, e.g. a water-soluble polymer such as polysaccharide or HPMC, or a sugar compound such as sucrose. The topcoat may further contain a large amount of pharma- ceutically or nutraceutical acceptable excipients, such as dyes or glidants. The topcoat does not essentially affect the release characteristics. A topcoat may be applied on the pharmaceutical or nutraceutical dosage form comprising the polymer-coated hard capsule in the final locking stage described herein. The average thickness of the topcoat layer is usually very thin, e.g. 15 μm or less, preferably 10 μm or less (0.1-0.6 mg / cm). 2 ).

[0137] Method for producing coated hard capsules A method is described for producing a polymer-coated hard capsule suitable as a container for pharmaceutical or nutraceutical bioactive ingredients, the hard capsule comprising a body and a cap, in a closed state, the cap overlapping the body in a pre-locked or final-locked state, the hard capsule being provided in a pre-locked state and being spray-coated with a coating solution, suspension or dispersion comprising a polymer or a mixture of polymers to produce a coating layer covering the outer surface of the hard capsule in the pre-locked state.

[0138] In a further method step, the prelocked hard capsule is provided with a fill containing a pharmaceutical or nutraceutical bioactive ingredient and closed to a final locking state.

[0139] In such a further method step, the polymer coated hard capsule in the pre-locked state is opened, filled with a fill comprising a pharmaceutical or nutraceutical bioactive ingredient and closed to a final locking state. Preferably, in this further method step, the coated hard capsule in the pre-locked state is fed to a capsule filling machine which opens the capsule, fills with a fill comprising a pharmaceutical or nutraceutical bioactive ingredient and closes the polymer coated hard capsule to a final locking state.

[0140] This additional process step produces a final locked polymer coated hard capsule that is a container for a pharmaceutical or nutraceutical bioactive ingredient. The final locked polymer coated hard capsule that is a container for a pharmaceutical or nutraceutical bioactive ingredient is a pharmaceutical or nutraceutical dosage form.

[0141] The pharmaceutical or nutraceutical dosage form comprises a polymer-coated hard capsule in a final locking stage, the polymer-coated hard capsule containing a fill containing a pharmaceutical or nutraceutical bioactive ingredient, the polymer-coated hard capsule comprising a coating layer comprising a polymer or polymer mixture, the coating layer covering an outer surface region of the capsule in a pre-locking stage but not covering an overlap region where the cap overlaps the body in the pre-locking stage.

[0142] The coating solution containing the polymer or polymer mixture and optional excipients may be a solution of the polymer in an organic solvent such as acetone, isopropanol or ethanol. The concentration of the dry material in the organic solvent may be about 5-50% by weight of the polymer. A suitable spray concentration is about 5-25% by dry weight.

[0143] The coating dispersion may be a dispersion of the polymer or polymer mixture and optional excipients in an aqueous medium, such as water or a mixture of 80% or more by weight of water and 20% or less by weight of a water-soluble solvent such as acetone or isopropanol. A suitable concentration of dry material in the aqueous medium may be about 5-50% by weight. A suitable spray concentration may be about 5-25% by dry weight.

[0144] Spray coating is preferably carried out by spraying the coating solution or dispersion onto the pre-lock capsules in a drum coater or fluidized bed coating equipment.

[0145] Method for Producing Fill for Dosage Form Suitable methods for producing the fill for pharmaceutical or nutraceutical forms are well known to those skilled in the art. A suitable method for producing the fill for pharmaceutical or nutraceutical forms disclosed herein is by forming a core containing the bioactive ingredient in pellet form by direct compression, compression of dry, wet or sintered granules, by extrusion followed by rounding, by wet or dry granulation, by direct pelleting, or by binding powders to beads or neutral cores without active ingredient or particles or pellets containing active ingredient, optionally by applying a coating layer in the form of an aqueous dispersion or organic solution by spraying, or by fluidized bed spray granulation.

[0146] Use / method of use / method steps The method of making the suitable polymer-coated hard capsule described herein may also be understood as a method of using a hard capsule comprising a body and a cap, in a closed state, the cap overlapping the body in a pre-locked or final-locked state, and the production of a polymer-coated hard capsule suitable as a container for a pharmaceutical or nutraceutical bioactive ingredient, includes the steps of: a) providing a pre-locked hard capsule; b) spray-coating with a coating solution, suspension or dispersion containing a polymer or a mixture of polymers to produce a coating layer covering the outer surface of the pre-locked hard capsule.

[0147] Preferably, spray coating may be performed using a drum coater or a fluidized bed coating apparatus. A suitable product temperature during the spray coating process may be about 15-40, preferably about 20-35°C. A suitable spray rate may be about 0.3-4.0, preferably 0.5-3.9 (g / min / kg). After spray coating, a drying step is included.

[0148] The pre-locked polymer coated hard capsule may be opened in step c) and filled with a fill containing a pharmaceutical or nutraceutical bioactive ingredient in step d) and then closed to final lock in step e).

[0149] Steps c) to e) may be performed manually or, preferably, by means of a suitable apparatus, such as a capsule filling machine. Preferably, the coated hard capsules in a pre-locked state are fed to a capsule filling machine which opens the capsule in step c), fills it with a fill containing a pharmaceutical or nutraceutical bioactive ingredient in step d) and closes the capsule to a final lock in step e).

[0150] All general or specific feature and method selections in the embodiments disclosed herein can be combined, without limitation, with any other general or specific material or numerical feature and embodiment selections disclosed herein, such as polymers, capsule materials, capsule sizes, coating thicknesses, bioactive ingredients, and any other embodiments disclosed.

[0151] Pharmaceutical or nutritional supplement forms Disclosed is a pharmaceutical or nutraceutical dosage form comprising a final locked polymer coated hard capsule containing a fill comprising a pharmaceutical or nutraceutical bioactive ingredient, the polymer coated hard capsule including a coating layer comprising a polymer or polymer mixture, the coating layer covering an exterior surface area of ​​the pre-locked capsule, whereby the exterior surface area of ​​the pre-locked capsule is greater than the exterior surface area of ​​the final locked capsule such that a portion of the polymer coating layer is hidden or nested between the body and cap of the hard capsule, thereby providing an efficient seal.

[0152] item The present invention relates to the following items. This disclosure should be understood by those skilled in the art in a broad sense as including, without limitation, any possible combination of any single item or any possible combination with any other item or other items.

[0153] Item 1: A method for producing a polymer-coated hard capsule suitable as a container for pharmaceutical or nutraceutical bioactive ingredients, wherein the hard capsule comprises a body and a cap, and in a closed state, the cap overlaps the body in a pre-locked or final-locked state, and the hard capsule is provided in a pre-locked state and is spray-coated with a coating solution, suspension or dispersion comprising a polymer or a mixture of polymers to produce a coating layer covering the outer surface of the hard capsule in the pre-locked state.

[0154] 2. The method according to item 1, wherein the polymer-coated hard capsule in the pre-locked state is opened, filled with a fill containing a pharmaceutical or nutraceutical bioactive ingredient, and closed to the final lock state.

[0155] 3. The method according to one or both of items 1 and 2, wherein the coated hard capsules in a pre-locked state are fed to a capsule filling machine which opens the capsules, fills them with a fill containing a pharmaceutical or nutraceutical bioactive ingredient, and closes the polymer-coated hard capsule to a final locking state.

[0156] 4. The method according to one or more of items 1 to 3, wherein the 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.

[0157] 5. The method according to one or more of items 1 to 4, wherein the polymer or polymer mixture in the coating layer is selected from the group of anionic polymers, cationic polymers or neutral polymers.

[0158] 6. The method according to one or more of items 1 to 5, wherein the polymer or polymer mixture in the coating layer is an anionic polymer selected from the group of (meth)acrylate copolymers and celluloses.

[0159] 7. The method according to one or more of items 1 to 6, wherein the anionic polymer in the coating layer is a copolymer of 25 to 95, preferably 40 to 95 and in particular 60 to 40 wt.-% of free-radically polymerized C1-C12 alkyl esters, preferably C1-C4 alkyl esters, of acrylic or methacrylic acid and 75 to 5, preferably 60 to 5 and in particular 40 to 60 wt.-% of (meth)acrylate monomers having an anionic group.

[0160] 8. The method according to one or more of items 1 to 7, wherein the polymer or polymer mixture in the coating layer comprises a cationic (meth)acrylate copolymer.

[0161] 9. The method according to one or more of items 1 to 8, wherein the cationic (meth)acrylate copolymer is polymerized from a monomer comprising a C1-C4 alkyl ester of acrylic acid or methacrylic acid and an alkyl ester of acrylic acid or methacrylic acid having a tertiary or quaternary ammonium group in the alkyl group.

[0162] 10. The method according to one or more of items 1 to 8, wherein the polymer or polymer mixture in the coating layer is selected from starch, alginic acid or an alginate, sodium alginate, pectin, shellac, zein, carboxymethylzein, modified starch, sponge collagen, chitosan, gellan gum, ethylcellulose and pectin, modified starch and alginic acid and / or pectin, shellac and alginic acid and / or pectin, shellac and inulin, whey protein and gum, zein and polyethylene glycol, sodium alginate and chitosan.

[0163] 11. The method according to one or more of items 1 to 10, wherein the body and the cap have an annular notch and / or a recess in the area where the cap overlaps the body, closing the capsule in the pre-locked or final locked state by a snap-fit ​​mechanism.

[0164] 12. The method according to one or more of items 1 to 11, wherein the body has a tapered periphery.

[0165] 13. The coating layer is approximately 0.7-20, 1.0-18, 2-10, 4-8, 1.0-8, 1.5-5.5, 1.5-4 mg / cm 2 The method according to one or more of items 1 to 12, wherein the amount of

[0166] 14. The method according to one or more of items 1 to 13, wherein the polymer in the coating layer is a core-shell polymer having 70-80 wt. % of a core comprising 65-75 wt. % of polymerized units of ethyl acrylate and 25-35 wt. % of methyl methacrylate and 20-30 wt. % of a shell comprising 45-55 wt. % of ethyl acrylate and 45-55 wt. % of methacrylic acid, the copolymer being obtained by a two-stage emulsion polymerization process.

[0167] 15. A polymer-coated hard capsule obtainable by the method according to one or more of items 1 to 14.

[0168] 16. A pharmaceutical or nutraceutical dosage form according to item 16, comprising a polymer-coated hard capsule in a final locking stage containing a fill comprising a pharmaceutical or nutraceutical bioactive ingredient, the polymer-coated hard capsule comprising a coating layer comprising a polymer or a mixture of polymers, the coating layer covering an outer surface region of the capsule in the pre-locking stage.

[0169] 17. The pharmaceutical or nutraceutical dosage form according to item 16, which after 120 minutes in 0.1N HCl, pH 1.2, is changed to a buffer solution of pH 6.8 or pH 7.4 (according to USP, e.g. USP 40), about 80% or more of the pharmaceutical or nutraceutical bioactive ingredient is released after a total of 165 minutes (120 + 45 minutes). The dissolution test is performed using USP Apparatus II, according to the United States Pharmacopeia (USP 40), at a paddle speed of 75 rpm. <711> The temperature of the test liquid should be adjusted to 37±0.5°C. Samples should be taken at appropriate times.

[0170] 18. The pharmaceutical or nutraceutical dosage form according to item 16 or 17, which is subjected to 120 minutes in 0.1N HCl, pH 1.2, followed by a change to a buffer of pH 6.5 or 6.8 for 60 minutes, and then a final change to a buffer of pH 7.2 or pH 7.4, such that at least about 80% of the bioactive ingredient is released after a total of 225 minutes or 240 minutes. The dissolution test is performed using USP Apparatus II, at a paddle speed of 75 rpm, according to the United States Pharmacopeia (USP 40). <711> The temperature of the test liquid should be adjusted to 37±0.5°C. Samples should be taken at appropriate times.

[0171] Working Example Polymers used in the examples: EUDRAGIT® FS is a copolymer of 25% by weight methyl methacrylate, 65% by weight methyl acrylate, and 10% by weight methacrylic acid. EUDRAGIT® FS30D is an aqueous dispersion containing 30% by weight EUDRAGIT® FS.

[0172] EUDRAGIT® L100-55 is a copolymer of 50% by weight ethyl acrylate and 50% by weight methacrylic acid. EUDRAGIT® L30D-55 is an aqueous dispersion containing 30% by weight EUDRAGIT® L100-55.

[0173] EUDRAGIT® NE is a copolymer containing free radically polymerized units of 30% by weight methyl methacrylate and 70% by weight ethyl acrylate. EUDRAGIT® NE30D is an aqueous dispersion containing 30% by weight EUDRAGIT® NE.

[0174] EUDRAGIT® EPO is a powdered copolymer of 25% by weight methyl methacrylate, 25% by weight butyl methacrylate, and 50% by weight dimethylaminoethyl methacrylate.

[0175] Example 1 1 shows the average dimensions and deviations of pre-locked and locked capsules for various commercially available capsules.

[0176] [Table 1]

[0177] [Table 2]

[0178] Example 2 - Surface area calculations and colon-targeted coating of pre-locked capsules using a drum coater For a particular coating layer thickness, the required amount of coating material depends on the surface area of ​​the material, since it is necessary to achieve the desired membrane function. For this reason, the amount of coating material is determined per cm 2 of substrate surface area. 2 Below is the equation for the surface area of ​​a pre-locked capsule, taking into account the average difference in the pre-locked and mated lengths of the separate capsule parts, the body and the cap:

[0179]

number

[0180] Calculation of coating formulation for functional enteric coating of reserve-lock capsules.

[0181]

number

[0182] Furthermore, the coating formulation may contain, in addition to the polymer, further suitable excipients such as plasticizers, anti-tack agents, etc. Suitable amounts of excipients (E i To calculate the weight gain, the amount % of each excipient needs to be calculated based on the dry polymer material. To calculate the total weight gain, the polymer weight gain needs to be multiplied by a factor (E).

[0183]

number

[0184] Calculation example 2 for the outer surface of the capsule in the pre-lock state

[0185] [Table 3]

[0186] FIG. 2 shows a schematic diagram of the body (left) and cap (right) of a hard capsule, Vcaps® Plus size 1, with relative dimensions in mm. These dimensions are used to calculate the capsule outer surface in the pre-locked state in calculation example 2. The dimensions are: Body: Length = 16.61 mm, Cylinder (length of cylindrical part) = 13.29 mm, Outer diameter = 6.63 mm Cap: Length = 9.78 mm, cylinder (length of cylindrical part) = 6.32 mm, outer diameter = 6.91 mm.

[0187]

number

[0188] [Table 4]

[0189] Dry polymer content:

[0190]

number

[0191] Total dry matter:

[0192]

number

[0193] Formulation Example 2 for Colon Targeting Using Size 1 Vcaps®plus EUDRAGIT® FS30D and EUDRAGIT® L30D-55 are aqueous polymer dispersions each having a polymer content of 30% by weight. The polymer dispersions EUDRAGIT® FS30D and EUDRAGIT® L30D-55 were mixed in a container. The excipients were added to the water with gentle stirring. The excipient suspension was added to the polymer dispersion mixture. The spray suspension was gently stirred during the coating process.

[0194] A drum coater was used to coat pre-locked Vcaps®plus size 1 capsules. The capsules were then manually filled with 200 mg of caffeine and closed to final lock.

[0195] [Table 5]

[0196] [Table 6]

[0197] LOD Capsule before coating 4.1% Capsule intermediate sample 2.5mg / cm 2 4.7% Capsule final sample 5mg / cm 2 4.6%

[0198] Dissolution test method: Equipment: ERWEKA DT 700 paddle equipment (USPII) Detection method: Online UV Temperature: 37.5℃ Test solution I: 700 ml of 0.1 N HCl adjusted to pH 1.20 (using 2 N NaOH and 2 N HCl) Test solution II: After 2 hours in test solution I, 194 ml of 0.2N Na3PO4 solution was added to raise the pH to 6.5 (pH was fine-tuned using 2N NaOH and 2N HCl). Test solution III: After another hour in test solution II, 67 ml of 0.2N Na3PO4 solution is added to raise the pH to 7.2 (pH is again fine-tuned using 2N NaOH and 2N HCl). Paddle speed: 75 rpm

[0199] [Table 7]

[0200] Another example of using polymer blends for colonic targeting. The results show good in vitro evaluation of resistance in stomach (pH 1.2) and upper small intestine (pH 6.5), as well as release at ileocecal valve / colon at pH 7.4. The coating process is well established and avoids significant water absorption of the capsule shell.

[0201] Example 3 - Enteric coating of pre-locked capsules with a drum coater EUDRAGIT® L30D-55 is provided as a 30% by weight aqueous polymer dispersion. Additional excipients were added to the water with gentle stirring. The excipient suspension was added to the polymer dispersion. The spray suspension was gently stirred during the coating process. The pre-locked capsules were coated using a drum coater. The capsules were then manually filled with 200 mg of caffeine and closed to final lock.

[0202] [Table 8]

[0203] [Table 9]

[0204] Dissolution Test Polymer-coated pre-locked capsules were manually filled with 200 mg of caffeine, closed to final lock, and subjected to dissolution testing.

[0205] method: Equipment: ERWEKA DT 700 paddle equipment (USPII) Detection method: Online UV Temperature: 37.5℃ Test solution I: 700 ml of 0.1 N HCl adjusted to pH 1.2 (using 2 N NaOH and 2 N HCl) Test solution II: After 2 hours in test solution I, 214 ml of 0.2N Na3PO4 solution was added to raise the pH to 6.8 (pH was fine-tuned using 2N NaOH and 2N HCl). Paddle speed: 75 rpm

[0206] [Table 10]

[0207] Example C4 (Comparative) - Fluid Bed Coating of Separate Capsule Parts (Body and Cap) EUDRAGIT® FS30D is provided as a 30% by weight aqueous polymer dispersion. The excipients were added to the water with gentle stirring. The suspension of excipients was added to the polymer dispersion. The spray suspension was gently stirred during the coating process.

[0208] The pre-locked capsules were coated using a fluid bed coater, and then the capsules were manually filled with 200 mg of caffeine.

[0209] [Table 11]

[0210] [Table 12]

[0211] Capsule roundness test for body and cap Device: Optical microscope ZEISS AXIO Zoom.V16 Objective lens ZEISS PlanNeoFluar Z 1x / 0.25 FWD 56mm Light source SCHOTT MC 1500 Incident light - ring light SCHOTT S80-55 Camera ZEISS Axiocam 503 color Software AxioVision SE64 Image analysis software Olympus Soft Imaging solutions GmbH

[0212] Sample preparation: The capsule parts, cap and body, were analyzed separately. For each test, n=10 samples per part were tested. Therefore, the capsule parts were placed in a sample holder with an open end in a vertical upward direction. The samples were then analyzed with the above-mentioned equipment.

[0213] Testing of samples: The microscope is adjusted to a magnification of 10x and the focal range is adjusted to the capsule shell so that it is viewed vertically downward. The capsule position is adjusted to avoid shadows in non-vertical positions. As the focal range is related, the light intensity and contrast should be adjusted appropriately.

[0214] Imaging and tabulation of results: The images were recorded as black and white images (Figure 3 for the capsule body and Figure 4 for the cap) and transferred to a scandium database. The software toolbox was used to select the perimeter of the capsule shell to be examined from below vertically. The area (mm 2 ), Feret diameter and perimeter were detected and calculated. Feret diameter is the dimension of an object along a particular direction. It can generally be defined as the distance between two parallel planes that bound the object perpendicular to that direction. It is therefore also called caliper diameter and refers to the size of an object measured using calipers. Perimeter area (mm2 The results are reported in the following table summarizing the minimum, maximum, mean and standard deviation of the Feret diameter and length. A total of 20 measurements were repeated for each capsule cap and body sample. The shape factor used was the aspect ratio, which is a function of the maximum diameter and the minimum diameter perpendicular to it.

[0215]

number

[0216] The normalized aspect ratio is approximately 1 for undeformed uncoated capsules and increases with the degree of deformation.

[0217] [Table 13]

[0218] SEM analysis SEM examination of the coated separate capsule parts, body and cap, showed that cracks formed at the tapered periphery. Furthermore, macroscopic and scanning microscope images showed that the separately coated cap and body exhibited a tendency to undergo significant deformation during the coating process that appeared to be irreversible. Such deformations make the manual encapsulation process difficult and presumably make an automated encapsulation process unfeasible, since only selected caps and bodies fit together. Thus, fluidized bed coating of capsules separately is not a suitable process for producing capsules with automated capsule filling.

[0219] The described formula and process of manual encapsulation resulted in a rejection rate of 85% considering first-time-right encapsulation. The following dissolution tests were performed with first-time-right filled capsules. First-time-right means that the capsules are filled in the first run and then closed.

[0220] Dissolution Test Capsules were manually filled with 200 mg of caffeine.

[0221] method: Equipment: ERWEKA DT 700 paddle equipment (USPII) Detection method: Online UV Temperature: 37.5℃ Test solution I: 700 ml of 0.1 N HCl adjusted to pH 1.20 (using 2 N NaOH and 2 N HCl) Test solution II: After 2 hours in test solution I, 214 ml of 0.2N Na3PO4 solution was added to raise the pH to 6.8 (pH was fine-tuned using 2N NaOH and 2N HCl). Test Solution III: After another hour in Test Solution II, 46 ml of 0.2N Na3PO4 solution is added to raise the pH to 7.4 (pH is again fine-tuned using 2N NaOH and 2N HCl). Paddle speed: 75 rpm

[0222] [Table 14]

[0223] Example 5 - Enteric coated pre-lock capsules and automatic capsule filling with drum coater To calculate the maximum weight gain suitable for the encapsulation process, the maximum layer thickness was estimated as being equal to the gap width between the capsule cap and body of the pre-locked or final-locked capsule. In Example 11, the average gap width of the Vcaps®Plus capsules was calculated to be 50 μm. Furthermore, the absolute density of the coating was calculated to be about 1 mg / cm 3 and this value was confirmed by scanning electron microscope examination of the samples.

[0224]

number

[0225] [Table 15]

[0226] The EUDRAGIT® polymer was mixed in a suitable sized container. Additional excipients were added to the water with gentle stirring. After a suitable time after stirring, the excipient suspension was added to the polymer dispersion. The spray suspension was gently stirred during the coating process. The pre-locked capsules were coated using a drum coater.

[0227] [Table 16]

[0228] [Table 17]

[0229] Encapsulation parameters Polymer coated pre-locked capsules were filled with 400 mg of a 50:50 blend of MCC and caffeine on an automated MG2Labby capsule filling machine using standard style powder filling equipment for size 0 that opened, transferred, filled and closed the capsules. The machine output was set at 2000 cps / hr.

[0230] The capsules were tested on an automatic capsule filling machine and showed total solids weight gains of 2.6 and 3.9 mg / cm 2 The total solids weight gain was 5.1 mg / cm 2 In the past, standard equipment was limited and could not operate with pre-locked capsules due to the increased layer thickness. 2 If the capsule diameter increases by more than 0.1, then modified tooling is required for testing to account for the increase in capsule diameter.

[0231] Explanation of SEM analysis of the body and cap Compared to coating separate capsules with a liquid, coating the pre-locked capsules allows the capsules to be filled better. Compared to separate capsule members, the pre-locked capsules have the advantage of providing better machine stability. Furthermore, coated pre-locked capsules ensure that the two capsule members fit together during the filling process. Furthermore, the tapered periphery remains intact, allowing the cap to slide over the body until the capsule is finally locked. It has been found that even if both members are slightly bridged, the pre-locked coated tablets can still be separated by the capsule filling machine.

[0232] Dissolution Test method: Equipment: ERWEKA DT 700 paddle equipment (USPII) Detection method: Online UV Temperature: 37.5℃ Test solution I: 700 ml of 0.1 N HCl adjusted to pH 1.20 (using 2 N NaOH and 2 N HCl) Test solution II: After 2 hours in test solution I, 214 ml of 0.2N Na3PO4 solution was added to raise the pH to 6.8 (pH was fine-tuned using 2N NaOH and 2N HCl). Paddle speed: 75 rpm

[0233] [Table 18]

[0234] Examples 6-9 - Enteric Coating and Colon Targeting of Pre-Locked Capsules with a Fluid Bed Coater Fluid bed coating examples and manual capsule filling The EUDRAGIT® polymer was mixed in a container. Additional excipients were added to the water with gentle stirring. After a suitable time after stirring, the excipient suspension was added to the polymer dispersion. The spray suspension was gently stirred during the coating process. The pre-locked capsules were coated using a fluid bed coater. The capsules were then manually filled with 200 mg of caffeine before being closed to final lock.

[0235] [Table 19]

[0236] Example 10 - Moisture prevention

[0237] [Table 20]

[0238] The sodium lauryl sulfate, stearic acid, and EUDRAGIT® EPO were stirred in the water using a dissolver plate until a pale yellow cloudy solution was obtained, approximately 1-1.5 hours. The talc was added to the polymer solution and homogenized with a dissolver plate for 15 minutes.

[0239] Process parameters Approximately 70-100 grams of pre-locked HPMC capsules were taken and loaded into a fluid bed coater (Pam Glatt GPCG1.1) using a Wurster component.

[0240] [Table 21]

[0241] Dissolution Test: method: Equipment: ERWEKA DT 700 paddle equipment (USPII) Detection method: Online UV Temperature: 37.5℃ Test solution I: 700 ml of 0.1 N HCl adjusted to pH 1.20 (using 2 N NaOH and 2 N HCl) Test solution II: 700 ml of phosphate buffer adjusted to pH 4.5 (using 2N NaOH and 2N HCl) Test solution III: 700 ml of phosphate buffer adjusted to pH 6.8 (using 2N NaOH and 2N HCl) Paddle speed: 75 rpm

[0242] Coat the capsules for dissolution testing to a total solids weight of 7.2 mg / cm 2 They were increased, manually filled with 200 mg of caffeine, and tested.

[0243] [Table 22]

[0244] Moisture absorption study EPO-coated HPMC capsules, either filled or unfilled with silica, were stored in a desiccator containing supersaturated potassium chloride solution at 20 ± 2 °C / 84 ± 5% RH.

[0245] [Table 23]

[0246] [Table 24]

[0247] This example also demonstrates the capabilities of the concept for moisture-resistant coatings. Silica-filled, locked capsules show significantly reduced water adsorption upon storage in a desiccator. This example demonstrates the capabilities of the concept especially for moisture-sensitive formulations.

[0248] Example 11 - Average Gap Width of Vcaps® Plus Hard Capsules As an example, the gap width between the capsule body and the cap in the pre-locked or final locked state for all sizes of Vcaps® Plus hard capsules was calculated based on a capsule cap wall thickness of 100 μm as described in the Capsugel product catalog (Dominique Cade; Vcaps® Plus Capsules - A New HPMC Capsule for Optimum Formulation). The capsule cap wall thickness was subtracted from the capsule cap outer diameter to obtain the capsule cap inner diameter. In the next step, the capsule cap inner diameter was subtracted from the capsule body outer diameter to obtain the average gap width between the capsule body and the cap in the pre-locked or final locked state. The gap width ranged from 25 μm for Vcaps® Plus size 3 to 75 μm for Vcaps® Plus size 00.

[0249] [Table 25] [Explanation of symbols]

[0250] 1. Body 11 Annular notch 12 Tapered periphery 2 Cap 21 Annular notch 22 Elongated depression

Claims

1. 1. A method for producing a polymer-coated hard capsule suitable as a container for a pharmaceutical or nutraceutical bioactive ingredient, said hard capsule comprising a body and a cap, said cap overlapping said body in a pre-locked or final-locked state in a closed state, 1) providing the hard capsule in the pre-locked state; 2) spray-coating a coating solution, suspension or dispersion containing a polymer or a mixture of polymers to prepare a coating layer covering the outer surface of the hard capsule in the pre-locked state; The coating layer has a thickness of 1.0 to 5.5 mg / cm ２ and the coating layer on the hard capsule has an average thickness of 10 to 50 μm; said polymer or polymer mixture is selected from the group of anionic polymers, cationic polymers, or any mixture thereof; the anionic polymer is an anionic (meth)acrylate copolymer; the cationic polymer is a cationic (meth)acrylate copolymer; the materials of the body and the cap are selected from hydroxypropyl methylcellulose, starch, pullulan, and copolymers of C1-C4 alkyl esters of (meth)acrylic acid and (meth)acrylic acid; the anionic polymer in the coating layer is a copolymer of 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; the anionic polymer does not include a core / shell anionic copolymer; the cationic (meth)acrylate copolymer is polymerized from a monomer comprising a C1-C4 alkyl ester of acrylic acid or methacrylic acid and an alkyl ester of acrylic acid or methacrylic acid having a tertiary or quaternary ammonium group on the alkyl group; The capsule in the final locked state does not include the band seal. The method, wherein the concentration of dry material in said coating solutions, said suspensions and said dispersions is 5-50% by weight.

2. 2. The method of claim 1, wherein the polymer coated hard capsule in the pre-locked state is opened, filled with a fill containing a pharmaceutical or nutraceutical bioactive ingredient, and closed to the final lock state.

3. 3. The method according to claim 1 or 2, wherein the polymer coated hard capsules in the pre-locked state are fed to a capsule filling machine which opens the capsules, fills them with a fill containing a pharmaceutical or nutraceutical bioactive ingredient and closes them to the final locked state.

4. 4. The method according to claim 1, wherein the body and the cap have an annular notch or recess in the area where the cap overlaps the body to close the capsule in the pre-locked or final locked state by a snap-into-place mechanism.

5. The method of any one of claims 1 to 4, wherein the body has a tapered periphery.

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