Hard shell capsule with at least one coating layer with low oxygen permeability

Abstract

The present invention relates to a pre-coated hard shell capsule having at least one coating layer with improved protection against atmospheric oxygen, suitable as a container for a medicamentously or nutritionally biologically active ingredient, and a method for preparing a pharmaceutical delivery system comprising the hard shell capsule and a fill, wherein the fill comprises a medicamentously or nutritionally biologically active ingredient.

Description

[Technical field]

[0001] The present invention relates to a pre-coated hard shell capsule with at least one coating layer suitable as a container for a medicamentarily or nutritionally active biological ingredient, providing improved protection against atmospheric oxygen, and a method for preparing a pharmaceutical delivery system comprising said hard shell capsule and a fill containing at least one medicamentarily or nutritionally active ingredient. [Background technology]

[0002] Hard shell capsules are usually made of gelatin or hydroxypropyl methylcellulose (HPMC). Capsules made of these materials dissolve relatively quickly in the gastrointestinal tract. One of the main functions of a capsule is to protect its contents from external influences. However, with respect to atmospheric oxygen, the protection effect is still insufficient.

[0003] Polymer-coated hard shell capsules in the field of pharmaceuticals or dietary supplements are disclosed, for example, in Patent Documents 1 to 3. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2019 / 096833 [Patent Document 2] International Publication No. 2020 / 229178 [Patent Document 3] International Publication No. 2020 / 229192 Summary of the Invention [Problem to be solved by the invention]

[0005] It has been found that even a thin film coating with a specific composition containing methyl methacrylate (co)polymer can significantly improve the protective effect against atmospheric oxygen. The application of this film coating in a pre-locked state to unfilled capsules provides a universally applicable protective container for a wide variety of fillings. [Means for solving the problem]

[0006] The present invention relates to a pre-coated hard shell capsule suitable as a container for a pharmaceutical or nutritional biologically active ingredient, the pre-coated hard shell capsule comprising at least one coating layer, the at least one coating layer comprising: i) at least one (meth)acrylate copolymer having a mass-average molar mass of 25000 to 900000 g / mol and a glass transition temperature (Tgm) of 0 to 200° C. and containing up to 50% by weight of methacrylic acid monomer units; ii) at least one plasticizer having a solubility in water of at least 50 g / l and in an amount of at most 50% relative to the amount of said (meth)acrylate copolymer; iii) at least one emulsifier having a melting point higher than 40° C. and a hydrophilic / lipophilic balance (HLB) of 3 to 6; iv) at least one emulsifier having a melting point below 40° C. and a hydrophilic / lipophilic balance (HLB) of 8 to 16; and the oxygen permeability of the at least one coating layer is at most 2,500 ml / (m2) when measured at a thickness of 100 μm of the at least one coating layer. 2 d atm).

[0007] The mass average molecular weight is measured by the method of Adler et al. (Martina Adler, Harald Pasch, Christian Meier, Raimund Senger, Hans-Guenter Koban, Michael Augenstein, Guenter Reinhold; “Molar mass characterization of hydrophilic copolymers. 1. Size exclusion chromatography of neutral and anionic (meth)acrylate copolymers.”, e-Polymers 2004, no. 055 and Martina Adler, Harald Pasch, Christian Meier, Raimund Senger, Hans-Guenter Koban, Michael Augenstein, Guenter Reinhold; “Molar mass characterization of hydrophilic copolymers, 2. Size exclusion chromatography of cationic (meth)acrylate copolymers.”, e-Polymers 2005, no. 057). The glass transition temperature Tgm is determined by differential scanning calorimetry (DSC) according to ISO 11357-2:2013-05. The measurements are carried out at a heating rate of 20 K / min. The glass transition temperature Tgm is determined by the half-step height method described in section 10.1.2 of DIN EN ISO 11357-2:2013-05. The hydrophilic / lipophilic balance (HLB) is determined by the method of Griffin, William C. (1954) ("Calculation of HLB Values ​​of Non-Ionic Surfactants" (PDF), Journal of the Society of Cosmetic Chemists, 5(4):249-56).

[0008] Preferably, at least one emulsifier has a melting point above 40° C. and a hydrophilic / lipophilic balance (HLB) between 3 and 6 and is present in an amount of up to 25% by weight relative to the amount of said (meth)acrylate, and at least one emulsifier has a melting point below 40° C. and a hydrophilic / lipophilic balance (HLB) between 8 and 16 and is present in an amount of up to 10% by weight relative to the amount of said (meth)acrylate copolymer. The base material for the hard shell capsule is selected from hydroxypropylmethylcellulose, starch, gelatin, pullulan and C1-C4 alkyl esters of (meth)acrylic acid and copolymers with (meth)acrylic acid. Preferably, said at least one coating layer further comprises at least one glidant, said glidant being present in an amount of 3-75% by weight based on the total weight of the at least one polymer. The at least one glidant is selected from silica, ground silica, fumed silica, kaolin calcium silicate, magnesium silicate, colloidal silicon dioxide, talc, stearates, sodium stearyl fumarate, starch and stearic acid or mixtures thereof. In a further embodiment, the glass transition temperature (Tgm) of the at least one (meth)acrylate copolymer is from 40 to 160°C.

[0009] The at least one plasticizer in the pre-coated hard shell capsule according to the present invention is preferably present in an amount of 2 to 40% by weight, based on the total weight of the at least one (meth)acrylate copolymer. The at least one plasticizer included in at least one coating layer of the pre-coated hard shell capsule according to the present invention is selected from alkyl citrates, alkyl phthalates, diethyl sebacate, polyethylene glycol, propylene glycol, or combinations thereof. At least one coating layer of the precoated hard shell capsule has a coating density of 0.1 to 5.8 mg / cm 2 is present in an amount of

[0010] The pre-coated hard shell capsule according to the present invention preferably comprises a body and a cap, said cap overlapping said body in a closed state, either in a pre-locked state or in a final locked state. "Precoated" in the context of the present invention means that the hard shell capsule is provided with a coating layer before being filled with a fill containing a pharma- ceutical or nutritionally active ingredient.

[0011] The present invention further relates to a method for preparing a pharmaceutical delivery system comprising a hard shell capsule and a fill, the fill comprising at least one pharma- ceutical or nutritional active ingredient, wherein the pre-coated hard shell capsule of the present invention is provided in a pre-locked state to a capsule filling machine, which performs the steps of separating the body and the cap, filling the body with the fill, and rejoining the body and the cap in a final locked state. The present invention further relates to a method for protecting a pharma- ceutical or nutritional active ingredient from atmospheric oxygen in a pharmaceutical delivery system comprising a hard shell capsule and a fill, said fill comprising at least one pharma- ceutical or nutritional active ingredient, wherein the pre-coated hard shell capsule of the present invention is provided in a pre-locked state to a capsule filling machine, which performs the steps of separating the body and the cap, filling the body with said fill, and rejoining the body and the cap in a final locked state. [Brief description of the drawings]

[0012] [Figure 1] A diagram of the layer thickness measurement principle is shown in Figure 1. [Diagram 2] FIG. 1 shows an apparatus for measuring the oxygen transmission rate of a film. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] Hard Shell Capsule 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 that includes two capsule halves, a body and a cap. The capsule body and cap material are usually hard, but may be made of brittle materials. A hard shell capsule includes a body and a cap. The body and cap are usually cylindrical with an open end and a closed rounded hemispherical end at the opposite end. The shape and size of the cap and body are such that the body can be telescoped with its open end into the open end of the cap. The body and cap include potentially overlapping matching areas (overlap areas) on the outside of the body and inside of the cap that partially overlap when the capsule is closed in a pre-locked state and fully overlap in a final-locked state. When the cap is partially slid over the overlapping matching areas of the body, the capsule is in the pre-locked state. When the cap is fully slid over the overlapping matching areas of the body, the capsule is in the final-locked state. Maintenance of the pre-locked or final-locked state is typically supported by a snap-in locking mechanism on the body and cap, such as matching surrounding notches or dimples, preferably elongated dimples. Typically, the body is longer than the cap. The overlapping area of ​​the outside of the body can be covered by the cap to close or lock the capsule. In the closed state, the cap covers the outside overlapping area of ​​the body in either the pre-locked state or the final locked state. In the final locked state, the cap completely covers the outside overlapping area of ​​the body, and in the pre-locked state, the cap only partially overlaps the outside overlapping area of ​​the body. The cap can typically be slid over the body to be fixed in one of two different positions that close the capsule in either the pre-locked state or the final locked state.

[0014] Hard shell capsules are commercially available in a variety of sizes. They are usually delivered as empty containers with the body and cap already pre-locked, and as separate capsule halves, bodies and caps, if desired. The pre-locked hard shell capsules can be fed into a capsule filling machine, which opens, fills and closes the capsule to a final locked state. Typically, hard shell capsules are filled with dry materials, such as powders or granules, or viscous liquids that contain biologically active ingredients.

[0015] The cap and the body are provided with closure means that are advantageous for the pre-locked (temporary) and / or final locking of the capsule. Thus, the inner wall of the cap can be provided with raised points and the outer wall of the body with somewhat larger recessed points arranged so that the raised points fit into the recesses when the capsule is closed. Alternatively, the raised parts may be formed on the outer wall of the body and the recesses on the inner wall of the cap. The arrangement is such that the raised parts or recesses are arranged in a ring or spiral around the wall. Instead of a point-like arrangement of raised parts and recesses, they can surround the wall of the cap or the body in an annular arrangement, but advantageously with recesses and openings that allow the exchange of gases to and from the capsule interior. One or more raised parts 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 locking position of the capsule, the raised parts on the cap are located adjacent to the raised parts on the body. Sometimes the outside of the body is formed with a ridge adjacent to the open end and the cap is formed with a recess adjacent to the open end, such that in the final locked position of the capsule the ridge on the body latches into the recess on the cap. The ridge may be such that the cap can be opened in a pre-locked state at any time without damaging the capsule, or alternatively, once the cap is closed it cannot be reopened without destroying the capsule. Capsules with one or more such latching mechanisms (latches) (e.g. two surrounding grooves) are preferred. More preferred are capsules with at least two such latching means that secure the two capsule parts to different degrees. In such parts the first latching means (dimple or surrounding notch) is formed near the opening of the capsule cap and capsule body, and the second latching means (surrounding notch) may be shifted somewhat further towards the closed end of the capsule part. The first latching means does not secure the two capsule parts as strongly as the second latching means. This variant has the advantage that after production of the empty capsule, the capsule cap and the capsule body can be joined together initially pre-locked by means of the first latch mechanism. To fill the capsule, the two capsule parts are then separated again.After filling, the two capsule parts are pressed together until a second set of latches securely secures the capsule parts in a final locked condition.

[0016] Preferably, the body and cap of the hard shell capsule each include a circumferential notch and / or dimple in the area where the cap can slide over the body. The circumferential notch of the body and the dimple of the cap fit together to provide a snap-in or snap-in type mechanism. The dimple may be circular or elongated (oval) in the longitudinal direction. The circumferential notch of the body and the circumferential notch of the cap (closely fitting rings) also fit together to provide a snap-in or snap-in mechanism. This allows the capsule to be closed in either a pre-locked or final locked state by the snap-in mechanism. Preferably, a matching circumferential notch on the body and an elongated dimple on the cap are used to secure the body and cap together in the pre-locked condition. Matching circumferential notches on the body and cap are preferably used to secure or lock the body and cap together in the final locked condition.

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

[0018] Typically, a dimple is preferred to secure the body and cap in the prelocked condition. As a non-binding rule, the matching area of ​​the dimple is smaller than the matching area of ​​the surrounding notch. A dimple thus snapped in can be snapped out again by applying a force less than that required to snap out a fastening snapped in by matching the surrounding notch. The dimples of the body and the cap are located in the area where the cap can slide over the body and fit together in a pre-locked manner by a snap-in or snap-in-place mechanism. There may be, for example, 2, 4 or preferably 6 notches or dimples arranged in a circular distribution around the circumference of the cap.

[0019] Typically, the dimples on the cap and the peripheral notches on the body in the area where the cap can slide over the body match up with each other, so that the capsule can be closed in the pre-locked state by a snap-in mechanism. In the pre-locked state, the hard shell capsule requires relatively little force to open and can be reopened manually or mechanically without damage. Thus, the "pre-locked state" can also be referred to as "loosely capped".

[0020] Typically, surrounding notches or matching locking rings on the body and cap in the area where the cap can slide over the body fit together so that they can close the capsule by a snap-in mechanism in a final locked state in which the hard shell capsule cannot or hardly can be reopened manually or mechanically without damage due to the relatively large force required to open it.

[0021] Typically, the dimples and surrounding notches are formed in the capsule body or capsule cap such that when the capsule parts with these ridges and recesses are mated together, an ideally defined uniform gap of 10 microns to 150 microns, more specifically 20 microns to 100 microns, is formed along the interface between the capsule body and the capsule cap placed thereon. Preferably, the body of the hard shell capsule includes a tapered rim which prevents the body and cap rim from colliding and being damaged when the capsule is closed manually or mechanically.

[0022] In contrast to hard shell capsules, soft shell capsules are welded integral encapsulation capsules. Soft gel capsules are often made from blown soft gelling materials and are usually filled with a liquid containing a biologically active ingredient by injection. The present invention does not relate to welded soft shell integral encapsulation capsules.

[0023] Hard Shell Capsule Size The total length of the closed final locked hard shell capsule may range from about 5 to 40 mm. The cap diameter may range from about 1.3 to 12 mm. The body diameter may range from about 1.2 to 11 mm. The cap length may range from about 4 to 20 mm and the body length may range from 8 to 30 mm. The fill volume may be between about 0.004 to 2 ml. The difference between the pre-locked length and the final locked length may be about 1 to 5 mm. The capsules can be divided into standardized sizes, e.g. sizes 000 to 5. A closed capsule of size 000 has, for example, an outer diameter of the cap of about 9.9 mm and an outer diameter of the body of about 9.5 mm, and a total length of about 28 mm. The length of the cap is about 14 mm and the length of the body is about 22 mm. The filling volume is about 1.4 ml.

[0024] Body and cap material The base of the body and cap can be selected from hydroxypropylmethylcellulose, starch, gelatin, pullulan and copolymers of C1-C4 alkyl esters of (meth)acrylic acid and (meth)acrylic acid. Preferably, the body and cap are hard shell capsules comprising or consisting of HPMC or gelatin, most preferably HPMC due to its good adhesive properties to polymeric coatings.

[0025] At least one coating layer A polymer or polymer mixture contained in at least one coating layer The at least one (meth)acrylate copolymer contained in the at least one coating layer is preferably a film-forming polymer and can be selected from the group of anionic, cationic and neutral (meth)acrylate copolymers or any mixtures thereof, having a mass average molar mass between 25,000 and 900,000 g / mol and a glass transition temperature (Tgm) between 0 and 200° C., these (meth)acrylate copolymers comprising up to 50% by weight of methacrylic acid monomer units.

[0026] The mass average molecular weight is measured by the method of Adler et al. (Martina Adler, Harald Pasch, Christian Meier, Raimund Senger, Hans-Guenter Koban, Michael Augenstein, Guenter Reinhold; “Molar mass characterization of hydrophilic copolymers. 1. Size exclusion chromatography of neutral and anionic (meth)acrylate copolymers.”, e-Polymers 2004, no. 055 and Martina Adler, Harald Pasch, Christian Meier, Raimund Senger, Hans-Guenter Koban, Michael Augenstein, Guenter Reinhold; “Molar mass characterization of hydrophilic copolymers, 2. Size exclusion chromatography of cationic (meth)acrylate copolymers.”, e-Polymers 2005, no. 057). The glass transition temperature Tgm is determined by differential scanning calorimetry (DSC) according to ISO 11357-2:2013-05. The measurements are carried out at a heating rate of 20 K / min. The glass transition temperature Tgm is determined by the half-step height method described in section 10.1.2 of DIN EN ISO 11357-2:2013-05. The coating layer may contain a (meth)acrylate copolymer containing 0 to a maximum of 50 mass% of polymerization units of methacrylic acid and selected from a copolymer containing polymerization units of 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 containing polymerization units of methacrylic acid and ethyl acrylate and a copolymer containing polymerization units of methyl methacrylate and ethyl acrylate, and a mixture of a copolymer containing polymerization units of methacrylic acid, methyl acrylate, and methyl methacrylate and a copolymer containing polymerization units of methyl methacrylate and ethyl acrylate. The coating layer may contain a (meth)acrylate copolymer containing polymerized monomer units of 60 to 65 mass % methyl methacrylate, 30 mass % ethyl acrylate, and 5 to 10 mass % 2-(trimethylamino)ethyl methacrylate. The coating layer may comprise a (meth)acrylate copolymer including polymerized monomer units of 30% by weight methyl methacrylate and 70% by weight ethyl acrylate. The coating layer may contain a (meth)acrylate copolymer containing 40 to 50 mass % of methacrylic acid and 50 to 60 mass % of ethyl acrylate as polymerized monomer units. For example, a copolymer containing 50 mass % of methacrylic acid and 50 mass % of ethyl acrylate as polymerized monomer units is suitable. The coating layer may contain a (meth)acrylate copolymer containing polymerized units of 5 to 15 mass% methacrylic acid, 60 to 70 mass% methyl acrylate, and 20 to 30 mass% methyl methacrylate. A copolymer in which 25 mass% methyl methacrylate, 65 mass% methyl acrylate, and 10 mass% methacrylic acid are polymerized is suitable. The coating layer may contain a (meth)acrylate copolymer containing polymerized monomer units of 60 to 80% by mass of ethyl acrylate and 40 to 20% by mass of methyl methacrylate. The coating layer is a (meth)acrylate copolymer containing 40 to 50 mass % of polymerization units of methacrylic acid and 60 to 50 mass % of methyl methacrylate, and preferably containing 50 mass % of polymerization units of methyl methacrylate and 50 mass % of methacrylic acid. The coating layer is a (meth)acrylate copolymer containing 20 to 40% by mass of methacrylic acid and 60 to 80% by mass of methyl methacrylate, preferably 70% by mass of methyl methacrylate and 30% by mass of polymerized monomer units. The coating layer may include both a (meth)acrylate copolymer including 30% by weight of polymerized monomer units of methyl methacrylate and 70% by weight of ethyl acrylate, and a (meth)acrylate copolymer including 50% by weight of ethyl acrylate and 50% by weight of methacrylic acid. The coating layer may be a single layer or may comprise or consist of two or more individual layers and may comprise in total 10-100, 20-95, 30-90% by weight of one or more polymers, preferably (meth)acrylate copolymers. The proportions of the monomers mentioned for each polymer above generally add up to 100% by weight.

[0027] Plasticizer At least one coating layer of the hard shell capsule comprises at least one plasticizer (e.g., derived from a fatty acid) having a solubility in water of at least 50 g / l, up to 50% by weight relative to the amount of (meth)acrylate copolymer. Plasticizers lower the glass transition temperature by physical interaction with the polymer, but also promote film formation depending on the amount added. Suitable substances usually have a molecular weight of 100-20,000 g / mol and contain one or more hydrophilic groups in the molecule, such as hydroxyl, ester or amino groups. Examples of suitable plasticizers include alkyl citrates, alkyl sebacates, diethyl sebacate, polyethylene glycols, and polypropylene glycols. Preferred plasticizers are triethyl citrate (TEC), acetyl triethyl citrate (ATEC), diethyl sebacate, polyethylene glycols, and polypropylene glycols, or mixtures thereof. The addition of the plasticizer to the formulation can be carried out in a known manner, either directly, in an aqueous solution or after a thermal pretreatment of the mixture. Mixtures of plasticizers may be used.

[0028] emulsifier At least one coating layer of the precoated hard shell capsule according to the present invention comprises at least one emulsifier having a melting point (Tm) higher than 40° C. and a hydrophilic / lipophilic balance (HLB) between 3 and 6 and at least one emulsifier having a melting point below 40° C. and a hydrophilic / lipophilic balance (HLB) between 8 and 16. Both types of emulsifiers (HLB=3-6 with Tm>40° C. and HLB=8-16 with Tm<40° C.) are preferably non-ionic surfactants.

[0029] The HBL value can be determined according to Griffin, William C. (1954), "Calculation of HLB Values ​​of Non-Ionic Surfactants" (PDF), Journal of the Society of Cosmetic Chemists, 5(4):249-56. Suitable emulsifiers with a melting point higher than 40° C. and an HLB of 3-6 are, for example, glycerol monostearate (Tm: 56-58° C., HLB: about 3.8) or sorbitan monostearate (Span 60, Tm=53-57° C.; HLB=4.7). Suitable emulsifiers having a melting point below 40°C and an HLB of 8 to 16 are, for example, polysorbate 80 (Tm: -21°C, HLB: about 12), polyoxyethylene (4) lauryl ether (Brij® 30, Tm=14°C, HLB=9.7), polyoxyethylene (10) oleyl ether (Brij® 97, Tm=10°C, HLB=12.4) or sorbitan monolaurate (Span 20, liquid at 21°C, HLB=8.6).

[0030] Glidants At least one coating layer may further comprise at least one flow promoter present in an amount of 3 to 75% by weight based on the total weight of the at least one polymer. Flow promoters are usually lipophilic. They prevent agglomeration of the core during film formation of the film-forming polymer. The at least one glidant is preferably selected from silica, ground silica, fumed silica, calcium kaolin silicate, magnesium silicate, colloidal silicon dioxide, talc, stearates, stearates such as sodium stearyl fumarate, starch, stearic acid, e.g. commercially available under the trade names RXCIPIENTS® GL100 or RXCIPIENTS® GL200, and preferably talc, magnesium stearate, and colloidal silicon dioxide, or mixtures thereof. A typical proportion range for using the flow promoter in the coating of the present invention is 0.5-100% by weight, preferably 3-75% by weight, more preferably 5-50% by weight, and most preferably 5-30% by weight, based on the total weight of the at least one polymer.

[0031] The amount and thickness of at least one coating layer At least one functional coating layer has a thickness of 0.1 to 5.8 mg / cm2 to build a closure membrane on the hard shell capsule, as determined by calculation or measured by scanning electron microscopy (SEM) or micro-computed tomography (micro-CT). 2 Preferably, the amount is 2.2 to 4.8 mg / cm 2is present in an amount of

[0032] The amount of coating layer on the hard shell capsule should not be too high. If too much coating layer is applied, the subsequent processing of the polymer-coated prelocked hard shell capsules in the capsule filling machine may be difficult. The amount of coating layer is 5.8 mg / cm 2 Less than 2-4mg / cm 2 or 1-5mg / cm 2 or 1 to 5.8 mg / cm 2 In this case, there is usually no problem with a standard capsule filling machine without modification. 2 In the range of about 1 to about 8 mg / cm2, the capsule filling machine can still be used, but the shape of the body and cap should be adjusted to be somewhat wider. Such adjustment can be easily performed by a mechanical engineer. Therefore, the capsule filling machine can be used when the amount of the coating layer is about 1 to about 8 mg / cm2. 2 It can be advantageously used within the range.

[0033] The amount of coating layer on size #0 hard shell capsules should not be too high. If too much coating layer is applied, it may cause difficulties in the later processing of the polymer-coated prelocked hard shell capsules in the capsule filling machine. A coating layer amount of 5 mg / cm 2 Less than 1-4mg / cm 2 In this case, there is usually no problem with a standard capsule filling machine without modification. 2 In the range of about 1 to about 8 mg / cm2, the capsule filling machine can still be used, but the shape of the body and cap should be adjusted to be somewhat wider. Such adjustment can be easily performed by a mechanical engineer. Therefore, the capsule filling machine can be used when the amount of the coating layer is about 1 to about 8 mg / cm2. 2 It can be advantageously used within the range.

[0034] The amount of coating layer on size #1 hard shell capsules should not be too high. If too much coating layer is applied, it may cause difficulties in the later processing of the polymer-coated prelocked hard shell capsules in the capsule filling machine. A coating layer amount of 4 mg / cm 2 Less than 1-3.5mg / cm 2 In this case, there is usually no problem in using a standard capsule filling machine without modification. 2 In the range of about 1 to about 8 mg / cm2, the capsule filling machine can still be used, but the shape of the body and cap should be adjusted to be somewhat wider. Such adjustment can be easily performed by a mechanical engineer. Therefore, the capsule filling machine can be used with a coating layer amount of about 1 to about 8 mg / cm2. 2 It can be advantageously used within the range.

[0035] The amount of coating layer for size #3 hard shell capsules should not be too high. If too much coating layer is applied, it may cause difficulty in later processing of the polymer-coated prelocked hard shell capsules in the capsule filling machine. A coating layer amount of 3 mg / cm 2 Less than 1-2.5mg / cm 2 In this case, there is usually no problem with a standard capsule filling machine without modification. 2 A capsule filling machine can still be used for coating layers up to about 1 to about 6 mg / cm2, but the shape of the body and cap should be adjusted to be somewhat wider. Such adjustments can be easily made by a mechanical engineer. Thus, the capsule filling machine can be used for coating layers up to about 1 to about 6 mg / cm2. 2 It can be advantageously used within the range.

[0036] If too much coating layer is applied, there will also be an assembly with too much coating layer on the rim of the cap where the gap between the body and the cap is in the pre-locked state. Then, when the coated pre-locked hard shell capsule is opened manually or mechanically, cracks in the coating layer may occur after drying. The cracks may later lead to capsule leakage. Finally, if the coating is too thick, it may be difficult or impossible to close the opened coated hard shell capsule until it is in the final locking state, since the coating layer is thicker than the gap in the overlapping area between the body and the cap.

[0037] In summary, the coating layer on the hard shell capsule is 0.1-10, 0.5-9, 1.0-8, 1.5-5.5, 1.5-4 mg / cm 2 (=total mass increase). In summary, the average thickness of the coating layer on the hard shell capsule may be about 5-100, 10-50, 15-75 μm. In summary, the dry weight of the coating layer on the hard shell capsule can be applied in an amount of 5-50, preferably 8-40% dry weight based on the weight of the prelocked capsule. Using this guidance, one skilled in the art can adjust the amount of coating layer to range between the extremes of low and high. At least one coating layer has an oxygen permeability of up to 2,500 ml / (m2) when measured at a thickness of 100 μm. 2 ·d·atm).

[0038] Example of coating thickness measurement (determination) by scanning electron microscope (SEM) investigation To perform the coating layer thickness evaluation, the following procedure is applied, which consists of calculating the appropriate sample size, randomly sampling the number of samples, preparing the samples, determining the layer thickness, and evaluating the results.

[0039] Sample size calculation formula

[0040]

number

[0041] [Table 1] <Calculation example> N = 457,200 [units] e = 0.1 z = 1.96 p=0.5

[0042]

number

[0043] biologically active ingredients The disclosed method relates to polymer-coated hard shell capsules filled with a filler containing at least one biologically active ingredient. A biologically active ingredient may be defined as an ingredient that can provide a prophylactic or therapeutic effect in an animal or human body after delivery or ingestion. The biologically active ingredient is preferably a pharmacologic active ingredient and / or a nutritional active ingredient. The biologically active ingredient is preferably a pharmaceutical active ingredient and / or a nutritional active ingredient and / or a cosmetic active ingredient.Even if a certain biologically active ingredient can be contained in each coating layer, it is preferred that the biologically active ingredient is contained in the filling.In particular, when the biologically active ingredient is nucleic acid, the biologically active ingredient is contained only in the filling.

[0044] Pharmaceutically or nutritionally active ingredients contained in pharmaceutical delivery systems The present invention is preferably useful in pharmaceutical or nutritional dosage forms formulated for immediate, delayed or sustained release, comprising a charge of a medicamentously or nutritionally active ingredient. Suitable therapeutic and chemical classes of pharmaceutical active ingredients which may be used as fill for the described polymer coated hard shell capsules are e.g. analgesics, antibiotics or anti-infectives, antibodies, antiepileptics, plant derived antigens, antirheumatics, benzimidazole derivatives, β-blockers, cardiovascular drugs, chemotherapeutic drugs, central nervous system drugs, digitalis glycosides, gastrointestinal drugs such as proton pump inhibitors, enzymes, hormones, liquid or solid natural extracts, oligonucleotides, peptides, hormones, proteins, therapeutic bacteria, peptides, protein (metal) salts, i.e. aspartates, chlorides etc., urological drugs, vaccines. In a preferred embodiment, the pharmaceutical active ingredient is a nucleic acid, and more preferably, the nucleic acid agent may be DNA, RNA, or a combination thereof. In an embodiment, the nucleic acid agent may be an oligonucleotide and / or a polynucleotide. In an embodiment, the nucleic acid agent may be an oligonucleotide and / or a modified oligonucleotide (including but not limited to, modified via phosphorylation); an antisense oligonucleotide and / or a modified antisense oligonucleotide (including but not limited to, modified via phosphorylation). In an embodiment, the nucleic acid agent may include cDNA and / or genomic DNA. In an embodiment, the nucleic acid agent may include non-human DNA and / or RNA (e.g., viral, bacterial, or fungal nucleic acid sequences). In an embodiment, the nucleic acid agent may be a plasmid, a cosmid, a gene fragment, an artificial and / or natural chromosome (e.g., yeast artificial chromosome), and / or a part thereof. In an embodiment, the nucleic acid agent may be a functional RNA (e.g., mRNA, tRNA, rRNA, and / or ribozyme). In some embodiments, the nucleic acid agent may be an RNAi-inducing agent, a small interfering RNA (siRNA), a short hairpin RNA (shRNA), and / or a microRNA (miRNA). In some embodiments, the nucleic acid agent may be a peptide nucleic acid (PNA). In some embodiments, the nucleic acid agent may be a polynucleotide that includes synthetic analogs of nucleic acids that may be modified or unmodified. In some embodiments, the nucleic acid agent may include various structural forms of DNA, including single-stranded DNA, double-stranded DNA, supercoiled DNA, and / or triplex DNA; Z-DNA; and / or combinations thereof. Further suitable nucleic acids are disclosed, for example, in International Publication No. 2012103035, which is incorporated herein by reference.

[0045] Further examples of drugs that may be used as fill for the polymer coated hard shell capsules disclosed herein include, for example, acamprosate, aescin, amylase, acetylsalicylic acid, adrenaline, 5-aminosalicylic acid, aureomycin, bacitracin, balsalazine, beta carotene, bicalutamide, bisacodyl, bromelain, budesonide, calcitonin, carbamacipine, carboplatin, cephalosporins, cetrorelix, clarithromycin, chloromycetin, and the like. , cimetidine, cisapride, cladribine, clorazepate, cromalin, 1-deaminocysteine-8-D-arginine-vasopressin, deramciclane, detirelix, dexlansoprazole, diclofenac, didanosine, digitoxin and other digitalis glycosides, dihydrostreptomycin, dimethicone, divalproex, drospirenone, duloxetine, enzymes, erythromycin, esomeprazole, estrogen, etoposide, famotidine, fluoride, garlic oil, glucagon, granulocyte colony-stimulating factor G-CSF, heparin, hydrocortisone, human growth hormone (hGH), ibuprofen, ilaprazole, insulin, interferon, interleukin, intron A, ketoprofen, lansoprazole, leuproreductase, lipoic acid, lithium, quinine, memantine, mesalazine, methenamine, miramerin, minerals, minoprazole, naproxen, natamycin, nitrofurantion, novobiocin, olsalazine, omeprazole, orotate, punk Retin, pantoprazole, parathyroid hormone, paroxetine, penicillin, perprazole, pindolol, polymyxin, potassium, pravastatin, prednisone, preglumetasin progabide, prosomatostatin, protease, quinapril, rabeprazole, ranitidine, ranolazine, reboxetine, rutoside, somatostatin, streptomycin, subtilin, sulfasalazine, sulfanilamide, tamsulosin, tenatoprazole, trypsin, valproic acid, vasopressin, vitamins, zinc, their salts, derivatives, polymorphs, isomorphs,or any type of mixture or combination thereof.

[0046] It will be apparent to those skilled in the art that the terms "pharmaceutical active ingredient", "nutritionally active ingredient" (nutraceutical active ingredient), "excipient" and "composition" each overlap broadly with pharmaceutical or nutritional dosage forms. Many substances listed as dietary supplements may also be used as pharmaceutical active ingredients. Depending on the particular application and the laws and classifications of local authorities, the same substance may be listed as a pharmaceutical active ingredient or a nutritionally active ingredient, which is a pharmaceutical composition or a nutraceutical composition, respectively, or even both.

[0047] Nutraceuticals are well known to those skilled in the art. Nutraceuticals are often defined as extracts of foods that are claimed to have medical effects on human health. Nutraceutical active ingredients (nutraceutically active ingredients) may therefore also exhibit pharmaceutical activity. Examples of nutritional active ingredients include resveratrol from grape products as an antioxidant, soluble dietary fiber products such as psyllium seed husks to reduce hypercholesterolemia, broccoli (sulfanes) as cancer prevention agents, and soybeans or clover (isoflavonoids) to improve arterial health. It is therefore clear that many substances listed as nutraceuticals can also be used as pharmaceutical active ingredients. Exemplary nutraceuticals or nutritional actives that can be used as fills for the described polymer-coated hard shell capsules may include probiotics and prebiotics. Probiotics are live microorganisms that are believed to support the health of humans or animals when ingested. Prebiotics are nutraceuticals or nutritional actives that induce or promote the growth or activity of beneficial microorganisms in the intestines of humans or animals. Examples of dietary supplements include resveratrol from grape products, omega-3 fatty acids or proanthocyanins from blueberries as antioxidants, soluble dietary fiber products such as psyllium seed husks to reduce hypercholesterolemia, broccoli (sulfanes) as cancer prevention agents, and soybeans or clover (isoflavonoids) to improve arterial health.Other examples of dietary supplements are flavonoids, antioxidants, alpha-linoleic acid from flaxseed, beta-carotene from marigold petals, or anthocyanins from berries.In some cases, the term dietary supplement or nutraceutical is used as a synonym for dietary supplement.Preferred biologically active ingredients are metoprolol, mesalamine, and omeprazole.

[0048] Method for producing coated hard shell capsules The present invention provides a method for the preparation of a polymer-coated hard shell capsule suitable as a container for biologically active ingredients, wherein the hard shell capsule comprises a body and a cap, the cap overlapping the body in either a pre-locked or final locked state in a closed state, the hard shell capsule being provided in a pre-locked state and being spray-coated with a coating solution, suspension or dispersion according to the present invention to form a coating layer covering the exterior surface of the hard shell capsule in the pre-locked state.

[0049] In a further process step, the pre-locked hard shell capsule can be provided with a fill containing at least one biologically active ingredient and closed to a final locking state. In the further process steps, the polymeric coated hard shell capsule in the pre-locked state can be opened, filled with a fill material comprising a biologically active ingredient, and closed in a final locked state. This further process step is preferably carried out by feeding the coated hard shell capsule in the pre-locked state to a capsule filling machine, which opens the polymeric coated hard shell capsule, fills it with a fill material comprising at least one biologically active ingredient, and closes it in a final locked state. The further process steps result in a final locked polymer coated hard shell capsule that is a container for at least one biologically active ingredient. The final locked polymer coated hard shell capsule as a container for at least one biologically active ingredient is a pharmaceutical or dietary supplement dosage form.

[0050] The dosage form preferably comprises a final locked polymer coated hard shell capsule containing a fill comprising at least one biologically active ingredient, the polymer coated hard shell capsule comprising a coating layer according to the present invention, the coating layer covering the outer surface area of ​​the pre-locked capsule but not covering the overlap area where the pre-locked cap covers the body. The coating suspension, which includes at least one polymer, at least one flow promoter, and at least one emulsifier, may contain an organic solvent, such as acetone, isopropanol, or ethanol. The concentration of the dry weight material in the organic solvent may be about 5-50% by weight of the polymer. A suitable spray concentration may be about 5-25% by dry weight.

[0051] The coating suspension may be a dispersion of at least one polymer, at least one flow promoter, and at least one emulsifier in an aqueous medium, such as water, or a mixture of 80% or more water and 20% or less water-soluble solvent, such as acetone or isopropanol, by weight. A suitable concentration of the dry weight materials in the aqueous medium may be about 5-50% by weight. A suitable spray concentration may be about 5-25% by dry weight. Spray coating is preferably carried out in a drum coater or fluidized bed coating equipment by spraying the coating solution or dispersion onto the pre-locked capsules. The surface tension of the coating solution, suspension or dispersion is preferably determined according to the measurements described in Example 1.

[0052] Method for producing fillers for dosage forms Suitable methods for preparing the filling for pharmaceutical or nutritional dosage forms are well known to those skilled in the art.Suitable processes for preparing the filling for at least one pharmaceutical or nutritional dosage form disclosed herein can be by forming the core containing biologically active ingredients in the form of pellets by direct compression, compression of dry, wet or sintered granules, extrusion and then rolling, wet or dry granulation, direct pelleting, or by binding powder on active ingredient-free beads or neutral cores or active ingredient-containing particles or pellets, and in some cases by applying a coating layer in the form of aqueous dispersion or organic solution in a spray process, or by fluidized bed spray granulation.

[0053] Capsule filling machine The polymer-coated hard shell capsules are fed in a pre-locked state to a capsule filling machine which performs the steps of separating the body and the cap, filling the body with a filler, and recombining the body and the cap in a final locked state. The capsule filling machine used may be a capsule filling machine, preferably a capsule filling machine, capable of producing filled and finally closed capsules at a speed with an output of 1,000 or more capsules per hour. Capsule filling machines, preferably fully automated capsule filling machines, are well known in the art and are commercially available from several companies. The capsule filling machine used is preferably capable of operating at a speed of at least 1,000, preferably at least 10,000, at least 100,000, up to between 10,000 and 500,000 capsules, which are filled and finally closed, per hour.

[0054] Typical operation of a capsule filling machine Prior to the capsule filling process, the capsule filling machine is provided with a sufficient number or quantity of pre-locked, pre-coated hard shell capsules, and also includes a sufficient amount of fill material to be filled during operation. The hard shell capsules in the pre-locked state may be dropped by gravity into a feed tube or chute. The capsules may be uniformly aligned by mechanically measuring the difference in diameter between the cap and the body. The hard shell capsules are then typically fed into a two-section housing or brush in the proper orientation. The diameter of the upper bushing or housing is typically larger than the diameter of the capsule body bushing, so the capsule cap may be held in the upper bushing while the body is pulled into the lower bushing by vacuum. Once the capsule is opened / body and cap are separated, the upper and lower housings or bushings are separated to position the capsule body for filling. The open capsule body is then filled with the fill material. Various types of filling mechanisms can be applied for different fill materials such as granules, powders, pellets, or minitablets. Capsule filling machines generally use different mechanisms to handle different dosing ingredients as well as different numbers of filling stations. The dosing system is usually based on the volume or amount of the fill material, which is determined by the capsule size and the capacity of the capsule body. The empty capsule manufacturer usually provides a reference table indicating the volume capacity of the capsule body and the maximum fill mass for different capsule sizes based on the density of the fill material. After filling, the body and cap are rejoined by the machine in a final locked state or position.

[0055] Use / How to use / Method process The process for preparing a suitable polymer-coated hard shell capsule as described herein comprises a body and a cap, in a closed state, the cap overlaps the body in either a pre-locked state or a final locking state. A method of using a hard shell capsule for preparing a polymer-coated hard shell capsule suitable as a container for biologically active ingredients of pharmaceutical or nutritional foods, comprising the steps of: a) providing said hard shell capsules in a pre-locked state to a capsule filling machine; and b) spray-coating a coating solution, suspension or dispersion containing a polymer or a polymer mixture to form a coating layer covering the outer surface of the pre-locked hard shell capsule; It can be understood as: Spray coating can be preferably applied by using a drum coater or a fluidized bed coating device. A suitable product temperature during the spray coating process may range from about 15 to 40°C, preferably from about 20 to 35°C. A suitable spray rate may range from about 0.3 to 17.0, preferably from 0.5 to 14 [g / min / kg]. After spray coating, a drying step is included.

[0056] The pre-locked polymer coated hard shell capsule can be opened in step c), filled with a fill containing a pharmaceutical or nutritional bioactive ingredient in step d), and then closed in step e) to a final lock state. Steps c) to e) can be carried out manually or preferably with the aid of a suitable device, such as a capsule filling machine. Preferably, the coated hard shell capsules in a pre-locked state are fed to a capsule filling machine which performs the opening step c), the filling with a filling material comprising a medicamentally or nutritionally biologically active ingredient in step d) and the closing of the capsules to a final locked state in step e). Any of the process choices in any of the general or specific features and embodiments thereof as disclosed herein may be combined without limitation with any other general or specific choices of materials or numerical features and embodiments as disclosed herein, such as polymers, capsule materials, capsule sizes, coating thicknesses, biologically active components, and any other embodiments as disclosed.

[0057] Preparation of pharmaceutical or nutritional dosage forms A method is disclosed for preparing a pharmaceutical or nutritional dosage form comprising a polymer-coated hard shell capsule in a final locked state containing a fill comprising at least one pharmaceutical or nutritional biologically active ingredient, wherein the polymer-coated hard shell capsule comprises a coating layer comprising a polymer or polymer blend, the coating layer covering the outer surface area of ​​the capsule in a pre-locked state. Since the outer surface area of ​​the capsule in the pre-locked state is greater than the outer surface area of ​​the capsule in the final locked state, a portion of the polymer coating layer is hidden or enclosed between the body and the cap of the hard shell capsule, thereby providing an efficient seal.

[0058] Also provided is a method for protecting a pharmaceutical or nutritionally active ingredient from atmospheric oxygen in a pharmaceutical delivery system comprising a hard shell capsule and a fill comprising at least one pharmaceutical or nutritionally active ingredient, comprising providing a pre-coated hard shell capsule according to the invention described herein in a pre-locked state to a capsule filling machine, which separates a body and a cap, fills the body with the fill, and rejoins the body and the cap in a final locked state.

[0059] item 1. A pre-coated hard shell capsule suitable as a container for a pharmaceutical or nutritional biologically active ingredient, comprising at least one coating layer, the at least one coating layer comprising: i) at least one (meth)acrylate copolymer having a mass-average molar mass of 25000 to 900000 g / mol and a glass transition temperature (Tgm) of 0 to 200° C. and containing up to 50% by weight of methacrylic acid monomer units; ii) at least one plasticizer having a solubility in water of at least 50 g / l and in an amount of at most 50% relative to the amount of said (meth)acrylate copolymer; iii) at least one emulsifier having a melting point higher than 40° C. and a hydrophilic / lipophilic balance (HLB) of 3 to 6; iv) at least one emulsifier having a melting point below 40° C. and a hydrophilic / lipophilic balance (HLB) of 8 to 16; and the oxygen permeability of the at least one coating layer is at most 2,500 ml / (m2) when measured at a thickness of 100 μm. 2 Pre-coated hard shell capsules.

[0060] 2. The pre-coated hard shell capsule according to 1, wherein at least one emulsifier having a melting point higher than 40°C and a hydrophilic / lipophilic balance (HLB) of 3 to 6 is present in an amount of up to 25% by weight based on the amount of said (meth)acrylate copolymer, and at least one emulsifier having a melting point lower than 40°C and a hydrophilic / lipophilic balance (HLB) of 8 to 16 is present in an amount of up to 10% by weight based on the amount of said (meth)acrylate copolymer.

[0061] 3. The precoated hard shell capsule according to 1 or 2, wherein the base of the hard shell capsule is selected from hydroxypropyl methylcellulose, starch, gelatin, pullulan, and copolymers of C1-C4 alkyl esters of (meth)acrylic acid and (meth)acrylic acid.

[0062] 4. The pre-coated hard shell capsule of any one of claims 1 to 3, wherein the at least one coating layer further comprises at least one flow enhancer, the flow enhancer being present in an amount of 3 to 75% by weight based on the total weight of the at least one polymer.

[0063] 5. The pre-coated hard shell capsule of claim 4, wherein the at least one glidant is selected from silica, milled silica, fumed silica, kaolin calcium silicate, magnesium silicate, colloidal silicon dioxide, talc, stearates, sodium stearyl fumarate, starch, and stearic acid, or mixtures thereof.

[0064] 6. The pre-coated hard shell capsule according to any one of 1 to 5, wherein the glass transition temperature (Tgm) of the at least one (meth)acrylate copolymer is 40 to 160°C.

[0065] 7. The pre-coated hard shell capsule of any one of claims 1 to 6, wherein the at least one plasticizer is present in an amount of 2 to 40% by weight, based on the total weight of the at least one (meth)acrylate copolymer.

[0066] 8. The pre-coated hard shell capsule of any one of 1-7, wherein the at least one plasticizer is selected from alkyl citrates, diethyl sebacate, polyethylene glycol, and propylene glycol, or combinations thereof.

[0067] 9. The at least one coating layer has a thickness of 0.1 to 5.8 mg / cm 2 9. The precoated hard shell capsule of any one of claims 1 to 8, wherein the precoated hard shell capsule is present in an amount of

[0068] 10. The pre-coated hard shell capsule of any one of claims 1 to 9, comprising a body and a cap, said cap overlapping said body in a closed state in either a pre-locked state or a final locked state.

[0069] 11. The pre-coated hard shell capsule of any one of claims 1 to 5, wherein the at least one coating layer has a glass transition temperature, Tgm, of 45°C or less as measured by differential scanning calorimetry (DSC) according to ISO 11357-2:2013-05.

[0070] 12. The pre-coated hard shell capsule of claim 11, wherein the at least one coating layer has a glass transition temperature, Tgm, in the range of -60°C to 45°C as measured by differential scanning calorimetry (DSC) according to ISO 11357-2:2013-05.

[0071] 13. A method for preparing a pharmaceutical delivery system comprising a hard shell capsule and a fill, the fill comprising at least one pharma- ceutical or nutritional active ingredient, wherein a pre-coated hard shell capsule according to 1-12 is provided in a pre-locked state to a capsule filling machine, which performs the steps of separating a body and a cap, filling the body with the fill, and rejoining the body and the cap in a final locked state.

[0072] 14. A method for protecting a medicamentarily or nutritionally active ingredient from atmospheric oxygen in a pharmaceutical delivery system comprising a hard shell capsule and a fill, said fill comprising at least one medicamentarily or nutritionally active ingredient, comprising providing a pre-coated hard shell capsule according to 1-12 in a pre-locked state to a capsule filling machine, said capsule filling machine performing the steps of separating a body and a cap, filling said body with said fill, and rejoining said body and said cap in a final locked state.

[0073] 15. A precoated hard shell capsule suitable as a container for a pharmaceutical or nutritional biologically active ingredient, comprising at least one coating layer, the at least one coating layer comprising: i) at least one (meth)acrylate copolymer having a mass-average molar mass of 25000 to 900000 g / mol and a glass transition temperature (Tgm) of 0 to 200° C. and containing up to 50% by weight of methacrylic acid monomer units; ii) at least one plasticizer having a solubility in water of at least 50 g / l and in an amount of at most 50% relative to the amount of said (meth)acrylate copolymer; iii) at least one emulsifier having a melting point higher than 40° C. and a hydrophilic / lipophilic balance (HLB) of 3 to 6; iv) at least one emulsifier having a melting point below 40° C. and a hydrophilic / lipophilic balance (HLB) of 8 to 16; and 2. The method according to claim 1, wherein the glass transition temperature, Tgm, as measured by differential scanning calorimetry (DSC) according to ISO 11357-2:2013-05 is less than or equal to 45°C, more preferably, as measured by differential scanning calorimetry (DSC) according to ISO 11357-2:2013-05 is in the range of -60°C to 45°C, and most preferably, as measured by differential scanning calorimetry (DSC) according to ISO 11357-2:2013-05 is in the range of -60°C to 40°C. EXAMPLES

[0074] Comparative Example: Oxygen Permeability of HPMC Film Film preparation: Methocel™ VLV was slowly added to water with continuous stirring to prepare a 20% w / w aqueous solution. Films were prepared by casting using a 500 μm squeegee (four-sided applicator frame) and a Teflon-coated metal plate. Films of size 30×6 cm were allowed to dry at room temperature for 24 hours. The film thickness after drying was approximately 150 μm. Oxygen permeability measurement: The oxygen permeability of this film was measured using the device shown in Figure 2. In an oxygen-containing atmosphere, the device was filled and closed by screwing two Creanit® plates. In a normal atmosphere, the oxygen permeation / time was measured using a PSt9 sensor, which is commonly used for measuring trace amounts of gaseous oxygen (e.g., provided by PreSens Precision Sensing GmbH, Germany).

[0075] [Table 2] Example of the invention: Formulation 1 Preparation of solutions and films Water and polysorbate 80 were heated to 72°C with continuous stirring. Glycerol monostearate (GMS, 40-55%, type II) was added and the mixture was stirred at 72°C for 30 minutes. After cooling to below 50°C, triethyl citrate (TEC) was added with continued stirring. After cooling to room temperature, the resulting suspension was added to aqueous polymer dispersion A (30% solids, mass average molar mass of about 450,000 g / mol, glass transition temperature (Tgm): about 28°C). After stirring for an additional 30 minutes, the resulting dispersion was passed through a 260 μm sieve. Films were prepared by casting using a 500 μm squeegee (four-sided applicator frame) and a Teflon-coated metal plate. Films measuring 30×6 cm were allowed to dry at room temperature for 24 hours. The film thickness after drying was approximately 150 μm. Oxygen permeability measurement: The oxygen permeability of this film was measured using the device shown in FIG.

[0076] Comparative example: Formulation 2 Preparation of solutions and films To the aqueous polymer dispersion A (30% solids, same as formulation 1 used), water and dibutyl sebacate were added. After stirring for 30 minutes, the dispersion was passed through a 260 μm sieve. Films were prepared by casting using a 500 μm squeegee (four-sided applicator frame) and a Teflon-coated metal plate. Films measuring 30×6 cm were allowed to dry at room temperature for 24 hours. The film thickness after drying was approximately 150 μm. Oxygen permeability measurement: The oxygen permeability of the film was measured using an apparatus as shown in Figure 2.

[0077] Formulation composition:

[0078] [Table 3] *Based on dry polymer material [%] **Polymer Dispersion A: A core-shell polymer consisting of 75% ethyl acrylate and methyl methacrylate (2:1) and 25% methyl methacrylate and methacrylic acid (1:1), commercially available under the trade name EUDRAGIT® FL30D-55. ***Water was added in addition to the water contained in 30% Aqueous Polymer Dispersion A.

[0079] Oxygen permeation results of the obtained films:

[0080] [Table 4] The glass transition temperatures of the coating compositions were determined using differential scanning calorimetry (DSC) according to ISO 11357-2:2013-05, and the results are shown in the table below.

[0081] [Table 5]

Claims

1. 1. A pre-coated hard shell capsule suitable as a container for a pharmaceutical or nutritional biologically active ingredient, comprising at least one coating layer, the at least one coating layer comprising: i) at least one (meth)acrylate copolymer having a weight average molar mass of 25,000 to 900,000 g / mol and a glass transition temperature (Tgm) of 0 to 200° C. and containing up to 50% by weight of methacrylic acid monomer units; ii) at least one plasticizer having a solubility in water of at least 50 g / l and in an amount of at most 50% relative to the amount of said (meth)acrylate copolymer; iii) at least one emulsifier having a melting point greater than 40° C. and a hydrophilic / lipophilic balance (HLB) of 3 to 6; iv) at least one emulsifier having a melting point below 40° C. and a hydrophilic / lipophilic balance (HLB) of 8 to 16; and the oxygen permeability of the at least one coating layer is at most 2,500 ml / (m2) when measured at a thickness of 100 μm. ２ .d.atm) precoated hard shell capsules.

2. 2. The pre-coated hard shell capsule of claim 1, wherein at least one emulsifier having a melting point above 40° C. and a hydrophilic / lipophilic balance (HLB) of 3 to 6 is present in an amount of up to 25% by weight based on the amount of the (meth)acrylate copolymer, and at least one emulsifier having a melting point below 40° C. and a hydrophilic / lipophilic balance (HLB) of 8 to 16 is present in an amount of up to 10% by weight based on the amount of the (meth)acrylate copolymer.

3. The base material of the hard shell capsule is hydroxypropyl methylcellulose, starch, gelatin, pullulan and C of (meth)acrylic acid. １ ~C ４ 2. The precoated hard shell capsule of claim 1, wherein the copolymer is selected from copolymers of alkyl esters and (meth)acrylic acid.

4. 10. The pre-coated hard shell capsule of claim 1, wherein the at least one coating layer further comprises at least one glidant, the glidant being present in an amount of 3 to 75% by weight based on the total weight of the at least one polymer.

5. 5. The pre-coated hard shell capsule of claim 4, wherein the at least one glidant is selected from silica, milled silica, fumed silica, kaolin calcium silicate, magnesium silicate, colloidal silicon dioxide, talc, stearates, sodium stearyl fumarate, starch, and stearic acid, or mixtures thereof.

6. 2. The pre-coated hard shell capsule of claim 1, wherein the glass transition temperature (Tgm) of the at least one (meth)acrylate copolymer is from 40 to 160°C.

7. 10. The pre-coated hard shell capsule of claim 1, wherein the at least one plasticizer is present in an amount of 2 to 40 weight percent, based on the total weight of the at least one (meth)acrylate copolymer.

8. 10. The pre-coated hard shell capsule of claim 1, wherein the at least one plasticizer is selected from alkyl citrates, diethyl sebacate, polyethylene glycol, and propylene glycol, or combinations thereof.

9. The at least one coating layer has a thickness of 0.1 to 5.8 mg / cm ２ 2. The precoated hard shell capsule of claim 1, wherein the precoated hard shell capsule is present in an amount of

10. 10. The pre-coated hard shell capsule of claim 1, comprising a body and a cap, said cap overlapping said body in a closed state in either a pre-locked state or a final locked state.

11. 10. The pre-coated hard shell capsule of claim 1, wherein the at least one coating layer has a glass transition temperature, Tgm, of 45° C. or less as measured by differential scanning calorimetry (DSC) according to ISO 11357-2:2013-05.

12. 12. The pre-coated hard shell capsule of claim 11, wherein the at least one coating layer has a glass transition temperature, Tgm, in the range of -60°C to 45°C as measured by differential scanning calorimetry (DSC) according to ISO 11357-2:2013-05.

13. 10. A method for preparing a pharmaceutical delivery system comprising a hard shell capsule and a fill, the fill comprising at least one pharma- ceutical or nutritional active ingredient, wherein the pre-coated hard shell capsule of claim 1 is provided to a capsule filling machine in a pre-locked state, the capsule filling machine performing the steps of separating a body and a cap, filling the body with the fill, and rejoining the body and the cap in a final locked state.

14. 1. A method for protecting a medicamentally or nutritionally active ingredient from atmospheric oxygen in a pharmaceutical delivery system comprising a hard shell capsule and a fill, the fill comprising at least one medicamentally or nutritionally active ingredient, comprising providing the pre-coated hard shell capsule of claim 1 in a pre-locked state to a capsule filling machine, the capsule filling machine performing the steps of separating a body and a cap, filling the body with the fill, and rejoining the body and the cap in a final locked state.

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