PROCESS FOR PREPARING A COATED HARD-SHELL CAPSULE

Abstract

The invention discloses a process for preparing a polymer-coated hard shell capsule, suitable as a container for pharmaceutical or nutraceutical biologically active ingredients, wherein the hard shell capsule comprises a body and a cap, wherein, in the closed state, the cap overlaps the body, or 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 polymer mixture to create a coating layer that covers the outer surface of the hard shell capsule in the pre-locked state.

Description

1 / 65 Descriptive Report of the Invention Patent for "PROCESS FOR PREPARING A COATED HARD-SHELL CAPSULE" FIELD OF THE INVENTION

[001] The invention is found in the field of processes for preparing polymer-coated hard-shell capsules. BACKGROUND OF THE TECHNIQUE

[002] US patent 4138013 describes hard-shell capsules with enteric properties. The hard-shell capsules comprise a telescopically engaged body and cap portions. The capsule body and cap portions are formed by dip molding using a homogeneous film-forming mixture comprising select, from hydroxypropyl methyl cellulose (HPMC), a mixture of (1) hydroxypropyl methyl cellulose and an ammonium salt of cellulose acetate phthalate or (2) gelatin and an ammonium salt of a copolymer of (meth)acrylic acid and methacrylic acid alkyl ester. The capsules themselves already have enteric properties without the application of an additional enteric coating layer.

[003] Huyghebaert et al., European Journal of Pharmaceutical Sciences 21 (2004) 617 to 623, describe an alternative method for enteric coating of HPMC capsules in which ready-to-use enteric capsule parts are obtained. It is reported that, unlike gelatin capsules, HPMC capsules can be enteric coated relatively easily from aqueous preparations. However, it is necessary to additionally apply a seal between the capsule halves, for example, using a gelatin solution applied manually, in order to prevent leakage of the capsule and uncontrolled escape of contents into the stomach. Another technique is to apply water / ethanol mixtures between the capsule halves and join the parts at 40 to 60 °C.

[004] By using aqueous preparations (EUDRAGIT® FS 30 D, EUDRAGIT® L 30 D-55, Aquoat® AS-HF or Sureteric®) based on (meth)acrylate or polyvinyl acetate phthalate copolymer, plasticizers such as triethyl citrate and additional auxiliaries such as talc, it is possible to provide HPMC capsules with an enteric film of separately coated bodies and caps. A separate sealing step can be avoided in the case of this coating technology. In particular, HPMC capsules coated with copolymers of Petition 870200059460, dated 05 / 13 / 2020, pp. 158 / 230 2 / 65 (meth)acrylate as particularly advantageous in the sum of its properties.

[005] Document WO 2011 / 012369A1 describes a coating composition for enteric coating of capsule halves made of water-soluble or water-swellable polymeric material.

[006] US patent 8590278B2 describes a method for fluid-proof sealing of drug-filled capsules. The capsule parts are filled with a gas that is at a different temperature or pressure, or both, from the temperature or pressure outside the capsule. The capsule parts are fitted together so that it results in a reduction of differential pressure in the capsule body and the capsule cap. A leak-proof seal is provided in the gap between the capsule body and the capsule cap, wherein the gap is about 20 to 50 microns.

[007] US document 20170035699A1 describes an acid-resistant bandage solution for acid-resistant two-piece hard capsules.

[008] WO 2015 / 177028 describes a capsule containing a non-liquid load and comprising a modified release, characterized in that the capsule is sealed by a band beneath the modified release coating. The modified release coating may be a delayed-release coating or a controlled-release coating, which may be an enteric coating. Film-forming agents for the enteric coating may be selected from anionic (meth)acrylate copolymers or anionic celluloses. The amount of coating may be in the range of about 2 to 12 mg per cm² of the relevant capsule surface area. Before the coating is applied to the pre-loaded and closed capsules, the gap between the body and the cap is sealed with a band to prevent leakage.

[009] Documents WO2013 / 1710012A2, WO2007 / 070052A2, WO2011 / 151722A2 and WO2017 / 120592A1 contain examples in which hard-shell capsules are loaded with powder formulations containing active ingredient, are sealed and subsequently coated with enteric (meth)acrylate copolymers. FIGURES

[010] Figure 1 / 4 includes Figures 1a, 1b and 1c.

[011] Figure 1a) shows an example for a capsule comprising a body and a lid separately. Petition 870200059460, dated 05 / 13 / 2020, pages 159 / 230 3 / 65

[012] Figure 1b) shows the body and cover in the pre-locked state.

[013] Figure 1c) shows the body and lid in the final locked state = Body = Surrounding notch = Tapered rim = Lid = Surrounding notch = Elongated concavities FIGURE 2 / 4

[014] Figure 2 / 2 shows a schematic drawing of the body (left) and lid (right) of a size 1 Vcaps® Plus hard shell capsule with the relevant dimensions in mm. The dimensions are used in Example 2 for the calculation of the outer capsule surface in the pre-locked state.

[015] Body: length = 16.61 mm, cylinder (length of the cylindrical part) = 13.29 mm, outer diameter = 6.63 mm

[016] Cover: length = 9.78 mm, cylinder (length of the cylindrical part) = 6.32 mm, outer diameter = 6.91 mm FIGURE 3 / 4

[017] Figure 3 / 4 refers to Comparative Example C4, in which bodies and caps were separately spray-coated with a polymer. Figure 3 / 4 shows microscopic images of the open side, respectively, of the rim line of ten randomly selected bodies from the spray-coating process, numbered B1 to B10. The images were recorded and reduced to black and white images to provide a clear reproduction. As shown in figures B1 to B10, the separate coating process of the bodies leads to different types of deformation of the originally round rims. FIGURE 4 / 4

[018] Figure 4 / 4 refers to Comparative Example C4, in which bodies and lids were separately spray-coated with a polymer. Figure 3 / 4 shows microscopic images of the open side, respectively, of the rim line of ten randomly selected lids from the spray-coating process, numbered C1 to C10. The images were recorded and reduced to black and white to provide a clear reproduction. As shown in the figures Petition 870200059460, dated 05 / 13 / 2020, pages 160 / 230 4 / 65 From C1 to C10, the separate coating process of the caps leads to different types of deformation of the originally round rims. SUMMARY OF THE INVENTION

[019] The invention relates to a process for preparing a polymer-coated hard shell capsule, suitable as a container for pharmaceutical or nutraceutical biologically active ingredients, wherein the hard shell capsule comprises a body and a cap, wherein, in the closed stage, the cap overlaps the body, or 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 or dispersion comprising a polymer or a polymer mixture to create a coating layer that covers the outer surface of the hard shell capsule in the pre-locked state.The invention also relates to a polymer-coated hard shell capsule obtained from the process as described and to a pharmaceutical or nutraceutical dosage form comprising the polymer-coated hard shell capsule in the final locked stage containing a load comprising a pharmaceutical or nutraceutical biologically active ingredient.

[020] In Huyghebaert et al., European Journal of Pharmaceutical Sciences 21 (2004) 617 to 623, describes the separate coating of hard shell capsule bodies and caps with certain polymers. The bodies and caps can be loaded with an active ingredient and do not exhibit leakage in release tests. There is also no need for additional banding. A disadvantage of this method is, however, that the separately polymer-coated bodies and caps need to be subsequently loaded and manually closed. Since bodies and caps often have tolerances, compatible bodies and caps must be manually selected. Furthermore, the previous shape of the uncoated bodies and caps may suffer from the coating process as their round shape may be distorted. In this way, the percentage of out-of-specification parts is usually increased; meaning that separately coated caps and bodies do not fit together.Therefore, compatible caps and bodies must be manually selected, which requires multiple iterations and is not a process that can be done right the first time. The need for manual processing limits its large-scale industrial application. Petition 870200059460, dated 05 / 13 / 2020, pages 161 / 230 5 / 65

[021] Conventional capsule loading machines are designed to process uncoated capsules in the pre-locked state by opening, loading with active ingredient or composition containing active ingredient, and closing to the final locked state. However, there appear to be no conventional machines that could separately process polymer-coated bodies and caps. Therefore, specifically designed machines would have to be built. These machines would also have to deal with the problem of increased percentage of distorted circularity of separately coated bodies and caps, which could lead to significant technical stresses.

[022] Thus, there is a need for a polymer coating process for hard shell capsules that avoids the need for additional banding of the closed capsules and results in well-sealed capsules without unwanted leakage of active ingredient. The problem of distorted circularity of bodies and caps by a polymer coating process that can occur when bodies and caps are separately coated by polymer should be avoided. The process should be suitable for use with conventional capsule loading machines.

[023] Compared with the separate coating as described in Huyghebaert et al., European Journal of Pharmaceutical Sciences 21 (2004) 617 to 623, the described process has the advantage that only one coating process is required. No coating material is sprayed inside the capsule halves. In this way, the loss of coating solution or costly dispersion is significantly less. It was found that when capsules are used in the pre-locked state there is little or no distortion of the circularity of the body and cap. This modified capsule stability is also related to a stabilizing effect of the two capsule halves in the overlapping area in the pre-locked state.Thus, the pre-locked state provides sufficient mechanical stability during the coating and drying process in conventional coating equipment such as fluidized bed coating application devices and drum coating application devices. Furthermore, no selection of compatible bodies and caps needs to be made since the delivered pre-locked capsule parts, body and cap, are already compatible with each other. As a consequence of the improvements, the polymer-coated capsules in this state... Petition 870200059460, dated 05 / 13 / 2020, pages 162 / 230 6 / 65 pre-locked capsules can be further processed by conventional capsule loading machines. In this way, pre-locked coated capsules are suitable as part of large-scale industrial production, for example, capsules coated in the pre-locked state opening, loading with an active ingredient or composition containing an active ingredient and closing in the final locked state, of pharmaceutical or nutraceutical dosage forms comprising a polymer-coated hard shell capsule in the final locked stage containing a load comprising a pharmaceutically or nutraceutically active ingredient.

[024] It has been surprisingly found that hard-shell capsules coated in the inventive process are well sealed and do not exhibit leakage even though only a portion of the overlapping area between the body and the cap is sealed by a coating. The described process is especially useful for providing well-sealed polymer-coated hard-shell capsules for pharmaceutical or nutraceutical dosage forms with gastric resistance and a desired rapid release in the small intestine. The described process is also useful for providing polymer-coated hard-shell capsules and pharmaceutical or nutraceutical dosage forms based on this type of capsule with enhanced moisture protection properties, especially with decreased moisture absorption during storage.

[025] The term “a polymer” or “a polymer blend” should be understood as a polymer or a blend of two or more polymers, for example, a blend of two or three polymers. It is also possible that the coating layer may comprise or consist of several individual layers, perhaps two layers, each containing a polymer or a polymer blend, which may comprise the same or different polymers in the two or more layers. Preferably, the coating layer comprises or consists of only one coating layer, preferably only one polymer or a blend of two polymers. A polymer should mean only one polymer or only a primary polymer with the addition of negligible amounts of additional polymers (percentage of 5 or 2 or 1 or less by weight calculated on the basis of the weight of the primary polymer) which do not essentially influence the function of the primary polymer.Negligible amounts of additional polymers may be added to. Petition 870200059460, dated 05 / 13 / 2020, pp. 163 / 230 7 / 65 excipient functions such as enhancing the adhesion of the coating layer to the capsule material. DETAILS OF THE INVENTION HARD-SHELL CAPSULES

[026] Hard shell capsules for pharmaceutical or nutraceutical purposes are well known to one skilled in the art. A hard shell capsule is a two-piece encapsulation capsule comprising two capsule halves, referred to as the body and the cap. The capsule body and cap material is usually made of hard and sometimes brittle material. The hard shell capsule comprises a body and a cap. The body and cap are usually of an open-ended cylindrical shape with rounded hemispherical ends closed at the opposite end. The shape and size of the cap and body are such that the body can be pushed telescopically with its open end towards the open end of the cap.

[027] The body and lid comprise a compatible area of ​​potential overlap (overlap area) outside the body and inside the lid that partially overlaps when the capsule is closed in the pre-locked stage and fully overlaps in the final locked stage. When the lid is partially slid over the body's overlap compatibility area, the capsule is in the pre-locked stage. When the lid is fully slid over the body's overlap compatibility area, the capsule is in the final locked stage. Maintenance of the pre-locked stage or the final locked stage is usually supported by body and lid press-fit mechanisms such as compatible circular notches or recesses, preferably elongated recesses.

[028] Usually, the body is longer than the cap. The overlapping area outside the body may be covered by the cap in order to close or lock the capsule. In the closed state, the cap covers the overlapping area outside the body either in a pre-locked state or in a final locked state. In the final locked state, the cap covers the overlapping area outside the body entirely; in the pre-locked state, the cap overlaps the overlapping area outside the body only partially. The cap may be slid over the body to be fixed usually in one of two different positions in which the capsule is closed either in a pre-locked state or in a final locked state. Petition 870200059460, dated 05 / 13 / 2020, pages 164 / 230 8 / 65

[029] Hard shell capsules are commercially available in different sizes. Hard shell capsules are usually delivered as empty containers with the body and cap already positioned in the pre-locked state and as requested as separate halves of capsules, bodies and caps. Pre-locked hard shell capsules can be supplied to a capsule loading machine, which performs the opening, loading and closing of the capsule to the final locked state. Usually, hard shell capsules are loaded with dry materials, for example, with powders or granules comprising a biologically active ingredient.

[030] The lid and body are equipped with locking mechanisms that are advantageous for pre-locking (temporarily) and / or final locking of the capsule.

[031] Therefore, raised points may be provided on the inner wall of the lid and slightly larger recessed points are provided on the outer wall of the body, which are arranged so that, when the capsule is closed, the elevations fit into the recesses. Alternatively, the elevations may be formed on the outer wall of the body and the recesses on the inner wall of the lid. Arrangements in which the elevations or recesses are arranged in a ring or spiral around the wall. Instead of the point-type configuration of the elevations and recesses, they may encircle the wall of the lid or body in an annular configuration, although advantageously recesses and openings are provided that allow for gas exchange into and out of the inner capsule.

[032] One or more elevations may be provided in an annular arrangement around the inner wall of the lid and the outer wall of the body so that, in the final locked position of the capsule, an elevation on the lid is situated adjacent to an elevation on the body. Sometimes, elevations are formed on the outside of the body near the open end and recesses are formed in the lid near the open end so that the elevations on the body lock into the recesses on the lid in the final locked position of the capsule. The elevations may be such that the lid can be opened in the pre-locked state at any time without damaging the capsule or, alternatively, so that, once closed, the capsule cannot be opened again without destroying it.

[033] Capsules with one or more of these locking mechanisms (locks) (e.g., two surrounding grooves) are preferred. Even more preferred are those Petition 870200059460, dated 05 / 13 / 2020, pages 165 / 230 9 / 65 capsules with at least two such locking means that fasten the two capsule parts together to varying degrees. In one such part, a first locking means (surrounding concavities or notches) may be formed near the openings in the capsule cap and capsule body, and a second locking means (surrounding notches) may be offset in some way toward the closed end of the capsule parts. The first locking means fasten the two capsule parts together with less force than the second. This variant has the advantage that, after the production of empty capsules, the capsule cap and capsule body may initially be pre-locked together using the first locking mechanism. In order to load the capsule, the two capsule parts are then separated again. After loading, the two capsule parts are pushed together until the second set of locks firmly fastens the capsule parts together in a final locked stage.

[034] Preferably, the body and lid of the hard-shell capsule each comprise surrounding notches and / or concavities in the area where the lid can be slid onto the body. Surrounding notches of the body and concavities of the lid are compatible with each other to provide a snap-in or snap-in mechanism. The concavities may be circular or elongated (oval) in the longitudinal direction.

[035] The surrounding notches of the body and the surrounding notches of the lid (strictly compatible rings) are also compatible with each other to provide a snap-in or snap-in-place mechanism. This allows the capsule to be closed by a snap-in-place mechanism either in a pre-locked state or in a final locked state.

[036] Preferably, compatible surrounding notches of the body and elongated concavities of the lid are used to secure the body and lid to each other in the pre-locked state. Compatible surrounding notches of the body and lid are preferably used to secure or lock the body and lid to each other in the final locked state.

[037] The area where the lid can be slid over the body can be called the body-lid overlap area or, in short, the overlap area. If the lid overlaps the body only partially, perhaps 20 to 90 or 60 to 85% of the overlap area, the hard shell capsule is only partially Petition 870200059460, dated 05 / 13 / 2020, pages 166 / 230 10 / 65 closed (pre-locked). Preferably, in the presence of a locking mechanism, such as compatible surrounding notches and / or concavities in the body and lid, the partially closed capsule may be termed pre-locked. When the capsule is polymer-coated in the pre-locked stage, the coating will completely cover the outer surface, including that part of the body-lid overlap area that is not overlapped by the lid in that pre-locked stage. When the capsule is polymer-coated in the pre-locked stage and then closed to the final locked stage, the coating of that part of the body-lid overlap area that was not overlapped by the lid in the pre-locked stage will then be covered by the lid. The presence of that part of the coating, which is then confined in the final locked stage between the body and the lid, is sufficient for the hard-shell capsule to be well sealed. This was not a means to be anticipated.

[038] If the lid overlaps the body, the total overlapping area of ​​the body, the hard shell capsule is finally closed or in the final locked state. Preferably, in the presence of a locking mechanism, such as compatible surrounding notches and / or concavities in the body and lid, the fully closed capsule may be termed final locked.

[039] Usually, concavities are preferred for securing the body and cover in the pre-locked state. As a non-binding rule, the compatible area of ​​concavities is smaller than the compatible area of ​​surrounding notches. In this way, press-fitted concavities can be press-unfitted again by applying less force than would be required to press-unfit a press-fitted fastening with compatible surrounding notches.

[040] The body and cover recesses are located in the area where the cover can be slid onto the body, and are compatible with each other in the pre-locked state by a press-fit or snap-in-place mechanism. There may be, for example, 2, 4, or preferably 6 recesses or recesses located in a circular pattern around the cover.

[041] Usually, the concavities of the lid are the surrounding notches of the body in the area where the lid can be slid over the body; they are compatible with each other so that they do not allow the capsule to be closed by a snap-in mechanism in the pre-locked state. In the pre-locked state, the capsule of Petition 870200059460, dated 05 / 13 / 2020, pp. 167 / 230 11 / 65 hard casing can be reopened manually or by machine without damage, due to the fact that the forces required for opening are relatively small. Therefore, the “pre-locked state” is sometimes also referred to as “clearly capped”.

[042] Usually, the surrounding notches or compatible locking rings of the body and lid in the area where the lid can be slid over the body are compatible with each other so that they do not allow the capsule to be closed by a snap-in mechanism in the final locked state. In the final locked state, the hard shell capsule cannot or can only be forcibly opened again manually or by a machine without damage, due to the fact that the forces required for opening are comparatively large.

[043] Usually, the surrounding concavities and notches are formed in the capsule body or capsule lid. When capsule parts with these elevations and recesses are fitted together, ideally defined uniform gaps of 10 microns to 150 microns, more particularly 20 microns to 100 microns, are formed along the contact surface between the capsule body and the capsule lid placed on it.

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

[045] Unlike a hard-shell capsule, a soft-shell capsule is a welded one-piece encapsulation capsule. A soft gel capsule is often produced from blow-molded gelling substances and is usually loaded with liquids comprising a biologically active ingredient by injection. The invention does not relate to welded one-piece soft-shell encapsulation capsules. HARD SHELL CAPSULE SIZES

[046] A closed-end locked hard shell capsule may have a total length in the range of about 5 to 40 mm. The cap diameter may be found in the range of about 4 to 12 mm. The body diameter may be found in the range of about 2 to 11 mm. The cap length may be found in the range of about 4 to 20 mm and that of the body in the range of 8 to 30 mm. The loading volume may be found in the range of about 0.1 to 2 ml. The difference between the length Petition 870200059460, dated 05 / 13 / 2020, pages 168 / 230 12 / 65 pre-locked and the final locked length can be approximately 1 to 5 mm.

[047] Capsules can be divided into standardized sizes, for example, from sizes 000 to 5. A closed capsule of size 000 has, for example, a total length of about 28 mm with an outer diameter of the cap of about 9.9 mm and an outer diameter of the body of about 9.5 mm. The length of the cap is about 14 mm, that of the body, about 22 mm. The loading volume is about 1.4 ml.

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

[049] A size 0 capsule may show a length of about 23 to 24 mm in the pre-locked stage and about 20.5 to 21.5 mm in the final locked stage. Thus, the difference between the pre-locked length and the final locked length may be about 1 to 3 mm. HARD-SHELL CAPSULE (COATED)

[050] The invention relates to a polymer-coated hard-shell capsule, obtained from a process as described herein. BODY AND LID MATERIAL

[051] The body and cap material may be selected from hydroxypropyl methylcellulose, starch, gelatin, pullulan and a C1- to C4-alkyl ester copolymer of (meth)acrylic acid and (meth)acrylic acid. Hard shell capsules are preferred in which the body and cap comprise or consist of HPMC or gelatin, with HPMC being preferred due to its good adhesion properties for the polymer coating. POLYMER OR POLYMER MIXTURE COMPRISED IN THE COATING LAYER

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

[053] The selection of generic or specific characteristics or modalities of Petition 870200059460, dated 05 / 13 / 2020, pages 169 / 230 13 / 65 polymer, as disclosed in this document, may be combined without restriction with any other generic or specific selection of material or features or numerical embodiments disclosed in this document, such as capsule materials, capsule sizes, coating thicknesses, biologically active ingredients, and any other features or embodiments as disclosed. ANIONIC POLYMERS - ENTERIC COATING AND GASTRIC RESISTANCE

[054] The process described is especially useful for providing tightly sealed polymer-coated hard shell capsules for pharmaceutical or nutraceutical dosage forms with gastric resistance and a desired rapid release in the small intestine (enteric coating) or large intestine (colon targeting).

[055] The polymer or polymer mixture comprised in the coating layer may be an anionic polymer selected from the groups of anionic (meth)acrylate copolymers, anionic polyvinyl polymers or anionic copolymers and celluloses.

[056] The anionic polymers mentioned above are also called “enteric polymers”. In the coating layer, these polymers have the ability to provide enteric protection to the capsule.

[057] Enteric protection means that, when the capsule is in the final sealed state and comprises a load comprising a pharmaceutical or nutraceutical biologically active ingredient, less than 10% of the biologically active ingredient comprised will be released after 120 min in 0.1 HCl, pH 1.2. Most preferably, after 120 minutes in 0.1 HCl pH 1.2 and subsequent change to a buffered medium of pH 6.8, about 80% or more of the biologically active ingredient comprised will be released after a total time of 165 minutes or 180 minutes.

[058] Colon targeting means that, when the capsule is in the final sealed state and comprises a load comprising a pharmaceutical or nutraceutical biologically active ingredient, less than 10% of the comprised biologically active ingredient will be released after 120 min in 0.1 HCl, pH 1.2. Preferably, after 120 min in 0.1 HCl pH 1.2 and subsequent change to a buffered medium of pH 6.8, approximately 80% or more of the comprised biologically active ingredient will be released after a total time of 165 min. With maximum Petition 870200059460, dated 05 / 13 / 2020, pages 170 / 230 14 / 65 preferably, after 120 min in 0.1 HCl pH 1.2 and 60 min in a subsequent intermediate change to a buffered medium of pH 6.5 or 6.8 and subsequent final change to a buffered medium of pH 7.2 or pH 7.4, approximately 80% or more of the biologically active ingredient will be released after a total time of 225 min or 240 min.

[059] The dissolution test is carried out in accordance with chapter <711> From the U.S. Pharmacopoeia 40 (USP), using the USP Apparatus II with a paddle speed of 75 rpm. The temperature of the test medium will be adjusted to 37 ± 0.5 °C. Samples will be collected at appropriate times. ANIONIC (MET)ACRYLATE COPOLYMERS

[060] Preferably, the anionic (meth)acrylate copolymer comprises 25 to 95, preferably 40 to 95, in particular 60 to 40% by weight of free-radical polymerized C1 to C12-alkyl esters, preferably C1 to C4-alkyl esters of acrylic or methacrylic acid and 75 to 5, preferably 60 to 5, in particular 40 to 60% by weight of (meth)acrylate monomers with an anionic group. The proportions mentioned normally add up to 100% by weight. However, it is also possible, without this leading to a decrease or alteration of the essential properties, that small quantities in the range of 0 to 10, for example, 1 to 5% by weight of other monomers with vinyl copolymerization capacity, such as, for example, hydroxyethyl methacrylate or hydroxyethyl acrylate, are present. It is preferable that no other monomers with vinyl copolymerization capacity are present.

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

[062] A (meth)acrylate monomer with an anionic group is, for example, acrylic acid, preferably methacrylic acid.

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

[064] EUDRAGIT® L is a copolymer polymerized from 50% by weight of methyl methacrylate and 50% by weight of methacrylic acid. The pH at the beginning of Petition 870200059460, dated 05 / 13 / 2020, pages 171 / 230 15 / 65 release of the specific active ingredient into intestinal juice or simulated intestinal fluid can be declared at pH 6.0.

[065] EUDRAGIT® L 100-55 is a copolymer polymerized from 50% by weight ethyl acrylate and 50% by weight methacrylic acid. EUDRAGIT® L 30 D-55 is a dispersion comprising 30% by weight of EUDRAGIT® L 100-55. The pH at which the specific active ingredient begins to release into intestinal juice or simulated intestinal fluid can be stated as pH 5.5.

[066] Anionic copolymers of (meth)acrylate polymerized from 20 to 40% by weight of methacrylic acid and 80 to 60% by weight of methyl methacrylate (type EUDRAGIT® S) are equally suitable. The pH at which the release of the specific active ingredient begins in intestinal juice or simulated intestinal fluid can be stated as pH 7.0.

[067] Suitable (meth)acrylate copolymers are polymerized from 10 to 30% by weight of methyl methacrylate, 50 to 70% by weight of methyl acrylate and 5 to 15% by weight of methacrylic acid (type EUDRAGIT® FS). The pH at the onset of release of the specific active ingredient into intestinal juice or simulated intestinal fluid may be stated as pH 7.0.

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

[069] A copolymer composed of 34% by weight methacrylic acid and / or acrylic acid, 69% by weight methyl acrylate, and 40% by weight ethyl acrylate and / or, where appropriate, 10% by weight of additional monomers with vinyl copolymerization capability is suitable, provided that the glass transition temperature of the copolymer according to ISO 11357 2, subsection 3.3.3, is not greater than 60 °C. This (meth)acrylate copolymer is particularly suitable, due to its good elongation-at-break properties, for compacting pellets into tablets.

[070] A copolymer polymerized from 33% by weight of methacrylic acid and / or acrylic acid is suitable, Petition 870200059460, dated 05 / 13 / 2020, pages 172 / 230 16 / 65 to 30% by weight of methyl acrylate, and to 40% by weight of ethyl acrylate, and more than 10 to 30% by weight of butyl methacrylate and, where appropriate, 0 to 10% by weight of additional monomers with vinyl copolymerization capability, wherein the proportions of the monomers add up to 100% by weight, provided that the glass transition temperature of the copolymer according to ISO 11357 2, subsection 3.3.3 (midpoint temperature Tmg), is 55 to 70 °C. Copolymers of this type are particularly suitable, due to their good mechanical properties, for compacting pellets into tablets.

[071] The copolymer preferably consists essentially or exclusively of 90, 95 or 99 to 100% by weight of the monomers of methacrylic acid, methyl acrylate, ethyl acrylate and ethyl acrylate and butyl methacrylate in the ranges of amounts indicated above. However, it is possible, without this necessarily leading to a decrease in the essential properties, to include small amounts in the range of 0 to 10, for example, 1 to 5% by weight of other monomers with vinyl copolymerization capacity, such as, for example, methyl methacrylate, butyl acrylate, hydroxyethyl methacrylate, hydroxyethyl methacrylate, vinylpyrrolidone, vinylmalonic acid, styrene, vinyl alcohol, vinyl acetate and / or derivatives thereof.

[072] Suitable additional anionic copolymers of (meth)acrylate may be referred to as core / shell polymers, as described in WO 2012 / 171575A2 or 2012 / 171576A1. A suitable core / shell polymer is a copolymer of a two-step emulsion polymerization process with a 75% by weight core comprising polymerized units of 30% by weight of ethyl acrylate and 70% by weight of methyl methacrylate and a shell of polymerized units comprising 25% by weight of polymerized units from 50% by weight of ethyl acrylate and 50% by weight of methacrylic acid.

[073] A suitable core-shell polymer may be a copolymer of a two-stage emulsion polymerization process with a core of 70 to 80% by weight, comprising polymerized units of 65 to 75% by weight of ethyl acrylate and 25 to 35% by weight of methyl methacrylate and a shell of 20 to 30% by weight, comprising polymerized units of 45 to 55% by weight of acrylate Petition 870200059460, dated 05 / 13 / 2020, pages 173 / 230 17 / 65 ethyl and 45 to 55% by weight of methacrylic acid. ANIONIC CELLULOSES

[074] Anionic celluloses can be selected from carboxymethyl ethyl cellulose and its salts, cellulose acetate phthalate (CAP), cellulose acetate succinate (CAS), cellulose trimellitate acetate (CAT), hydroxypropyl methyl cellulose phthalate (HPMCP, HP50, HP55), hydroxypropyl methyl cellulose acetate succinate (HPMCAS-LF, -MF, -HF). ANIONIC VINYL COPOLYMERS

[075] Anionic vinyl copolymers can be selected from unsaturated carboxylic acids other than acrylic acid or methacrylic acid, as exemplified by polyvinyl acetate phthalate or a copolymer of vinyl acetate and crotonic acid (preferably in a 9:1 ratio). Cationic Polymers - Protection Against Moisture

[076] The process described is particularly useful for providing polymer-coated hard shell capsules and pharmaceutical or nutraceutical dosage forms based on this type of capsule with enhanced moisture protection properties, for example, with reduced moisture absorption during storage. For this purpose, a coating with a cationic polymer is suggested, preferably with a cationic copolymer of (meth)acrylate.

[077] A suitable cationic copolymer of (meth)acrylate comprising the coating layer may be polymerized from monomers comprising C1 to C4-alkyl esters of acrylic or methacrylic acid and an alkyl ester of acrylic or methacrylic acid with a tertiary or quaternary ammonium group in the alkyl group.

[078] The water-soluble cationic (meth)acrylate copolymer can be partially or fully polymerized into alkyl from acrylates and / or alkyl methacrylates with a tertiary amino group on the alkyl radical. A coating comprising this type of polymer can have the advantage of providing moisture protection to the hard shell capsule. Moisture protection should be understood as reduced moisture or water uptake during storage of the ready-loaded and end-lock capsules.

[079] A suitable cationic copolymer of (meth)acrylate can be polymerized from 30 to 80% by weight of C1 to C4-alkyl esters of acrylic or methacrylic acid. Petition 870200059460, dated 05 / 13 / 2020, pages 174 / 230 18 / 65 and 70 to 20% by weight of alkyl(meth)acrylate monomers with a tertiary amino group on the alkyl radical.

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

[081] A commercially available (meth)acrylate copolymer specifically suited with tertiary amino groups is polymerized from 25% by weight methyl methacrylate, 25% by weight butyl methacrylate and 50% by weight dimethylaminoethyl methacrylate (EUDRAGIT® E100 or EUDRAGIT® E PO (powder form)). EUDRAGIT® E 100 and EUDRAGIT® E PO are soluble in water below approx. pH 5.0 and are therefore also soluble in gastric juice.

[082] A suitable (meth)acrylate copolymer may consist of 85 to 98% by weight of C1 to C4-alkyl esters polymerized by free radicals of acrylic or methacrylic acid and 15 to 2% by weight of (meth)acrylate monomers with a quaternary amino group on the alkyl radical.

[083] The preferred C1 to C4-alkyl esters of acrylic or methacrylic acid are methyl acrylate, ethyl acrylate, butyl acrylate, butyl methacrylate and methyl methacrylate.

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

[085] 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-trimethylammoniummethyl methacrylate chloride.

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

[087] A suitable additional (meth)acrylate copolymer may be polymerized from 85 to less than 93% by weight of C1 to C4-alkyl esters of acrylic or methacrylic acid and more than 7 to 15% by weight of (meth)acrylate monomers with a quaternary amino group on the alkyl radical. Such (meth)acrylate monomers are commercially available and have long been used for flame-retardant coatings. Petition 870200059460, dated 05 / 13 / 2020, pages 175 / 230 19 / 65 release.

[088] A specifically suitable copolymer is polymerized from 60% by weight of methyl methacrylate, 30% by weight of ethyl acrylate and 10% by weight of 2-trimethylammonium ethyl methacrylate chloride (EUDRAGIT® RS). NEUTRAL POLYMERS

[089] Neutral polymers are defined as polymers that are polymerized from neutral monomers and less than 5, preferably less than 2% by weight or more preferably not all monomers with ionic groups.

[090] Suitable neutral polymers for hard shell capsule coating are methacrylate copolymers, preferably ethyl acrylate and methyl methacrylate copolymers such as EUDRAGIT® NE or EUDRAGIT® NM, neutral celluloses such as methyl, ethyl or propyl cellulose ethers, for example, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl acetate or polyvinyl alcohol.

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

[092] Neutral methacrylate copolymers are polymerized from at least to an extent of more than 95% by weight, in particular to an extent of at least 98% by weight, preferably to an extent of at least 99% by weight, in particular to an extent of at least 99% by weight, more preferably to 100% by weight, of (meth)acrylate monomers with neutral radicals, especially C1 to C4-alkyl radicals.

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

[094] Methacrylate monomers with anionic radicals, for example, acrylic acid and / or methacrylic acid, may be present in small amounts less than 5% by weight, preferably not more than 2% by weight, more preferably not more than 1 or 0.05 to 1% by weight.

[095] Suitable examples are neutral or virtually neutral (meth)acrylate copolymers polymerized from 20 to 40% by weight of ethyl acrylate, 60 to 80% by weight of methyl methacrylate and 0 to less than 5% by weight, preferably 0 to 2 or 0.05 to 1% by weight of methacrylic acid or acrylic acid. Petition 870200059460, dated 05 / 13 / 2020, pages 176 / 230 20 / 65

[096] Suitable examples are neutral or virtually neutral (meth)acrylate copolymers polymerized from 20 to 40% methyl methacrylate by weight, 60 to 80% ethyl acrylate by weight 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. (type EUDRAGIT® NE or EUDRAGIT® NM).

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

[098] Preference is given to neutral or essentially neutral methyl acrylate copolymers which, according to WO 01 / 68767, were prepared as dispersions using 1 to 10% by weight of a non-ionic emulsifier with an HLB value of 15.2 to 17.3. The latter offer the advantage that there is no phase separation with the formation of crystalline structures by the emulsifier (such as EUDRAGIT® NM).

[099] According to document EP 1 571 164 A2, corresponding copolymers of practically neutral (meth)acrylate with small proportions of 0.05 to 1% by weight of monoolefinically unsaturated C3-C8-carboxylic acids can, however, also be prepared by emulsion polymerization in the presence of comparatively small amounts of anionic emulsifiers, for example, 0.001 to 1% by weight. NATURAL POLYMERS

[0100] Especially for nutraceutical dosage forms, so-called “natural polymer” coatings are preferred by many customers. Natural polymers are based on a source from nature, plants, microorganisms or animals, but are sometimes chemically processed. Natural polymers for coatings can be selected from polymers such as starch, alginates or alginate salts, preferably sodium alginate, pectin, shellac, zein, carboxymethyl zein, modified starch, for example, EUDRAGUARD® Natural, marine sponge collagen, chitosan, gel gum. Suitable polymer mixtures may include:

[0101] Ethylcellulose and pectin, modified starch (EUDRAGUARD® Natural) and alginate and / or pectin, shellac and alginate and / or pectin, shellac and inulin, whey proteins and gums (such as guar gum or tragacanth gum), Petition 870200059460, dated 05 / 13 / 2020, pages 177 / 230 21 / 65 zein and polyethylene glycol, sodium alginate and chitosan. COATING LAYER

[0102] The hard shell capsule is coated with a coating layer comprising the polymer or polymer mixtures as disclosed and optionally excipients, preferably acceptable pharmaceutical or nutraceutical excipients.

[0103] The coating layer may 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 by weight or 100% by weight of the polymer or polymer blend as disclosed herein. The coating layer may comprise 10 to 100%, 10 to 90%, 12 to 80%, 15 to 70%, 18 to 60% or 20 to 50% by weight of the polymer as disclosed herein.

[0104] The coating layer may optionally comprise up to 10, up to 20, up to 30, up to 40, up to 50, up to 60, up to 70, up to 80, up to 90% by weight of excipients, preferably pharmaceutical and / or nutraceutical excipients (pharmaceutically or nutraceutical acceptable excipients). The coating layer may comprise 0 to 100, 10 to 90, 20 to 88, 30 to 85, 40 to 82 or 50 to 80% by weight of excipients, preferably pharmaceutical and / or nutraceutical excipients. The polymer or polymer mixture and the optionally included pharmaceutical and / or nutraceutical excipients may total 100%. QUANTITY AND THICKNESS OF THE COATING LAYER

[0105] The amount of coating layer (= total weight gain of the coating layer) applied must be sufficient to allow capillary loading between the outer overlap area of ​​the body covered by the cap. If the amount of coating layer applied is too low, this may result in no bridging or the bridging being too low. There may not be enough coating layer between the body and the cap when the capsule is closed in the final locked stage, which may result in insufficient tightness and capsule leakage.

[0106] For hard shell capsules, the amount of coating layer should not be too high. If the amount of coating layer applied is too high, this may result in difficulties in processing the pre-locked hard shell capsules coated with polymer subsequently in a machine. Petition 870200059460, dated 05 / 13 / 2020, pages 178 / 230 22 / 65 Capsule Loading. If the coating thickness is less than 8 mg / cm2, for example, 1 to 8 mg / cm2, or 1 to 5 mg / cm2, or 1 to 4 mg / cm2, there will usually be no problem with standard capsule loading machines without modification. In the range of 4 and up to about 8 mg / cm2, capsule loading machines can still be used; however, the shapes of the bodies and caps should be adjusted to be slightly wider. Such an adjustment can be easily performed by a mechanical engineer. In this way, capsule loading machines can be advantageously used within a coating thickness range of about 1 to about 8 mg / cm2.

[0107] For a size 0 hard shell capsule, the amount of coating layer should not be too high. If the amount of coating layer applied is too high, this may result in difficulties in processing the polymer-coated pre-locked hard shell capsules subsequently in a capsule loading machine. If the amount of coating layer is less than 5 mg / cm2, for example, 1 to 4 mg / cm2, usually no problem will occur with standard capsule loading machines without modification. In the range of 4 and up to about 8 mg / cm2, capsule loading machines can still be used; however, the shapes of the bodies and caps should be adjusted to be slightly wider. Such adjustment can be easily performed by a mechanical engineer.Therefore, capsule loading machines can be advantageously used within a coating thickness range of approximately 1 to approximately 8 mg / cm2.

[0108] For a size 1 hard shell capsule, the amount of coating layer should not be too high. If the amount of coating layer applied is too high, this may result in difficulties in processing the polymer-coated pre-locked hard shell capsules subsequently in a capsule loading machine. If the amount of coating layer is less than 4 mg / cm2, for example, 1 to 3.5 mg / cm2, usually no problem will occur with standard capsule loading machines without modification. In the range of 3.5 and up to about 8 mg / cm2, capsule loading machines can still be used, however, the Petition 870200059460, dated 05 / 13 / 2020, pages 179 / 230 23 / 65 The shapes of the bodies and caps should be adjusted to be slightly wider. Such an adjustment can be easily performed by a mechanical engineer. In this way, capsule loading machines can be advantageously used within a range of a coating thickness of about 1 to about 8 mg / cm2.

[0109] For a size 3 hard shell capsule, the amount of coating layer should not be too high. If the amount of coating layer applied is too high, this may result in difficulties in processing the polymer-coated pre-locked hard shell capsules subsequently in a capsule loading machine. If the amount of coating layer is less than 3 mg / cm2, for example, 1 to 2.5 mg / cm2, usually no problem will occur with standard capsule loading machines without modification. In the range of 2.5 and up to about 6 mg / cm2, capsule loading machines can still be used; however, the shapes of the bodies and caps should be adjusted to be slightly wider. Such adjustment can be easily performed by a mechanical engineer.Therefore, capsule loading machines can be advantageously used within a coating thickness range of approximately 1 to approximately 6 mg / cm2.

[0110] Above 8 mg / cm2 and up to about 20 mg / cm2, careful manual opening, loading, and closing of the polymer-coated capsule in the pre-locked state may still be possible without causing damage to the polymer coating. If the coating layer is thicker than the gap between the uncoated body and the cap, pre-locked coated capsules cannot be closed without damaging the applied coating, as the cap will hardly be able to slide over the body to the final locked state. The upper limit for manually closing pre-locked hard shell capsules to the final locked state without causing damage may be up to a coating layer quantity of about 20 mg / cm2. Above 20 mg / cm2, even very precise and careful manual closing of the capsule may no longer be possible without causing damage.

[0111] If the amount of coating layer applied is too high, there will also be a buildup of too much coating layer on the lid rim, where the gap between the body and the lid is in the pre-locked stage. This can result Petition 870200059460, dated 05 / 13 / 2020, pages 180 / 230 24 / 65 after drying, cracks may appear in the coating layer when the pre-locked coated hard shell capsule is opened manually or by machine. The cracks may result in subsequent leakage of the capsule. Finally, a coating that is too thick may result in difficulties or make it impossible to close the opened coated hard shell capsule to the final locking stage, since the coating layer is thicker than the gap in the overlap area between the body and the lid.

[0112] As a general rule, the coating layer on the hard shell capsule can be applied in an amount (= a total weight gain) of 0.7 to 20, 1.0 to 18, 2 to 10, 4 to 8, 1.0 to 8, 1.5 to 5.5, 1.5 to 4 mg / cm2.

[0113] As a general rule, the coating layer on the hard shell capsule can have an average thickness of about 5 to 100, 10 to 50, 15 to 75 pm.

[0114] As a general rule, the coating layer on the hard shell capsule can be applied in an amount of 5 to 50, preferably 8 to 40% by dry weight relative to the weight of the pre-locked capsule.

[0115] With this guidance, someone skilled in the art can adjust the coating layer quantities within a range from very low to very high. PREFERRED OPTIONS

[0116] A first preferred embodiment discloses a process for preparing a polymer-coated hard shell capsule, suitable as a container for pharmaceutical or nutraceutical biologically active ingredients, wherein the hard shell capsule comprises a body and a cap, wherein, in the closed stage, the cap overlaps the body, or 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 or dispersion comprising a polymer or a polymer mixture to create a coating layer covering the outer surface of the hard shell capsule in the pre-locked state, wherein the coating layer comprises 90, preferably 70 to 85% by weight of a polymer mixture and 10 to 40, preferably 15 to 30% by weight of acceptable pharmaceutical or nutraceutical excipients, comprising at least one plasticizer and a Petition 870200059460, dated 05 / 13 / 2020, pages 181 / 230 25 / 65 emulsifier, preferably glycerol monostearate (GMS), triethyl citrate (TEC) and polyoxyethylene(20)-sorbitane monooleate (polysorbate 80), wherein the polymer mixture and acceptable pharmaceutical or nutraceutical excipients total 00%, wherein the polymer mixture comprises 60 to 90, preferably 70 to 85% by weight of (meth)acrylate copolymers polymerized from 10 to 30% by weight of methyl methacrylate, 50 to 70% by weight of methyl acrylate and 5 to 15% by weight of methacrylic acid (type EUDRAGIT® FS) and 10 to 40, preferably 15 to 30% by weight of a (meth)acrylate copolymer polymerized from 40 to 60% by weight of methacrylic acid and 60 to 40% by weight of ethyl acrylate (type EUDRAGIT® L 100 55), wherein the amount of the coating layer (total weight gain) is 1 to 8, preferably 1 to 4 mg / cm2.

[0117] The polymer-coated hard shell capsule of the first embodiment can be advantageously combined with a load of the active pharmaceutical ingredients mesalamine or caffeine.

[0118] A second preferred embodiment discloses a process for preparing a polymer-coated hard shell capsule, suitable as a container for pharmaceutical or nutraceutical biologically active ingredients, wherein the hard shell capsule comprises a body and a cap, wherein, in the closed stage, the cap overlaps the body, or 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 or dispersion comprising a polymer or a polymer mixture to create a coating layer covering the outer surface of the hard shell capsule in the pre-locked state, wherein the coating layer comprises 85, preferably 70 to 80% by weight of a polymer, and 40, preferably 20 to 30% by weight of acceptable pharmaceutical or nutraceutical excipients, comprising at least one plasticizer and one emulsifier,preferably glycerol monostearate, triethyl citrate and polysorbate 80, wherein the polymer and acceptable pharmaceutical or nutraceutical excipients total 100%, wherein the polymer is a (meth)acrylate copolymer, Petition 870200059460, dated 05 / 13 / 2020, pp. 182 / 230 26 / 65 polymerized from 40 to 60% by weight of methacrylic acid and 60 to 40% by weight of ethyl acrylate (type EUDRAGIT® L 100 55), and wherein the amount of the coating layer (total weight gain) is 1 to 8, preferably 1 to 4 mg / cm2.

[0119] The polymer-coated hard shell capsule of the second embodiment can be advantageously combined with a load of the active pharmaceutical ingredients metoprolol or omeprazole.

[0120] A third preferred embodiment discloses a process for preparing a polymer-coated hard shell capsule, suitable as a container for pharmaceutical or nutraceutical biologically active ingredients, wherein the hard shell capsule comprises a body and a cap, wherein, in the closed stage, the cap overlaps the body, or 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 or dispersion comprising a polymer or a polymer mixture to create a coating layer covering the outer surface of the hard shell capsule in the pre-locked state, wherein the coating layer comprises 85, preferably 70 to 80% by weight of a polymer, and 40, preferably 20 to 30% by weight of acceptable pharmaceutical or nutraceutical excipients, comprising at least one plasticizer and one emulsifier,Preferably glycerol monostearate, triethyl citrate and polysorbate 80, wherein the polymer and acceptable pharmaceutical or nutraceutical excipients total 100%, wherein the polymer is a (meth)acrylate copolymer, with 10 to 30% by weight of methyl methacrylate, 50 to 70% by weight of methyl methacrylate and 5 to 15% by weight of methacrylic acid (type EUDRAGIT® FS), and wherein the amount of the coating layer is 1 to 8, preferably 1 to 4 mg / cm2.

[0121] The polymer-coated hard shell capsule of the third embodiment can be advantageously combined with a load of the active pharmaceutical ingredients mesalamine or metoprolol. Petition 870200059460, dated 05 / 13 / 2020, pages 183 / 230 27 / 65 BIOLOGICALLY ACTIVE INGREDIENT

[0122] The biologically active ingredient is preferably a pharmaceutical active ingredient and / or a nutraceutical active ingredient. Pharmaceutical or nutraceutical active ingredients

[0123] The invention is preferably useful for pharmaceutical or nutraceutical dosage forms formulated for immediate, enteric or sustained release with a load of pharmaceutical or nutraceutical active ingredients.

[0124] Suitable therapeutic and chemical classes of pharmaceutical active ingredients whose members can be used as filler for the polymer-coated capsules described are, for example: analgesics, antibiotics or anti-infectives, antibodies, antiepileptics, plant antigens, antirheumatics, benzimidazole derivatives, beta-blockers, cardiovascular drugs, chemotherapeutic agents, CNS drugs, digitalis glycosides, gastrointestinal drugs, for example, proton pump inhibitors, enzymes, hormones, liquid or solid natural extracts, oligonucleotides, peptide hormone proteins, therapeutic bacteria, peptides, protein salts (metal), i.e., aspartates, chlorides, orates, urology drugs, vaccines.

[0125] Other examples of medications that can be used as filler for the described polymer-coated capsules are, for example, acamprosat, aescin, amylase, acetylsalicylic acid, adrenaline, 5-aminosalicylic acid, aureomycin, bacitracin, balsalazine, beta-carotene, bicalutamide, bisacodyl, bromelain, bromelain, budesonide, calcitonin, carbamacipin, carboplatin, cephalosporins, cetrorelix, clarithromycin, chloromycetin, cimetidine, cisapride, cladribine, clorazepate, cromalyn, 1-desaminocysteine-8-D-arginine vasopressin, deramcyclane, detirelix, dexlansoprazole, diclofenac, didanosine, digitoxin and other digitalis glycosides, dihydrotreptomycin, dimethicone, divalproex, drospirenone, duloxetine, enzymes, erythromycin, esomeprazole, estrogens, etoposide, famotidine, fluorides, garlic oil, glucagon, granulocyte colony-stimulating factor (GCSF), heparin, hydrocortisone, human growth hormone (hGH), ibuprofen, ilaprazole, insulin,Interferon, Interleukin, Intron A, ketoprofen, lansoprazole, leuprolide acetate lipase, lipoic acid, lithium, kinin, memantine, mesalazine, methenamine, milameline, minerals, minoprazole, naproxen, natamycin, nitrofurazone, novobiocin, olsalazine, omeprazole, orotates, pancreatin, pantoprazole, parathyroid hormone. Petition 870200059460, dated 05 / 13 / 2020, pages 184 / 230 28 / 65 paroxetine, penicillin, pericorazine, pindolol, polymyxin, potassium, pravastatin, prednisone, preglumetacin progabide, prosomatostatin, protease, quinapril, rabeprazole, ranitidine, ranolazine, reboxetine, rutosid, somatostatin, streptomycin, subtilin, sulfasalazine, sulfanilamide, tamsulosin, tenatoprazole, trypsin, valproic acid, vasopressin, vitamins, zinc, including its salts, derivatives, polymorphs, isomorphs, or any types of mixtures or combinations thereof.

[0126] It is evident to one skilled in the art that there is a wide overlap between the terms pharmaceutical and nutraceutical active ingredients, excipients and compositions, respectively, a pharmaceutical or nutraceutical dosage form. Many substances listed as nutraceuticals may also be used as pharmaceutical active ingredients. Depending on the specific application and the legislation and classification of local authorities, the same substance may be listed as a pharmaceutical or nutraceutical active ingredient, respectively, a pharmaceutical or nutraceutical composition, or even both.

[0127] Nutraceuticals are well known to those skilled in the art. Nutraceuticals are often defined as food extracts that claim to have medical effects on human health. Thus, active nutraceutical ingredients may also exhibit pharmaceutical activities: Examples of active nutraceutical ingredients may be resveratrol from grape products as an antioxidant, soluble fiber products in the diet such as psyllium seed husk to reduce hypercholesterolemia, broccoli (sulfate) as a cancer preservative, and soy or clover (isoflavonoids) to improve arterial health. Therefore, it is clear that many substances listed as nutraceuticals may also be used as active pharmaceutical ingredients.

[0128] Typical nutraceuticals or active nutraceutical ingredients that may be used as filler for the polymer-coated hard shell capsules described may also include probiotics and prebiotics. Probiotics are live microorganisms believed to support human or animal health when consumed. Prebiotics are nutraceuticals or active nutraceutical ingredients that induce or promote the growth or activity of beneficial microorganisms in the human or animal gut.

[0129] Examples of nutraceuticals are resveratrol from grape products, omega-3 fatty acids or proanthocyanidins from blueberries as antioxidants, products of Petition 870200059460, dated 05 / 13 / 2020, pages 185 / 230 29 / 65 soluble dietary fibers, such as psyllium seed husk to reduce hypercholesterolemia, broccoli as a cancer preservative, and soy or soybean or clover (isoflavonoids) to improve arterial health. Other nutraceutical examples are flavonoids, antioxidants, alpha-linolenic acid from flaxseed, beta-carotene from marigold petals, or anthocyanins from berries. Sometimes the expression nutraceuticals or nutraceuticals is used synonymously with nutraceuticals.

[0130] The preferred biologically active ingredients are metoprolol, mesalamine and omeprazole. EXCIPIENTS

[0131] The excipients are well known to one skilled in the art and are frequently formulated together with the biologically active ingredient contained in the hard-shell coated capsule and / or with the polymer coating of the hard-shell capsule as disclosed and claimed herein. All excipients used must be toxicologically safe and used in pharmaceutical or nutraceutical products without risk to patients or consumers.

[0132] The dosage form may comprise excipients, preferably acceptable pharmaceutical or nutraceutical excipients, selected from the group of antioxidants, bleaching agents, binding agents, flavorings, flow aids, fragrances, glidants, penetration enhancers, pigments, plasticizers, emulsifiers, pore-forming agents or stabilizers or combinations thereof. The pharmaceutically or nutraceutically acceptable excipients may be comprised in the core and / or coating layer comprising the polymer, as disclosed. An acceptable pharmaceutical or nutraceutical excipient is an excipient that can be used for application in the pharmaceutical or nutraceutical field.

[0133] The coating layer may comprise 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 or no (0%) excipient, respectively, pharmaceutically or nutraceutically acceptable excipients. Preferably, except for the polymer or polymer mixture of the coating layer, no other polymer (excipient) is present in the coating layer. PLASTICIZERS

[0134] The polymer coating of the hard shell capsule may comprise one or more plasticizers. The plasticizers achieve this through physical interaction. Petition 870200059460, dated 05 / 13 / 2020, pages 186 / 230 30 / 65 with a polymer a reduction in the glass transition temperature and promote film formation, depending on the amount added. Suitable substances generally have a molecular weight between 100 and 20,000 and comprise one or more hydrophilic groups in the molecule, for example, hydroxyl, ester or amino groups.

[0135] Examples of suitable plasticizers are alkyl citrates, glycerol esters, alkyl phthalates, alkyl sebacates, sucrose esters, sorbitan esters, diethyl sebacate, dibutyl sebacate, propylene glycol, and polyethylene glycols 200 to 12,000. Preferred plasticizers are triethyl citrate (TEC), acetyl triethyl citrate (ATEC), diethyl sebacate, and dibutyl sebacate (DBS). In addition, esters that are generally liquid at room temperature, such as citrates, phthalates, sebacates, or castor oil, should be mentioned. Esters of citric acid and sebacinic acid are preferably used. Glycerol monostearate (MSG) has plasticizing properties. In the context of this revelation, glycerol monostearate (GMS), although it also has some sliding properties and is sometimes referred to as a sliding agent, is considered here to be a plasticizer.

[0136] The addition of plasticizers to the formulation can be carried out in a known manner, directly, in aqueous solution or after thermal pretreatment of the mixture. It is also possible to employ mixtures of plasticizers. However, since the polymer, as disclosed herein, shows a minimum film forming temperature (MFFT) of 35 °C or less, it is possible to apply the polymer coating, for example, from an aqueous polymer dispersion, without the addition of a plasticizer. The polymer coating of the hard shell capsule may comprise one or more plasticizers, preferably 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 in the polymer or polymer mixture, of a plasticizer or no plasticizer may be included.Ideally, 20 to 30 by weight of a mixture of glycerol monostearate (GMS) and triethylethylated compounds, calculated based on the polymer or the extent of the polymer content, may be included in the coating layer. CARGO

[0137] Standard fillers are generally added to the inventive formulation during the processing of coating and bonding agents. The amounts introduced and the use of standard fillers in pharmaceutical coatings or overlays are familiar to those skilled in the art. Examples of standard fillers are Petition 870200059460, dated 05 / 13 / 2020, pages 187 / 230 31 / 65 releasing agents, pigments, stabilizers, antioxidants, pore-forming agents, penetration enhancers, bleaching agents, fragrances, or flavoring agents. These are used as processing aids and are intended to ensure a reliable and reproducible preparation process, as well as good long-term storage stability, or to achieve additional advantageous properties in the pharmaceutical form. They are added to polymer formulations before processing and can influence the permeability of the coatings. This property can be used, if necessary, as an additional control parameter. SLIDING AGENTS (RELEASE AGENTS):

[0138] Glidants or release agents generally have lipophilic properties and are usually added to suspensions by spraying; they prevent the agglomeration of nuclei during film formation. Suitable glidants are talc, Mg or Ca stearate, ground silica, kaolin, or nonionic emulsifiers with an HLB value between 2 and 8. Standard proportions for the use of release agents in the coating and in the binding agents of the invention range from 0.5 to 100% by weight relative to the polymer.

[0139] In a particularly advantageous embodiment, the glide or release agent is added in concentrated form as the outer layer. Application occurs in powder form or by spraying from an aqueous suspension with 5 to 30% (by weight) solid content. The required concentration is lower than incorporation into the polymer layer and reaches 0.1 to 2% by weight relative to the weight of the pharmaceutical form.

[0140] The coating layer of the dosage form may, for example, comprise 20 to 80, preferably 30 to 70% by weight of the polymer of the invention as disclosed and 20 to 80, 30 to 70% by weight of talc. The polymer and talc of the invention may total up to 100% by weight. PIGMENTS

[0141] Only rarely is a pigment added in soluble form. As a rule, pigments such as aluminum oxide or iron oxide are used in dispersed form. Titanium dioxide is used as a whitening pigment. Standard proportions for the use of pigments are between 10 to 200, 20 to 200% by weight relative to the polymer or polymer mixture in the coating layer. Proportions up to Petition 870200059460, dated 05 / 13 / 2020, pages 188 / 230 32 / 65 200% by weight calculated on the polymer or polymer blend can be easily processed.

[0142] In a particularly advantageous embodiment, the pigment is used directly in concentrated form as an additional outer layer, the so-called top layer. Application occurs in powder form or by spraying from an aqueous suspension with 5 to 35% (by weight) solid content. The required concentration is lower than incorporation into the polymer layer and reaches 0.1 to 2% by weight relative to the weight of the pharmaceutical form. OPTIONAL TOP AND BOTTOM LININGS

[0143] Optionally, the hard shell capsule may be additionally coated with a bottom coating or a top coating or both.

[0144] A bottom coating may be located between the capsule and the coating layer, comprising the polymer or polymer blend, as disclosed. A bottom coating essentially has no influence on the release characteristics of the active ingredient, but may, for example, improve the adhesion of the polymer coating layer. A bottom coating is preferably essentially water-soluble, for example, it may consist of substances such as HPMC as a film former. The average thickness of a bottom coating layer is generally very thin, for example, no more than 15 µm, preferably no more than 10 µm (0.1 to 0.6 mg / cm2). A bottom coating or a top coating does not necessarily have to be applied to the hard shell capsule in the pre-locked state.

[0145] A top coating may be located over the coating layer, which comprises the polymer or polymer blend, as disclosed. A top coating is also preferably water-soluble or essentially water-soluble. A top coating may have the function of coloring the pharmaceutical or nutraceutical form or protecting against environmental influences, for example, against moisture during storage. The top coating may consist of a binder, for example, a water-soluble polymer such as a polysaccharide or HPMC, or a sugar compound such as sucrose. The top coating may further contain pharmaceutically or nutraceutically acceptable excipients, such as pigments or glidants, in quantities Petition 870200059460, dated 05 / 13 / 2020, pages 189 / 230 33 / 65 elevated. The top coating has no influence on the release characteristics. A top coating may be applied on top of the pharmaceutical or nutraceutical dosage form comprising the polymer-coated hard shell capsule at the final locked stage, as described herein. The average thickness of a top coating layer is generally very thin, for example, no more than 15 µm, preferably no more than 10 µm (0.1 to 0.6 mg / cm2). PROCESS FOR PREPARING A COATED HARD-SHELL CAPSULE

[0146] A process is described for preparing a polymer-coated hard shell capsule, suitable as a container for pharmaceutical or nutraceutical biologically active ingredients, wherein the hard shell capsule comprises a body and a cap, wherein, in the closed state, the cap overlaps the body, or 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 polymer mixture to create a coating layer that covers the outer surface of the hard shell capsule in the pre-locked state.

[0147] In another stage of the process, the pre-locked hard shell capsule may be fitted with a load comprising a pharmaceutical or nutraceutical biologically active ingredient and is closed in the final locked state.

[0148] In a later stage of this process, the polymer-coated hard shell capsule in the pre-locked state can be opened, loaded with a payload comprising a pharmaceutical or nutraceutical biologically active ingredient, and closed in the final locked state. This additional process step is preferably carried out insofar as the coated hard shell capsule, in the pre-locked state, is fed to a capsule loading machine, which performs the opening, loading with a payload comprising a pharmaceutical or nutraceutical biologically active ingredient, and closing of the polymer-coated hard shell capsule to the final locked state.

[0149] This further process step results in a final polymer-coated hard shell capsule, which is a container for a pharmaceutical or nutraceutical biologically active ingredient. The final polymer-coated hard shell capsule, which as a container for the ingredient Petition 870200059460, dated 05 / 13 / 2020, pages 190 / 230 34 / 65 biologically active pharmaceutical or nutraceutical is a pharmaceutical or nutraceutical dosage form.

[0150] The pharmaceutical or nutraceutical dosage form comprises a polymer-coated hard shell capsule in the final locked stage containing a load comprising a pharmaceutical or nutraceutical biologically active ingredient, wherein the polymer-coated hard shell capsule comprises a coating layer comprising a polymer or a polymer blend, wherein the coating layer covers the outer surface area of ​​the capsule in the pre-locked stage, but not the overlapping area where the cap covers the body in the pre-locked stage.

[0151] A coating solution comprising the polymer or polymer mixture and optional excipients may be a solution of the polymer in an organic solvent, for example, acetone, isopropanol or ethanol. The concentration of material by dry weight in the organic solvent may be from about 5 to 50% by weight of polymer. A suitable spray concentration may be from about 5 to 25% by dry weight.

[0152] A coating dispersion may be the dispersion of a polymer mixture or of polymer and optional excipients in an aqueous medium, for example, water or a mixture of 80% or more by weight of water and 20% or less by weight of water-soluble solvents such as acetone or isopropanol. A suitable concentration of material by dry weight in the aqueous medium may be from about 5 to 50% by weight. A suitable spray concentration may be from about 5 to 25% by dry weight.

[0153] Spray coating is preferably carried out by spraying the coating solution or dispersing it onto pre-locked capsules in a drum coating application device or in a fluidized bed coating equipment. PROCESS FOR PREPARING A LOAD FOR DOSING FORM

[0154] The appropriate processes for preparing the feedstock for the pharmaceutical or nutraceutical dosage form are well known to one skilled in the art. A suitable process for preparing the feedstock for the pharmaceutical or nutraceutical dosage form as disclosed herein may be by forming a core that Petition 870200059460, dated 05 / 13 / 2020, pages 191 / 230 35 / 65 comprises the biologically active ingredient in the form of granules by direct compaction, compaction of dry, wet or sintered granules, by extrusion and subsequent rounding, by wet or dry granulation, by direct granulation or by linking powders to active ingredient-free microspheres or neutral cores or particles or granules containing active ingredient and, optionally, by applying coating layers in the form of aqueous dispersions or organic solutions in spraying processes or by fluidized bed spray granulation. USE / METHOD OF USE / METHOD STEPS

[0155] The process for preparing a suitable polymer-coated hard shell capsule as described herein may be understood as a method of using a hard shell capsule comprising a body and a cap, wherein in the closed stage the cap overlaps the body in a locked state or in a final locked state, to prepare a polymer-coated hard shell capsule suitable as a container for pharmaceutical or nutraceutical biologically active ingredients, comprising the steps of a) provide the hard shell capsule in the pre-locked state, and b) Coating by spraying with a coating solution, suspension or dispersion comprising a polymer or a polymer mixture to create a coating layer that covers the outer surface of the hard shell capsule in the pre-locked state.

[0156] Spray coating can preferably be applied using drum coating equipment or fluidized bed coating equipment. A suitable product temperature during the spray coating process can be in the range of about 15 to 40 °C, preferably about 20 to 35 °C. A suitable spray rate can be in the range of about 0.3 to 4.0 °C, preferably 0.5 to 3.9 °C [g / min / kg]. After spray coating, a drying step is included.

[0157] The polymer-coated hard shell capsule in the pre-locked state can be opened in step c), loaded with a load comprising a pharmaceutical or nutraceutical biologically active ingredient in step d) and is then closed in step e) to the final locked state.

[0158] Steps c) and e) can be performed manually or, preferably, Petition 870200059460, dated 05 / 13 / 2020, pages 192 / 230 36 / 65 supported by suitable equipment, for example, a capsule loading machine. Preferably, the hard-shell coated capsule in the pre-locked state is supplied to a capsule loading machine, which performs the opening step (c), loading with a load comprising a pharmaceutical or nutraceutical biologically active ingredient in step (d), and closing the capsule to the final locked state in step (e).

[0159] The selection of processes in all their generic or specific features and embodiments, as disclosed in this document, may be combined without restriction with any other generic or specific selections of materials or numerical features and embodiments disclosed in this document, such as polymers, capsule materials, capsule sizes, coating thicknesses, biologically active ingredients, and any other embodiments as disclosed. PHARMACEUTICAL OR NUTRACEUTICAL DOSAGE FORM

[0160] A pharmaceutical or nutraceutical dosage form is disclosed comprising a polymer-coated hard shell capsule in the final locked stage containing a load comprising a pharmaceutical or nutraceutical biologically active ingredient, wherein the polymer-coated hard shell capsule comprises a coating layer comprising a polymer or a polymer blend, wherein the coating layer covers the outer surface area of ​​the capsule in the pre-locked stage. Since the outer surface area of ​​the capsule in the pre-locked stage is larger than the outer surface area of ​​the capsule in the final locked stage, a portion of the polymer coating layer is concealed or confined between the body and the cap of the hard shell capsule, which provides an efficient seal. ITEMS

[0161] The invention relates to the following items. Disclosure should be understood by one skilled in the art in a broad sense as including any possible combination of any single item or with any other item or items without limit.

[0162] Item 1: Process for preparing a polymer-coated hard shell capsule, suitable as a container for pharmaceutical or nutraceutical biologically active ingredients, wherein the hard shell capsule comprises a Petition 870200059460, dated 05 / 13 / 2020, pp. 193 / 230 37 / 65 body and a lid, wherein, in the closed state, the lid overlaps the body, or 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 polymer mixture to create a coating layer that covers the outer surface of the hard shell capsule in the pre-locked state.

[0163] 2. Process, according to item 1, in which the polymer-coated hard shell capsule in the pre-locked state is opened, loaded with a load comprising a pharmaceutical or nutraceutical biologically active ingredient, and closed in the final locked state.

[0164] 3. Process, according to one or more of items 1 or 2, in which the hard-shell coated capsule in the pre-locked state is supplied to a capsule loading machine, which performs opening, loading with a charge comprising a pharmaceutical or nutraceutical biologically active ingredient and closing of the polymer-coated hard-shell capsule in the final locked state.

[0165] 4. Process, according to one or more of items 1 to 3, wherein the body and cap material is selected from hydroxypropyl methyl cellulose, starch, gelatin, pullulan and a copolymer of C1- to C4-alkyl ester of (meth)acrylic acid and (meth)acrylic acid.

[0166] 5. Process, according to one or more of items 1 to 4, in which the polymer or polymer mixture comprising the coating layer is selected from the groups of anionic polymers, cationic polymers or neutral polymers.

[0167] 6. Process, according to one or more of items 1 to 5, wherein the polymer or polymer mixture comprised in the coating layer is an anionic polymer selected from the (meth)acrylate and cellulose copolymer groups.

[0168] 7. Process, according to one or more of items 1 to 6, wherein the anionic polymer comprised in the coating layer is a copolymerized from 25 to 95%, preferably 40 to 95%, in particular 60 to 40%, by weight of C1- to C12-alkyl free radical polymerized esters, preferably C1- to C4-alkyl esters of acrylic or methacrylic acid and 75 to 5%, preferably 60 to 5%, in particular 40 to 60% by weight of (meth)acrylate monomers with an anionic group.

[0169] 8. Process, according to one or more of items 1 to 7, wherein the polymer Petition 870200059460, dated 05 / 13 / 2020, pages 194 / 230 38 / 65 or the polymer mixture comprised in the coating layer comprises a cationic (meth)acrylate copolymer.

[0170] 9. Process, according to one or more of items 1 to 8, in which the cationic (meth)acrylate copolymer is polymerized from monomers comprising C1- to C4-alkyl esters of acrylic or methacrylic acid and an alkyl ester of acrylic or methacrylic acid with a tertiary or quaternary ammonium group in the alkyl group.

[0171] 10. Process, according to one or more of items 1 to 8, wherein the polymer or polymer mixture comprising the coating layer is selected from starch, alginates or alginate salts, sodium alginate, pectin, shellac, zein, carboxymethyl zein, modified starch, marine sponge collagen, chitosan, gel gum, ethyl cellulose and pectin, starch and modified alginate and / or pectin, shellac and alginate and / or pectin, shellac and inulin, whey protein and gums, zein and polyethylene glycol, sodium alginate and chitosan.

[0172] 11. Process, according to one or more of items 1 to 10, wherein the body and the lid comprise surrounding notches and / or concavities in the area where the lid overlaps the body, which allow the capsule to be closed by a snap-in mechanism in place or in the pre-locked state or in the final locked state.

[0173] 12. Process, according to one or more of items 1 to 11, wherein the body comprises a conical ring.

[0174] 13. Process, according to one or more of items 1 to 12, in which the coating layer is applied in an amount of approximately 0.7 to 20, 1.0 to 18, 2 to 10, 4 to 8, 1.0 to 8, 1.5 to 5.5, 1.5 to 4 mg / cm2.

[0175] 14. Process, according to one or more of items 1 to 13, wherein the polymer comprised in the coating layer is a Core-Shell polymer, which is a copolymer of a two-stage emulsion polymerization process with a core of 70 to 80% by weight, comprising polymerized units of 65 to 75% by weight of ethyl acrylate and 25 to 35% by weight of methyl methacrylate, and a shell of 20 to 30% by weight, comprising polymerized units of 45 to 55% by weight of ethyl acrylate and 45 to 55% by weight of methacrylic acid.

[0176] 15. Hard-shell capsule coated with polymer obtained from a process in accordance with one or more of items 1 to 14. Petition 870200059460, dated 05 / 13 / 2020, pages 195 / 230 39 / 65

[0177] 16. Pharmaceutical or nutraceutical dosage form, according to item 16, comprising a polymer-coated hard shell capsule in the final locked stage containing a load comprising a pharmaceutical or nutraceutical biologically active ingredient, wherein the polymer-coated hard shell capsule comprises a coating layer comprising a polymer or a polymer blend, wherein the coating layer covers the outer surface area of ​​the capsule in the pre-locked stage.

[0178] 17. Pharmaceutical or nutraceutical dosage form according to item 16, in which, after 120 min in 0.1 HCl pH 1.2 and subsequent change to a buffered medium (according to USP, for example, USP 40) of pH 6.8 or pH 7.4, approximately 80% or more of the comprised pharmaceutical or nutraceutical biologically active ingredient is released after a total time of 165 min (120 + 45 min). The dissolution test is performed according to chapter <711> From the U.S. Pharmacopoeia 40 (USP), using the USP Apparatus II with a paddle speed of 75 rpm. The temperature of the test medium will be adjusted to 37 + / - 0.5 °C. Samples will be collected at appropriate times. [01 79] 18. Pharmaceutical or nutraceutical dosage form, according to item or 17, wherein, after 120 min in 0.1 HCl pH 1.2 and 60 min to a subsequent intermediate change to a buffered medium of pH 6.5 or 6.8 and a subsequent final change to a buffered medium of pH 7.2 or pH 7.4, approximately 80% or more of the comprised biologically active ingredient is released after a total time of 225 min or 240 min. The dissolution test is performed in accordance with the United States Pharmacopeia (USP 40) chapter <711> Using the USP Apparatus II with a paddle speed of 75 rpm, the temperature of the test medium will be adjusted to 37 + / - 0.5 °C. Samples will be collected at appropriate times. EXAMPLES

[0180] Polymers used in the examples: EUDRAGIT® FS is a copolymer polymerized from 25% by weight methyl methacrylate, 65% by weight methyl acrylate and 10% by weight methacrylic acid. EUDRAGIT® FS 30 D is an aqueous dispersion comprising 30% by weight of EUDRAGIT® FS. EUDRAGIT® L 100-55 is a copolymer polymerized from 50% by weight ethyl acrylate and 50% by weight methacrylic acid. EUDRAGIT® L 30 D-55 Petition 870200059460, dated 05 / 13 / 2020, pp. 196 / 230 40 / 65 is an aqueous dispersion comprising 30% by weight of EUDRAGIT® L 100-55. EUDRAGIT® NE is a copolymer comprising free-radical polymerized units of 30% by weight methyl methacrylate and 70% by weight ethyl acrylate. EUDRAGIT® NE 30 D is an aqueous dispersion comprising 30% by weight of EUDRAGIT® NE. EUDRAGIT® E PO is a copolymer in powder form polymerized from 25% by weight methyl methacrylate, 25% by weight butyl methacrylate and 50% by weight dimethylaminoethyl methacrylate. EXAMPLE 1

[0181] Dimensions and tolerances of different commercially available capsules in relation to the average difference between pre-locked and locked lengths. TABLE 1: HARD SHELL CAPSULE DIMENSIONS (1 / 2) Manufacturer Capsugel Capsugel Capsugel Color Transparent White Transparent Size No. 0 Vcaps® plus No. 0 Vcaps® plus No. 1 Vcaps® plus Locking Stage Unlocked Pre-locked End Lock Unlocked Pre-locked End Lock Unlocked Pre-locked End Lock Length [mm] 29.16 23.65 21.38 29.16 23.76 20.91 26.39 21.19 19.03 DP [mm] 0.19 0.2 0.16 0.17 0.15 0.07 Minimum [mm] 23.25 21 23.43 20.67 20.95 18.9 Maximum [mm] 23.95 21.7 23.99 21.31 21.4 19.15 Overlap Length [mm] 5.51 2.27 5.4 2.85 5.2 2.16 Total Overlap Length [mm] 7.78 8.25 7.36 Overlap Level 71% 100% 65% 100% 71% 100% TABLE 2: HARD-SHELL CAPSULE DIMENSIONS (2 / 2) Petition 870200059460, dated 05 / 13 / 2020, pages 197 / 230 41 / 65 Manufacturer Capsugel ACG ACG Color Transparent Transparent White Size No. 3 Vcaps® plus No. 0 Naturecaps No. 0EL Naturecaps Locking Stage Unlocked Pre-locked Final Locked Unlocked Pre-locked Final Locked Unlocked Pre-locked Final Locked Length [mm] 21.67 17.69 15.74 29.2 23.04 20.92 32 25.17 22.87 DP [mm] 0.16 0.17 0.12 0.16 0.07 0.17 Minimum [mm] 17.39 15.23 22.65 20.68 25.01 22.59 Maximum [mm] 17.94 15.98 23.21 21,22 25,29 23,1 Overlap Length [mm] 3.98 1.95 6.16 2.12 6.83 2.3 Total Overlap [mm] 5.93 8.28 9.13 Overlap Level 67% 100% 74% 100% 75% 100% EXAMPLE 2 - CALCULATION OF SURFACE AREA AND DIRECTIONAL COATING IN THE COLON OF PRE-LOCKING CAPSULES IN DRUM COATING APPLICATION DEVICE

[0182] Since a certain coating layer thickness is required to achieve the desired functionality of the film, the amount of coating material needed depends on the surface area of ​​the substrate. For this reason, coating quantities are expressed in mg of total dry substance per cm2 of substrate surface area. Below is described the equation for the surface of the pre-locked capsule, considering the average difference between the pre-locked state and the accumulated length of the separate capsule halves, body and cap. Ainfera =2(^π -Ί ^Ci lindro,corpo 27^2)(^ superposition) Petition 870200059460, dated 05 / 13 / 2020, pages 198 / 230 42 / 65 Aci lindro,tampa Ac Apsula-segmento = A^Esfera + Aci lindro Pre-locked capsule = Body + Cylinder

[0183] Calculation of a coating formulation for a functional enteric coating of pre-locked capsules. Polymeric dry substance [g] Batch size [g] ™Pre-locked capsule [mg] Γ mg 1 / = weight of polymer [ * ] ^pre-locked capsule [mm2] I

[0184] In addition, a coating formulation may include, besides the polymer, other suitable excipients, such as plasticizer, anti-adherent, etc. In order to calculate appropriate amounts of excipient [Ei], it is necessary to calculate the amount of each respective excipient based on the dry polymer substance in percentage. To calculate the total weight gain, the weight gain of the polymer must be multiplied by the factor [E]. _ 100% + E1 + E2+ - + EnE= 100% Total dry matter [g] Batch size [g] Pre-locked capsule [mg] , rmi ,r= polymer weight range [ * ] Pre-locked capsule [mm2] I

[0185] Example calculation 2 for calculating the outer capsule surface in the pre-locked state. TABLE 3: VCAPS® PLUS CAPSULE SPECIFICATIONS: Size 00el 00 0el 0 1 1el 2 3 4 Weight Weight [mg] 130 122 107 96 76 81 61 47 38 Tolerance [mg] ± 10 ± 7 ± 7 ± 6 ± 5 ± 5 ± 4 ± 3 ± 3 Capsule half length (body and cap) Body [mm] 22.20 20.22 20.19 18.44 16.61 17.70 15.27 13.59 12.19 Tolerance [mm] ±0.46 ±0.46 ±0.46 ±0.46 ± 0.46 ± 0.46 ± 0.46 ± 0.46 ± 0.46 Lid [mm] 12.95 11.74 11.68 10.72 9.78 10.49 8.94 8.08 7.21 Tolerance ±0.46 ±0.46 ±0.46 ±0.46 ± 0.46 ± 0.46 ± 0.46 ± 0.46 ± 0.46 Petition 870200059460, dated 05 / 13 / 2020, pages 199 / 230 43 / 65 [mm] Body Outer Diameter [mm] 8.18 8.18 7.34 7.34 6.63 6.63 6.07 5.57 5.05 Cover [mm] 8.53 8.53 7.65 7.64 6.91 6.91 6.35 5.82 5.32 Overall Length in Final Locked State Length [mm] 25.3 23.30 23.5 21.70 19.40 20.40 18.00 15.90 14.30 Tolerance [mm] ±0.30 ±0.30 ±0.30 ±0.30 ±0.30 ±0.30 ±0.30 ±0.30 ±0.30

[0186] Figure 2 / 4 shows a schematic drawing of the body (left) and lid (right) of a size 1 Vcaps® Plus hard shell capsule with the relevant dimensions in mm. The dimensions are used in Calculation Example 2 for the calculation of the outer capsule surface in the pre-locked state. The dimensions are: Body: length = 16.61 mm, cylinder (length of the cylindrical part) = 13.29 mm, outer diameter = 6.63 mm Lid: length = 9.78 mm, cylinder (length of the cylindrical part) = 6.32 mm, outer diameter = 6.91 mm Ai =2(-—) π = 69.05[mm ] sphere,Body 2 2 / 6.63 AaUndro,body = 2π (—) (13.29 - 5.2) = 168.50 [mm] A i ^E sphere, Lid Aci lindro,Tampa / 6,91\2= 2 ( 2 )π= 75,00[mm ] ( 6,91\ 2π (—) 6.32 = 137.20 [mm] AcApsuia-corpo = 69.05 + 168.50 = 237.55 [mm] Cap-lid = 75.00 + 137.20 = 212.20 [mm] Pre-locked capsule = 237.55 + 212.20 = 449.75 [mm] TABLE 4: CAPSULE SURFACE AREA Parameter Body Cover A1 / 2 Ball [mm2] 69.05 75.00 A Cylinder [mm2] 168.50 137.20 Petition 870200059460, dated 05 / 13 / 2020, pp. 200 / 230 44 / 65 Segment [mm2] 237.55 212.20 Pre-locked capsule [mm2] 449.75

[0187] Amount of dry polymer substance: γ mg ι / 300 [tj]\ Dry polymeric substance [g] = 5 [y^------] 449.75[mm2] ( ---j) = 88.77 [ty]

[0188] Total dry matter quantity: 100% + 17% + 10% + 2.5% = ------------------------- = 1.295 100% r mg -i, ί300 [α]\ Total dry substance [g] = 5 [j^------] 449.75[mm2] ( ---j) 1.295 = 114.96 [g] EXAMPLE OF FORMULATION 2 FOR TARGETING IN THE COLON WITH VCAPS® PLUS SIZE 1

[0189] EUDRAGIT® FS 30 D and EUDRAGIT® L 30 D-55 are aqueous polymer dispersions, each with a 30% by weight polymer content. The EUDRAGIT® FS 30 D and EUDRAGIT® L 30 D-55 polymer dispersions were mixed in a container. Excipients were added to the water during gentle stirring. The excipient suspension was added to the polymer dispersion mixture. The spray suspension was gently stirred during the coating process.

[0190] Vcaps® plus size 1 capsules were coated in the pre-locked state using a drum coating application device. Subsequently, the capsules were manually loaded with 200 mg of caffeine and closed to the final locked state. TABLE 5: EXAMPLE OF FORMULATION 2 - VCAPS® PLUS SIZE 1 (BATCH SIZE 300 G) Material Composition Quantities Dry Substance Percentage of Solid Composition EUDRAGIT® FS 30 D 4.0 mg / cm2 295.89 g 88.77 g 77.21 % EUDRAGIT® FS 30 D 1.0 mg / cm2 Glyceryl Monostearate (40 to 55%) 8.5% in ds* 7.55 g 7.55 g 6.57 % Polysorbate 80 (33% aq) 10.3% in 27.81 g 9.18 g 7.99 % Petition 870200059460, dated 05 / 13 / 2020, pp. 201 / 230 45 / 65 ds* Triethyl citrate 10.7% ds* 9.46 g 9.46 g 8.23% Demineralized Water On demand 425.34 g / cm² Total n / a 766.35 g 114.95 g Solids content 15% by weight Total solids gain 6.5 mg / cm² *Quantity based on dry polymeric substance [%] TABLE 6: EXAMPLE OF PROCESS PARAMETER 2 Parameter Value Machine Lõdige LHC Nozzle bore [mm] 1.0 Inner tube diameter [mm] 1.0 Delivery system Verder Lab peristaltic pump Atomization pressure [bar] 0.4 Flat pattern pressure [bar] 0.4 Travel speed [rpm] 20 to 22 Inlet air volume [m3 / h] 90 to 92 Inlet air temperature [°C] 29 to 39 Exhaust air temperature [°C] 26 to 30 Product temperature [°C] 26 to 30 Spray rate [g / min / kg] 0.8 to 2.7 Exhaust air humidity [% RH] 30.0 to 37.5 LOD

[0191] Capsule before coating 4.1%

[0192] Intermediate sample of capsule 2.5 mg / cm24.7%

[0193] Final sample of capsule 5 mg / cm24.6%

[0194] Dissolution test method:

[0195] Apparatus: ERWEKA DT 700 Paddle Apparatus (USP II) Petition 870200059460, dated 05 / 13 / 2020, pp. 202 / 230 46 / 65

[0196] Detection method. UV online

[0197] Temperature: 37.5 °C

[0198] Medium I: 700 ml of 0.1 N HCl adjusted to pH 1.20 (by using 2 N NaOH and 2 N HCl)

[0199] Medium II: After 2 hours in medium I, 194 ml of 0.2 N NasPO4 solution was added to raise the pH to 6.5 (pH fine-tuned using 2 N NaOH and 2 N HCl)

[0200] Medium III: After another hour in Medium II, 67 ml of 0.2 N NasPO4 solution was added to raise the pH to 7.2 (again, fine-tuning of the pH using 2 N NaOH and 2 N HCl).

[0201] Blade Speed: 75 rpm TABLE 7: DISSOLUTION RESULTS EXAMPLE 2 Medium Time [min] Sample 1 6.5 mg / cm2 [% released] Sample 2 6.5 mg / cm2 [% released] Sample 3 6.5 mg / cm2 [% released] Sample 1 5.2 mg / cm2 [% released] Sample 2 5.2 mg / cm2 [% released] Sample 3 5.2 mg / cm2 [% released] 0.1N HCl 0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 pH 6.5 135 0.00 0.00 0.00 0.00 0.00 0.00 pH 6.5 150 0.00 0.00 0.00 0.00 0.00 0.00 pH 6.5 165 0.41 0.11 0.13 0.00 0.00 0.00 pH 6.5 180 1.00 0.62 0.77 0.47 0.24 0.11 pH 7.4 185 1.47 1.10 1.37 0.87 0.49 0.32 pH 7.4 190 2.05 2.87 2.11 3.16 0.92 1.03 pH 7.4 195 17.67 7.70 2.98 19.66 24.48 22.23 pH 7.4 210 92.26 45.15 63.04 96.67 99.78 90.81 pH 7.4 225 99.92 99.79 99.93 99.88 99.88 99.83 pH 7.4 240 99.88 99.86 99.86 99.93 99.92 99.92 pH 7.4 255 99.95 99.92 99.91 99.95 99.94 99.92 pH 7.4 270 99.96 99.94 99.93 99.96 99.96 99.92 pH 7.4 300 100.01 100.00 99.97 99.99 99.97 99.97 Petition 870200059460, dated 05 / 13 / 2020, pages 203 / 230 47 / 65

[0202] Another example using a polymeric blend for targeting in the colon. The results show a successful in vitro evaluation with resistance in the stomach (pH 1.2) and upper small intestine (pH 6.5) and release at the ileocecal valve / colonic pH 7.4. The coating process was well established, preventing significant water absorption from the capsule. EXAMPLE 3 - ENTERIC COATING OF PRE-LOCKED CAPSULES IN A DRUM COATING APPLICATION DEVICE

[0203] EUDRAGIT® L 30 D-55 was supplied as 30% by weight aqueous polymer dispersion. Additional excipients were added to the water during gentle stirring. The excipient suspension was added to the polymer dispersion. The spray suspension was gently stirred during the coating process. The capsules were coated in the pre-locked state using a drum coating application device. Subsequently, the capsules were manually loaded with 200 mg of caffeine and closed to the final locked state. TABLE 8: EXAMPLE OF FORMULATION 3 - VCAPS® PLUS SIZE 1 (BATCH SIZE: 300 G) Material Composition Percentage of Solid Composition EUDRAGIT® FS 30 D 5.5 mg / cm2 77.77% Glyceryl Monostearate (40 to 55%) 7.5% ds* 5.83% Polysorbate® 80 3.0% ds* 2.33% Triethyl Citrate 18.1% ds* 14.07% Demineralized Water On demand n / a Solids content 16% by weight Total solid weight gain 7.1 mg / cm2 *Quantity based on dry polymeric substance [%] TABLE 9: PROCESS PARAMETER EXAMPLE 3 Parameter Value Machine Logistics LHC Petition 870200059460, dated 05 / 13 / 2020, pages 204 / 230 48 / 65 Batch size [g] 91 Nozzle hole [mm] 1.2 Inner tube diameter [mm] 1.0 Verder lab peristaltic pump Atomization pressure [bar] 0.4 Flat pattern pressure [bar] 0.4 Ambient temperature [°C] 22.8 to 24.1 Ambient humidity [% RH] 36.6 to 38.7 Travel speed [rpm] 22 Inlet air volume [m3 / h] 74 to 76 Inlet air temperature [°C] 28.6 to 33.5 Exhaust air temperature [°C] 26.6 to 29.5 Product temperature [°C] 25.8 to 27.4 Spray rate [g / min / kg] 0.9 to 4.6 Exhaust air humidity [% RH] 31.8 to 38.0 Process times [min] 68 Dissolution Test

[0204] Pre-locked polymer-coated capsules were manually loaded with 200 mg of caffeine, closed in the final locked state, and tested in a dissolution test. METHOD:

[0205] Apparatus: ERWEKA DT 700 Paddle Apparatus (USP II)

[0206] Detection method: UV online

[0207] Temperature: 37.5 °C

[0208] Medium I: 700 ml of 0.1 N HCl adjusted to pH 1.2 (by using 2 N NaOH and 2 N HCl)

[0209] Medium II: After 2 hours in medium I, 214 ml of 0.2 N NaaPO4 solution was added to raise the pH to 6.8 (fine-tuning of pH using 2 N NaOH and 2 N HCl)

[0210] Blade Speed: 75 rpm TABLE 10: DISSOLUTION RESULTS - EXAMPLE 3 Petition 870200059460, dated 05 / 13 / 2020, pages 205 / 230 49 / 65 Medium Time [min] Sample 1 7.1 mg / cm2 [% released] Sample 2 7.1 mg / cm2 [% released] Sample 3 7.1 mg / cm2 [% released] Sample 1 5.1 mg / cm2 [% released] Sample 2 5.1 mg / cm2 [% released] Sample 3 5.1 mg / cm2 [% released] 0.1N HCl 0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 HCL 0.1 N 120 0.00 0.00 0.00 0.00 0.00 0.00 pH 6.8 130 0.28 0.13 0.08 0.18 0.10 -0.03 pH 6.8 140 73.21 43.84 45.92 54.60 50.76 64.65 pH 6.8 150 99.83 87.28 97.74 92.97 85.50 95.25 pH 6.8 165 100.07 99.87 100.36 99.46 99.70 99.93 pH 6.8 180 100.07 99.99 100.07 99.79 100.32 99.86 pH 6.8 210 100.14 99.93 100.26 99.81 100.18 99.98 pH 6.8 240 100.10 99.98 100.37 99.83 100.48 100.35 EXAMPLE C4 (COMPARATIVE EXAMPLE) - FLUIDIZED BED LINING OF SEPARATE CAPSULE HALVES (BODY AND CAP)

[0211] EUDRAGIT® FS 30 D was supplied as a 30% by weight aqueous polymer dispersion. The excipients were added to the water during gentle stirring. The excipient suspension was added to the polymer dispersion. The spray suspension was gently stirred during the coating process.

[0212] The capsules were coated in the pre-locked state using a fluidized bed coating application device. Subsequently, the capsules were manually loaded with 200 mg of caffeine. TABLE 11: EXAMPLE OF FORMULATION C4 - VCAPS® PLUS SIZE Material Composition | Percentage of solid composition | Capsule segment | Bodies | Caps Petition 870200059460, dated 05 / 13 / 2020, pages 206 / 230 50 / 65 Batch size (Initial capsule weight) 36 g 35 g EUDRAGIT® FS 30 D 6.0 mg / cm2 6.0 mg / cm2 83.67% Glyceryl Monostearate (40 to 55%) 8.5% ds* 8.5% ds* 7.11% Polysorbate® 80 0.34% ds* 0.34% ds* 0.28% Triethyl Citrate 10.66% ds* 10.66% ds* 8.92% Demineralized Water On demand On demand n / a Solids content 10% by weight2 10% by weight2 Total solid weight gain 7.2 mg / cm2 7.2 mg / cm2 *Quantity based on dry polymeric substance [%] TABLE 12: PROCESS PARAMETER EXAMPLE C4 Parameter Value Value Bosch Hüttlin Mycrolab machine with small product container Batch size [g] 36 35 Nozzle bore [mm] 0.8 0.8 Inner tube diameter [mm] 1.0 1.0 Flocon periflo 1003 peristaltic pump Atomization pressure [bar] 1.0 1.0 Microclimate [bar] 0.2 to 0.4 0.2 Ambient temperature [°C] 23.4 to 23.6 22.4 to 22.9 Ambient humidity [% RH] 35.1 to 38.5 35.5 to 37.0 Inlet air volume [m3 / h] 19.9 to 23.0 19.0 to 22.0 Inlet air temperature [°C] 25.0 to 27.1 24.9 to 28.0 Exhaust air temperature [°C] Product temperature [°C] 19.4 to 21.5 18.9 to 21.5 22.5 to 25.2 21.0 to 23.6 Spray rate [g / min] 1.6 to 2.8 1.6 to 2.6 Petition 870200059460, dated 05 / 13 / 2020, pp. 207 / 230 51 / 65 Exhaust air humidity [% RH] 33.1 to 46.9 34.4 to 48.2 Process time [min] 99 73 INVESTIGATION OF CIRCULARITY OF CAPSULE BODIES AND LIDS EQUIPMENT:

[0213] ZEISS AXIO Zoom.VI 6 Light Optical Microscope

[0214] Objektive ZEISS PlanNeoFluar Z 1x / 0.25 FWD 56mm

[0215] SCHOTT MC 1500 light source

[0216] Incident light - annular light SCHOTT S80-55

[0217] ZEISS Axiocam 503 color camera

[0218] AxioVision SE64 Software

[0219] Software for image analysis Olympus Soft Imaging Solutions GmbH SAMPLE PREPARATION:

[0220] The capsule halves, cap and body, were analyzed separately. For each investigation, n = 10 samples of the halves were investigated. Therefore, the capsule halves were placed in a sample holder with the open end in the vertical upward direction. Subsequently, the samples were analyzed with the equipment listed above. SAMPLE INVESTIGATION:

[0221] The microscope was set up with a magnification of 10 times, the focal area decreases the capsule housing, as observed from the vertical direction downwards. The position of the capsules was adjusted to avoid shadows related to a non-vertical position. As the focal area is relevant, the light intensity and contrast need to be adjusted appropriately. IMAGING AND RESULTS TABLE:

[0222] The images were recorded as black and white images (capsule bodies figure 3 / 4 and caps figure 4 / 4) and transferred to the scandium database. The circumference of the capsule shell, investigated from the vertical downward position, was selected using the software toolbox. For this circumference, the area [mm2], the feret diameter, and circumference length were detected and calculated. The feret diameter is a measure of the size of an object along a specified direction. In Petition 870200059460, dated 05 / 13 / 2020, pages 208 / 230 52 / 65 overall, can be defined as the distance between two parallel planes that constrain the object perpendicular to that direction. It is therefore also called the caliper diameter, referring to the measurement of the object's size with calipers. The results are presented in the table below, describing the minimum, maximum, average, and standard deviation for the circumference area [mm2], caliper diameter, and length. The measurement was repeated for each capsule cap and body sample a total of 20 times. The format factor used is the aspect ratio, a function of the larger diameter and the smaller diameter orthogonal to it: ~ . __ .dmin Aspect ratio = —--dmax

[0223] The normalized aspect ratio ranges from about 1 for an uncoated capsule without deformation and increases in value depending on the degree of deformation. Petition 870200059460, dated 05 / 13 / 2020, pages 209 / 230 TABLE 13: CAPSULE CIRCULARITY RESULTS BODY Image No. Average Area Size Compression Ratio of [2D Object] to Aspect Ratio [mm2] [mm] [mm] B1 39.1 7.39 26.33 1.51 B2 40.6 7.37 28.31 1.17 B3 41.7 7.43 25.06 1.15 B4 42.3 7.43 24.77 1.22 B5 41.6 7.34 24.51 1.09 B6 39.6 7.33 24.75 1.32 B7 38.6 7.29 24.44 1.48 B8 38.9 7.33 24.57 1.45 B9 42.0 7.44 24.69 1.29 B10 41.3 7.32 24.34 1.08 Min 38.6 7.29 24.34 1.08 Average 40.6 7.37 25.18 1.28 Max 42.3 7.44 28.31 1.51 Petition 870200059460, dated 05 / 13 / 2020, pp. 210 / 230 COVER Image No. Average Area Size Compression Ratio of [2D Object] to Aspect Ratio [mm2] [mm] [mm] C1 44.7 7.69 26.77 1.28 C2 42.6 7.61 28.63 1.42 C3 45.2 7.69 30.36 1.20 C4 44.7 7.64 28.76 1.20 C5 45.1 7.61 26.22 1.02 C6 43.8 7.56 28.26 1.12 C7 44.5 7.64 26.33 1.22 C8 43.4 7.59 27.37 1.29 C9 44.2 7.64 27.19 1.28 C10 44.1 7.60 26.53 1.25 Min 42.6 7.56 26.22 1.02 Average 44.2 7.63 27.64 1.23 Max 45.2 7.69 30.36 1.42 53 / 65 54 / 65 ANALYSIS WITHOUT

[0224] SEM investigation of separately coated capsule halves, bodies and caps, showed that cracks formed around the tapered rim. Furthermore, microscopic and scanning electron microscopy images showed that the separately coated caps and body exhibited significant deformation tendencies during the coating process, which appears to be irreversible. This deformation leads to difficulties during the manual encapsulation process, suggesting that an automated encapsulation process is not feasible, as only selected caps and bodies fit together. Therefore, fluidized bed coating of separate capsules is not a suitable process for producing capsules that allow for automated capsule loading.

[0225] Manual encapsulation of the described formulation and process led to a rejection rate of 85% considering a first-time correct encapsulation. The dissolution test below was performed with capsules that were loaded for the first time correct. First-time correct means that the capsules were loaded and closed in a first iteration. Dissolution Test

[0226] Manually loaded capsule containing 200 mg of caffeine METHOD:

[0227] Apparatus: ERWEKA DT 700 Paddle Apparatus (USP II)

[0228] Detection method: UV online

[0229] Temperature: 37.5 °C

[0230] Medium I: 700 ml of 0.1 N HCl adjusted to pH 1.20 (by using 2 N NaOH and 2 N HCl)

[0231] Medium II: After 2 hours in medium I, 214 ml of 0.2 N Na3PO4 solution was added to raise the pH to 6.8 (pH fine-tuning was performed using 2 N NaOH and 2 N HCl)

[0232] Medium III: After another hour in Medium II, 46 ml of 0.2 N Na3PO4 solution was added to raise the pH to 7.4 (again fine-tuning of pH using 2 N NaOH and 2 N HCl).

[0233] Blade Speed: 75 rpm TABLE 14: DISSOLUTION RESULTS EXAMPLE C4 Medium Temp Sample 1 Sample 2 Sample 3 Sample 1 Sample 2 Sample 3 Petition 870200059460, dated 05 / 13 / 2020, pages 211 / 230 55 / 65 o [min] 7,2 mg / cm2 [% liberado] 7,2 mg / cm2 [% liberado] 7,2 mg / cm2 [% liberado] 6 mg / cm2 [% liberado] 6 mg / cm2 [% liberado] 6 mg / cm2 [% liberado] HCl 0,1 N 0 0,00 0,00 0,00 0,00 0,08 0,00 HCl 0,1 N 15 0,00 0,00 0,00 0,00 0,06 0,00 HCl 0,1N 30 0,00 0,00 0,00 0,00 0,11 0,00 HCl 0,1N 60 0,00 0,00 0,00 0,00 0,15 0,24 HCl 0,1N 120 0,00 0,00 0,00 0,00 0,31 1,12 pH 6,8 135 0,00 0,00 0,00 0,00 0,34 1,96 pH 6,8 150 0,00 0,00 0,00 0,00 0,43 2,28 pH 6,8 165 0,00 0,00 0,00 0,00 0,50 2,52 pH 6,8 180 0,00 0,00 0,00 0,00 0,46 5,50 pH 7,4 185 0,00 0,00 0,00 0,00 0,39 6,20 pH 7,4 190 0,00 0,00 0,00 0,00 0,51 5,84 pH 7,4 195 0,00 0,00 0,00 0,00 2,14 5,95 pH 7,4 210 77,00 0,78 79,88 75,40 99,76 100,56 pH 7,4 225 99,69 99,58 99,44 99,64 99,86 99,30 pH 7,4 240 99,76 99,86 99,92 99,85 100,13 99,16 pH 7,4 255 99,81 99,94 100,07 99,91 100,15 99,59 pH 7,4 270 99,83 100,07 99,91 100,10 100,14 100,37 pH 7,4 285 99,94 99,95 99,93 99,93 100,12 100,27 pH 7,4 300 99,82 99,95 99,96 99,96 100,18 101,53 EXAMPLE 5 - ENTERIC COATING OF PRE-LOCKED CAPSULES IN AN AUTOMATIC DRUM COATING APPLICATION AND CAPSULE LOADING DEVICE

[0234] To calculate the appropriate maximum weight gain for an encapsulation process, the maximum layer thickness was assumed to be equal to the gap width between the capsule cap and the body of pre-locked or final-locked capsules. In example 11, the average gap width of Vcaps® Plus capsules was calculated with Petition 870200059460, dated 05 / 13 / 2020, pages 212 / 230 56 / 65 pm. Furthermore, the absolute density of a coating was predicted to be approximately... mg / cm3, the value was verified by scanning electron microscopy of the samples. Layer thickness [μτη] vmg * 10.0001 = total weight gain ----------absolute density g * 1.000' cm J TABLE 15: PREDICTED LAYER THICKNESS Total weight gain Predicted layer thickness 2.6 mg / cm2 26 pm 3.9 mg / cm2 39 pm 5.1 mg / cm2 51 pm

[0235] The EUDRAGIT® polymer (or polymers) was mixed in a suitably sized container. Additional excipients were added to the water during gentle stirring. After a suitable post-stirring period, the excipient suspension was added to the polymer dispersion. The spray suspension was gently stirred during the coating process. The capsules were coated in the pre-locked state using a drum coating application device. TABLE 16: EXAMPLE OF FORMULATION 5 - VCAPS® PLUS SIZE 0 (BATCH SIZE 300 G) Material Composition Percentage of Solid Composition EUDRAGIT® FS 30 D 4 mg / cm2 77.77% Glyceryl Monostearate (40 to 55%) 7.5% ds* 5.83% Polysorbate® 80 3.0% ds* 2.33% Triethyl Citrate 18.1% ds* 14.07% Demineralized water On demand n / a Solids content 16% by weight Total solid weight gain 5.1 mg / cm2 *Quantity based on dry polymeric substance [%] TABLE 17: PROCESS PARAMETER EXAMPLE 5 Petition 870200059460, dated 05 / 13 / 2020, pages 213 / 230 57 / 65 Parameter Value Lodige LHC Machine Batch Size [g] 300 Nozzle Bore [mm] 1.0 Inner Tube Diameter [mm] 1.0 Verder Lab Peristaltic Pump Atomization Pressure [bar] 0.5 Flat Pattern Pressure [bar] 0.5 Ambient Temperature [°C] 22.6 to 23.1 Ambient Humidity [% RH] 39.6 to 47.0 Travel Speed ​​[rpm] 15 Inlet Air Volume [m3 / h] 90 to 92 Inlet Air Temperature [°C] 35.0 to 42.7 Exhaust Air Temperature [°C] 24.7 to 28.4 Product Temperature [°C] / Spray Rate [g / min / kg] 3.5 to 10.5 Exhaust Air Humidity [% RH] 37.1 to 53.2 Process Time [min] 81 ENCAPSULATION PARAMETER

[0236] A 400 mg capsule of a 50:50 mixture with MCC and caffeine was placed into pre-locked polymer-coated capsules using an automatic MG2 Labby Capsule loading machine with a powder loading setup using standard size 0 format tools for capsule opening, transport, loading, and closing. The machine output was set to 2,000 cps / h.

[0237] Capsules tested on an automatic capsule loading machine, total solid weight gain of 2.6 and 3.9 mg / cm2, feasible for automatic processing. With a total weight gain of 5.1 mg / cm2, the limitation was the standard tooling which lacked the capacity to operate with the pre-locked capsules due to the increased layer thickness. To investigate whether polymer weight gains above 4 mg / cm2 for this specific formulation could Petition 870200059460, dated 05 / 13 / 2020, pages 214 / 230 58 / 65 observe modified tools, would be necessary considering the increase in capsule diameter. DESCRIPTION OF THE ANALYSIS WITHOUT BODIES AND CAPS

[0238] The coating of pre-locked capsules allows for the loading of top capsules compared to separate capsules with fluid coating. The advantage is that pre-locked capsules provide more mechanical stability compared to separate capsule parts. Furthermore, pre-locked coated capsules ensure that, during the loading process, the two capsule parts fit together. Additionally, the tapered rim remains intact and supports the sliding of the caps over the body until the capsule is finally locked. It has been proven that pre-locked coated tablets can be separated in a capsule loading machine even when the two parts are slightly bridged. Dissolution Test METHOD:

[0239] Apparatus: ERWEKA DT 700 Paddle Apparatus (USP II)

[0240] Detection method: UV online

[0241] Temperature: 37.5 °C

[0242] Medium I: 700 ml of 0.1 N HCl adjusted to pH 1.20 (by using 2 N NaOH and 2 N HCl)

[0243] Medium II: After 2 hours in medium I, 214 ml of 0.2 N NaaPO4 solution was added to raise the pH to 6.8 (pH fine-tuning was performed using 2 N NaOH and 2 N HCl)

[0244] Blade Speed: 75 rpm TABLE 18: DISSOLUTION RESULTS EXAMPLE 5 Half Time [min] Sample 1 2.6 mg / cm2 [% released] Sample 2 2.6 mg / cm2 [% released] Sample 3 2.6 mg / cm2 [% released] Sample 1 3.9 mg / cm2 [% released] Sample 2 3.9 mg / cm2 [% released] Sample 3 3.9 mg / cm2 [% released] 0.1N HCl 0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.1N HCl 30 0.06 0.03 0.00 0.09 0.11 0.04 0.1N HCl 60 0.05 0.08 0.04 0.11 0.15 0.05 Petition 870200059460, dated 05 / 13 / 2020, pages 215 / 230 59 / 65 N HCL 0.1 N 90 0.07 0.09 0.05 0.12 0.17 0.07 HCL 0.1 N 120 0.12 0.12 0.06 0.11 0.17 0.05 pH 6.8 125 0.23 0.26 0.17 0.19 0.30 0.16 pH 6.8 130 95.59 87.88 73.04 16.93 49.07 29.61 pH 6.8 135 99.36 99.46 96.27 96.96 78.31 89.08 pH 6.8 140 99.72 100.00 98.18 99.62 94.18 98.65 pH 6.8 150 99.86 99.96 100.18 99.77 99.73 100.00 pH 6.8 165 99.96 100.05 100.20 99.91 100.19 99.98 pH 6.8 180 100.29 100.06 100.38 99.90 99.81 100.01 Petition 870200059460, dated 05 / 13 / 2020, pages 216 / 230 EXAMPLES 6 TO 9 - ENTERIC COATING AND COLON GUIDANCE OF PRE-LOCKED CAPSULES IN A FLUIDIZED BED COATING APPLICATION DEVICE EXAMPLES OF FLUIDIZED BED COATING AND MANUAL CAPSULE LOADING

[0245] The EUDRAGIT® polymer (or polymers) was mixed in a container. Additional excipients were added to the water during gentle stirring. After an appropriate post-stirring period, the excipient suspension was added to the polymer dispersion. The spray suspension was gently stirred during the coating process. The capsules were coated in the pre-locked state using a fluidized bed coating application device. Subsequently, the capsules were manually loaded with 200 mg of caffeine and then closed to the final locked state. TABLE 19: EXAMPLES OF FORMULATION 6 TO 9 - VARIOUS TYPES OF CAPSULES Example No. Capsule Size Capsule Shell API Formula % Total Solid Weight Gain [mg / cm2] % Drug Release of Trademark Claim < 10% after 2 h 0.1 N HCl** % Release after 45 min at pH 6.8 / 7.4*** 6 Size 0 HPMC pre-locked EUDRAGIT® L 30 D-55 / EUDRAGIT® NM 30 D (mixing ratio 9:1) + 10% TEC in ds* Diluent water. Solid content 10% by weight Metoprolol 5% (0.9) 10% (1.8) 15% (2.7) Yes Yes Yes 99% 97% 96% 7 Size 0 HPMC pre-locked EUDRAGIT® L 30 D-55 / EUDRAGIT® NM 30 D (ratio of Metoprolol 10% (1.8) 15% (2.7) Yes Yes 97%** 92%** 60 / 65 Petition 870200059460, dated 05 / 13 / 2020, pp. 217 / 230 Mixture 7:3) + 10% TEC in ds* Diluent water. Solid content 10% by weight 8 Size 0 HPMC prelock EUDRAGIT®L 30 D-55 + 50% TEC in ds* Diluent water. Solid content 10% by weight Metoprolol 5% (0.9) 8% (1.5) Yes Yes 96% 96% 9 Size 3 HPMC prelock EUDRAGIT®L 30 D-55 + 50% TEC in ds* Diluent water. Solid content 10% by weight Metoprolol 5% (0.9) 8% (1.2) Yes Yes 98% 96% Omeprazole 8% (1.2) Yes 86%** * Quantity based on dry polymeric substance [%] ** In the case of FS 30D, drug release of the trademark claim below 10% after 2 hours in 0.1 N HCl, followed by 1 hour at pH 6.8 *** In the case of FS 30D, drug release after 1 hour in pH 7.4 buffer 61 / 65 Petition 870200059460, dated 05 / 13 / 2020, pp. 218 / 230 62 / 65 EXAMPLE 10 - PROTECTION AGAINST MOISTURE TABLE 20: EXAMPLE OF FORMULATION 10 - VCAPS® PLUS SIZE Material Composition Percentage of Solid Composition EUDRAGIT® E PO 11.1 mg / cm2 57.15% Sodium lauryl sulfate 10% ds* 5.71% Stearic acid 15% ds* 8.57% Talc 50% ds* 28.57% Demineralized Water On demand n / a Solids content 10% by weight2 Total solid weight gain 19.4 mg / cm2 *Quantity based on dry polymeric substance [%] Sodium lauryl sulfate, stearic acid, and EUDRAGIT® E PO are successively stirred in water using a dissolving plate until a cloudy, light yellow solution is obtained, which lasts approximately 1 to 1.5 hours. Talc is added to the polymer solution and homogenized with a dissolving plate for 15 minutes. PROCESS PARAMETER

[0246] Approximately 70 to 100 pre-locked HPMC capsules were collected and loaded into the fluidized bed coating application device (Pam Glatt GPCG 1.1) with the Wuster assembly. TABLE 21: PROCESS PARAMETER EXAMPLE 10 Parameter Value Nozzle hole [mm] 0.8 Wuster column height [mm] 45 Product temperature [°C] 25 to 30 Inlet air temperature [°C] 35 to 40 Spray rate [g / min] 1 to 3 Air flow [CFM] 25 to 40 Atomizing air pressure [bar] 1.0 to 1.2 Petition 870200059460, dated 05 / 13 / 2020, pages 219 / 230 63 / 65 DISSOLUTION: METHOD:

[0247] Apparatus: ERWEKA DT 700 Paddle Apparatus (USP II)

[0248] Detection method: UV online

[0249] Temperature: 37.5 °C

[0250] Medium I: 700 ml of 0.1 N HCl adjusted to pH 1.20 (by using 2 N NaOH and 2 N HCl)

[0251] Medium II: 700 ml of Phosphate buffer adjusted to pH 4.5 (using 2 N NaOH and 2 N HCl)

[0252] Medium III: 700 ml of Phosphate buffer adjusted to pH 6.8 (using 2 N NaOH and 2 N HCl)

[0253] Blade Speed: 75 rpm

[0254] Capsules for dissolution testing were coated with 7.2 mg / cm2 of total solid weight gain and manually loaded with 200 mg of caffeine and tested. TABLE 22: DISSOLUTION RESULTS EXAMPLE 10 Time HCl 0.1 N Phosphate buffer pH 4.5 Phosphate buffer pH 6.8 min % release DP % release DP % release DP 0 0.0 0.0 0.0 0.0 0.0 0.0 15 40.9 9.9 29.1 12.8 0.2 0.0 30 83.5 10.7 82.5 9.1 17.0 12.7 45 95.6 1.5 98.4 4.2 58.7 18.0 60 97.5 0.3 101.3 2.3 85.5 12.3 90 97.6 0.5 101.2 2.3 98.8 1.5 120 97.8 0.4 101.3 2.3 100.6 0.7 MOISTURE ABSORPTION STUDY

[0255] EPO-coated HPMC capsules loaded with and without Silica were stored at 20±2 °C / 84 ± 5% RH in a desiccator with a supersaturated Potassium chloride solution. TABLE 23: MOISTURE ABSORPTION DATA FOR SILICA-COATED AND UNCOATED CAPSULES. Petition 870200059460, dated 05 / 13 / 2020, pages 220 / 230 64 / 65 Days only Silica HPMC Capsule without Silica HPMC Capsule with Silica 3 mg / cm2 6.6 mg / cm2 9.8 mg / cm2 13.9 mg / cm2 16.7 mg / cm2 19.4 mg / cm2 0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1 20.31 8.06 7.93 5.06 4.36 3.46 2.09 1.65 1.42 2 30.86 9.68 17.05 10.14 7.90 6.02 4.54 3.77 3.25 3 33.59 11.29 22.72 14.02 11.44 8.28 6.17 5.36 5.07 4 33.59 11.29 26.49 17.90 14.09 10.83 8.08 6.95 6.11 7 33.59 11.29 30.27 25.96 21.16 16.50 12.44 10.66 9.76 8 33.59 11.29 30.27 27.75 23.23 18.20 14.07 12.24 10.81 9 33.59 11.29 30.27 28.34 25.00 19.90 15.16 13.30 11.85 10 33.59 11.29 30.27 28.34 25.88 21.04 16.52 14.36 12.89 11 33.59 11.29 30.27 28.34 26.18 22.17 17.34 15.16 13.67 14 33.59 11.29 30.27 28.34 27.94 25.29 20.33 17.80 16.28 15 33.59 11.29 30.27 28.64 28.24 25.57 21.42 18.60 16.80 17 33.59 11.29 30.27 28.94 28.53 26.99 23.05 20.45 18.63 18 33.59 11.29 30.27 28.94 28.53 27.27 23.60 20.98 19.67 TABLE 24: MOISTURE ABSORPTION DATA FOR COATED AND UNCOATED CAPSULES WITHOUT SILICA. HPMC capsule without silica 3 mg / cm2 6.6 mg / cm2 9.8 mg / cm2 13.9 mg / cm2 16.7 mg / cm2 19.4 mg / cm2 0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 1 8.06 8.22 7.14 5.26 4.55 4.24 3.97 2 9.68 9.59 9.52 6.32 5.45 5.08 4.76 5 11.29 9.59 9.52 7.37 7.27 6.78 6.35 6 11.29 9.59 9.52 7.37 7.27 6.78 6.35 8 11.29 9.59 9.52 7.37 7.27 6.78 6.35 9 11.29 9.59 9.52 7.37 7.27 6.78 6.35

[0256] The example demonstrates the capabilities of the formulation concept also for moisture protection coatings. Capsules loaded with silica and locked together show a significant decrease in water sorption when stored. Petition 870200059460, dated 05 / 13 / 2020, pages 221 / 230 65 / 65 in a desiccator. This example demonstrates the capabilities of the concept, especially for moisture-sensitive formulations. EXAMPLE 11 - AVERAGE WIDTH OF A HARD-SHELL CAPSULE VCAPS® PLUS

[0257] For example, for the entire Vcaps® Plus hard shell capsule size range, the gap width between the capsule body and the cap in the pre-locked or final locked state was calculated based on a capsule cap thickness value of 100 µm as described in the Capsugel Product Brochure [Dominique Cadé; Vcaps® Plus Capsules - A New HPMC Capsule for Optimum Formulation]. The capsule cap wall thickness was subtracted from the capsule cap outer diameter, arriving at the capsule cap inner diameter. In the next step, the capsule cap inner diameter was subtracted from the capsule body outer diameter, resulting in the average gap width between the capsule body and cap in the pre-locked or final locked state. The gap width varies between 25 µm for Vcaps® Plus size 3 and 75 µm for Vcaps® Plus size 00. TABLE 25: AVERAGE GAP WIDTH OF VCAPS® PLUS HARD-SHELL CAPSULE Size 00el 00 0el 0el 0 1 1el 2 3 4 Average Wall Thickness of Lid [μm]* 100 100 100 100 100 100 100 100 100 100 Body Outer Diameter [mm] 8.18 8.18 7.34 7.36 7.34 6.63 6.63 6.07 5.57 5.05 Lid [mm] 8.53 8.53 7.65 7.66 7.64 6.91 6.91 6.35 5.82 5.32 Gap Width [μm] 75 75 55 50 50

Claims

1 / 2 CLAIMS 1. A process characterized by preparing a polymer-coated hard shell capsule, suitable as a container for pharmaceutical or nutraceutical biologically active ingredients, wherein the hard shell capsule comprises a body and a cap, wherein, in the closed state, the cap overlaps the body, either in a pre-locked state or in a final locked state, comprising the steps of: providing the hard shell capsule in the pre-locked state and spray-coating it with a coating solution, suspension or dispersion comprising a polymer or a polymer mixture to create a coating layer covering the outer surface of the hard shell capsule in the pre-locked state, wherein the coating layer is applied in an amount of 1 to 5.5 mg / cm2, and the polymer or a mixture of polymers is selected from the groups of an anionic polymer, a cationic polymer, a neutral polymer or any mixture thereof,wherein the anionic polymer is an anionic (meth)acrylate copolymer, the cationic polymer is a cationic (meth)acrylate copolymer, and the neutral polymer is a neutral (meth)acrylate copolymer.

2. Process, according to claim 1, characterized in that the polymer-coated hard shell capsule in the pre-locked state is opened, loaded with a load comprising a pharmaceutical or nutraceutical biologically active ingredient, and closed in the final locked state.

3. A process, according to any one of claims 1 or 2, characterized in that the polymer-coated hard shell capsule in the pre-locked state is supplied to a capsule loading machine, which performs opening, loading with a charge comprising a pharmaceutical or nutraceutical biologically active ingredient, and closing in the final locked state.

4. Process, according to any one of claims 1 to 3, characterized in that the body and cap material is selected from hydroxypropyl methyl cellulose, starch, gelatin, pullulan and a copolymer of a C1- to C4-alkyl ester of (meth)acrylic acid and (meth)acrylic acid.

5. Process, according to any one of claims 1 to 4, characterized in that the anionic polymer comprised in the coating layer is Petition 870220105505, dated 11 / 14 / 2022, page 19 / 23 2 / 2 a copolymerized from 25 to 95% by weight of C1- to C12-alkyl esters of acrylic acid or methacrylic acid and 75 to 5% by weight of (meth)acrylate monomers with an anionic group.

6. Process, according to any one of claims 1 to 5, characterized in that the cationic (meth)acrylate copolymer is polymerized from monomers comprising C1- to C4-alkyl esters of acrylic or methacrylic acid and an alkyl ester of acrylic or methacrylic acid with a tertiary or quaternary ammonium group in the alkyl group.

7. A process, according to any one of claims 1 to 6, characterized in that the body and the lid comprise surrounding notches and / or concavities in the area where the lid overlaps the body, which allow the capsule to be closed by a snap-in mechanism in the pre-locked state or in the final locked state.

8. A process, according to any one of claims 1 to 7, characterized in that the body comprises a tapered ring.

9. Hard-shell capsule coated with polymer, characterized by being obtained from a process as defined in any one of claims 1 to 8.

10. Pharmaceutical or nutraceutical dosage form characterized by comprising a polymer-coated hard shell capsule, as defined in claim 9, in the final locked stage containing a load comprising a pharmaceutical or nutraceutical biologically active ingredient, wherein the polymer-coated hard shell capsule comprises a coating layer comprising a polymer or a polymeric mixture, wherein the coating layer covers the outer surface area of ​​the capsule in the pre-locked stage. Petition 870220105505, dated 11 / 14 / 2022, pp. 20 / 23

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