Method for producing coated hard capsules

Abstract

To provide a process for preparing a polymer-coated hard shell capsule, suitable as a container for pharmaceutical or nutraceutical biologically active ingredients.SOLUTION: A hard shell capsule comprises a body and a cap, wherein in a closed state, the cap overlaps the body either in a pre-locked state or in a final-locked state, wherein the hard shell capsule is provided in the pre-locked state and spray-coated with a coating solution, suspension or dispersion comprising a polymer or a mixture of polymers to create a coating layer which covers an outer surface of the hard shell capsule in the pre-locked state.SELECTED DRAWING: None

Description

[Technical Field]

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

[0002] U.S. Patent No. 4,138,013 describes an enteric-coated hard capsule. The hard capsule comprises a telescopically interlocking body and cap portion. The capsule body and cap portion are formed by dip-molding using a homogeneous film-forming mixture containing a material selected from hydroxypropyl methylcellulose (HPMC), (1) a mixture of hydroxypropyl methylcellulose 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 ester of methacrylic acid. 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 capsule leakage and uncontrolled leakage of contents in the stomach, an additional seal must be applied between the capsule members, for example, by manually applying a gelatin solution. Another technique involves applying a water / ethanol mixture between the capsule members and welding them 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 auxiliaries such as talc (EUDRAGIT® FS30D, EUDRAGIT® L30D-55, Aquoat® AS-HF, or Sureteric®), it is possible to provide HPMC capsules with enteric membranes from separately coated bodies and caps. This coating technique makes it possible to avoid 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] U.S. Patent No. 8,590,278 describes a method for fluid-tight sealing of filled drug capsules. The capsule members are filled with a gas at a temperature, pressure, or both different from the temperature, pressure, or both outside the capsule. The capsule members are assembled so 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, which is approximately 20 to 50 microns.

[0007] US Patent Application 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 containing a non-liquid fill and characterized by a band seal under a modified-release coating. The modified-release coating may be a delayed-release coating or a controlled-release coating, or may be an enteric coating. The film-forming agent for the enteric coating may be selected from anionic (meth)acrylate copolymers or anionic celluloses. The coating amount is determined based on the surface area of ​​the capsule concerned (1 cm). 2 The amount may be about 2-12 mg per capsule. Before applying the coating to the immediately filled and closed capsules, 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 in which an active ingredient, including a powder formulation, is filled into a hard capsule, which is closed and then coated with an enteric (meth)acrylate copolymer. Summary of the Invention

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

[0011] Huyghebaert et al., European Journal of Pharmaceutical Sciences 21 (2004) 617-623, describe separately coating the body and cap of a hard capsule with a polymer. The body and cap can be filled with the active ingredient and show no leakage in release tests. Furthermore, 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. Because the bodies and caps often have variations in size, matching bodies and caps 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 components often increases, and separately coated caps and bodies do not easily fit together. Therefore, matching caps and bodies must be manually selected, which requires repeated repetition, making this method unsuitable from the start. The need for manual processing limits large-scale industrial application.

[0012] Conventional capsule filling machines are designed to process capsules by opening uncoated capsules in a pre-locked state, filling them with an active ingredient or a composition containing an active ingredient, and then closing them to a final lock state. However, there appears to be no conventional equipment capable of processing bodies and caps that are separately polymer-coated. Thus, specifically designed equipment must be designed and manufactured. These equipment must also address the problem of increased circular deformation rates of separately coated bodies and caps, requiring a high level of technical 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 result in unwanted leakage of the active ingredient. The polymer coating process should avoid the problem of distorting the roundness of the body and cap, which can occur when the body and cap are polymer coated separately. The process should be suitable for use with conventional capsule filling machines.

[0014] Compared to the separate coating method described by Huyghebaert et al., European Journal of Pharmaceutical Sciences 21 (2004) 617-623, the described method has the advantage of requiring only one coating process. The interior of the capsule member is not sprayed with the coating material. Thus, the loss of expensive coating solution or dispersion is significantly reduced. It was found that when pre-locked capsules are used, the circular shapes of the body and cap are not deformed or are barely deformed. This change in capsule shape stability may be related to the stabilizing effect of the two capsule members in the overlapping area of ​​the pre-locked state. Thus, the pre-locked state provides sufficient equipment stability for the coating and drying processes 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 pre-locked state are already matched, there is no need to select a matching body and cap. As a result of this improvement, pre-locked polymer-coated capsules can be further processed in conventional capsule filling machines. Thus, the pre-locked coated capsules are suitable as part of the 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 them with the active ingredient or active ingredient-containing composition, and closing them to the final lock state.

[0015] Surprisingly, it has been found that hard capsules coated by the method of the present invention are tightly closed and exhibit no leakage, even though only a portion of the overlapping area between the body and cap is sealed by the coating. The described method is particularly useful for providing a tightly closed, polymer-coated hard capsule for pharmaceutical or nutraceutical dosage forms with gastro-resistant properties and intended rapid release in the small intestine. The described method is also useful for providing polymer-coated hard capsules, and pharmaceutical or nutraceutical dosage forms based on this type of capsule, with improved moisture barrier properties, particularly to reduce moisture absorption during storage.

[0016] The term polymer or polymer mixture is understood to mean one polymer or a mixture of two or more polymers, for example, a mixture of two or three polymers. The coating layer can comprise or consist of several individual layers, possibly two layers each containing one polymer or polymer mixture, and these two or more layers can 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 small amount of additional polymer (not more than 5, 2, or 1% by weight, calculated on the weight of the main polymer) that does not essentially affect the function of the main polymer is added. A small amount of additional polymer can be added for additive functions, such as improving the adhesion of the coating layer to the capsule material. [Brief explanation 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. [Figure 2]Figure 2 shows a schematic diagram of the body (left) and cap (right) of a Vcaps® Plus #1 size hard capsule with relative dimensions in mm. The dimensions are used to calculate the outer capsule surface in the pre-lock state in Example 2. 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 [Figure 3] Figure 3 shows Comparative Example C4, in which the body and cap were spray-coated separately with polymer. Figure 3 shows microscopic images of the open-side edges of ten bodies, numbered B1 through B10, randomly selected during the spray-coating process. The images were recorded in black and white for clarity. As shown in images B1 through B10, the process of separately coating the bodies results in various deformations of the originally circular edges. [Figure 4] Figure 4 shows Comparative Example C4, in which the body and cap were spray-coated separately with polymer. Figure 4 shows microscopic images of the open-side edges of ten caps, numbered C1 through C10, randomly selected during the spray-coating process. The images were recorded in black and white for clarity. As shown in images C1 through C10, the process of separately coating the caps results in various deformations of the originally circular edges. DETAILED DESCRIPTION OF THE INVENTION

[0018] Hard capsule Hard capsules for pharmaceutical or nutritional supplement 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 capsule body and the cap are often made of hard, sometimes brittle materials. Hard capsules include a body and a cap. Typically, the body and the cap are cylindrical with one open end and a 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 into the open end of the cap in a telescoping manner.

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

[0020] The body is typically 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 state, the cap covers the overlapping area on the outside of the body in either the 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: the position where the capsule is closed in the pre-locked or final-locked state.

[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 components. Pre-locked hard capsules can be fed into a capsule filling machine, which opens, fills, and closes the capsule to a final locking state. Typically, hard capsules are filled with dry material, such as a powder or granules containing a bioactive ingredient.

[0022] The cap and body are supplied closed and equipped with closure means 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, with the raised points positioned to fit into the recesses when the capsule is closed. 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 can be arranged in a circular or spiral pattern on the wall. While it is advantageous to provide recesses and openings to allow gas exchange inside the capsule, instead of a point-like arrangement of raised points and recesses, the wall of the cap or body can also be arranged in a circular pattern.

[0024] One or more annular ridges may be provided on the inner wall of the cap and the outer wall of the body so that the ridges on the cap are adjacent to the ridges on the body when the capsule is in its final locked position. The ridges may be formed on the outer side of the body near the open end, and the recesses may be formed near the open end of the cap, so that the ridges on the body engage with the recesses in the cap when the capsule is in its final locked position. The ridges 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 has at least two such locking means, which secure the two capsule parts to different degrees. In this type of component, one locking means (recess or annular notch) can be formed near the opening of the capsule cap and capsule body, while the second locking means (annular notch) can be moved slightly toward the closed end of the capsule part. The first locking means is weaker than the second and secures the two capsule parts together. This variant has the advantage that, after producing an empty capsule, 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 place 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 elongated in the longitudinal direction (e.g., 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] The corresponding annular notches on the body and the elongated recesses on the cap are preferably used to secure the body and the cap together in the pre-locked state, and the corresponding annular notches on the body and the cap are preferably used to secure or lock the body and the cap together in the final locked state.

[0029] The area where the cap can slide over the body can be referred to as the overlap area of ​​the body and 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 a locking mechanism, such as a corresponding annular notch and / or recess in the body and cap, a partially closed capsule can be referred to as pre-locked. When the capsule is polymer-coated in the pre-locking stage, this coating completely covers the outer surface, including the portion of the overlap area between the body and cap that is not overlapped by the cap in the pre-locking stage. After the capsule is polymer-coated in the pre-locking stage, when it is closed to the final locking stage, the coating in the portion of the overlap area between the body and 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 portion surrounded by the body and cap in the final locking stage is sufficient to tightly seal the hard capsule. This was not an expected approach.

[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 locking mechanisms such as corresponding annular notches and / or recesses in the body and cap, a finally closed capsule can be referred to as finally locked.

[0031] Typically, the recess is preferred for securing the body and 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. In this way, a snap-in recess can be re-released with less force than is required to release the snap-in locking 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, a recess in the cap where the cap can slide over the body and an annular notch in 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 the hard capsule can be reopened manually or by a device without damage. Therefore, the "pre-locked state" is sometimes referred to as the "loosely fitted state."

[0034] Typically, annular notches or corresponding locking rings on the body and cap in the area where the cap can slide over the body correspond to one another so as to close the capsule with a snap-fit ​​mechanism in the pre-locked state, whereas in the final locked state, the force required to open it is relatively high, making the hard capsule unable or barely re-openable by hand 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 protrusions and recesses are mated together, a uniform, ideally defined gap of 10 microns to 150 microns, more preferably 20 microns to 100 microns, is formed along the contact surface between the capsule body and the overlying capsule cap.

[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, enclosed capsules. Softgel capsules are often made from blow-molded softgel materials and are typically filled by injection with a liquid containing a bioactive ingredient. The present invention does not relate to sealed, one-piece, soft, enclosed capsules.

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

[0039] Capsules are available in standard sizes, e.g., sizes 000 to 5. A closed size 000 capsule has a total length of approximately 28 mm, a cap outer diameter of approximately 9.9 mm, and a body outer diameter of approximately 9.5 mm. The cap length is approximately 14 mm, and the body length is approximately 22 mm. The fill capacity is approximately 1.4 ml.

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

[0041] A size 0 capsule has 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 capsules The present invention relates to polymer-coated hard capsules obtainable by the process described herein.

[0043] Body and cap materials The materials for the body and cap can be selected from hydroxypropyl methylcellulose, starch, gelatin, pullulan, and copolymers of C1-C4 alkyl esters of (meth)acrylic acid with (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 to polymer coatings.

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

[0045] Any general or specific polymer feature or embodiment selection disclosed herein can be combined without limitation with any other general or specific material or numerical feature or embodiment selection disclosed herein, such as capsule material, capsule size, coating thickness, bioactive component, and other disclosed features or embodiments.

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

[0047] The polymer or polymer mixture 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] Enteric-protected means 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 0.1 N HCl, pH 1.2. Preferably, after 120 minutes in 0.1 N HCl, pH 1.2, and then changed 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 its 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 0.1 N HCl, pH 1.2. Preferably, after 120 minutes in 0.1 N HCl, pH 1.2, and then a change 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 0.1 N HCl, pH 1.2, a change to a pH 6.5 or 6.8 buffer for 60 minutes, and then a final change to a pH 7.2 or 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 solution 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 to 95, preferably 40 to 95, and especially 60 to 40, weight percent of a free-radically polymerized C1-C12 alkyl ester, preferably a C1-C4 alkyl ester of acrylic or methacrylic acid, and 75 to 5, preferably 60 to 5, and especially 40 to 60, weight percent of a (meth)acrylate monomer having an anionic group. The above proportions typically add up to 100 weight percent. However, it is also possible to include a small amount, e.g., 0 to 10 weight percent, e.g., 1 to 5 weight percent, of additional vinyl-copolymerizable monomers, such as hydroxyethyl methacrylate or hydroxyethyl acrylate, without damaging or altering essential properties. Preferably, no additional vinyl-copolymerizable monomers are present.

[0053] C1-C4 alkyl esters of acrylic or methacrylic acid are especially 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, and preferably methacrylic acid.

[0055] A suitable anionic (meth)acrylate copolymer is one in which 40 to 60% by weight of methacrylic acid is polymerized with 60 to 40% by weight of methyl methacrylate or 60 to 40% by weight of 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 approximately 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 is approximately 5.5.

[0058] Similarly, anionic (meth)acrylate copolymers (EUDRAGIT® S) are suitable, in which 20-40% by weight of methacrylic acid and 80-60% by weight of methyl methacrylate are polymerized. The pH at which certain active ingredients begin to be released in intestinal fluid or simulated intestinal fluid 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 approximately 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 wt. % 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. Due to its excellent elongation at break, this (meth)acrylate copolymer is particularly suitable for compressing pellets into tablets.

[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 vinyl copolymerizable monomer is polymerized; The proportion of the 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, unless the essential properties are necessarily impaired, the copolymer may further contain a small amount of 0 to 10% by weight, e.g., 1 to 5% by weight, of an additional vinyl-copolymerizable monomer, such as methyl methacrylate, butyl acrylate, hydroxyethyl methacrylate, vinylpyrrolidone, vinylmalonic 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 obtained by a two-stage emulsion polymerization process, having a core of 75% by weight containing polymerized units of 30% by weight of ethyl acrylate and 70% by weight of methyl methacrylate, and a shell of 25% by weight containing polymerized units of 50% by weight of ethyl acrylate and 50% by weight of methacrylic acid.

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

[0066] Anionic Cellulose The anionic cellulose may be selected from carboxymethylethyl cellulose and its salts, cellulose acetate phthalate (CAP), cellulose acetate succinate (CAS), cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP, HP50, HP55), and 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 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., reduced moisture absorption during storage. For this purpose, a coating comprising 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 a monomer comprising a C1-C4 alkyl ester of acrylic acid or methacrylic acid with an alkyl ester of acrylic acid or methacrylic acid having a tertiary or quaternary ammonium group in the alkyl group.

[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 to mean reduced absorption of moisture or water during storage of the filled, final-locked capsules.

[0071] Suitable cationic (meth)acrylate copolymers are prepared by polymerizing 30 to 80% by weight of a C1-C4 alkyl ester of acrylic or methacrylic acid with 70 to 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 is one in which 20-30% by weight of methyl methacrylate, 20-30% by weight of butyl methacrylate, and 60-40% by weight of dimethylaminoethyl methacrylate are polymerized (EUDRAGIT® E polymer).

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

[0074] Suitable (meth)acrylate copolymers may be composed of 85 to 98% by weight of free-radically polymerized C1-C4 alkyl esters of acrylic or methacrylic acid and 15 to 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 may contain polymerized monomer units of 2-trimethylammonium-ethyl methacrylate chloride or trimethylammonium-propyl methacrylate chloride.

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

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

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

[0080] A particularly suitable 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 with ionic groups, most preferably none of which are monomers with 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., hydroxypropyl cellulose, polyvinylpyrrolidone, polyvinyl acetate or polyvinyl alcohol.

[0083] Neutral methacrylate copolymers are often useful as 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 having 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 with anionic radicals, such as acrylic acid and / or methacrylic acid, may be present in small amounts of less than 5% by weight, preferably 2% or less, more preferably 1% or less or 0.05 to 1% by weight.

[0087] Suitable examples include neutral or substantially neutral (meth)acrylate copolymers in which 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 are polymerized.

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

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

[0090] According to WO 01 / 68767, neutral or substantially neutral methyl acrylate copolymers prepared as dispersions using 1 to 10% by weight of a nonionic emulsifier with an HLB value of 15.2 to 17.3 are preferred. "EUDRAGIT® NM type" has the advantage that the emulsifier does not cause phase separation, which would otherwise lead to the formation of crystalline structures.

[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 acid, 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 dosage forms, so-called "natural polymer" coatings are preferred by many users. Natural polymers are based on natural, plant, microbial or animal sources, but may also be chemically modified. Natural polymers for coatings 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 capsule is coated with a coating layer comprising the disclosed polymer or polymer mixture and, optionally, excipients, preferably pharmaceutically 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 contain up to 10, up to 20, up to 30, up to 40, up to 50, up to 60, up to 70, up to 80, or up to 90% by weight of excipients, preferably pharmaceutical and / or nutraceutical excipients (pharmaceutically or nutraceutical acceptable excipients). The coating layer may contain 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 blend and any optional pharmaceutical and / or nutraceutical excipients may total 100%.

[0096] Amount and thickness of the coating layer The amount of coating layer applied (= the 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 cross-linking. When the capsule is closed in the final locking stage, the amount of coating layer between the body and the cap may be insufficient, 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, it may be difficult to process the polymer-coated pre-locked hard capsules later in the capsule filling machine. A coating layer amount of 8 mg / cm 2 Less than, for example, 1-8 mg / cm 2 or 1-5 mg / cm 2 or 1-4 mg / cm 2In this case, there is usually no problem with standard capsule filling machines that have not been modified. 2 In this case, a capsule filling machine can still be used, but the body and cap shapes must be adjusted to be slightly wider. Such adjustments can be easily made by a mechanical engineer. In this way, 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 heavy. If too much coating layer is applied, it may be difficult to process the polymer-coated pre-locked hard capsules later in the capsule filling machine. A coating layer amount of 5 mg / cm 2 Less than, for example, 1-4 mg / cm 2 In this case, there is usually no problem with standard capsule filling machines that have not been modified. 2 In this case, a capsule filling machine can still be used, but the body and cap shapes must be adjusted to be slightly wider. Such adjustments can be easily made by a mechanical engineer. In this way, the coating layer amount is about 1 to about 8 mg / cm. 2 Within this range, a capsule filling machine can be used to advantage.

[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 subsequent processing in the capsule filling machine. A coating layer amount of 4 mg / cm 2 Less than, for example, 1 to 3.5 mg / cm 2 In this case, there is usually no problem with standard capsule filling machines that have not been modified. 2 In this case, a capsule filling machine can still be used, but the body and cap shapes must be adjusted to be slightly wider. Such adjustments can be easily made by a mechanical engineer. In this way, the coating layer amount is about 1 to about 8 mg / cm.2 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 heavy. If too much coating layer is applied, it may be difficult to process the polymer-coated pre-locked hard capsules later in the capsule filling machine. A coating layer amount of 3 mg / cm 2 Less than, for example, 1 to 2.5 mg / cm 2 In this case, there is usually no problem with standard capsule filling machines that have not been modified. 2 In this case, a capsule filling machine can still be used, but the body and cap shapes must be adjusted to be slightly wider. Such adjustments can be easily made by a mechanical engineer. In this way, 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, polymer-coated hard capsules 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 cap, the cap can no longer slide past the body to the final lock state, making it impossible to close the coated pre-locked capsule without damaging the applied coating. The upper limit for the amount of coating layer that can be used to manually close coated pre-locked hard capsules to the final lock state without damaging them is a maximum of about 20 mg / cm2. 2 20mg / cm 2 Above this, it may no longer be possible to close the capsule manually without damaging it, 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, a large amount of coating layer will accumulate around the periphery of the cap. As a result, when the coated pre-locked hard capsule is manually or mechanically opened, cracks may occur in the coating layer after drying. These cracks may later cause the capsule to leak. Finally, a coating that is too thick, or a coating layer that is thicker than the gap between the body and the cap in the overlapping area, may cause problems such as the inability to close the opened coated hard capsule to the final locking stage.

[0103] Roughly speaking, the coating layer on hard capsules 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 to 100, 10 to 50, or 15 to 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% by dry weight based on the weight of the pre-lock capsule.

[0106] Those skilled in the art will be able to adjust the amount of coating layer that is too little and too much according to 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, wherein in a closed stage, the cap overlaps the body in a pre-locked state or a final-locked state, 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 polymer mixture 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 pharmaceutically or nutraceutical acceptable excipient, the excipient including 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 pharmaceutically or nutraceutical acceptable excipient total 100%, the polymer blend comprising 60-90, preferably 70-85, weight percent (meth)acrylate copolymer (EUDRAGIT® FS) of 10-30 weight percent methyl methacrylate, 50-70 weight percent methyl acrylate, and 5-15 weight percent methacrylic acid polymerized together, and 10-40, preferably 15-30, weight percent (meth)acrylate copolymer (EUDRAGIT® L100-55) of 40-60 weight percent methacrylic acid and 60-40 weight percent ethyl acrylate polymerized together; The amount of the coating layer (total weight increase) is 1 to 8, preferably 1 to 4 mg / cm 2 is.

[0108] The polymer-coated hard capsule of the first embodiment can be advantageously combined with contents such as the pharmaceutically 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, wherein in a closed stage, the cap overlaps 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 or dispersion comprising a polymer or a polymer mixture 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 pharmaceutically 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 pharmaceutically or nutraceutical acceptable excipients total 100%, the polymer being a (meth)acrylate copolymer (EUDRAGIT® L100-55) comprising 40-60% by weight of methacrylic acid and 60-40% by weight of ethyl acrylate; The amount of the coating layer (total weight increase) is 1 to 8, preferably 1 to 4 mg / cm 2 is.

[0110] The polymer-coated hard capsule of the second embodiment can be advantageously combined with contents such as the pharmaceutically 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, wherein in a closed stage, the cap overlaps 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 or dispersion comprising a polymer or a polymer mixture 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 pharmaceutically 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 the pharmaceutically or nutraceutical acceptable excipient total 100%, the polymer is a (meth)acrylate copolymer (EUDRAGIT® FS) formed by polymerizing 10-30% by weight of methyl methacrylate, 50-70% by weight of methyl acrylate, and 5-15% by weight of methacrylic acid; Here, the amount of the coating layer is 1 to 8, preferably 1 to 4 mg / cm 2 is.

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

[0113] bioactive ingredients The bioactive ingredient is preferably a pharmaceutically active ingredient and / or a nutraceutical active ingredient.

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

[0115] Suitable pharmacological and chemical classes of pharmaceutically active ingredients that can be used as the contents of the mentioned polymer-coated hard capsules are, for example, 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., aspartate, chloride, orthate, urological drugs, vaccines.

[0116] Further examples of drugs that can be used as the contents of the mentioned 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, cladribine, benzodiazepine, benzocaine, benzoyl peroxidase ... methicone, 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 Zon, human growth hormone (hGH), ibuprofen, ilaprazole, insulin, interferon, interleukin, intron A, ketoprofen, lansoprazole, leuprolide acetate lipase, lipoic acid, lithium, kainin, memantine, mesalamine, methenamine, miramelin, 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 kind of mixture or combination thereof.

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

[0118] Nutraceuticals are well known to those skilled in the art. Nutraceuticals are often defined as food extracts that have a medical effect on human health. Thus, nutraceutical active ingredients may also exhibit pharmaceutical activity. Examples of nutraceutical active ingredients include resveratrol from grape products as an antioxidant, soluble dietary fiber products such as psyllium seed husks that reduce hypercholesterolemia, broccoli (sulfanes) as cancer prevention agents, and soy or clover (isoflavonoids) that 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 the health of humans or animals 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 products, omega-3 fatty acids or proanthocyanins from blueberries as antioxidants, soluble 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 synonymously with 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 formulated with the bioactive ingredients contained in the coated hard capsule and / or the polymer coating of the hard capsule as disclosed and claimed herein. Any excipients used must be toxicologically safe and must be suitable for use 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 consisting of antioxidants, glazing agents, binders, flavoring agents, flow aids, fragrances, glidants, penetration enhancers, dyes, plasticizers, emulsifiers, pore formers, or stabilizers, or combinations thereof, and preferably comprises a pharmaceutically or nutraceutical acceptable excipient. The pharmaceutically or nutraceutical acceptable excipient may be included in the core and / or coating layer comprising the disclosed polymer. The pharmaceutically 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 pharmaceutically 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. Depending on the amount added, plasticizers lower the glass transition temperature through physical interactions with the polymer, promoting film formation. Suitable materials typically have a molecular weight of 100 to 20,000 and contain one or more hydrophilic groups, such as hydroxyl, ester, or amino groups, in the molecule.

[0126] Examples of suitable plasticizers include alkyl citrates, glycerol esters, alkyl phthalates, alkyl sebacates, sucrose esters, sorbitan esters, diethyl sebacate, dibutyl sebacate, propylene glycol, and polyethylene glycols 200-12,000. Preferred plasticizers are triethyl citrate (TEC), acetyl triethyl citrate (ATEC), diethyl sebacate, and dibutyl sebacate (DBS). Additional examples include esters that are normally liquid at room temperature, such as citrates, phthalates, sebacates, or castor oil. Esters of citric acid and sebacic acid are preferred. Glycerol monostearate (GMS) has plasticizing properties. While GMS also possesses some glidant properties and is sometimes designated as a glidant, in this disclosure it is referred to as a plasticizer.

[0127] The plasticizer can be added directly to the aqueous solution or added to the formulation after preheating the mixture using known methods. Mixtures of plasticizers can also be used. However, because 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, from an aqueous polymer dispersion, without the addition of a plasticizer. The polymer coating of the hard capsule can preferably contain one or more plasticizers in an amount of 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, 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 Typically, standard fillers are added to the formulations of the present invention during processing into coatings and binders. The amounts incorporated and the use of standard fillers in pharmaceutical coatings or surfaces are well known to those skilled in the art. Examples of standard fillers include release agents, dyes, stabilizers, antioxidants, pore formers, permeation enhancers, gloss agents, fragrances, or flavoring agents. These are used as processing adjuvants and are intended to ensure reliable and reproducible manufacturing methods and excellent long-term storage stability, or to achieve additional advantageous properties in the pharmaceutical dosage form. They are added to the polymer formulation before processing and can affect the permeability of the coating, which 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 spray suspensions. They prevent the cores from agglomerating during film formation. Suitable glidants are talc, Mg or Ca stearate, powdered silica, kaolin, or nonionic emulsifiers with an HLB value of 2 to 8. The typical use ratio of release agents and binders in the coatings of the present invention is in the range of 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 an aqueous suspension with a solids content of 5-30% (weight / weight (w / w)). The required concentration is lower than when mixed 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 comprise, for example, 20-80, preferably 30-70 wt. % of the disclosed inventive polymer and 20-80, preferably 30-70 wt. % of talc, with the inventive polymer and talc totaling 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. Typical pigment proportions are 10-200, 20-200% by weight of the polymer or polymer mixture in the coating layer. A proportion 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 in concentrated form as an additional outer layer, the so-called topcoat, either as powder or by spraying an aqueous suspension with a solids content of 5 to 35% (w / w). The required concentration is lower than that required for incorporation into the polymer layer, amounting to 0.1 to 2% by weight relative to the weight of the pharmaceutical form.

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

[0135] A subcoat can be disposed between the capsule and coating layer, comprising the disclosed polymer or polymer mixture. The subcoat has essentially 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-forming component. The average thickness of the subcoat layer is usually very thin, e.g., 15 μm or less, preferably 10 μm or less (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 a polysaccharide or HPMC, or a sugar compound such as sucrose. The topcoat may further contain a large amount of pharmaceutically 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 for producing polymer-coated hard capsules suitable as containers for pharmaceutical or nutraceutical bioactive ingredients is described, 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.

[0138] In a further method step, the pre-locked 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 capsules in a pre-locked state are opened, filled with a fill comprising a pharmaceutical or nutraceutical bioactive ingredient, and closed to a final lock state. Preferably, in this further method step, the coated hard capsules in a pre-locked state are fed to a capsule filling machine, which opens the capsules, fills with a fill comprising a pharmaceutical or nutraceutical bioactive ingredient, and closes the polymer-coated hard capsules to a final lock state.

[0140] This further 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 final-locked polymer-coated hard capsule, 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 the pre-locked stage but not covering an overlap region where the cap overlaps the body in the pre-locked 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 polymer. A suitable spray concentration is about 5-25% by dry weight.

[0143] The coating dispersion may be a dispersion of a 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 a fill for a dosage form Suitable methods for producing fills for pharmaceutical or nutraceutical dosage forms are well known to those skilled in the art. A suitable method for producing the fills for pharmaceutical or nutraceutical dosage 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 powder binding to active ingredient-free beads or neutral cores or active ingredient-containing particles or pellets, 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 for producing suitable polymer-coated hard capsules described herein may also be understood as a method for using hard capsules comprising a body and a cap, wherein in a closed state the cap overlaps the body in a pre-locked or final locked state, and the production of polymer-coated hard capsules suitable as containers for pharmaceutical or nutraceutical bioactive ingredients includes: 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 form a coating layer covering the outer surface of the pre-locked hard capsule.

[0147] Preferably, spray coating may be carried out using a drum coater or a fluidized bed coater. A suitable product temperature during the spray coating process may be about 15 to 40°C, preferably about 20 to 35°C. A suitable spray rate may be about 0.3 to 4.0, preferably 0.5 to 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), filled with a fill containing a pharmaceutical or nutraceutical bioactive ingredient in step d), and then closed to a final lock in step e).

[0149] Steps c) to e) may be carried out 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 capsules in step c), fills them with a fill containing a pharmaceutical or nutraceutical bioactive ingredient in step d), and closes the capsules 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 embodiment 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 effective 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, 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 a pharmaceutical or nutraceutical bioactive ingredient, wherein the hard capsule comprises a body and a cap, and in a closed state, the cap overlaps the body in a pre-locked state or a 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 a polymer-coated hard capsule in a pre-locked state is opened, filled with a fill containing a pharmaceutical or nutraceutical bioactive ingredient, and closed to a 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 capsules 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, 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, in particular 40 to 60 wt. % of (meth)acrylate monomers having anionic groups.

[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 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, and a snap-fit ​​mechanism closes the capsule in the pre-locked state or the final locked state.

[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 to 20, 1.0 to 18, 2 to 10, 4 to 8, 1.0 to 8, 1.5 to 5.5, or 1.5 to 4 mg / cm 2 The method according to one or more of items 1 to 12, wherein the amount of the hydroxybenzoate is applied in an 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 to 80% by weight of a core containing 65 to 75% by weight of polymerized units of ethyl acrylate and 25 to 35% by weight of methyl methacrylate, and 20 to 30% by weight of a shell containing 45 to 55% by weight of ethyl acrylate and 45 to 55% by weight of polymerized units of methacrylic acid, and is a copolymer obtained by a two-stage emulsion polymerization process.

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

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

[0169] 17. The pharmaceutical or nutraceutical dosage form according to item 16, wherein after 120 minutes in 0.1 N HCl, pH 1.2, the pharmaceutical or nutraceutical dosage form is changed to a pH 6.8 or pH 7.4 buffer (according to USP, e.g., USP 40), and 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 Pharmacopoeia (USP 40) at a paddle speed of 75 rpm. <711> The temperature of the test solution 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, wherein after 120 minutes in 0.1 N HCl, pH 1.2, a change to a pH 6.5 or 6.8 buffer for 60 minutes, and then a final change to a pH 7.2 or pH 7.4 buffer, approximately 80% or more of the bioactive ingredient is released after a total of 225 or 240 minutes. The dissolution test is performed using USP Apparatus II at a paddle speed of 75 rpm according to the United States Pharmacopoeia (USP 40). <711> The temperature of the test solution should be adjusted to 37±0.5°C. Samples should be taken at appropriate times.

[0171] 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® FS 30D 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 calculation and colon-targeted coating of pre-locked capsules using a drum coater The amount of coating material required depends on the surface area of ​​the substrate, since for a particular coating layer thickness it is necessary to achieve the desired membrane function. For this reason, the amount of coating material required is determined per cm of substrate surface area. 2 Below is the equation for the surface area of ​​a pre-lock capsule, taking into account the average difference between 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 % amount of each excipient based on the dry polymer material, the weight gain of the polymer must be multiplied by a factor (E) to calculate the total weight gain.

[0183]

number

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

[0185] [Table 3]

[0186] Figure 2 shows a schematic diagram of the body (left) and cap (right) of a Vcaps® Plus size 1 hard capsule with relative dimensions in mm. These dimensions are used to calculate the outer capsule surface in the pre-lock 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 mass:

[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, which were then manually filled with 200 mg of caffeine and closed to final lock.

[0195] [Table 5]

[0196] [Table 6]

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

[0198] Dissolution test method: Device: ERWEKA DT 700 paddle device (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, add 194 ml of 0.2 N NaPO solution to raise the pH to 6.5 (pH fine-tuned with 2 N NaOH and 2 N HCl). Test Solution III: After another hour in Test Solution II, 67 ml of 0.2 N NaPO solution was added to raise the pH to 7.2 (pH was again finely adjusted using 2 N NaOH and 2 N HCl). Paddle speed: 75 rpm

[0199] [Table 7]

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

[0201] Example 3 - Enteric coating of pre-locked capsules using 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. A drum coater was used to coat the pre-locked capsules. 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-lock capsules were manually filled with 200 mg of caffeine, closed to the final lock state, and subjected to dissolution testing.

[0205] method: Device: ERWEKA DT 700 paddle device (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, add 214 ml of 0.2 N NaPO solution to raise the pH to 6.8 (pH fine-tuned with 2 N NaOH and 2 N HCl). Paddle speed: 75 rpm

[0206] [Table 10]

[0207] Example C4 (Comparative) - Fluidized Bed Coating of Separate Capsule Components (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 excipient suspension 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 fluidized bed coater, and then 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 ZEISS PlanNeoFluar Z 1x / 0.25 FWD 56mm objective lens Light source SCHOTT MC 1500 Incident light - SCHOTT S80-55 ring light ZEISS Axiocam 503 color camera Software AxioVision SE64 Image analysis software Olympus Soft Imaging solutions GmbH

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

[0213] Testing of samples: Set the microscope to 10x magnification and focus on the capsule shell so that it is viewed vertically from below. Adjust the capsule position to avoid shadows in non-vertical positions. Light intensity and contrast should be adjusted appropriately for the relevant focus range.

[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 vertically below. The area (mm) of the perimeter was calculated. 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 table below, 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 for undeformed, uncoated capsules is approximately 1, and increases with the degree of deformation.

[0217] [Table 13]

[0218] SEM analysis SEM examination of the coated separate capsule components, the body and cap, showed that cracks had formed around the tapered periphery. Furthermore, macroscopic and scanning microscope images showed that the separately coated cap and body exhibited a tendency toward significant, seemingly irreversible, deformation during the coating process. This deformation makes manual encapsulation difficult and presumably makes automated encapsulation impractical, since only selected caps and bodies fit together. Therefore, fluidized-bed coating of capsules separately is not a suitable process for producing capsules with automated capsule filling.

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

[0220] Dissolution test The capsules were manually filled with 200 mg of caffeine.

[0221] method: Device: ERWEKA DT 700 paddle device (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, add 214 ml of 0.2 N NaPO solution to raise the pH to 6.8 (pH fine-tuned with 2 N NaOH and 2 N HCl). Test Solution III: After another hour in Test Solution II, 46 ml of 0.2 N Na3PO4 solution is added to raise the pH to 7.4 (pH is again finely adjusted using 2 N NaOH and 2 N HCl). Paddle speed: 75 rpm

[0222] [Table 14]

[0223] Example 5 - Enteric coated pre-lock capsules and automatic capsule filling with a drum coater To calculate the maximum weight gain suitable for the encapsulation process, the maximum layer thickness was estimated as 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 approximately 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 using an automated MG2Labby capsule filler, using standard format size 0 powder filling equipment to open, transfer, fill, and close the capsules. The output of the machine was set at 2000 cps / hr.

[0230] The capsules were tested on an automatic capsule filling machine and showed a total solids weight gain of 2.6 and 3.9 mg / cm 2 The total solid weight gain was 5.1 mg / cm 2 In this case, standard equipment was limited and could not operate with pre-locked capsules due to the increased layer thickness. 2 If the capsule diameter is increased by more than 1000 ppm, modified tooling is required for testing to account for the increased capsule diameter.

[0231] Explanation of SEM analysis of body and cap Compared to coating separate capsules with a liquid, coating pre-locked capsules allows for better filling of the capsules. Compared to separate capsule members, 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 slight bridging between the two members allows pre-locked coated tablets to be separated by the capsule filling machine.

[0232] Dissolution test method: Device: ERWEKA DT 700 paddle device (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, add 214 ml of 0.2 N NaPO solution to raise the pH to 6.8 (pH fine-tuned with 2 N NaOH and 2 N HCl). Paddle speed: 75 rpm

[0233] [Table 18]

[0234] Examples 6-9 - Enteric coating and colon targeting of pre-locked capsules with a fluidized bed coater Fluid bed coating example 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 fluidized bed coater. 200 mg of caffeine was then manually filled into the capsules before closing them to the 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 water using a dissolver plate for approximately 1-1.5 hours until a pale yellow, cloudy solution was obtained. Talc was added to the polymer solution and homogenized using 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: Device: ERWEKA DT 700 paddle device (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] The capsules for dissolution testing were coated 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] Water 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, for all sizes of Vcaps® Plus hard capsules, the gap width between the capsule body and cap in the pre-locked or final locked state 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 determine the capsule cap inner diameter. In a next step, the capsule cap inner diameter was subtracted from the capsule body outer diameter to determine the average gap width between the capsule body and 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 Caps 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, 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 position; 1) providing the hard capsule in the pre-locked state; 2) spray-coating the hard capsule with a coating solution, suspension, or dispersion containing 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; 3) feeding the polymer-coated hard capsule including the body and the cap in the pre-locked state into a capsule filling machine; 4) separating the body and the cap; 5) filling the body with a filler containing the bioactive ingredient and recombining the body and the cap to the final locked state; The coating layer has a thickness of 1.0 to 5.5 mg / cm ２ The method is applied in an amount of

2. 2. The method of claim 1, 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.

3. 3. The method of claim 1 or 2, wherein the polymer or polymer mixture in the coating layer is selected from the group of anionic polymers, cationic polymers or neutral polymers.

4. 4. The method of claim 3, wherein the polymer or polymer mixture in the coating layer is an anionic polymer selected from the group of anionic (meth)acrylate copolymers and anionic celluloses.

5. 5. The method according to claim 3, wherein 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.

6. The method of any one of claims 1 to 5, wherein the polymer or polymer mixture in the coating layer comprises a cationic (meth)acrylate copolymer.

7. 7. The method of claim 6, wherein the cationic (meth)acrylate copolymer is polymerized from monomers comprising a C1-C4 alkyl ester of acrylic acid or methacrylic acid and an alkyl ester of acrylic acid or methacrylic acid bearing a tertiary or quaternary ammonium group on the alkyl group.

8. 8. The method according to any one of claims 1 to 7, wherein the polymer or polymer mixture in the coating layer is selected from starch, alginic acid or alginates, 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.

9. 9. The method of 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 by a snap-into-place mechanism in the pre-locked state or the final locked state.

10. The method of any one of claims 1 to 9, wherein the body has a tapered periphery.

11. The coating layer is 1.5 to 4 mg / cm ２ The method according to any one of claims 1 to 10, wherein the amount of the coating material is applied in an amount of

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