Method for producing filled hard-shell capsule with (meth) acrylate copolymer-based coating by means of capsule filling machine

Abstract

The present invention relates to a method for preparing a polymer coated hard shell capsule filled with a filling comprising a bioactive ingredient wherein the hard shell capsule comprises a body and a cap wherein in a closed state the cap overlaps with the body in a pre-locked state or in a final locked state, wherein the material of the main body and the cap comprises cellulose ethyl ether, cellulose methyl ether or cellulose propyl ether, starch or pullulan, the hard shell capsule is coated with a coating layer, the coating layer covers the hard shell capsule in a pre-locked state, the coating layer comprises one or more (meth) acrylate copolymers, and the one or more (meth) acrylate copolymers comprise one or more (meth) acrylate copolymers. Wherein the coating layer is present in an amount of about 1 to 5.8 mg / cm2 wherein a dry film having a thickness of 250 [mu] m corresponding to the composition of the coating layer exhibits an elongation at break of about 15 to 500%, and wherein the polymer coated hard shell capsule is provided to a capsule filling machine in a pre-locked state, the capsule filling machine performs the steps of separating the body and the cap, filling the body with a filler, and reconnecting the body and the cap in a final locked state.

Description

[0001] This application is a divisional application of the Chinese patent application with application number 202080036006.8 and invention name “Method for preparing filled hard-shell capsules with a coating based on (meth)acrylate copolymer using a capsule filling machine”. Field of the Invention

[0002] The present invention belongs to the field of a method for preparing polymer-coated filled hard-shell capsules using a capsule filling machine. Technical Background

[0003] US 4138013 describes a hard shell capsule with enteric properties. The hard shell capsule comprises a body and a cap member that are telescopically coupled. The capsule body and the cap member are formed by dip molding using a homogeneous film-forming mixture comprising a polymer selected from hydroxypropyl methylcellulose (HPMC), (1) an ammonium salt of hydroxypropyl methylcellulose and cellulose acetate phthalate, or (2) a mixture of gelatin and an ammonium salt of a copolymer of (meth)acrylic acid and an alkyl methacrylate. The capsule itself already has enteric properties, eliminating the need for an enteric coating layer.

[0004] Xujin Lu and Pankaj Shah, “Dissolution of Gelatin Capsules: Evidence and Confirmation of Crosslinking,” Dissolution Technologies, August 2017, 6–20. The authors describe crosslinking as a common problem in the dissolution of gelatin capsules.

[0005] AAAtama (2007) "Polyelectrolyte Complexes od L30D-55 and Gelatin, Antinociceptive Activity of Entrapped Piroxicam". The authors elaborated Interaction of L 30D-55 with gelatin. L 30D-55 is a 30% aqueous dispersion of an anionic copolymer based on methacrylic acid and ethyl acrylate. Type A gelatin is produced by acid pretreatment of pig skin. The isoelectric point (IEP) of gelatin is between 7 and 9. At a pH below 8, gelatin A is positively charged and reacts with negatively charged L 30D-55 interaction.

[0006] Huyghebaert et al., European Journal of Pharmaceutical Sciences 21 (2004) 617-623 describe an alternative method for the enteric coating of capsules prepared from HPMC, wherein a ready-to-use enteric capsule component is obtained. It is reported that HPMC capsules can be enteric coated relatively easily from aqueous preparations compared to gelatin capsules. However, it is necessary to apply a seal between the two half capsules, for example by manually applying a gelatin solution, to avoid leakage of the capsule in the stomach and uncontrolled escape of the contents. Another technique is to apply a water / ethanol mixture between the two half capsules and weld the components together at 40-60°C. Using an aqueous preparation based on (meth)acrylate copolymers or polyvinyl acetate phthalate ( FS 30D, L 30D-55), plasticizers such as triethyl citrate and other adjuvants such as talc can provide an enteric coating for HPMC capsules by means of a separately coated body and cap. In the case of this formulation process, a separate sealing step can be avoided. In particular, HPMC capsules coated with (meth)acrylate copolymers have been described as being particularly advantageous in terms of their performance profile.

[0007] WO 2011 / 012369 A1 describes a coating composition for enteric coating of half capsules made of a water-soluble or water-swellable polymer material.

[0008] JP2003-325642A describes an enteric-coated hard empty capsule and a method for manufacturing such a capsule. The capsule cap is semi-locked to the capsule body, and an enteric film is formed over the entire surface. The capsule cap is then removed from the capsule body and filled with the contents. These components are then connected in a locked state. This avoids the application of a coating after filling the capsule, which would be a thermal load on the contents. Furthermore, since the coating overlaps in the locked state, it seals the gap between the capsule cap and the capsule body, thus avoiding adhesive sealing after filling. The capsule can be filled with desired contents such as propolis, raw royal jelly, or black vinegar extract. The capsule is made from gelatin through a dip-coating process by immersing a metal mold in a dispersion of gelatin and water. The mold is pulled up, rotated, cooled, and dried. This results in a cylindrical film of uniform thickness that can be cut into the desired size for the capsule cap or capsule body. The capsule cap and capsule body are semi-locked. The enteric substance can be applied by spraying.

[0009] Enteric substances according to JP2003-325642A can be plant or animal proteins derived from wheat, soy, collagen, gelatin, etc., cellulose acetate phthalate, cellulose acetate succinate, cellulose acetate maleate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetate phthalate, polyvinyl butyrate phthalate. The amount of coating is 20 to 80% by weight more than that achieved by conventional enteric capsule formation, desirably 40 to 60% by weight. The film thickness is about 0.1 to about 0.5 mm. These film thicknesses are greater than the tolerance variation of the capsule body outer diameter and the capsule cap inner diameter.

[0010] JP S61-221117A describes a method for forming enteric hard capsules to be used in, for example, the medical field. These capsules are coated in a pre-locked state before filling to avoid the disadvantages of conventional hard capsules coated with enteric solvents after filling, such as the loss of expensive drugs. The coating in the pre-locked state causes the body and the cap to partially overlap, which has sufficient compression to prevent gastric fluid from entering the capsule from the mating part of the cap and the body. The present invention uses ordinary gelatin capsules that can adopt the so-called "snap-fit" locking method. Hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, and methacrylic acid-methyl methacrylate copolymer can be used as enteric solvents. In an embodiment, capsule No. 1 is coated with 14 mg and 38 mg of hydroxypropyl methylcellulose phthalate (HP-55, Shin-Etsu Chemical Co., Ltd.). It was found that 18 mg per capsule and a film thickness of about 80 μm are preferred. JP S61-221117A mentions methacrylic acid-methyl methacrylate copolymers as a further possible coating. SUMMARY OF THE INVENTION

[0011] In principle, hard-shell capsules that are enteric-coated in a pre-locked state, opened, filled with a filling, and then closed to a final locked state are known from JP2003-325642A and JP S61-221117A. Both references describe the use of gelatin capsules that tend to crosslink during storage (Xujin Lu and Pankaj Shah, "Dissolution of Gelatin Capsules: Evidence and Confirmation of Crosslinking", Dissolution Technologies, August 2017, 6-20). Gelatin capsules are pre-coated with zein (JP2003-325642A) or hydroxypropyl methylcellulose acetate phthalate (HP-55 JP2003-325642A).

[0012] The use of enteric coated capsules in a pre-locked state appears to be advantageous because an additional sealing step can be avoided, as discussed by Huyghebaert et al. (European Journal of Pharmaceutical Sciences 21 (2004) 617-623). In addition, thermal loading of the fill material that occurs when the coating is applied after filling can be avoided by coating in a pre-locked state before the capsules are filled.

[0013] For industrial-scale production, processes with high turnover rates and high output are desirable. Such high turnover rates and high output can be achieved using automated capsule filling machines. Semi-automatic and fully automated capsule filling machines can process capsules that have been coated in a pre-locked state and quickly perform the steps of separating the body and cap, filling the body with the filler, and reconnecting the body and cap in the final locked state. The steps of separating the body and cap, filling the body with the filler, and reconnecting the body and cap in the final locked state are performed. Fully automated machines can operate at speeds of 1,000 or even more capsules per hour. However, high speeds can place high mechanical stress on the pre-locked capsules, especially on the mechanical resistance of the coating. Therefore, there is a need to provide a method that allows capsules coated in a pre-locked state to be processed in a capsule filling machine without compromising various properties, such as resistance in acidic media (less than 10% active ingredient release over 120 minutes at pH 1.2) and rapid dissolution at higher pH values (pH 5.5 or higher, pH 6.8).

[0014] The present invention relates to a method for preparing a polymer-coated hard-shell capsule, wherein the capsule is filled with a filler comprising a bioactive ingredient, wherein the hard-shell capsule comprises a body and a cap, wherein the cap overlaps with the body in a closed state, in a pre-locked state or in a final locked state, wherein the materials of the body and the cap comprise cellulose ethyl ether, cellulose methyl ether or cellulose propyl ether, starch or pullulan, wherein the hard-shell capsule is coated with a coating layer, wherein the coating layer covers the hard-shell capsule in the pre-locked state, wherein the coating layer comprises one or more (meth)acrylate copolymers, and wherein the coating layer has a concentration of about 1 to 5.8 mg / cm 2 , preferably 2 to 5 mg / cm 2 The present invention relates to a method for preparing a polymer-coated hard shell capsule comprising: providing a polymer-coated hard shell capsule to a capsule filling machine, wherein the polymer-coated hard shell capsule is present in an amount of 500 μm, wherein a dry film having a thickness of 250 μm corresponding to the composition of the coating layer exhibits an elongation at break of about 15 to 500%, preferably 50 to 450%, wherein the polymer-coated hard shell capsule is provided in a pre-locked state to a capsule filling machine, said capsule filling machine performing the steps of separating the body and the cap, filling the body with a filler, and reconnecting the body and the cap in a final locked state.

[0015] Bioactive ingredients

[0016] The disclosed method involves polymer-coated hard shell capsules filled with a filler comprising a bioactive ingredient. A bioactive ingredient can be defined as an ingredient that can impart a prophylactic or therapeutic effect to an animal or human upon delivery or ingestion. The bioactive ingredient is preferably a pharmaceutically active ingredient and / or a nutritionally active ingredient.

[0017] Pharmaceutical or nutritional active ingredients

[0018] The present invention is preferably used for immediate release, enteric coated or sustained release pharmaceutical or nutraceutical dosage forms filled with pharmaceutical or nutraceutical active ingredients.

[0019] Suitable therapeutic and chemical classes of pharmaceutical active ingredients, members of which can be used as fill for the polymer-coated hard shell capsules, are for example: analgesics, antibiotics or anti-infectives, antibodies, antiepileptics, antigens from plants, antirheumatic drugs, benzimidazole derivatives, beta-blockers, cardiovascular drugs, chemotherapeutics, central nervous system drugs, digitalis glycosides, gastrointestinal drugs such as proton pump inhibitors, enzymes, hormones, liquid or solid natural extracts, oligonucleotides, peptide hormone proteins, therapeutic bacteria, monoclonal microorganisms, microbial components, peptides, proteins and their (metal) salts, i.e. aspartates, chlorides, orotates, urological drugs and vaccines.

[0020] Other examples of drugs that can be used as fillers for the polymer-coated hard shell capsules are, for example, acamprosat, aescin, amylase, acetylsalicylic acid, epinephrine, 5-aminosalicylic acid, chlortetracycline, bacitracin, balsalazine, β-carotene, bicalutamide, bisacodyl, bromelain, budesonide, calcitonin, carbamacipine, carboplatin, cephalosporins, cetrorelix, clarithromycin, chloramphenicol, cimetidine, cisapride, cladribine, clorazepate, cromalyn, 1-deaminocysteine-8-D-arginine-vasopressin, (1-deaminocysteine-8-D-arginine-vasopressin), deramciclane, detirapril, dexlansoprazole, diclofenac, didanosine, digitoxin and other digitalis glycosides, dihydrostreptomycin, polydimethylsiloxane, bis-tetoprazole, drospirenone, duloxetine, enzymes, erythromycin, esomeprazole, estrogen, etoposide, famotidine, fluoride, garlic oil, glucagon, granulocyte colony-stimulating factor (G-CSF), heparin, hydrocortisone, human growth hormone (hGH), ibuprofen, ilaprazole, insulin, interferon, interleukin, Intron A, ketoprofen, lansoprazole, leuprorelin, lipase (leuprolidacetat lipase), lipoic acid, lithium, kinin, memantine, mesalamine, methenamine, miramerine, minerals, minoprazole, naproxen, natamycin, nitrofurantoin, novobiocin, olsalazine, omeprazole, orotates, pancreatic enzymes, pantoprazole, parathyroid hormone, paroxetine, penicillin, perprazol, pindolol, polymyxin, potassium, pravastatin, prednisone, preglumetacin, progambillium, growth promoter pro-somatostatin, protease, quinapril, rabeprazole, ranitidine, ranolazine, reboxetine, rutosid, somatostatin, streptomycin, subtilisin, sulfasalazine, sulfonamide, tamsulosin, tenatoprazole, trypsin, valproic acid, vasopressin, vitamins, zinc, including their salts, derivatives, polymorphs, isomorphs, or any mixture or combination thereof.

[0021] It will be apparent to those skilled in the art that there is extensive overlap between the terms pharmaceutical and nutraceutical active ingredients, excipients, and compositions and pharmaceutical or nutritional dosage forms. Many substances listed as nutrients can also be used as pharmaceutical active ingredients. Depending on the specific application and local regulations and classifications, the same substance may be listed as a pharmaceutical or nutraceutical active ingredient, a pharmaceutical or nutritional composition, or even both.

[0022] Nutrients are well known to those skilled in the art. Nutrients are generally defined as extracts of foods that are claimed to have a medicinal effect on human health. Therefore, nutrient active ingredients may also exhibit pharmaceutical activity: examples of nutrient active ingredients may be resveratrol from grape products as an antioxidant, soluble dietary fiber products such as psyllium husks for reducing hypercholesterolemia, broccoli (sulfanes) as anti-cancer drugs, and soy or clover (isoflavones) for improving arterial health. Therefore, it is obvious that many substances listed as nutrients can also be used as pharmaceutical active ingredients.

[0023] Typical nutrients or nutritionally active ingredients that can be used as fillers for the polymer-coated hard shell capsules may also include probiotics and prebiotics. Probiotics are live microorganisms believed to support human or animal health when ingested. Prebiotics are nutrients or nutritionally active ingredients that induce or promote the growth or activity of beneficial microorganisms in the human or animal intestine.

[0024] Examples of nutrients are resveratrol from grape products as antioxidants, omega-3 fatty acids or (pro)anthocyanines, for example from blueberries or blackcurrants; soluble dietary fiber products such as psyllium husk for lowering hypercholesterolemia; broccoli (sulfanes) as a cancer preventive; and soy or clover (isoflavonoids) for improving arterial health. Other examples of nutrients are flavonoids, antioxidants, α-linoleic acid from flaxseed, β-carotene from marigold petals, or anthocyanins from berries. Sometimes, the expressions "neutraceuticals" or "nutritionals" are used as synonyms for nutrients.

[0025] Preferred biologically active ingredients are metoprolol, mesalamine and omeprazole.

[0026] polymer-coated hard shell capsules

[0027] The present invention relates to a method for preparing a polymer-coated hard-shell capsule comprising a body and a cap. In a closed state, the cap overlaps the body in a pre-locked state or a final locked state. The hard-shell capsule is typically commercially available in a pre-locked state and is then preferably sprayed with a coating solution or dispersion comprising one or more (meth)acrylate copolymers to produce a coating layer that covers the outer surface of the hard-shell capsule in the pre-locked state.

[0028] Hard shell capsules

[0029] Hard shell capsules for pharmaceutical or nutritional purposes are well known to those skilled in the art. A hard shell capsule is a two-piece encapsulated capsule consisting of two half capsules (referred to as a body and a cap). The capsule body and the cap material are typically made of hard and sometimes brittle materials. A hard shell capsule comprises a body and a cap. The body and the cap are typically in the form of a cylinder with one end open and a closed circular hemispherical end at the opposite end. The shape and size of the cap and the body allow the body to telescopically push its open end into the open end of the cap.

[0030] The body and the cap include a potential overlapping matching area (overlapping area) on the outside of the body and the inside of the cap, which partially overlap when the capsule is closed in the pre-locked state and completely overlap in the final locked state. When the cap partially slides over the overlapping matching area of the body, the capsule is in the pre-locked state. When the cap completely slides over the overlapping matching area of the body, the capsule is in the final locked state. Maintaining the pre-locked state or the final locked state is typically supported by a snap-in locking mechanism (such as matching circumferential notches or dimples, preferably elongated dimples) of the body and the cap.

[0031] The body is typically longer than the cap. The outer overlapping region of the body can be covered by the cap to close or lock the capsule. In the closed state, the cap covers the outer overlapping region of the body in either the pre-locking state or the final locked state. In the final locked state, the cap completely covers the outer overlapping region of the body; in the pre-locking state, the cap only partially overlaps the outer overlapping region of the body. The cap can slide over the body and typically be secured in one of two different positions, in which the capsule is closed in either the pre-locking state or the final locked state.

[0032] Hard-shell capsules are commercially available in various sizes. Hard-shell capsules are typically delivered empty, with the body and cap already positioned in a pre-locked state, and as individual capsule halves (i.e., body and cap) as needed. Pre-locked hard-shell capsules can be supplied to a capsule filling machine, which performs the opening, filling, and closing of the capsules into the final locked state. Hard-shell capsules are typically filled with dry material, such as a powder or granules containing a biologically active ingredient.

[0033] The cap and the body are provided with closing means facilitating pre-locking (temporary) and / or final locking of the capsule.

[0034] Thus, it is possible to provide raised points on the inner wall of the cap and slightly larger recessed points on the outer wall of the body, with these points arranged so that the projections fit into the recesses when the capsule is closed. Alternatively, the projections can be formed on the outer wall of the body and the recesses on the inner wall of the cap. It is also possible to arrange the projections or recesses in a circular or spiral arrangement around the wall. Instead of a dotted configuration of the projections and recesses, they can be arranged in an annular configuration around the wall of the cap or body, but advantageously providing grooves and openings to allow for the exchange of gas in and out of the capsule interior.

[0035] One or more protrusions may be provided in an annular arrangement around the inner wall of the cap and the outer wall of the body, such that in the final locked position of the capsule, the protrusions on the cap are adjacent to the protrusions on the body. Sometimes, a protrusion is formed on the outer side of the body near the open end, and a recess is formed in the cap near the open end, such that in the final locked position of the capsule, the protrusion on the body locks into the recess in the cap. The protrusions may allow the cap to be opened at any time without damaging the capsule in the pre-locked state, or may prevent the capsule from being opened again without damage once it has been closed.

[0036] Capsules with one or more such locking mechanisms (locking catches, e.g., two circumferential grooves) are preferred. More preferred are capsules with at least two such locking mechanisms, each securing the two capsule components to varying degrees. In some cases, the first locking mechanism (recess or circumferential notch) can be formed closer to the openings in the capsule cap and the capsule body, and the second locking mechanism (circumferential notch) can be moved slightly further, toward the closed end of the capsule components. The first locking mechanism does not secure the two capsule components as strongly as the second locking mechanism. This variant has the advantage that, after the empty capsule is produced, the capsule cap and the capsule body can initially be pre-locked together using the first locking mechanism. To fill the capsule, the two capsule components are then separated again. After filling, the two capsule components are pushed together until the second set of locking catches securely secures the capsule components in the final locked state.

[0037] Preferably, the body and cap of the hard shell capsule each include a circumferential notch and / or a recess in the area where the cap can slide over the body. The circumferential notch of the body and the recess of the cap match each other to provide a snap-to-place mechanism. The recess can be annular or longitudinally elongated (oval).

[0038] The circumferential notch of the body and the circumferential notch of the cap (closely matching rings) also match each other to provide a snap or snap-in mechanism. This allows the capsule to be closed in a pre-locked state or a final locked state by the snap-in mechanism.

[0039] Preferably, the body and the cap are fixed to each other in a pre-locked state using the matching surrounding notch of the body and the elongated recess of the cap. Preferably, the body and the cap are fixed to each other or locked in a final locked state using the matching surrounding notch of the body and the cap.

[0040] The area where the cap can slide over the body can be referred to as the overlap area of the body and cap, or simply the overlap zone. If the cap only partially overlaps the body, perhaps 20 to 90% or 60 to 85% of the overlap zone, the hard-shell capsule is only partially closed (pre-locked). Preferably, in the presence of a locking mechanism (such as matching circumferential notches and / or recesses in the body and cap), this partially closed capsule can be referred to as pre-locked. When the capsule is polymer-coated in the pre-locked state, the coating will cover the entire outer surface, including the portion of the overlap zone between the body and cap that is not covered by the cap in the pre-locked state. When the capsule is polymer-coated in the pre-locked state and subsequently closed to the final lock stage, the coating in the portion of the overlap zone between the body and cap that is not covered by the cap in the pre-locked state will be covered by the cap. The presence of this portion of the coating, subsequently enclosed between the body and cap in the final lock state, is sufficient to tightly seal the hard-shell capsule. This is by no means foreseeable.

[0041] If the cap overlaps the entire overlapping area of the body, the hard shell capsule is finally closed or in a finally locked state. Preferably, the finally closed capsule may be referred to as finally locked in the presence of a locking mechanism such as matching circumferential notches and / or recesses in the body and cap.

[0042] Typically, dimples are preferably used to secure the body and cap in the pre-locked state. As a non-binding rule, the mating area of the dimples is smaller than the mating area of the surrounding notches. Consequently, a snap-in dimple can be disengaged with less force than would be required to disengage a snap-in securement by mating with the surrounding notches.

[0043] The recesses of the body and cap are located in the area where the cap can slide over the body and cooperate with each other in a pre-locked state by a snap or snap-in-place mechanism. There can be, for example, 2, 4 or preferably 6 notches or recesses distributed around the cap.

[0044] Typically, the recess of the cap and the surrounding notch of the body in the area where the cap can slide over the body cooperate to allow the capsule to be closed in a pre-locked state by a snap-in mechanism. In the pre-locked state, the hard-shell capsule can be reopened manually or by machine without damage, as the force required to open it is relatively small. For this reason, the "pre-locked state" is sometimes also referred to as "loosely capped."

[0045] Typically, circumferential notches or matching locking rings of the body and cap in the area where the cap can slide over the body cooperate with one another so that they allow the capsule to be closed in a final locked state by a snap-in mechanism. In the final locked state, the hard-shell capsule cannot be reopened manually or by machine without damage, or only with difficulty, due to the relatively high force required for opening.

[0046] Typically, recesses and circumferential indentations are formed in the capsule body or the capsule cap. When the capsule parts provided with these protrusions and recesses mate with each other, an ideally defined uniform gap of 10 to 150 microns, more particularly 20 to 100 microns, is formed along the contact surface between the capsule body and the capsule cap placed thereon.

[0047] Preferably, the body of the hard shell capsule comprises a tapered outer rim which prevents the body and the outer rim of the cap from colliding and becoming damaged when the capsule is closed manually or by machine.

[0048] In contrast to hard-shell capsules, soft-shell capsules are fused, one-piece capsules. Softgel capsules are often made from a blow-molded soft gelling mass and are typically filled with a liquid containing a bioactive ingredient by injection. The present invention does not involve fused, soft-shell, one-piece capsules.

[0049] Hard shell capsule size

[0050] Polymer coated hard shell capsules may be derived from standard size 000, 00, 0, 1, 2, 3, 4, 5 or 9 uncoated hard shell capsules.

[0051] The closed, final locked hard shell capsule can have a total length of about 5 to 40 mm. The diameter of the cap can be in the range of about 4 to 12 mm. The diameter of the body can be in the range of about 2 to 11 mm. The length of the cap can be in the range of about 4 to 20 mm, and the length of the body can be in the range of 8 to 30 mm. The fill volume can be 0.1 to 2 ml. The difference between the pre-lock length and the final lock length can be about 1 to 5 mm.

[0052] Capsules are available in standardized sizes, such as sizes 000 to 5. A size 000 closed capsule, for example, has an overall length of approximately 28 mm, with a cap outer diameter of approximately 9.9 mm and a body outer diameter of approximately 9.5 mm. The cap is approximately 14 mm long and the body is approximately 22 mm long. The fill volume is approximately 1.4 ml.

[0053] A size 5 closed capsule has, for example, a total length of approximately 10 mm, a cap outer diameter of approximately 4.8 mm, and a body outer diameter of approximately 4.6 mm. The cap length is approximately 5.6 mm, and the body length is approximately 9.4 mm. The fill volume is approximately 0.13 ml.

[0054] A size 0 capsule may have a length of about 23 to 24 mm in the pre-locked state and a length of about 20.5 to 21.5 mm in the final locked state. Thus, the difference between the pre-locked length and the final locked length may be about 2 to 3 mm.

[0055] Body and cap material

[0056] The material of the body and the cap includes cellulose ethyl ether, cellulose methyl ether or cellulose propyl ether, starch or pullulan. Cellulose ether is a derivative of cellulose in which the hydrogen atoms of the hydroxyl groups are partially or completely replaced by alkyl groups such as ethyl, methyl or propyl groups. These cellulose derivatives are well known to those skilled in the art in the field of pharmacy and herbal preparations. Suitable materials are methylcellulose (MC), ethylcellulose (EC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC) and / or hydroxypropylmethylcellulose (HPMC). Hydroxypropylmethylcellulose (HPMC) is preferred.

[0057] coating layer

[0058] The hard shell capsule is provided in a pre-locked state and sprayed with a coating solution, suspension or dispersion to produce a corresponding coating layer, which covers the outer surface of the hard shell capsule in the pre-locked state.

[0059] The coating layer may be a single layer, or may include or consist of two or more separate layers.

[0060] The hard shell capsule is coated with a coating layer, which covers the hard shell capsule in the pre-locked state. The coating layer comprises one or more (meth)acrylate copolymers, which preferably have a glass transition temperature T of 125° C. or lower. gm (determined by differential scanning calorimetry (DSC) according to ISO 11357-2:2013-05), wherein the coating layer is about 1 to 5.8 mg / cm 2 , preferably 2 to 5 mg / cm 2 The amount of the coating layer is present, wherein the dry film corresponding to the coating layer composition exhibits an elongation at break of about 15 to 500%. According to DIN EN ISO 527-3:2018 (February 2019), the elongation at break is determined using a test specimen (sample type 1B, 20 mm / min).

[0061] The coating layer, which may be a single layer or may comprise or consist of two or more separate layers, may comprise a total of 10 to 100%, 20 to 95%, 30 to 90% by weight of one or more (meth)acrylate copolymers.

[0062] The coating layer, which may be a single layer or may comprise or consist of two or more separate layers, may contain a total of 90 to 0 wt%, 80 to 5 wt%, 70 to 10 wt% of pharmaceutical or nutritional excipients.

[0063] The one or more (meth)acrylate copolymers and the pharmaceutical or nutritional excipient may add up to 100%.

[0064] "Multiple coatings"

[0065] The coating layer may be a single coating layer or may comprise one or two or more separate layers.

[0066] Advantageous systems comprising a coating layer comprising two separate coatings may include an inner coating comprising a partially neutralized anionic (meth)acrylate copolymer or a water-soluble neutral polymer and an outer coating comprising an anionic (meth)acrylate copolymer that is less neutralized than the inner coating material or is not neutralized at all (see WO 2008 / 135090 A1).

[0067] Glass transition temperature T gm

[0068] Methacrylic acid-methyl methacrylate copolymers such as L 100 or S100 exhibits a glass transition temperature T gm ,for For L 100 polymer, T gm is about 150℃ or slightly above 150℃, for For S100 polymer, T gm It is relatively high, about 160 ° C or slightly above 160 ° C. It should be noted that because its functional groups begin to decompose at 150 ° C, L 100 or S100 T gm The desired elasticity (elongation at break) of the coating layer can be achieved by adding relatively large amounts of plasticizers and / or emulsifiers and / or detacking agents.

[0069] The present inventors have found that, in a preferred embodiment, the coating layer may comprise one or more glass transition temperatures T gm(Meth)acrylate copolymers having a temperature of 125°C or lower, preferably between -10°C and +115°C. These polymers are less brittle and more flexible, supporting the coating layer to withstand the high mechanical forces occurring during processing in the capsule filling machine. The desired elasticity (elongation at break) of the coating layer can be achieved by adding smaller amounts of plasticizers and / or emulsifiers and / or anti-sticking agents in combination with these polymers. In this embodiment, methacrylic acid-methyl methacrylate copolymers can generally be excluded.

[0070] Thus, the coating layer may comprise one or more glass transition temperatures T gm The (meth)acrylate copolymer has a temperature of 125°C or lower, preferably -10°C to 115°C.

[0071] Thus, the coating layer may comprise one or more glass transition temperatures T gm (Meth)acrylate copolymers having a temperature of 125° C. or lower, preferably -10° C. to 115° C., excluding copolymers composed of polymerized units of methacrylic acid and methyl methacrylate.

[0072] Glass transition temperature T gm Determined by differential scanning calorimetry (DSC) according to ISO 11357-2:2013-05. The determination is carried out at a heating rate of 20 K / min. Glass transition temperature T gm Determined by the half-step height method as described in Section 10.1.2 of DIN EN ISO 11357-2.

[0073] Thickness of coating layer

[0074] The coating layer is about 1 to 5.8 mg / cm 2 , preferably 2 to 5 mg / cm 2 The amount exists.

[0075] The thickness of the coating layer can be determined by calculating the amount of coating material applied to the empty pre-locked capsule (e.g. during spraying) relative to the surface area of the empty pre-locked capsule (see also Examples 8 and 9, Figure 1 / 1). The coating layer may be a single layer, or may include or consist of two or more separate layers. In the case of two or more separate layers, the thickness of the separate layers is added together to give the total thickness of the coating layer.

[0076] Elongation at break

[0077] The inventors have found that processing in a capsule filling machine requires a certain elasticity of the coating layer. The elasticity of the coating layer is characterized in that the dry film corresponding to the composition of the coating layer exhibits an elongation at break of about 15 to 500%, preferably 20 to 250%.

[0078] For films and sheets with a thickness of less than 1,000 μm, the elongation at break can be determined according to DIN EN ISO 527-1:2012-06 (general principles, especially Chapter 8) and 527-3:2018 (February 2019), Determination of Tensile Properties. The elongation at break is the percentage increase in length that a material will achieve before breaking. The value is expressed as a percentage. A suspension of the composition for the coating layer is spread on a glass plate and dried to a film with a thickness of 250 μm. The elongation at break is determined according to DIN EN ISO 527-3:2018 (February 2019) using a test specimen (sample type 1B, 20 mm / min).

[0079] Examples of polymer film preparation and testing:

[0080] preparation:

[0081] 30 g of polymer dispersion = 9 g of solids for 250 μm film (after drying).

[0082] equipment:

[0083] A glass plate 20cm x 20cm surrounded by a 1cm glass strip 0.5-0.7cm high, forming a 361cm 2 The glass plate is additionally covered with a self-adhesive polytetrafluoroethylene foil (i.e. )cover.

[0084] Processing

[0085] Mix the polymer and diluent on a magnetic stirrer at low speed for 10 minutes. The polymer solution or suspension must be air-free to prevent voids from forming in the polymer foil. Place a Teflon-covered glass plate flat in an oven and pour the polymer solution or dispersion onto it. Dry the mixture at 40°C for approximately 4 days. After drying, condition the foil or sheet at 23°C and 50% relative humidity for 16 hours.

[0086] The thickness of the obtained film was about 250 μm.

[0087] The same method can be used to produce films of coating suspensions. In this case, the coating suspension is prepared in the usual way (e.g. using an Ultra Turrax). An aliquot of 9 g of total solids (including formulation excipients) is diluted with demineralized water to a total amount of 100 g.

[0088] (Meth)acrylate copolymer

[0089] The coating layer may comprise a (meth)acrylate copolymer selected from the group consisting of: a copolymer comprising polymerization units of methacrylic acid and ethyl acrylate, methacrylic acid and methyl methacrylate, ethyl acrylate and methyl methacrylate, or methacrylic acid, methyl acrylate and methyl methacrylate; a mixture of a copolymer comprising polymerization units of methacrylic acid and ethyl acrylate and a copolymer comprising polymerization units of methyl methacrylate and ethyl acrylate; and a mixture of a copolymer comprising polymerization units of methacrylic acid, methyl acrylate and methyl methacrylate and a copolymer comprising polymerization units of methyl methacrylate and ethyl acrylate.

[0090] The coating layer may comprise a (meth)acrylate copolymer comprising polymerized units of 40 to 60 wt % of methacrylic acid and 60 to 40 wt % of ethyl acrylate ( L 100-55 type). Suitable second polymers are L 100-55 (Evonik Nutrition & Care GmbH, Darmstadt, Germany), which is a copolymer comprising polymerized units of 50 wt% methacrylic acid and 50 wt% ethyl acrylate. L 30D-55 is 30% by weight L 100-55 aqueous dispersion. Glass transition temperature T of L 100-55 gm It is about 110°C.

[0091] The coating layer may comprise a (meth)acrylate copolymer comprising polymerized units of 5 to 15 wt % of methacrylic acid, 60 to 70 wt % of methyl acrylate and 20 to 30 wt % of methyl methacrylate. FS type). Suitable copolymers are FS is a copolymer obtained by polymerizing 25 wt% of methyl methacrylate, 65 wt% of methyl acrylate and 10 wt% of methacrylic acid. FS 30D is a kind of Dispersion of FS. Glass transition temperature T of FS gm is about 45°C.

[0092] The coating layer may comprise a (meth)acrylate copolymer comprising polymerized units of 60 to 80 wt % of ethyl acrylate and 40 to 20 wt % of methyl methacrylate ( NE type or NM type). NE and NM is a copolymer comprising free radically polymerized units of 28 to 32 weight percent methyl methacrylate and 68 to 72 weight percent ethyl acrylate. Glass transition temperature T of NE gm It is about -8°C.

[0093] The coating layer may comprise a (meth)acrylate copolymer comprising polymerized units of 40 to 60 wt % of methacrylic acid and 60 to 40 wt % of methyl methacrylate ( L 100 type). L 100 is a copolymer composed of 50% by weight of methyl methacrylate and 50% by weight of methacrylic acid. Glass transition temperature T of L 100 gm About or slightly above 150°C.

[0094] The coating layer may comprise a (meth)acrylate copolymer comprising polymerized units of 20 to 40 wt % of methacrylic acid and 60 to 80 wt % of methyl methacrylate ( S100 model). S100 is a copolymer composed of 70 wt% methyl methacrylate and 30 wt% methacrylic acid. Glass transition temperature T of S1000 gm It is about 160°C or slightly above 160°C.

[0095] Mixture of (meth)acrylate copolymers

[0096] The coating layer may comprise the above L 100-55 and NE type or A mixture of NM type (meth)acrylate copolymers. NE and Glass transition temperature T of NM gm It is about -8°C.

[0097] NE type or The NM type (meth)acrylate copolymer is a (meth)acrylate copolymer comprising polymerization units of 60 to 80% of ethyl acrylate and 40 to 20% by weight of methyl methacrylate. NE and NM is a copolymer comprising free radically polymerized units of 28 to 32 wt% methyl methacrylate and 68 to 72 wt% ethyl acrylate. The coating layer may comprise a (meth)acrylate copolymer comprising polymerized units of 60 to 80% ethyl acrylate and 40 to 20 wt% methyl methacrylate.

[0098] Preference is given to (meth)acrylate copolymers which have been prepared as dispersions according to WO 01 / 68767 using 1-10% by weight of nonionic emulsifiers with an HLB value of 15.2 to 17.3. The latter have the advantage that the emulsifier ( NM type) forms a crystal structure without phase separation.

[0099] Preferably, the coating layer may include a mixture of a (meth)acrylate copolymer containing polymerization units of 40 to 60 wt% of methacrylic acid and 60 to 40 wt% of ethyl acrylate and a (meth)acrylate copolymer containing polymerization units of 60 to 80% of ethyl acrylate and 40 to 20 wt% of methyl methacrylate in a weight ratio of 10:1 to 1:10.

[0100] The coating layer may comprise the above FS type and A mixture of (meth)acrylate copolymers of the L 100-55 type.

[0101] Preferably, the coating layer may include a mixture of a (meth)acrylate copolymer containing polymerization units of 5 to 15 wt% of methacrylic acid, 60 to 70 wt% of methyl acrylate, and 20 to 30 wt% of methyl methacrylate and a (meth)acrylate copolymer containing polymerization units of 40 to 60 wt% of methacrylic acid and 60 to 40 wt% of ethyl acrylate in a weight ratio of 1:1 to 5:1.

[0102] The coating layer may also comprise a mixture of (meth)acrylate copolymers in the form of a core-shell polymer from two (meth)acrylate copolymers. The coating layer may comprise a (meth)acrylate copolymer as a core-shell polymer comprising 50 to 90% by weight, preferably 70 to 80% by weight, of a core comprising 60 to 80% by weight, preferably 65 to 75% by weight, of polymerized units of ethyl acrylate and 40 to 20% by weight, preferably 35 to 25% by weight, of a shell comprising 40 to 60% by weight, preferably 45 to 55% by weight, of polymerized units of ethyl acrylate and 60 to 40% by weight, preferably 55 to 45% by weight, of methacrylic acid.

[0103] Suitable core-shell polymers are FL 30D-55 (Evonik Nutrition & Care GmbH, Darmstadt, Germany), a commercially available 30 wt% aqueous copolymer dispersion obtained from a two-stage emulsion polymerization process, having an approximately 75 wt% core comprising polymerized units of approximately 70 wt% ethyl acrylate and 30 wt% methyl methacrylate and an approximately 25 wt% shell comprising polymerized units of 50 wt% ethyl acrylate and 50 wt% methacrylic acid. Glass transition temperature T of FL 30D-55 polymer gm is about 8°C.

[0104] Pharmaceutical or nutritional excipients

[0105] Pharmaceutical or nutraceutical excipients are well known to those skilled in the art and are often formulated with the biologically active ingredients contained in the coated hard shell capsules and / or with the polymer coating of the hard shell capsules as disclosed and claimed herein. All pharmaceutical or nutraceutical excipients used must be toxicologically safe for use in pharmaceuticals or nutraceuticals without risk to patients or consumers.

[0106] Pharmaceutically or nutraceutically acceptable excipients may be selected from antioxidants, whitening agents, binding agents, flavorings, flow aids, spices, glidants, penetration enhancers, pigments, plasticizers, polysaccharide polymers, emulsifiers, pore formers or stabilizers or their combinations. Pharmaceutically or nutraceutically acceptable excipients are excipients that are allowed to be used in the applications of medicine or nutraceuticals.

[0107] The pharmaceutical or nutraceutical excipient may preferably comprise one or more plasticizers and / or one or more anti-adherents.

[0108] Adding a plasticizer to a (meth)acrylate copolymer will typically lower the glass transition temperature of the mixture and typically increase the elongation at break. This effect may depend on the type and amount of the plasticizer added. The plasticizer can be selected from alkyl citrates, glycerides, alkyl phthalates, alkyl sebacates, sucrose esters, sorbitan esters, glycerol, propylene glycol, and polyethylene glycol. Preferred plasticizers are triethyl citrate, polyethylene glycol 20,000, and propylene glycol. Based on the weight of the (meth)acrylate copolymer, the amount of plasticizer added can be in the range of 2 to 50 weight %, preferably 5 to 30 weight %.

[0109] Adding an anti-adherent to the (meth)acrylate copolymer generally reduces the viscosity of the respective mixture of the coating film. The anti-adherent can be selected from calcium stearate or magnesium stearate, glyceryl monostearate, and talc. The amount of the anti-adherent added can be in the range of 2 to 60 wt %, preferably 5 to 55 wt %, based on the weight of the (meth)acrylate copolymer.

[0110] The coating layer may further comprise an emulsifier, preferably polysorbate 80. The amount of the emulsifier added may be in the range of 1 to 30 wt%, preferably 3 to 25 wt%, based on the weight of the (meth)acrylate copolymer.

[0111] Top coat

[0112] The coating layer may comprise or include an amount of 0.2 to 0.8 mg / cm 2 The top coating may also include other excipient polymers such as polyvinyl alcohol (PVA), hydroxypropyl cellulose (HPC) or Preferably, the top coating layer does not comprise a necessary amount of a (meth)acrylate copolymer or does not comprise a (meth)acrylate copolymer at all.

[0113] Colon delivery combination

[0114] For colonic delivery, it is particularly preferred to add an excipient polymer that is a polysaccharide polymer selected from the group consisting of starch, amylose, amylopectin, chitosan, chondroitin sulfate, cyclodextrin, dextran, pullulan, carrageenan, scleroglucan, chitin, curdulan and fructan in a coating layer comprising one or more (meth)acrylate copolymers with a pH threshold of 5 or higher (see EP 2018159B1). The ratio of the polysaccharide polymer to the one or more (meth)acrylate copolymers can be up to 50:50, preferably up to 35:65. The (meth)acrylate copolymer with a pH threshold of 5 is preferably L100 or The pH threshold is the pH value below which the one or more (meth)acrylate copolymers are insoluble but at or above which they are soluble in a buffer, intestinal fluid or simulated intestinal fluid.

[0115] capsule filling machine

[0116] The polymer coated hard shell capsules are provided to a capsule filling machine in a pre-locked state, and the capsule filling machine performs the steps of separating the body and the cap, filling the body with the filler and reconnecting the body and the cap in a final locked state.

[0117] The capsule filling machine used can be a capsule filling machine capable of producing filled and closed capsules at an output of 1,000 or more filled and finally closed capsules per hour, preferably a fully automatic capsule filling machine. Capsule filling machines, preferably fully automatic capsule filling machines, are well known in the art and commercially available from several companies. A suitable capsule filling machine used in the examples is, for example, the AFT Lab model from ACG.

[0118] The capsule filling machine used may preferably be operated with an output speed of 1,000 or more, preferably 10,000 or more, 100,000 or more, 10,000 to 500,000 filled and finally closed capsules per hour.

[0119] General Operation of Capsule Filling Machine

[0120] Before the capsule filling process, the capsule filling machine is provided with a sufficient number or quantity of pre-coated hard shell capsules in a pre-locked state. The capsule filling machine is also provided with a sufficient amount of filler to be filled during operation.

[0121] In the pre-locked state, the hard-shell capsules can be gravity-fed into a feed tube or chute. Uniform alignment of the capsules can be achieved by mechanically adjusting the diameter difference between the cap and body. The hard-shell capsules are then typically fed into a two-piece housing or sleeve in the proper orientation.

[0122] The diameter of the upper sleeve or shell is typically larger than the diameter of the capsule body sleeve; thus, the capsule cap can be retained within the upper sleeve while the body is pulled into the lower sleeve by vacuum. Once the capsule is opened / the body and cap are separated, the upper and lower shells or sleeves are separated to position the capsule body for filling.

[0123] The open capsule body is then filled with the filler. Various filling mechanisms are used for different fillers, such as granules, powders, pellets, or microtablets. Capsule filling machines typically employ a variety of mechanisms and a varying number of filling stations to handle a variety of dosage ingredients. Dosing systems are typically based on the volume or amount of filler, which is governed by the capsule size and the volume of the capsule body. Manufacturers of empty capsules typically provide a reference table that indicates the volume capacity and maximum fill weight of the capsule body for different capsule sizes, based on the density of the filler material. After filling, the machine reconnects the body and cap in their final locked state or position. Example

[0124] Elongation at break values of the dry films corresponding to the compositions of the coating layers of Examples 1 to 7.

[0125] For plastic foils and sheets with a thickness of less than 1,000 μm, the elongation at break can be determined according to DIN EN ISO 527-1:2019-02, Determination of tensile properties. The elongation at break is the percentage increase in length achieved by a material before breaking. This value is expressed as a percentage. A suspension of the composition for the coating layer is spread on a glass plate and dried to a film with a thickness of 250 μm. These samples are used to determine the elongation at break according to DIN EN ISO 527-3:2019-02.

[0126] Examples of polymer film preparation and testing:

[0127] preparation:

[0128] 30 g of polymer dispersion = 9 g of solids for 250 μm film (after drying).

[0129] equipment:

[0130] A glass plate 20cm x 20cm surrounded by a 1cm glass strip 0.5-0.7cm high, forming a 361cm 2 The glass plate is additionally covered with a self-adhesive polytetrafluoroethylene foil (i.e. )cover.

[0131] Processing

[0132] Mix the polymer and diluent on a magnetic stirrer at low speed for 10 minutes. The polymer solution or suspension must be air-free to prevent voids from forming in the polymer foil. Place a Teflon-covered glass plate flat in an oven and pour the polymer solution or dispersion onto it. Dry the mixture at 40°C for approximately 4 days. After drying, condition the foil or sheet at 23°C and 50% relative humidity for 16 hours.

[0133] The thickness of the obtained film was about 250 μm.

[0134] The same method can be used to make a film of a coating suspension. In this case, the coating suspension is prepared in the usual way (e.g. using an Ultra Turrax). An aliquot of 9 g of total solids (including formulation excipients) is diluted with demineralized water to a total amount of 100 g.

[0135] result

[0136]

[0137] Example 1 (Invention) - Coating of pre-locked capsules in a drum coater L30D-55 and NM 30D combination for enteric coating and automatic capsule filling

[0138] Will The polymers are mixed in a container of suitable size. Additional excipients are added to the water while gently stirring. After an appropriate post-stirring time, the excipient suspension is added to the polymer dispersion. The sprayed suspension is gently stirred during the coating process. The capsules are coated using a drum coater in the pre-locked state.

[0139] Table 1: Formulation Example 1 - HPMC coating on size 0 capsules (batch size 90 g, i.e. 833 capsules)

[0140]

[0141] *Based on the amount of dry polymer matter [%]

[0142] Table 2. Process parameters of Example 1

[0143] parameter value machine Neocota 5D Batch size [g] 90 Nozzle hole [mm] 0.8 Inner tube diameter [mm] 3.0 Peristaltic pump Flowtech Atomization pressure [bar] 1.5 Flat pattern pressure [bar] 0.5 Room temperature [℃] 21-24 Indoor humidity [% relative humidity] 50-55 Coating pan speed (Pan speed) [rpm] 11 Inlet air temperature [℃] 33-38 Exhaust air temperature [℃] 28-31 Product temperature [℃] 28-29 Injection rate [g / min / kg] 8-16 Processing time [min] 190

[0144] Package parameters

[0145] 557 mg of omeprazole pellets (5% omeprazole) were filled into polymer coated pre-locked capsules using an automated capsule filling machine AFTLAB (ACG) using pellet filling settings, using standard tooling for opening, transporting, filling, and closing the capsules. The machine output was set to 5,000-5,400 cps / hour.

[0146] Capsules tested in an automatic capsule filling machine, 3.0 mg / cm 2 polymer or 3.6mg / cm 2 The total solids weight gain is feasible for automated processing. The capsule filling operation is smooth, with the capsule body and cap easily opening and fitting into the machine components. A 98% yield can be achieved on an automated capsule filling machine (with only 2% of capsules rejected by the machine).

[0147] Dissolution testing

[0148] method:

[0149] Apparatus: Labindia DS 8000 Paddle Apparatus (USPII) with sinker

[0150] Detection method: HPLC analysis

[0151] Temperature: 37.5℃

[0152] Medium I: 500 ml 0.1N HCl, 2 hours

[0153] Medium II: 900 ml KH2PO4 pH 6.8 buffer for 1 hour

[0154] Propeller speed: 100rpm

[0155] Table 3: Dissolution results (n=12) Example 1

[0156] medium Time [min] Average value [% released] SD 0.1N HCl 0 0.0 0.0 0.1N HCl 120 2.8 1.8 pH 6.8 135 27.5 9.4 pH 6.8 150 89.0 10.2 pH 6.8 165 97.0 2.0 pH 6.8 180 95.7 1.5

[0157] Example 2 (comparative) - Coating of filled and locked capsules (omeprazole pellets) with L 30D-55 and Enteric coating of NM 30D combination

[0158] Package parameters

[0159] 590 mg of omeprazole pellets (5% omeprazole) were filled into Kcaps HPMC size 0 capsules using an automated capsule filling machine AFTLAB (ACG) using pellet filling settings, using standard size 0 tooling for opening, transporting, filling, and closing the capsules. The machine output was set to 5,000-5,400 cps / hour.

[0160] The capsule filling operation is smooth, with the capsule body and cap opening easily and fitting into the machine components. A 99.7% yield can be achieved on the automatic capsule filling machine (only 0.3% of the capsules are rejected by the machine).

[0161] Enteric coating on omeprazole filled capsules:

[0162] Will The polymers were mixed in a container of suitable size. Additional excipients were added to the water while stirring gently. After a suitable post-stirring time, the excipient suspension was added to the polymer dispersion. The sprayed suspension was gently stirred during the coating process. The omeprazole-filled capsules were coated in the locked state using a drum coater. Table 4: Formulation Example 2 - Omeprazole-filled HPMC coating on size 0 capsules (batch size 550 g, i.e. 833 capsules)

[0163]

[0164] *Based on the amount of dry polymer matter [%]

[0165] Table 5. Process parameters of Example 2

[0166] parameter value machine Neocota 5D Batch size [g] 550 Nozzle hole [mm] 0.8 Inner tube diameter [mm] 3.0 Peristaltic pump Flowtech Atomization pressure [bar] 1.5 Plate mode pressure [bar] 0.5 Room temperature [℃] 21-24 Indoor humidity [% relative humidity] 50-55 Coating pan speed (Pan speed) [rpm] 11 Inlet air temperature [℃] 35-38 Exhaust air temperature [℃] 29-30 Product temperature [℃] 28-29 Injection rate [g / min / kg] 1.36-2.72 Processing time [min] 120

[0167] Dissolution testing

[0168] method:

[0169] Apparatus: Labindia DS 8000 Paddle Apparatus (USPII) with sinker

[0170] Detection method: HPLC analysis

[0171] Temperature: 37.5℃

[0172] Medium I: 500 ml 0.1N HCl

[0173] Propeller speed: 100rpm

[0174] Table 6: Dissolution results (n=12) Example 1

[0175] medium Time [min] Average [% Release] SD 0.1N HCl 0 0.0 0.0 0.1N HCl 120 25.8 20.4

[0176] The dissolution test of Example 2 was conducted in 0.1 N HCl for 2 hours only because acid release / degradation of omeprazole was observed after 2 hours of exposure to 0.1 N HCl. With the same coating, constructing the enteric polymer coating on the filled and locked capsules did not provide acid resistance compared to coating followed by filling on pre-locked capsules (Example 1).

[0177] Example 3 (comparative) - Drum coater on pre-locked capsules L30D-55 and NM 30D combination for enteric coating and automatic capsule filling

[0178] Will The polymers are mixed in a container of suitable size. Additional excipients are added to the water while gently stirring. After an appropriate post-stirring time, the excipient suspension is added to the polymer dispersion. The sprayed suspension is gently stirred during the coating process. The capsules are coated using a drum coater in the pre-locked state.

[0179] Table 4: Formulation Example 3 - HPMC coating on size 0 capsules (batch size 90 g, i.e. 833 capsules)

[0180]

[0181] *Based on the amount of dry polymer matter [%]

[0182] Table 8. Process parameters of Example 3

[0183] parameter value machine Neocota 5D Batch size [g] 90 Nozzle hole [mm] 0.8 Inner tube diameter [mm] 3.0 Peristaltic pump Flowtech Atomization pressure [bar] 1.5 Plate mode pressure [bar] 0.5 Room temperature [℃] 21-24 Indoor humidity [% relative humidity] 50-55 Coating pan speed [rpm] 11 Inlet air temperature [℃] 32-38 Exhaust air temperature [℃] 28-32 Product temperature [℃] 28-30 Injection rate [g / min / kg] 8-16 Processing time [min] 375

[0184] Package parameters

[0185] 595 mg of omeprazole pellets (5% omeprazole) were filled into polymer coated pre-locked capsules using an automated capsule filling machine AFTLAB (ACG) using pellet filling settings, using standard tooling, size 0, to open, transport, fill, and close the capsules. The machine output was set to 1,000-1,200 cps / hour.

[0186] The capsules were tested in an automatic capsule filling machine. 2 polymer or 6.0mg / cm 2 At the total solids weight gain, limitations were noted, as standard tooling could not be used with the pre-locked capsules due to the increased layer thickness. The capsule filling operation was not smooth; the capsule body and cap opened easily but did not fit into the machine components due to the increased coating thickness. Only a 67% yield was achieved, with 33% of the capsules rejected by the machine. Due to the high rejection rate, dissolution analysis was not performed on the filled capsules.

[0187] Example 4 (Invention) - Coating of pre-locked capsules in a drum coater FS 30D and L 30D-55 combination for enteric coating and automatic capsule filling

[0188] Will The polymers are mixed in a container of suitable size. Additional excipients are added to the water while gently stirring. After an appropriate post-stirring time, the excipient suspension is added to the polymer dispersion. The sprayed suspension is gently stirred during the coating process. The capsules are coated using a drum coater in the pre-locked state.

[0189] Table 9: Formulation Example 4 - HPMC coating on size 0 capsules (batch size 90 g, i.e. 833 capsules)

[0190]

[0191] *Based on the amount of dry polymer matter [%]

[0192] Table 10. Process parameters of Example 4

[0193] parameter value machine Neocota 5D Batch size [g] 90 Nozzle hole [mm] 0.8 Inner tube diameter [mm] 3.0 Peristaltic pump Flowtech Atomization pressure [bar] 1.5 Plate mode pressure [bar] 0.5 Room temperature [℃] 21-24 Indoor humidity [% relative humidity] 50-55 Coating pan speed [rpm] 11 Inlet air temperature [℃] 36-38 Exhaust air temperature [℃] 28-29 Product temperature [℃] 28-29 Injection rate [g / min / kg] 8 Processing time [min] 240

[0194] Package parameters

[0195] 525 mg of metoprolol pellets (40% metoprolol) were filled into polymer coated pre-locked capsules using an automated capsule filling machine AFTLAB (ACG) using pellet filling settings, opening, transporting, filling and closing the capsules using standard tooling, size 0. The machine output was set to 5,000-5,400 cps / hour.

[0196] Capsules tested in an automatic capsule filling machine, 3.0 mg / cm 2 polymer or 3.3mg / cm 2 Total solids weight gain is feasible for automated processing. The capsule filling operation is smooth, with the capsule body and cap easily opening and fitting into the machine components. A 97% yield can be achieved on an automated capsule filling machine (with only 3% of capsules rejected by the machine).

[0197] Dissolution testing

[0198] method:

[0199] Apparatus: Labindia DS 8000 Paddle Apparatus (USPII) with sinker

[0200] Detection method: HPLC analysis

[0201] Temperature: 37.5℃

[0202] Medium I: 500 ml 0.1N HCl, 2 hours

[0203] Medium II: 900 ml KH2PO4 pH 6.8 buffer for 1 hour

[0204] Medium III: 900 ml KH2PO4 pH 7.4 buffer for 2 hours

[0205] Paddle speed: 100 (medium 1) / 100 (medium 2) / 50 (medium 3)

[0206] Table 11: Dissolution results (n=12) Example 4

[0207] medium Time [min] Average [% Release] SD 0.1N HCl 0 0.00 0.00 0.1N HCl 120 0.18 0.34 pH 6.8 180 14.56 19.77 pH 7.4 195 34.89 20.80 pH 7.4 210 54.54 15.56 pH 7.4 225 71.56 9.94 pH 7.4 240 83.58 7.44 pH 7.4 270 90.44 6.71 pH 7.4 300 91.30 7.84

[0208] Example 5 (comparative) - Coating of filled and locked capsules (metoprolol pellets) with FS 30D and L 30D-55 combination for enteric coating

[0209] Package parameters

[0210] 517 mg of metoprolol pellets (40% metoprolol) were filled into Kcaps HPMC size 0 capsules using an automated capsule filling machine AFTLAB (ACG) using pellet filling settings, using standard size 0 tooling to open, transport, fill, and close the capsules. The machine output was set to 5,000-5,400 cps / hour.

[0211] The capsule filling operation is smooth, and the capsule body and cap are easy to open and fit into the machine parts. A 100% yield can be achieved on the automatic capsule filling machine.

[0212] Enteric coating on Metoprolol filled capsules:

[0213] Will The polymers are mixed in a container of suitable size. Additional excipients are added to the water while gently stirring. After an appropriate post-stirring time, the excipient suspension is added to the polymer dispersion. The sprayed suspension is gently stirred during the coating process. The locked metoprolol filled capsules are coated using a drum coater.

[0214] Table 12: Formulation Example 5 - Metoprolol Filled HPMC coating on size 0 capsules (batch size 550 g, i.e. 833 capsules)

[0215]

[0216] *Based on the amount of dry polymer matter [%]

[0217] Table 13. Process parameters of Example 5

[0218] parameter value machine Neocota 5D Batch size [g] 550 Nozzle hole [mm] 0.8 Inner tube diameter [mm] 3.0 Peristaltic pump Flowtech Atomization pressure [bar] 1.5 Plate mode pressure [bar] 0.5 Room temperature [℃] 21-24 Indoor humidity [% relative humidity] 50-55 Coating pan speed [rpm] 11 Inlet air temperature [℃] 36-38 Exhaust air temperature [℃] 28-30 Product temperature [℃] 28-29 Injection rate [g / min / kg] 1.36-2.72 Processing time [min] 140

[0219] Dissolution testing

[0220] method:

[0221] Apparatus: Labindia DS 8000 Paddle Apparatus (USPII) with sinker

[0222] Detection method: HPLC analysis

[0223] Temperature: 37.5℃

[0224] Medium I: 500 ml 0.1N HCl, 2 hours

[0225] Medium II: 900 ml KH2PO4 pH 6.8 buffer for 1 hour

[0226] Medium III: 900 ml KH2PO4 pH 7.4 buffer for 2 hours

[0227] Paddle speed: 100 (medium 1) / 100 (medium 2) / 50 (medium 3)

[0228] Table 14: Dissolution results (n=12) Example 5

[0229] medium Time [min] Average [% Release] SD 0.1N HCl 0 0.0 0.0 0.1N HCl 120 27.3 40.6 pH 6.8 180 84.9 16.0

[0230] The dissolution test of Example 5 was only conducted for 2 hours in 0.1N HCl and 1 hour in pH 6.8 buffer because complete release of metoprolol was observed in pH 6.8 buffer. Under the same coating, the construction of the enteric polymer coating on the filled and locked capsules did not provide acid resistance compared to the coating followed by filling on the pre-locked capsules (Example 4).

[0231] Example 6 (Invention) - Coating of pre-locked capsules in a drum coater L30D-55 and NM 30D combination for enteric coating followed by HPMC top coating and automatic capsule filling

[0232] Will The polymers are mixed in a suitably sized container. Additional excipients are added to the water while gently stirring. After an appropriate post-stirring period, the excipient suspension is added to the polymer dispersion. The sprayed suspension is gently stirred during the coating process. The capsules are coated using a drum coater in the pre-locked state. The top coat: HPMC is dissolved in water while stirring and sprayed onto the coated capsules using a drum coater.

[0233] Table 15: Formulation Example 6 - HPMC coating on size 0 capsules (batch size 500 g, i.e. 4595 capsules)

[0234]

[0235] *Based on the amount of dry polymer matter [%]

[0236] Table 16. Process parameters of Example 6

[0237]

[0238] Package parameters

[0239] 590 mg of omeprazole pellets (5% omeprazole) were filled into polymer coated pre-locked capsules using an automated capsule filling machine AFTLAB (ACG) using pellet filling settings, opening, transporting, filling and closing the capsules using standard tooling, size 0. The machine output was set to 5,000-5,400 cps / hour.

[0240] Capsules were tested in an automatic capsule filling machine, 2.5 (2.0 EUDRAGIT + 0.5 HPMC) mg / cm 2 Polymer or 2.9 (2.4EUDRAGIT + 0.5HPMC) mg / cm 2 Solid weight gain is feasible for automated processing. The capsule filling operation is smooth, with the capsule body and cap easily opening and fitting into the machine components. A 95% yield can be achieved on an automated capsule filling machine (only 5% of the capsules are rejected by the machine).

[0241] Dissolution testing

[0242] method:

[0243] Apparatus: Labindia DS 8000 Paddle Apparatus (USPII) with sinker

[0244] Detection method: HPLC analysis

[0245] Temperature: 37.5℃

[0246] Medium I: 500 ml 0.1N HCl, 2 hours

[0247] Medium II: 900 ml KH2PO4 pH 6.8 buffer for 1 hour

[0248] Propeller speed: 100rpm

[0249] Table 17: Dissolution results (n=6) Example 1

[0250] medium Time [min] Average [% Release] SD 0.1N HCl 0 0.0 0.0 0.1N HCl 120 1.7 0.6 pH 6.8 135 43.7 10.8 pH 6.8 150 91.6 7.1 pH 6.8 165 94.4 1.4 pH 6.8 180 93.3 1.3

[0251] Comparative Example 7 - Roller coating with a standard coating containing glyceryl monostearate (GMS) L 30D-55 coating enteric coating on pre-locked capsules followed by HPMC top coating and automatic capsule filling

[0252] A GMS emulsion was prepared by adding polysorbate 80 (33% solution), triethyl citrate and GMS in hot water (70-80°C) under a high shear homogenizer for 10 minutes. The prepared GMS emulsion was allowed to cool at room temperature and then added with overhead stirring. The polymer dispersion is gently stirred during the coating process. The capsules are coated using a drum coater in the pre-locked state. Top coat: HPMC is dissolved in water with stirring and sprayed onto the coated capsules using a drum coater.

[0253] Table 18: Formulation Example 7 - HPMC coating on size 0 capsules (batch size 90 g, i.e. 833 capsules)

[0254]

[0255] *Based on the amount of dry polymer matter [%]

[0256] Table 19. Process parameters of Example 7

[0257]

[0258] Package parameters

[0259] 590 mg of omeprazole pellets (5% omeprazole) were filled into polymer coated pre-locked capsules using an automated capsule filling machine AFTLAB (ACG) using pellet filling settings, opening, transporting, filling and closing the capsules using standard tooling, size 0. The machine output was set to 5,000-5,400 cps / hour.

[0260] Capsules were tested in an automatic capsule filling machine, 2.5 (2.0 EUDRAGIT + 0.5 HPMC) mg / cm 2 Polymer or 2.85 (2.35EUDRAGIT + 0.5HPMC) mg / cm 2 Solid weight gain is feasible for automated processing. The capsule filling operation is smooth, with the capsule body and cap easily opening and fitting into the machine components. A 98.36% yield can be achieved on an automated capsule filling machine (only 1.6% of the capsules are rejected by the machine).

[0261] Dissolution testing

[0262] method:

[0263] Instrument: Labindia DS 8000 Paddle Apparatus (USPII) with sedimentation plate detection method: HPLC analysis

[0264] Temperature: 37.5℃

[0265] Medium I: 500 ml 0.1N HCl, 2 hours

[0266] Medium II: 900 ml KH2PO4 pH 6.8 buffer, for 1 hour

[0267] Propeller speed: 100rpm

[0268] Table 20: Dissolution results (n=6) Example 1

[0269] medium Time [min] Average [% Release] SD 0.1N HCl 0 0.00 0.00 0.1N HCl 120 11.02 3.16 pH 6.8 135 43.63 17.04 pH 6.8 150 86.71 11.45 pH 6.8 165 90.61 14.95 pH 6.8 180 94.22 7.95

[0270] Example 8 - Determination of Capsule Overlap

[0271] Dimensions and tolerances of different commercially available capsules with respect to the average difference between pre-lock and lock lengths.

[0272] Table 21: Hard Shell Capsule Size (1 / 2)

[0273]

[0274] Table 22: Hard Shell Capsule Size (2 / 2)

[0275]

[0276] Example 9 - Surface Area Calculation and Colon Targeted Coating of Pre-Locked Capsules in a Drum Coater

[0277] Since a certain coating thickness is required to achieve the desired membrane function, the required amount of coating material depends on the surface area of the substrate. Therefore, the coating amount is expressed as mg total dry matter / cm 2 Substrate Surface Area. The following describes the equation for the surface area of the pre-locked capsule, taking into account the average difference between the pre-locked state and the cumulative length of the individual capsule halves (ie, body and cap).

[0278]

[0279] A 预锁定的胶囊 =A 主体 +A 圆柱体

[0280] A = surface area

[0281] h = length

[0282] d = diameter

[0283] Calculation Example 9 is used to calculate the outer surface of the capsule in the pre-locked state

[0284] Table 23: Plus capsule specifications:

[0285]

[0286] Figure 1 / 1Shows the relevant dimensions in mm Schematic diagram of the body (left) and cap (right) of the Plus 1 hard shell capsule. These dimensions are used to calculate the outer surface of the capsule in the pre-locked state in Example 9. These dimensions are:

[0287] Body: Length = 16.61 mm, Cylinder (length of cylindrical part) = 13.29 mm, Outer diameter = 6.63 mm

[0288] Cap: Length = 9.78 mm, Cylinder (length of cylindrical part) = 6.32 mm, Outer diameter = 6.91 mm

[0289]

[0290] A 胶囊-主体 =69.05+168,50=237.55[mm 2 ]

[0291] A 胶囊-帽盖 =75.00+137.20=212.20[mm 2 ]

[0292] A 预锁定的胶囊 =237.55+212.20=449.75[mm 2 ]

[0293] Table 24: Capsule surface area

[0294]

Claims

1. A method for preparing a polymer-coated hard-shell capsule, wherein the capsule is filled with a filler comprising a bioactive ingredient, wherein the hard-shell capsule comprises a body and a cap, wherein in a closed state, the cap overlaps with the body in a pre-locked state or in a final locked state, wherein the body and the cap are made of cellulose ethyl ether, cellulose methyl ether or cellulose propyl ether, starch or pullulan, wherein the hard-shell capsule is coated with a coating layer, wherein the coating layer covers the hard-shell capsule in the pre-locked state, wherein the coating layer comprises one or more (meth)acrylate copolymers, wherein the coating layer has a concentration of about 1 to 5.8 mg / cm 2 The present invention relates to a method for preparing a polymer-coated hard shell capsule, wherein a dry film having a thickness of 250 μm corresponding to the composition of the coating layer exhibits an elongation at break of about 15 to 500%, wherein the polymer-coated hard shell capsule is provided to a capsule filling machine in a pre-locked state, and the capsule filling machine performs the steps of separating the body and the cap, filling the body with a filler, and reconnecting the body and the cap in a final locked state.

2. The method according to claim 1, wherein the one or more (meth)acrylate copolymers have a glass transition temperature T of 125° C. or less. gm .

3. The method according to claim 1 or 2, wherein the material of the body and the cap comprises hydroxypropyl methylcellulose.

4. The method according to one or more of claims 1 to 3, wherein the coating layer comprises a (meth)acrylate copolymer selected from the group consisting of copolymers comprising polymerized units of methacrylic acid and ethyl acrylate, methacrylic acid and methyl methacrylate, ethyl acrylate and methyl methacrylate, or methacrylic acid, methyl acrylate and methyl methacrylate; mixtures of copolymers comprising polymerized units of methacrylic acid and ethyl acrylate and copolymers comprising polymerized units of methyl methacrylate and ethyl acrylate; and mixtures of copolymers comprising polymerized units of methacrylic acid, methyl acrylate and methyl methacrylate and copolymers comprising polymerized units of methyl methacrylate and ethyl acrylate.

5. The method according to one or more of claims 1 to 4, wherein the coating layer comprises a (meth)acrylate copolymer comprising polymerized units of 40 to 60% by weight of methacrylic acid and 60 to 40% by weight of ethyl acrylate.

6. The method according to one or more of claims 1 to 5, wherein the coating layer comprises a (meth)acrylate copolymer comprising polymerized units of 60 to 80% ethyl acrylate and 40 to 20% by weight methyl methacrylate.

7. The method according to one or more of claims 1 to 6, wherein the coating layer comprises a (meth)acrylate copolymer comprising polymerized units of 5 to 15% by weight of methacrylic acid, 60 to 70% by weight of methyl acrylate and 20 to 30% by weight of methyl methacrylate.

8. The method according to claim 1 , wherein the coating layer comprises a mixture of a (meth)acrylate copolymer containing polymerized units of 40 to 60% by weight of methacrylic acid and 60 to 40% by weight of ethyl acrylate and a (meth)acrylate copolymer containing polymerized units of 60 to 80% of ethyl acrylate and 40 to 20% by weight of methyl methacrylate in a weight ratio of 10:1 to 1:

10.

9. The method according to claim 1 , wherein the coating layer comprises a mixture of a (meth)acrylate copolymer containing polymerized units of 5 to 15% by weight of methacrylic acid, 60 to 70% by weight of methyl acrylate and 20 to 30% by weight of methyl methacrylate and a (meth)acrylate copolymer containing polymerized units of 40 to 60% by weight of methacrylic acid and 60 to 40% by weight of ethyl acrylate in a weight ratio of 1:1 to 5:

1.

10. The method according to one or more of claims 1 to 9, wherein the coating layer comprises 50 to 100% by weight of a (meth)acrylate copolymer and 50 to 0% of a pharmaceutical or nutraceutical excipient.

11. The method of claim 10, wherein the pharmaceutical or nutraceutical excipient comprises one or more plasticizers and / or one or more anti-adherent agents.

12. The method of claim 11, wherein the plasticizer is selected from the group consisting of alkyl citrates, glycerol esters, alkyl phthalates, alkyl sebacates, sucrose esters, sorbitan esters, glycerol, propylene glycol, and polyethylene glycol.

13. The method according to claim 11 or 12, wherein the anti-adherent agent is selected from calcium stearate or magnesium stearate, glyceryl monostearate and talc.

14. The method according to one or more of claims 1 to 13, wherein the capsule filling machine used operates with an output speed of 1,000 or more filled and finally closed capsules per hour.

15. The method according to one or more of claims 1 to 14, wherein the coating layer comprises an emulsifier, preferably polysorbate 80.

16. Hard shell capsules obtainable by the process according to one or more of claims 1 to 15.

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