Double layered delayed-release hard capsules targeting the ileum

Abstract

The invention discloses a double layered delayed-release hard capsules made by double dipping, that is by two consecutive dip molding steps with the same mold pin without removing the film, provided by the first dip molding step, from the mold pin between the two dip molding steps, but dipping the mold pin with this first film on the mold pin in the second dip molding step, each dip molding step is done with a different polymer melt, providing a double layered delayed-release capsule, which passes the stomach and the jejunum and opens in the ileum.

Description

[0001] DOUBLE LAYERED DELAYED-RELEASE HARD CAPSULES TARGETING THE ILEUM

[0002] The invention discloses a double layered delayed-release hard capsules made by double dipping, that is by two consecutive dip molding steps with the same mold pin without removing the film, provided by the first dip molding step, from the mold pin between the two dip molding steps, but dipping the mold pin with this first film on the mold pin in the second dip molding step, each dip molding step is done with a different polymer melt, providing a double layered delayed-release capsule, which passes the stomach and the jejunum and opens in the ileum.

[0003] BACKGROUND OF THE INVENTION

[0004] Capsules are a common dosage form for pharma, health & nutrition, and are usually required to dissolve in the stomach as fast as possible, releasing their content, but for certain purposes they are designed to pass through the stomach and into the intestine before dissolving. Such capsules are described by a variety of terms, including gastric-resistant, entero-soluble, enteric and delayed-release capsules.

[0005] WO 2022 / 112422 Al discloses an enteric double-layered two piece hard capsule prepared by double dipping.

[0006] The European Pharmacopeia describes an in-vitro dissolution test for delayed-release dosage forms such as capsules containing for example a pharmaceutical which calls for a release of the pharmaceutical staying below a certain threshold when treated in a first step with an acidic medium for 2 h, thus simulating the gastric fluid of the stomach, and an increased or better full release when treated in a second step with an aqueous buffer of pH 6.8 for a certain time, thus simulating the intestine jejunum.

[0007] To achieve both goals is a challenge, either too much of the pharmaceutical is already released in the first step under acidic conditions, or too little is released in the second step under pH 6.8 conditions. Capsules fulfilling both criteria are generally called "enteric" capsules or "delayed release" capsules; the content is released in the upper part of the small intestine, generally the jejunum.

[0008] To reach the ileum a capsule should not open within 2 h in acidic medium to simulate a safe passage through the stomach, and then it also should not open within 1 h at pH 6.8 in order to simulate a passage through the jejunum, instead the capsule should open at pH 7.4, which simulates the pH in the ileum. Next to the desired dissolution requirements, the mechanical properties of the capsules are also important. It is desired to have capsules that are sufficiently stable for storage under different relative humidity conditions. Mechanical properties are for example the capsule's brittleness, fracture and elasticity behavior (e.g. through the tube test), top strength (e.g. through a capsule top compression test), and (pre)lock force strength (e.g. through a (pre)lock force measurement test to characterize the forces associated with the pre-locked and locked state during production and filling of the capsule) can be important parameters which should be within acceptable ranges. Alternatively for assessing mechanical behavior, several mechanical properties can be measured on films formed by the gelling composition such as: deformation at break (e.g. through a film tensile test), impact resistance (e.g. through an impact energy for fracture test), piercing time by dissolution fluid (e.g. through a piercing time measurement test), or puncture resistance (e.g. through a puncture test).

[0009] A balance needs to be found between sufficient enteric characteristics to safeguard enteric release of the active ingredient and suitable mechanical properties of the capsules, also after storage.

[0010] Solvent based melts which contain at least one organic solvent are critical to be handled in production for safety reasons, since specific containment conditions of solvent vapors are required for environmental and health reasons and also measures need to be taken to avoid any ignition or explosion e.g. during production.

[0011] In addition there are concerns about residual solvent being present in capsules for e.g. pharmaceutical use when solvent based melts containing organic solvents are used. Due to these concerns about residual solvent, the tendency is not to use volatile solvents in non-aqueous melts. The volatility aggravates the mentioned inherent problems linked to the use of organic solvents.

[0012] Furthermore, also the dipping and drying properties of a solvent based melt are different from drying properties of aqueous based melts, so any experience in the dipping and drying behavior of solvent based melts can usually not be simply transferred to aqueous melts; it is not foreseeable if what is possible with solvent based melts is also possible with aqueous based melts. Also the behavior and interaction of two layers on the pin when the inner layer is made from an aqueous based melt and the outer layer is made from an solvent based melt (or vice versa) is different from the situation when both melts are aqueous based. These differences may lead to defects (for example swellings, wrinkles, bulges or cracks) depending on the various combinations of solvents and polymers in the two layers which again necessitates different process conditions, if such defects are curable at all. Also this different behavior and interaction is not predictable. There was a need for a capsule that targets the ileum, that is that passes the stomach and the jejunum and opens only in the ileum, and that has the required mechanical properties.

[0013] A delayed-release capsule prepared by a double dipping process was found to fulfill these requirements.

[0014] SUMMARY OF THE INVENTION

[0015] Subject of the invention is a hard capsule shell, the wall of the hard capsule shell comprises two layers, a first layer and a second layer, the first layer comprises a first polymer and a second polymer; the first polymer is hydroxypropylmethylcellulose (HPMC) and the second polymer is pullulan, low methoxyl pectin (pectin LM) or a mixture thereof; the second layer comprises ethyl cellulose (EC) and sodium alginate (SA), the two layers are prepared consecutively in a double dipping process, the double dipping process prepares at first the first layer on a mold pin by dip molding in a first dip molding step and thereafter the second layer onto the first layer by a dip molding said mold pin in a second dip molding step without removal of the the first layer from the mold pin before the application of the second layer onto the first layer in the second dip molding step.

[0016] DETAILED DESCRIPTION OF THE INVENTION

[0017] The term layer in the sense of the invention means a polymer film layer, or more shortly called polymer layer. The two layers of the wall of the hard capsule shell are two polymer film layers which are in direct contact with each other. Another terms for layer are shell layer or wall layer, that means that these two polymer film layers provide for the hard capsule shell, that is for the wall of the hard capsule shell, each of the two layers is part of the hard capsule shell, that is part of the wall of the hard capsule shell, and both layers together form the hard capsule shell.

[0018] Dip molding means dipping a mold pin into a solution of a film forming polymer; thereby a polymer film is formed and shaped on the mold pin.

[0019] Double dipping process means a process with two consecutive dip molding steps, wherein the first polymer film that is formed and shaped on the mold pin in the first dip molding step is not removed, but in the second dip molding step the pin which is covered by the first polymer film is dipped into a second solution of a film forming polymer. After the extraction of the mold pin from the second melt a film of the second film forming polymer forms on the film of the first film forming polymer which is on the mold pin.

[0020] The first solution of the first film forming polymer is also called the first melt. The second solution of the second film forming polymer is also called the second melt.

[0021] After the extraction of the mold pin from the first melt the first film forming polymer forms a film on the mold pin.

[0022] Preferably the second film forming polymer in the second melt is different from the first film forming polymer in the first melt.

[0023] So essentially, double dipping process means that the film formed and shaped on the mold pin in the first dipping step with the first melt, is not removed from the pin, but stays on the pin, and the pin with this first film on it is dipped in a second dipping step into the second melt.

[0024] A hard shell capsule, be it prepared by only one dip molding step, or be it a double dipped capsule, comprises two parts, a cap and a body, each the cap and the body are prepared separately by a double dipping process with a respective mold pin shaped to provide either the cap or the body.

[0025] Both the cap and the body have in longitudinal direction a closed end, which is usually dome shaped, and opposite thereto an open end. In between the open end and the closed end, both of the cap and the body respectively, there is a part of the wall which is cylindrically shaped; usually this part of the wall begins with the rim of the open end and extends in longitudinal direction towards the closed end. The diameters of the cap and the body are such that the cylindrical part of the body fits telescopically into the the cylindrical part of the cap; for closing the hard shell capsule the cap is slid telescopically over the body, in other words the body is inserted telescopically into the cap.

[0026] The term "capsule prepared by double dipping" means that both the cap and the body of the capsule are prepared each separately by a respective double dipping process.

[0027] A closed double dipped capsule, e.g., once the body is filled and closed by fitting the cap onto the body, is distinctly different from a closed coated capsule, which was not prepared by a double dipping process. Both a coated capsule and a capsule prepared by double dipping have two layers, a first layer and a second layer; the second layer is in radial direction relative to the first layer located on the outside of the first layer, the first layer is in radial direction and relative to the second layer located on the inside of the second layer.

[0028] In case of a coated capsule the outer layer is done by a coating step which is distinctly different from a mold dipping step. The coating of the capsule is done with the capsule being in a state, wherein the cap is at least partly engaged telescopically with the body; the coating is applied onto the capsule in said state, wherein the cap is at least partly engaged telescopically with the body. At least partly engaged means that the cap has been at least partly slid over the body.

[0029] Usually two such states, where the cap is slid over the body, are differentiated, a preclosed state and a closed state. In both states the cap engages telescopically with the body, in the preclosed state the cap has been slid over the body only until the preclosed position is reached, so the cap is telescopically only partly engaged with the body. In the closed state the cap is fully engaged with the body. In longitudinal direction the distance between the closed end of the cap and the closed end of the body is larger when the capsule is in the preclosed state than when it is in the closed state.

[0030] Usually there are constructive means in the wall of the body and / or the cap that allows fixing the cap in a preclosed state and fixing the cap in the closed state. Such means are usually locking rings, these locking rings are protrusions of the wall of the body and / or the cap which extend at least partly, preferably circumferentially around the body and / or the cap and usually extend radially into the interior of the body and / or the cap. Either the cap or the body may for example have two such protrusion with the respective other part having one such protrusion, for example the body may have one such locking ring and the cap may have two such locking rings separated from each other by a certain distance in axial direction of the cap, with the locking ring of the body engaging with the first locking ring of the cap, which is closer to the rim of the open end of the cap, in the preclosed state, and engaging with the second locking ring of the cap, which is closer to the closed end of the cap, in the closed state.

[0031] The capsule in the closed state is usually called a closed capsule, in the preclosed state a preclosed capsule. Usually the engagement of the cap with the body is a less tight engagement in the preclosed state than in the closed state. So removal of the cap from the body in the preclosed state is still possible without damaging any part of the capsule, whereas separating a cap from a body of a closed capsule is more difficult, part of the capsule may even be damaged.

[0032] Usually the capsule is closed only after the capsule has been filled with the desired content, since opening a closed capsule is usually difficult or even impossible without damaging the capsule. Whereas the preclosed position is such that a manageable and defined force, a so called pre-lock force, is required to separate the cap again from the body without damaging cap or body. Usually the empty capsule is produce in the preclosed state and is fed into a filling step in said preclosed state. The separation of the cap from the body of a preclosed capsule is usually done by a machine which subsequently also fills the body with the desired content and then slides the cap over the body until the closed state is reach, thereby closing the capsule. The preclosed capsule is for example used for shipping capsules after manufacture of the empty capsules but before filling, so cap and body are partly joined and can then be separated again for the filling step.

[0033] A coating is usually applied by spraying a coating solution onto the capsule. The coating step provides for a coating layer on the outside of the capsule.

[0034] When a coating is applied onto a capsule in the preclosed state then the capsule usually is empty, whereas when a coating is applied to closed capsule then the coating is applied usually only after the capsule has been filled and closed. The coating covers the outside of the closed or preclosed capsule completely, the slit between the cap and the body, which is visible when an non-coated capsule has been preclosed or closed, and which shows that the cap and the body are indeed two separate parts, is usually covered by the coating after the coating has been applied onto the closed or preclosed capsule, so the slit is no longer visible or approachable. This is in contrast to a double dipped capsule, where said slit is not covered, but still visible and approachable.

[0035] Enteric coating made from polymer dispersions generally show non uniform capsule films due, for example, to particle coalescence issues, whereas in comparison thereto the second layer in case of a double dipped capsule shows good film uniformity. For this reason also the technical performance of double layered capsules shows also less variability, it is less likely to have double dipped capsules with technical performance which is off spec than in case of coated capsules.

[0036] Another distinct difference between a coated capsule and a double dipped capsule is the area which is covered by the coating in case of a coated capsule versus a second layer which is applied by a double dipping process: As outlined above, since a coating is applied to a capsule in a preclosed or closed state from outside, obviously only the area accessibly from the outside will be coated. Since the cap telescopically at least partly engages with the body in case of a preclosed capsule and fully engages with the body in case of a closed capsule, there is an outside area of the body starting from the rim of the open end of the body and extending for a certain distance axially in the direction to the closed end of the body which will not be covered with a coating, since this area is covered by the cap which is telescopically at least partly engaged with the body. So this certain distance is the distance in axial direction from the rim of the open end of the body until the rim of the open end of the cap when the cap is telescopically engaged with the body either in the preclosed or in the closed state.

[0037] This area has the shape of a ring with a cylindrical extended shape starting from the rim of the open end of the body, the ring extends circumferentially fully around the body and extends so far from rim of the open end of the body in axially direction towards the closed end of the body as the cap has been slid over the body in the preclosed or closed state, when the coating is applied. And this area will not be accessible for the coating, so it remains uncoated.

[0038] This contrasts with the case of a second layer that was applied by a double dipping onto the body: the complete outside area of the body is covered with the second layer by the second dipping step.

[0039] The capsule is manufactured by a capsule manufacturing enterprise, whereas the coating in preclosed state with subsequent filling and closing, or the filling, closing and subsequent coating in closed state may be done by a different enterprise or by different enterprises, which may be a tool manufacturer or even a customer of the capsule manufacturer.

[0040] The term "hard capsule" refers to a capsule that is produced by at first producing a hard capsule shell, and then encapsulating contents in said hard capsule shell. A hard capsule shell is also called a two part hard capsule shell or two piece hard capsule shell, the two parts or two pieces are the cap and the body of the capsule shell as further detailed herein.

[0041] The hard capsule shell can comprise more layers in addition to said first and second layer, for example one or more coatings can be applied onto the outer layer.

[0042] Typical sizes of the hard capsule shell are known to the skilled person and may be for example expressed in the sizes 000, OOel, 00, Oel, 0, 1, 2, 3, 4, 5, or 9, for example as disclosed in Pharmaceutical Capsules, Second Edition, 2014, edited by F. Podczeck and B. E. Jones, Pharmaceutical Press, London, UK, page 84, Table 4.1. Closed joined length of the hard capsule shell may vary from 11 to 27 mm, cap length from 6 to 13 mm, body length from 9 to 23 mm, cap diameter from 4 to 10 mm and body diameter from 4 to 10 mm.

[0043] The hard capsule shell comprises the usual two halves of a hard capsule shell, the two halves are called the cap and the body of the capsule shell.

[0044] The term "half" does not mean that cap and body are of equal size; rather the term "half" is to be understood as "part" or "piece", so the hard capsule shell comprises the two parts or the two pieces of a hard capsule shell, one part which is the cap, and the another part which is the body.

[0045] The cap and the body are two separate parts. When joined together they form the hard capsule shell, which can be empty or filled. The words "capsule" and "capsule shell" are often used interchangeably, in the sense of the invention the term "capsule" is rather meaning a hard capsule shell filled with a content. The term "shell" refers usually to a capsule shaped polymer which forms the film which again forms the wall of the shell, that again is the shell, so a capsule shaped polymer is also called shell or capsule shell.

[0046] The cap and the body are telescopically engageable to provide the hard capsule shell. Typically, the cap and the body each have two regions, a dome shaped region, which is the closed end of the cap or of the body respectively, and an essentially cylindrically shaped region, which extends from the dome shaped region and which ends with the open end of the cap or of the body respectively.

[0047] The essentially cylindrically shaped region of the cap, or at least part of it, is telescopically engageable with the essentially cylindrically shaped region of the body, or at least with part of it. A closing of the hard capsule shell is essentially an inserting of the body into the cap. This inserting is typically a sliding of the cap over the body. Thereby the essentially cylindrically shaped region of the body, or at least part of this region of the body, is inside the cavity of the essentially cylindrically shaped region of the cap, or at least inside a part of the cavity of this region of the cap. The telescopical engagement happens co-axial with respect to the longitudinal axis of the cap and the body.

[0048] So usually the telescopically engaged cap and body is called the hard capsule shell.

[0049] The hard capsule shell in the sense of this invention means the cap and the body, which may be telescopically engaged with each other, when the capsule shell is closed, or separated from each other when the capsule shell is open.

[0050] The longitudinal or axial direction is the direction from the closed end of the cap to the closed end of the body and vice versa, whereas the radial direction is perpendicular to the longitudinal direction.

[0051] The terms "inner" and "outer" and the terms "inside" and "outside" refer to a position in radial direction relative to the location of the cavity and to the location of the exterior of the capsule shell. The cavity is the inside of the body or of the cap or of the hard capsule shell, the exterior is the outside of the body or of the cap or of the hard capsule shell, respectively. So for example when the second layer is defined to be on the first layer then this means that the first layer is on the inside relative to the second layer and facing the the cavity, whereas the second layer is on the outside relative to the first layer and facing to the exterior.

[0052] The hard capsule shell, that is the first and second layer of the wall of the hard capsule shell, is prepared by a double dipping process. Said double dipping process comprises actually two double dipping processes, one double dipping process for preparing the cap with a mold pin shaped to provide the cap, and another double dipping process for preparing the body with a mold pin shaped to provide the body. These two double dipping process are distinguished from each other essentially only by the different respective mold pins. For ease of reading the double dipping process as disclosed herein, also with all its embodiments, refers to each of these two double dipping processes for the cap and the body respectively.

[0053] The two layers of the hard capsule shell are prepared consecutively in a double dipping process which provides for the second layer being formed and shaped onto the outside of the first layer, this means the second layer is applied onto the outside surface of the first layer.

[0054] The second layer of the hard capsule shell is not prepared by a spray coating process wherein a coating is sprayed onto the first layer; in particular the second layer of the hard capsule shell is not prepared by a spray coating process wherein a coating is sprayed onto the first layer while the first layer having the shape of a capsule and while said capsule is in a closed or preclosed state during the application of the second layer.

[0055] The second layer of the hard capsule shell is not prepared by a coating process wherein a coating is applied onto the first layer while the first layer having the shape of a capsule and while said capsule is in a closed or preclosed state during the application of the second layer.

[0056] The first layer of the hard capsule shell is not prepared by a coating process which prepares the first layer other than with a double dipping process, a double dipping process which prepares the first and the second layer consecutively with the second layer being prepared on the first layer.

[0057] The second layer of the hard capsule shell is not prepared by a coating process which prepares the second layer other than with a double dipping process, a double dipping process which prepares the first and the second layer consecutively with the second layer being prepared on the first layer.

[0058] The first layer of the hard capsule shell is not prepared by a coating process which prepares the first layer other than with a double dipping process.

[0059] The second layer of the hard capsule shell is not prepared by a coating process which prepares the second layer other than with a double dipping process.

[0060] The outside of the first layer of the body of the hard capsule shell is completely covered by the second layer of the body. Completely covered means that the second layer covers the outside of first layer of the body from the closed end of the body up to the rim of the open end of the body. This covering of the outside of the first layer of the body by the second layer of the body is without any gap and without any area of the outside of the first layer of the body not being covered by the second layer. In particular no circumferential outside area of the first layer of the body starting from the rim of the open end of the body and extending axially at least for a certain distance towards the closed end of the body is not covered by the second layer of the body.

[0061] The first layer of the body of the hard capsule shell does not have an area on its outside which is not covered by the second layer; specifically the outside of the first layer of the body does not have an area extending circumferentially around the body and starting from the rim of the open end of the body and extending axially at least for a certain distance in the direction of the closed end of the body which is not covered by the second layer.

[0062] In the instant invention the HPMC methoxy and hydroxypropoxy contents are expressed according to US Pharmacopeia as the US Pharmacopeia reference is cited herein.

[0063] There are different types or grades of HPMC.

[0064] Therefore the term HPMC in the sense of the invention also comprises mixtures of more than one type or grade of HPMC.

[0065] The HPMC in the hard capsule shell can be one type of HPMC, it can also be a mixture of different types of HPMC.

[0066] The HPMC can for example be selected from the group of

[0067] HPMC 2910 containing about 7.0 to 12.0% hydroxypropoxy group and about 28.0 to 30.0% methoxy group,

[0068] HPMC 2906 containing about 4.0 to 7.5% hydroxypropoxy group and about 27.0 to 30.0% methoxy group,

[0069] HPMC 2208 containing about 4.0 to 12.0% of hydroxypropoxy group and about 19.0 to 24.0% of methoxy group,

[0070] HPMC 1828 containing about 23.0 to 32.0% hydroxypropy group and about 16.5 to 20.0% methoxy group, and mixtures thereof.

[0071] Preferably, the HPMC has a methoxy content of 27.0 to 30.0 % (w / w).

[0072] Preferably, the HPMC has a hydroxypropoxy content of 4.0 to 12.0 % (w / w).

[0073] More preferably, the HPMC has a methoxy content of 27.0 to 30.0 % (w / w) and a hydroxypropoxy content of 4.0 to 12.0 % (w / w). In an embodiment, the HPMC is HPMC 2906.

[0074] Preferably, the amount of HPMC in the first layer is at least 50 wt%, at least 55 wt%, at least 60 wt%, at least 65 wt% or at least 70 wt%, with a higher amount being more preferable over a lower amount; the wt% are base on the dry weight of the first layer.

[0075] Pectin has CAS 9000-69-5. Pectin is a natural polysaccharide found in the cell walls of plants, particularly abundant in fruits. It is composed primarily of galacturonic acid units linked by alpha-(l- >4) glycosidic bonds, so it contains free carboxylic acid residues.

[0076] Low Methoxyl (LM) pectin (also called pectin LM) has a low degree of esterification (DE) of the carboxylic acid residues, typically below 50%.

[0077] In contrast thereto the so called High Methoxyl (HM) Pectin (also called pectin HM) has a degree of esterification above 50%.

[0078] A subgroup of pectin LM is low methoxylated amidated (LA) pectin, also called pectin LA. Pectin LA is a specific type of pectin LM that has been chemically modified by amidation.

[0079] Preferably, the amount of pectin LM in the first layer is at least 5 wt%, at least 7 wt%, at least 8 wt% or at least 9 wt%, with a higher amount being more preferable over a lower amount; and / or the amount of pectin LM in the first layer is not more than 19 wt%, than 18 wt%, than 17 wt%, than 16 wt%, than 15 wt%, than 14 wt% or than 13 wt%, with a lower limit being more preferable over a higher limit; and / or the amount of pectin LM in the first layer is from 5 to 19 wt%, from 6 to 18 wt%, from 7 to 17 wt%, from 8 to 16 wt%, from 8 to 15 wt% or from 9 to 14 wt%, with a narrower range being more preferable over a broader range; the wt% are base on the dry weight of the first layer.

[0080] When the second polymer in the first layer is pectin LM, then preferably the amount of HPMC in the first layer is at least 50 wt%, at least 55 wt%, at least 60 wt%, at least 65 wt%, at least 70 wt%, at least 75 wt% or at least 80 wt%, with a higher amount being more preferable over a lower amount; the wt% are base on the dry weight of the first layer.

[0081] Preferably, the pectin LM is a pectin LA. Pullulan has CAS 9057-02-7. Pullulan is a polysaccharide produced by the fungus Aureobasidium pullulans through fermentation. It is composed of maltotriose units connected by alpha-(l->6) glycosidic bonds. Each maltotriose unit consists of three glucose molecules linked by alpha-(l->4) bonds.

[0082] Preferably, the amount of pullulan in the first layer is at least 5 wt%, at least 7 wt%, at least 8 wt% or at least 9 wt%, with a higher amount being more preferable over a lower amount; and / or the amount of pullulan in the first layer is not more than 30 wt%, than 28 wt%, than 26 wt%, than 24 wt%, than 23 wt%, than 22 wt% or than 21 wt%, with a lower limit being more preferable over a higher limit; and / or the amount of pullulan in the first layer is from 5 to 30 wt%, from 7 to 28 wt%, from 7 to 26 wt%, from 7 to 24 wt% or from 8 to 23 wt%, with a narrower range being more preferable over a broader range; the wt% are base on the dry weight of the first layer.

[0083] When the second polymer in the first layer is pullulan, then preferably the amount of HPMC in the first layer is at least 50 wt%, at least 55 wt%, at least 60 wt%, at least 65 wt% or at least 70 wt%, with a higher amount being more preferable over a lower amount; the wt% are base on the dry weight of the first layer.

[0084] In one embodiment, preferably, the amount of pullulan in the first layer is at least 5 wt%, at least 7 wt%, at least 8 wt% or at least 9 wt%, with a higher amount being more preferable over a lower amount; and / or the amount of pullulan in the first layer is not more than 30 wt%, than 25 wt%, than 21 wt%, than 18 wt%, than 16 wt%, than 14 wt% or than 12 wt%, with a lower limit being more preferable over a higher limit; and / or the amount of pullulan in the first layer is from 5 to 30 wt%, from 7 to 25 wt%, from 7 to 21 wt%, from 7 to 18 wt%, from 8 to 16 wt%, from 8 to 14 wt% or from 8 to 12 wt%, with a narrower range being more preferable over a broader range; the wt% are base on the dry weight of the first layer.

[0085] Preferably, the first layer does not contain ethyl cellulose, and / or the first layer does not contain sodium alginate.

[0086] Preferably, the second layer does not contain HPMC, and / or the second layer does not contain the first polymer, and / or the second layer does not contain the second polymer.

[0087] In an embodiment, the polymer part of the first layer consists of the first and the second polymer.

[0088] In an embodiment, the polymer part of the first layer consists of HPMC and pectin LM.

[0089] In an embodiment, the polymer part of the first layer consists of HPMC and pullulan.

[0090] In an embodiment, the first layer consists of the first and the second polymer.

[0091] In an embodiment, the first layer consists of HPMC and pectin LM.

[0092] In an embodiment, the first layer consists of HPMC and pullulan.

[0093] When the polymer part of the first layer or when the first layer consists only of the first and second polymer, then this is meant based on dry weight as there is always some residual water in the first layer; this can stem from preparation and drying process, which usually is not done until the last trace of water has been removed but some residual water remains in the first layer, and / or from uptake of moisture from the air during storage after drying.

[0094] Ethyl cellulose has CAS 9004-57-3, Ethyl cellulose is a cellulose ether derived from cellulose in which some of the hydroxyl groups are replaced by ethyl groups.

[0095] Preferably, the amount of ethyl cellulose in the second layer is at least 50 wt%, at least 52.5 wt%, at least 55 wt%, at least 57.5 wt% or at least 60 wt%, with a higher amount being more preferable over a lower amount; the wt% are base on the dry weight of the second layer.

[0096] Sodium alginate has CAS 9005-38-3, Sodium alginate is the sodium salt of alginic acid, a natural polysaccharide extracted primarily from the cell walls of brown seaweed (e.g., Laminaria, Macrocystis). It is composed of mannuronic acid (M) and guluronic acid (G) monomers arranged in blocks along the polymer chain.

[0097] Preferably, the amount of sodium alginate in the second layer is at least 2 wt%, at least 2.5 wt% or at least 3 wt%, with a higher amount being more preferable over a lower amount; and / or the amount of sodium alginate in the second layer is not more than 9.5 wt%, than 9 wt%, than 8.5 wt%, than 8 wt%, than 7.5 wt%, than 7 wt%, than 6.5 wt%, than 6 wt%, than 5.5 wt%, than 5 wt%, than 4.5 wt%, than 4 wt% or than 3.5 wt%, with a lower limit being more preferable over a higher limit; and / or the amount of sodium alginate in the second layer is from 2 to 9.5 wt%, 2 to 9 wt%, 2 to 8.5 wt%, from 2 to 8 wt%, from 2 to 7.5 wt%, from 2 to 7.5 wt%, 2 to 7 wt%, 2 to 6.5 wt%, 2 to 6 wt%, 2 to 5.5 wt%, 2 to 5 wt%, 2 to 4.5 wt%, 2 to 4 wt%, 2 to 3.5 wt% or 2.5 to 3.5 wt%, with a narrower range being more preferable over a broader range; the wt% are base on the dry weight of the second layer.

[0098] In case that the second polymer is pectin LM, then preferably, the amount of sodium alginate in the second layer is at least 2 wt%, at least 2.5 wt% or at least 3 wt%, with a higher amount being more preferable over a lower amount; and / or the amount of sodium alginate in the second layer is not more than 5.5 wt%, than 4.0 wt% than 4.5 wt%, than 4 wt% or than 3.5 wt%, with a lower limit being more preferable over a higher limit; and / or the amount of sodium alginate in the second layer is from 2 to 5.5 wt%, 2 to 5 wt%, 2 to 4.5 wt%, 2 to 4 wt%, 2 to 3.5 wt% or 2.5 to 3.5 wt%, with a narrower range being more preferable over a broader range; the wt% are base on the dry weight of the second layer.

[0099] Preferably, the second layer comprises one or more plasticizer; more preferably, a plasticizer is selected from the group dibutyl sebacate (DBS), triethyl citrate (TEC), Acetyl triethylcitrate (ATEC), glycerin, sorbitol, mannitol, trehalose, vegetable oil, a medium chain triglyceride, a triacetin, a phthalate, a phytosterol, a propylene glycol, a polysorbate and a polyethylene glycol; even more preferably, a plasticizer is selected from the group of dibutyl sebacate (DBS), triethyl citrate (TEC) and Acetyl triethylcitrate (ATEC); especially, the plasticizer is dibutyl sebacate (DBS).

[0100] Sorbitol can be D-sorbitol or sorbitan solution. Mannitol can be D-mannitol. Vegetable oil can be for example sesame oil or castor oil. A phthalate can be dioctyl phthalate. A polyethylene glycol can be macrogol. Preferably, the amount of plasticizer in the second layer is at least 1 wt%, at least 2 wt%, at least 3 wt%, at least 4 wt% or at least 5 wt%, with a higher amount being more preferable over a lower amount; and / or the amount of plasticizer in the second layer is not more than 30 wt%, than 27.5 wt% or than 25 wt%, with a lower limit being more preferable over a higher limit; and / or the amount of plasticizer in the second layer is from 1 to 30 wt%, 2 to 27.5 wt%, 3 to 27.5 wt%, from 4 to 27.5 wt%, from 5 to 27.5 wt% or from 5 to 25 wt%, with a narrower range being more preferable over a broader range; the wt% are base on the dry weight of the second layer.

[0101] In an embodiment, the second layer comprises cetyl alcohol (CA); preferably, the amount of CA in the second layer is at least 1 wt%, at least 2 wt%, at least 3 wt%, at least 4 wt%, at least 5 wt% or at least 6 wt%, with a higher amount being more preferable over a lower amount; and / or the amount of CA in the second layer is not more than 10 wt%, than 8 wt% or than 7 wt%, with a lower limit being more preferable over a higher limit; and / or the amount of CA in the second layer is from 1 to 10 wt%, 2 to 10 wt%, 3 to 10 wt%, from 4 to 8 wt%, from 5 to 8 wt% or from 6 to 7 wt%, with a narrower range being more preferable over a broader range; the wt% are base on the dry weight of the second layer; in an embodiment, the second layer comprises sodium lauryl sulfate (SLS); preferably, the amount of SLS in the second layer is at least 0.5 wt%, at least 1 wt%, at least 1.5 wt% or at least 2 wt%, with a higher amount being more preferable over a lower amount; and / or the amount of SLS in the second layer is not more than 5 wt%, than 4 wt% or than 3 wt%, with a lower limit being more preferable over a higher limit; and / or the amount of SLS in the second layer is from 0.5 to 5 wt%, 1 to 4 wt%, 1.5 to 4 wt% or from 2 to 3 wt%, with a narrower range being more preferable over a broader range; the wt% are base on the dry weight of the second layer; in an embodiment, the second layer comprises cetyl alcohol (CA) and sodium lauryl sulfate (SLS); with the amounts as stated herein, also in all possible combinations of these stated amounts. The EC can be provided for use in the instant invention as a pseudolatex and CA and SLS are used to maintain the nanoparticles of EC in suspension in the pseudolatex.

[0102] The hard capsule shell can comprise water. The water can stem from the production process which is using an aqueous composition for preparing the hard capsule shell, so the water in the hard capsule shell is typically residual water remaining in the hard capsule shell after drying. It can also stem from the humidity of the atmosphere, essentially of the relative humidity of the air surrounding the hard capsule shell. Typical upper limit of the amount of residual water in the hard capsule shell is 20 wt% or less, preferably 17.5 wt% or less, the wt% being based on the weight of the hard capsule shell.

[0103] Typical lower limit of the amount of residual water in the hard capsule shell is 3 wt%, preferably 4 wt%, more preferably 5 wt%, the wt% being based on the weight of the the hard capsule shell.

[0104] Any of the lower limit of the amount of residual water can be combined with any of the upper limit of the amount of residual water.

[0105] For example, the amount of residual water in the hard capsule shell can be from 3 to 20 wt%, preferably from 4 to 17.5 wt%, more preferably from 5 to 17.5 wt%, the wt% being based on the weight of the the hard capsule shell.

[0106] The amount of residual water may be characterized by the loss on drying (LOD). The dry weight of the hard capsule shell is the weight minus the weight that is lost when the LOD is determined, that is the remaining weight after the LOD determination.

[0107] The first layer, the second layer or both layers of the hard capsule shell, in particular the first layer, can comprise a gelling system.

[0108] The gelling system can be a gelling agent or a combination of a gelling agent with a gelling aid.

[0109] Typical the gelling agent is selected from the group of hydrocolloid such as agar gum, guar gum, locust bean gum (carob), carrageenan, xanthan, gellan gum, konjac mannan, gelatin, and mixtures thereof; preferably, the gelling agent is selected from the group of carrageenan, gellan gum, gelatin, and mixtures thereof.

[0110] Typical the gelling aid is a cation; the cation can be selected from the group of K+, Na+, Li+, NH4+, Ca2+, Mg2+, and mixtures thereof.

[0111] The gelling system can be contained in the first layer, in the second layer or in both layers, preferably in the first layer. The hard capsule shell can comprise from 0.01 to 10 wt%, preferably from 0.01 to 5 wt%, more preferably from 0.01 to 2 wt%, even more preferably from 0.01 to 1 wt%, of the gelling system, the wt% being based on the weight of HPMC in the case that the gelling system is contained in the first layer, or being based on the weight of ethyl cellulose in the case that the gelling system is contained in the second layer.

[0112] In one embodiment, the first layer does not comprise any gelling system.

[0113] In one embodiment, the second layer does not comprise any gelling system.

[0114] In one embodiment, the first layer and the second layer do not comprise any gelling system.

[0115] The hard capsule shell may comprise one or more an additives, the additive is selected from the group of pH regulator, sweetener, acidulant, preservative, flavor, taste modifiers, binder, thickener, colorant, and mixtures thereof.

[0116] An additive can be contained in the first layer, in the second layer or in both layers. A total amount of additives in each of the layers may be from 0.1 to 20 wt%, preferably from I to 15 wt%, more preferably from 1 to 10 wt%, the wt% being based on the weight of the HPMC in the case that additives are contained in the first layer, being based on the weight of ethyl cellulose, in the case that additives are contained in the outer layer.

[0117] Examples of the pH regulator include phosphoric acid, hydrochloric acid, citric acid, glycine, gluconic acid, succinic acid, acetic acid, tartaric acid, lactic acid, fumaric acid, boric acid, maleic acid, sulfuric acid, malic acid, ammonia, a hydroxide, an amine, and salts thereof.

[0118] Examples of the sweetener include aspartame, acesulfame potassium, amacha powder, liquid sugar, fructose, glucose, reduced maltitol syrup, licorice, xylitol, glycine, glycerin, glycyrrhizinate, brown sugar, saccharin, sucralose, stevia extract, refined white sugar, purification honey, D-sorbitol, maltitol, maltose and D-mannitol.

[0119] Examples of the acidulant include adipic acid, itaconic acid, citric acid, trisodium citrate, glucono-delta- lactone, gluconic acid, potassium gluconate, sodium gluconate, succinic acid, monosodium succinate, disodium succinate, sodium acetate, tartaric acid, lactic acid, sodium lactate, acetic acid, phytic acid, fumaric acid, malic acid and phosphoric acid.

[0120] Examples of the preservative include benzoic acid, sodium benzoate, p-hydroxybenzoate, sodium sulfite, sodium hyposulfite, sodium pyrosulfite, potassium pyrosulfite, propionic acid, calcium propionate, sodium propionate, storax extract, capillary artemisia extract, Milt protein extract, a sorbic acid compound, sodium dehydroacetate, nysin, sulfur dioxide, a pectin degradation product and epsilon-polylysine.

[0121] Examples of the flavor include various essences, flavors, peppermint, menthol, cinnamon, fennel, vanilla, lemon, and camphor.

[0122] Examples of the thickener include alginic acid, alginate, Arabic gum, karaya gum, guar gum, gellan gum, tamarind seed gum, tara gum, tragacanth gum, carrageenan, CMC-Ca, CMC-Na, glucosamine, sodium polyacrylate, methylcellulose, curdlan and modified starch; in case of a thickener for the second layer is can also be pullulan and / or pectin.

[0123] The strength of a capsule film can be increased by use of the thickener and binder.

[0124] A colorant may be a dye or a pigment with a black, white, such as TiOj, grey or any chromatic color. The term chromatic color herein refers to all colors except black, white and grey.

[0125] In one embodiment the hard capsule shell does not have an enteric coating on the inside of the first layer.

[0126] Preferably, the wall thickness of the hard capsule shell is at least 80, at least 85. at least 90 micrometer or at least 95 micrometer, with a higher value being more preferred over a lower value; and / or the wall thickness of the hard capsule shell according to the invention is not more than 150, not more than 145, not more than 140, not more than 135, not more than 130, not more than 125, not more than 120, or not more than 115 micrometer, with a higher value being more preferred over a lower value, with a lower value being more preferred over a higher value; and / or; the wall thickness of the hard capsule shell according to the invention is from 80 to 150, from 85 to 145, from 85 to 140, from 85 to 130, from 85 to 125, from 90 to 120, from 90 to 115 or from 95 to 115 micrometer, with a more narrow range preferred over a broader range.

[0127] The thickness of the first layer is smaller than the wall thickness of the hard capsule shell.

[0128] Preferably, the thickness of the first layer is at least 50, 60, 65, 68 or 75 micrometer, with a higher values being preferred over a lower value; and / or the thickness of the first layer is from 50 to 100, from 60 to 100, from 60 to 90, from 65 to 90. from 68 to 85 or from 68 to 80 micrometers, with a more narrow range preferred over a broader range.

[0129] The upper limit of the thickness of the second layer is the difference between the wall thickness of the hard capsule shell and the thickness of the first layer.

[0130] Preferably, the thickness of the second layer is at least 10, 15, 20 or 25 micrometer, with a larger value being more preferred than a smaller value; and / or the thickness of the second layer is from 10 to 40, from 15 to 35 or from 20 to 35 micrometer, with a more narrow range preferred over a broader range.

[0131] The generally targeted standard average thickness of a hard capsule shell wall is 100 micrometer with tolerances + / - 10 micrometer, preferably + / - 5 micrometer.

[0132] The hard capsule shell according to the invention is used to be filled with a filling, the filling comprises a substance which actually is to be administered to the person using the capsule, the substance can be an active pharmaceutical ingredient (API), pharmaceutical dosage form, medicament, live biotherapeutic product, nutritional product or mixtures thereof. The hard capsule shell according to the invention is a capsule of the type used in pharmaceutical or healthcare or nutrition applications. An example for an API are lyophilized nanoparticles of RNA. Live biotherapeutic product may for example be a microbiome.

[0133] Further subject of the invention is the hard capsule shell, wherein the hard capsule shell contains an active ingredient, the active ingredient is selected from the group of active pharmaceutical ingredient, pharmaceutical dosage form, medicament, live biotherapeutic product, nutritional product and mixtures thereof; with the hard capsule shell as defined herein, also with all its embodiments.

[0134] Further subject of the invention is the use of the hard capsule shell for filling with the active ingredient; with the hard capsule shell and with the active ingredient as defined herein, also with all their embodiments.

[0135] Further subject of the invention is the use of the hard capsule shell, filled with the active ingredient, for oral intake; with the hard capsule shell and with the active ingredient as defined herein, also with all their embodiments.

[0136] Preferably, the active ingredient in filled into the cavity of the hard capsule shell.

[0137] Preferably, the hard capsule shell contains the active ingredient in the cavity of the hard capsule shell. Preferably, the first layer of the hard capsule shell does not contain the active ingredient, and / or the second layer of the hard capsule shell does not contain the active ingredient.

[0138] Preferably, the hard capsule shell contains the active ingredient in form of a formulation, wherein the formulation comprises the active ingredient.

[0139] The formulation can be a liquid or a solid formulation, a solid formulation can have for example the form of a powder, a granulate, nanoparticles, a caplet or a tablet.

[0140] The formulation can comprise the active ingredient in an amount from 0.05 to 100 wt%, preferably from 0.5 to 90 wt%, more preferably from 1 to 50 wt%, even more preferably from 5 to 30 wt%, the wt% being based on the dry weight of the formulation.

[0141] A known process for the production of capsules is dip molding, a mold pin is dipped into a so called melt, which can also be called bath, which is a mixture of a film forming polymer with water, usually a solution or dispersion of the film forming polymer in water, and subsequent extraction of the mold pin from the melt, thereby the polymer forms a film on the mold pin after drying.

[0142] The cap is obtained from by a mold pin having the respective geometric shape complementary to the desired shape of the cap. The body is formed and shaped by a mold pin having the respective geometric shape complementary to the desired shape of the body. By using the respective mold pin in the dip molding either the cap or the body is obtained.

[0143] Further subject of the invention is a method for preparation of a hard capsule shell by a dip molding process, the dip molding process comprises a first dip molding step and a second dip molding step, the second dip molding step is done after the first dip molding step; in the first dip molding step a mold pin is dipped a into first aqueous mixture and then withdrawn from the first aqueous mixture, the first aqueous mixture comprises the first polymer, the second polymer and water, after the withdrawal from the first aqueous mixture a first polymer film forms on a mold pin, in the second dip molding step the mold pin, with the first polymer film from the first dip molding step on it, is dipped into a second aqueous mixture and then withdrawn from the second aqueous mixture, the second aqueous mixture comprises the ethyl cellulose, the sodium alginate and water, after the withdrawal from the second aqueous mixture a second polymer film forms on the first polymer film which is on the mold pin, with the hard capsule shell, first polymer, second polymer, ethyl cellulose and sodium alginate as defined herein, also with all their embodiments.

[0144] The first polymer film on the mold pin is the first layer of the hard capsule shell.

[0145] The second polymer film on the first polymer films which is on mold pin is the second layer of the hard capsule shell.

[0146] The dip molding process can also be called a double dipping process.

[0147] The first polymer film forms on a mold pin after the withdrawal of the mold pin from the first aqueous mixture by partial drying of the first aqueous mixture on the mold pin.

[0148] The second polymer film forms on the first polymer film after the withdrawal of the mold pin from the second aqueous mixture by partial drying of the second aqueous mixture on first polymer film which is on the mold pin.

[0149] Any drying of the first aqueous mixture and of the second aqueous mixture while still on the mold pin is preferably done by air drying, preferably at ambient pressure, it can be done at ambient temperature or at elevated temperature.

[0150] The first aqueous mixture and the second aqueous mixture are also called melts by the skilled person, so they can be called the first melt and the second melt.

[0151] Preferably, the first aqueous mixture does not contain any organic solvents, and / or the second aqueous mixture does not contain any organic solvents, and / or the first aqueous mixture does not contain any solvent other than water, and / or the second aqueous mixture does not contain any solvent other than water, and / or the first aqueous mixture is not a solvent based melt, and / or the second aqueous mixture is not a solvent based melt.

[0152] The first aqueous mixture can comprise a plasticizer and / or a gelling system and / or one or more additive; and / or. the second aqueous mixture can comprise a plasticizer and / or a gelling system and / or one or more additives; with the gelling system, plasticizer and additive as defined herein, also with all there embodiments.

[0153] The amounts of any plasticizer, gelling system and additive in any of the two aqueous mixtures are chosen such that the respective targeted amount in the hard capsule shell is provided.

[0154] The first aqueous mixture and the second aqueous mixture are prepared by mixing the respective components; thereby the first aqueous mixture and the second aqueous mixture are provided for the dip molding process.

[0155] The first aqueous mixture is a dispersion or a solution of HPMC in water comprising the first polymer and the second polymer. The first polymer in the first aqueous mixture is a dispersion or a solution of the first polymer in the water. The second polymer in the first aqueous mixture is a dispersion or a solution of the second polymer in the water.

[0156] The second aqueous mixture is a dispersion or a solution of ethyl cellulose in water comprising the sodium alginate. The sodium alginate in the second aqueous mixture is a dispersion or a solution of sodium alginate in the water.

[0157] The first dip molding step comprises the steps of

[0158] (1-1) dipping the mold pin for one of the halves of the hard capsule shell into the first aqueous mixture;

[0159] (1-2) withdrawing the mold pin from the first aqueous mixture;

[0160] (1-3) allowing the first polymer film to form on the mold pin by drying.

[0161] The second dip molding step comprises the steps of

[0162] (2-1) dipping the mold pin, with the first polymer film on the mold pin, from the first dip molding step into the second aqueous mixture;

[0163] (2-2) withdrawing the mold pin from the second aqueous mixture; (2-3) allowing the second polymer film to form on the first polymer film on the mold pin by drying.

[0164] The time between the first dip molding step and the second dip molding step is usually short, such as seconds, minutes or at most few hours. In production the double dipping process is done in an automated and continuous way by a respective machine, the second dip molding step is usually done within a short period of time after the first dip, such as some seconds or some minutes, at most an hour after the first dip molding step, rather seconds or minutes than an hour.

[0165] In one embodiment, the time between the withdrawal of the mold pin from the first aqueous mixture in first dip molding step and the dipping of said mold pin with the first polymer film on it into the second aqueous mixture in the second dip molding step, that is the time between the first and the second dipping, is the time where the first polymer film forms on the mold pin by drying of the first aqueous mixture that was attached to the surface of the mold pin when it was withdrawn from the first aqueous mixture; this time can be called the first drying time.

[0166] Preferably, the first drying time is not longer than 5 h, more preferably not longer than 2 h, even more preferably not longer than 1.5 h, especially not longer than 1 h.

[0167] The first drying time can be from 1 sec to 5 h, preferably from 2 sec to 2 h, more preferably from 5 sec to 1.5 h, even more preferably from 5 sec to 1 h.

[0168] The second dip molding step provides one part of the hard capsule shell in the mold pin, this part is either the body or the cap of the hard capsule shell, depending in the respectively chosen mold pin. After the second dip molding step that is after the withdrawal of the mold pin from the second aqueous mixture, the second aqueous mixture that is attached to the first polymer film which is on the mold pin is allowed to dry at least partially in order that the second polymer film forms. The part of the hard capsule shell on the mold pin is removed from the mold pin once the mechanical stability has increased sufficiently by the at least partial drying for a safe removal without damage of the formed part of the hard capsule shell.

[0169] Also after removal of the half of the hard capsule shell from the mold pin, the hard capsule shell may be further dried.

[0170] The dip molding process is done with a mold pin which is shaped to provide for the cap of the hard capsule shell, and with a mold pin which is shaped to provide the body of the hard capsule shell. After the preparation of both cap and body of the hard capsule shell, cap and body are joined with each other to provide the hard capsule shell.

[0171] The part of the hard capsule shell which is removed from the mold pin can be cut to the desired length either while still being on the mold pin or after removal from the mold pin.

[0172] In order to form a polymer film with uniform thickness on a mold pin by dip molding, the melt needs to have gelling ability and / or a certain minimum viscosity so that material from the melt will stick to the surface of the mold pin when it is withdrawn from the melt. So both the first aqueous mixture and the second aqueous mixture need to have gelling ability and / or viscosity.

[0173] A gelling ability is characterized by a temperature at which gelling sets in.

[0174] The gelling nature of a melt is called conventional gelling if the melt is liquid above its gelling temperature and gels below its gelling temperature. Gelatin for example shows the gelling nature of conventional gelling.

[0175] Whereas the gelling nature, where the melt is liquid below its gelling temperature and gels at temperatures above its gelling temperature, is called thermal gelling. Certain types of HPMC for example shows the gelling nature of thermal gelling.

[0176] Depending on the gelling nature of the melt, the mold pin may have a higher or a lower temperature with respect to the temperature of the melt.

[0177] The gelling temperature of a melt can be determined by a measurement of the viscosity by progressively heating or cooling of the melt, depending on the gelling nature. The temperature at which the viscosity starts to sharply increase is the gelling temperature. As an example, for a concentration of about 20 wt% in water, HPMC type 2906 has a gelling temperature of about between 30 and 50 °C.

[0178] In case of thermal gelling, a temperature of a mold pin can be 5 °C or more, preferably 10 °C or more, more preferably 15 °C or more, above the gelling temperature of the melt.

[0179] In case of conventional gelling, a temperature of a mold pin can be 5 °C or more, preferably 10 °C or more, more preferably 15 °C or more, below the gelling temperature of the melt. If the polymer does not have a specific gelling temperature at which gelation sets in, then the film forming temperature is characterized by a Minimum Film Forming Temperature (MFFT), usually the temperature needs to be above the MFFT in order that a film forms.

[0180] Any drying of a polymer film on the mold pin after the first dip molding step or after the second dip molding step can be done by air drying, preferably at ambient pressure.

[0181] Further subject of the invention is the hard capsule shell obtainable by the dip molding process; with the hard capsule shell and with the dip molding process as defined herein, also with all their embodiments.

[0182] Materials, abbreviations and definitions

[0183] API active pharmaceutical ingredient

[0184] ATEC acetyl triethylcitrate CAS 77-89-4, also called triethyl-2-acetylcitrat

[0185] DBS used in the examples:

[0186] Dibutyl sebacate, Sigma Aldrich, D27802, purity >= 97 %. ethylcellulose (Ashland) used in the examples

[0187] Aquarius Control ECD EAA119026 CLEAR Coating System, Ashland, Material No 909818

[0188] Ingredients according to COA:

[0189] Ethylcellulose (EC) CAS-No. 9004-57-3 26.5 wt%

[0190] Water CAS-No.7732-18-5

[0191] Cetyl Alcohol (CA) CAS-No. 36653-82-4 2.8 wt%

[0192] Sodium Lauryl Sulfate (SLS) CAS-No. 151-21-3 1.1 wt%

[0193] LOD (Loss Of Drying): 69.6 wt%

[0194] The ethyl cellulose used herein was this product of Ashland, which is a dispersion.

[0195] HPMC hydroxypropyl methylcellulose, also called hypromellose or Cellulose, 2- hydroxypropyl methyl ether or cellulose hydroxypropyl methyl ether, CAS 9004-65-3.

[0196] The definitions of Hypromellose which are used in instant invention can be found in:

[0197] US Pharmacopeia

[0198] Official Date: Official as of l-May-2019 Document Type: USP & NF

[0199] Docld: l_GUID-6A0B0F3C-FA70-433C-AD55-2020BBC64718_4_en-US

[0200] Printed from: https: / / online.uspnf.com / uspnf / document / l_GUID-

[0201] 6A0B0F3C-FA70-433C-AD55-2020BBC64718_4_en-US

[0202] © 2020 USPC

[0203] Most Recently Appeared In:

[0204] Pharmacopeial Forum: Volume No. 42(5)

[0205] HPMC used in the examples: powder, Hydroxypropyl methylcellulose, also called Hypromellose, HPMC

[0206] 2906, Tylopur 65SH-5, Shin-Etsu Chemical Co., Tokyo, Japan

[0207] LOD Loss on Drying

[0208] European Pharmacopeia: acidic test media:

[0209] European Pharmacopeia 11.0-4.1.1 Reagents - hydrochloric acid diluted (1043503), page 571 test media pH 6.8:

[0210] European Pharmacopeia 11.0 - 4.1.3 buffer solutions - Phosphate buffer solution pH 6.8 (4003300), page 682 test media pH 7.4:

[0211] European Pharmacopeia 11.0-4.1.3 buffer solutions - Phosphate buffer pH 7.4 (4004600) page 683

[0212] Pectin LA used in the examples is a pectin LM which is amidated: powder, AGLUPECTIN LA-S20HBG from JRS, J. RETTENMAIER & SOHNE GMBH + CO KG, Rosenberg, Germany, is a low methoxyl amidated (LA) pectin extracted from citrus peels. pullulan used in the examples: powder, Pharmaceutical Grade Pullulan, Hayashibara, (NAGASE America LLC, US) relative amounts wt% means weight percent, also called percent by weight

[0213] (w / w) means weight by weight

[0214] (w / v) means weight by volume rpm rotations per minute sodium alginate (SA) used in the examples: powder, PROTANAL CR8133 from International Flavors & Fragrances Inc.

[0215] (IFF), New York, US

[0216] TEC triethyl citrate

[0217] USP US Pharmacopeia dissolution bath USP II dissolution bath: Varian VanKel VK7000 Dissolution System, Varian,

[0218] Inc. North Carolina, USA

[0219] EXAMPLES

[0220] Example 1

[0221] Preparation of a solution of HPMC and pectin LA:

[0222] • Mix HPMC (72 g) and pectin LA (10 g) to provide a powder mix.

[0223] • Add the powder mix within 30 min into 418 g of distilled water at 80 °C contained in a beaker under mixing with a three-blade propeller at 500 rpm in the middle of the beaker.

[0224] • Stir for 1 h at 80 °C, then switch off the heating, exchange the three-blade propeller against a magnetic rod, let it stir overnight at 500 rpm.

[0225] • Table 1 shows the amounts in the formulation, the [% w / w] are based on the dry weight of first layer.

[0226] Example 2

[0227] Preparation of a solution of HPMC

[0228] • Add HPMC (84 g) to distilled water (316 g) at 80 °C contained in a beaker under mixing with a three-blade propeller at 500 rpm in the middle of the beaker and let stir and dissolve for 1 h.

[0229] • Then decrease the stirring to 300 rpm and switch off the heating to reach the room temperature.

[0230] • Exchange the three-blade propeller against a magnetic rod, let it stir overnight at 500 rpm. • Table 2 shows the amounts in the formulation, the [% w / w] are based on dry weight of first layer.

[0231] Example 3

[0232] Preparation of a solutions of Pullulan and HPMC

[0233] STEP 1 : Preparation of pullulan solution 20% (w / w) for 300g

[0234] • Add pullulan (60 g) to water (240 g) of 25 °C contained in a beaker under mixing with a three- blade propeller at 250 rpm in the middle of the beaker

[0235] • Decrease the speed of the propeller to 100 rpm and stir for 1 h.

[0236] • Switch off the stirring and let it stand for 4 h to remove bubbles.

[0237] • The addition and any further stirring is done without heating.

[0238] STEP 2 : Mixing of pullulan and HPMC to provide a solution of pullulan and HPMC

[0239] • Add a pullulan solution 40 g (a) or 80 g (b), prepared according to example 3, STEP 1) into a HPMC solution (360 g, prepared according to example 2) at 28 °C in a beaker while stirring with an anchor at 120 rpm and keep stirring for 1 h.

[0240] • Then switch off the stirring and let it stand overnight at 28 °C.

[0241] Table 3 shows the amounts in the formulation, the [% w / w] are based on the dry weight of first layer.

[0242] Example 10 including Example 10-3 and Example 10-9

[0243] Preparation of a solution of sodium alginate, ethyl cellulose and dibutyl sebacate (DBS)

[0244] STEP 1: Preparation of a solution of sodium alginate 3% (w / w)

[0245] Add sodium alginate to distilled water, the amount according to Example 10-3 and Example 10-9, at 70 °C contained in a beaker under mixing with a three-blade propeller at 550 rpm in the middle of the beaker. • After complete dissolution of the powder (ca. 30 min) switch off the heating

[0246] Amount of sodium alginate Amount of water

[0247] Example 10-3, STEP 1 6 g 194 g

[0248] Example 10-9, STEP 1 18 g 182 g

[0249] STEP 2: Mixture of the solution of sodium alginate with ethylcellulose

[0250] • The ethylcellulose (Ashland) was filtered through a filter with 80 pm pore size.

[0251] • Filtered ethylcellulose (Ashland) (200 g) was mixed with DBS (20 g) in a beaker while stirring with a magnetic rod at 700 rpm to provide a mixture of ethylcellulose (Ashland) with DBS.

[0252] • Solution of sodium alginate (100 g, prepared according to example 10, STEP 1) was added to the mixture of ethylcellulose (Ashland) with DBS in a beaker while stirring with a three-blade propeller at 500 rpm, the resulting mixture was stirred for 30 min.

[0253] • Then the three-blade propeller was removed and the mixture was mixed with an ultra-turrax for 10 sec at 21'500 rpm.

[0254] • Then the mixture was stirred overnight in a beaker with a magnetic rod at 500 rpm.

[0255] • The viscosity (measured with a Brookfield viscometer, spindle 31) was adjusted with water to be within specifications which are from 200 and 500 mPa*s

[0256] Two respective solution of sodium alginate, ethyl cellulose and dibutyl sebacate (DBS) were hereby provided: (1) the [% w / w] are based on the dry weight of wet formulation

[0257] (2) the [% w / w] are based on the dry weight of second layer Table 9 shows the amounts in the formulation.

[0258] Example 20 - Casting of Films

[0259] Double layered films with a total target thickness of 100 micrometers were cast. For this purpose at first a first layer film was cast, then a second layer film was cast onto the first layer film after the first layer film had dried.

[0260] The first layer films were not removed from the plates onto which they had been cast, but the second layer film was cast onto these first layer films on the plates immediately after the drying process with the temperature of the respective final drying step.

[0261] Target thickness of the first film was 70 to 80 micrometers.

[0262] (20-1) Casting of the first layer film

[0263] (20-1 A) First film HPMC and pectin LA

[0264] With a solution of HPMC and pectin LA, prepared according to example 1, a first film was cast at room temperature and dried at 60 °C for 30 min.

[0265] The average thickness of the film (20-1 A) was determined to be 70 microns.

[0266] (20-1 B) First film HPMC

[0267] With a solution of HPMC, prepared according to example 2, a first film was cast at 60 °C and dried at 60 °C for 1 h.

[0268] The average thickness of the film (20-1 B) was determined to be 70 microns.

[0269] (20-1C a) and (20-1C b) First film HPMC and pullulan

[0270] With a solution of pullulan and HPMC, prepared according to example 3 (a) and (b), two first films was cast at 60 °C and dried at 60 °C for 45 min, providing a "first" first film (20-1C a) with 10 wt% pullulan and a "second" first film (20-1C b) with 20 wt% pullulan.

[0271] The average thickness of the film (20-1 C a) was determined to be 70 microns.

[0272] The average thickness of the film (20-1 C b) was determined to be 100 microns.

[0273] (20-2) Casting of second layer film to provide a casted double layered film A second layer film was cast with a solution prepared according to example 10-3 or example 10-9 onto each of the first layer films, prepared according to examples (20-1 A), (20-1 B), (20-1 C a) and (20-1 C b), the casting of the second layer film was done immediately after the casting of the respective first layer film.

[0274] Directly after casting the second layer film, the freshly cast double layered film was exposed to a first drying for 5 min at 60 °C, then a second drying for 1 h at 40 °C and 35% RH, and thereafter a so called curing step, for the curing step the double layered films were removed from the plates, put on a grid and exposed to 40 °C and 35 RH for 18 h; thereby both sides of the double layered film were exposed to curing conditions. The procedure provided cast double layered films:

[0275] Film Amount of sodium alginate in the second layer film

[0276] (20-2 A 3) 3 wt%

[0277] (20-2 B 3) 3 wt%

[0278] (20-2 C 3 a) 3 wt% (10 wt% pullulan)

[0279] (20-2 C 3 b) 3 wt% (20 wt% pullulan)

[0280] (20-2 A 9) 9 wt%

[0281] (20-2 B 9) 9 wt%

[0282] (20-2 C 9) 9 wt% with the wt% being based on the amount of ethyl cellulose.

[0283] The average thickness of the double layered films that was exposed to the test media was determined to be:

[0284] (20-2 A 3) 100 microns

[0285] (20-2 B 3) 100 microns

[0286] (20-2 C 3 a) 100 microns (10 wt% pullulan)

[0287] (20-2 C 3 b) 125 microns (20 wt% pullulan)

[0288] Subtraction of the average film thickness of the first layer from the thickness of the double layered film give an average thickness for the second layer of:

[0289] (20-2 A 3) 30 microns

[0290] (20-2 B 3) 30 microns

[0291] (20-2 C 3 a) 30 microns (10 wt% pullulan)

[0292] (20-2 C 3 b) 25 microns (20 wt% pullulan) Example 30 - Piercing Tests

[0293] The piercing test was done with a dissolution bath.

[0294] 1. A first bowl of the dissolution bath was filled with European Pharmacopeia acidic test media.

[0295] 2. A second bowl of the dissolution bath was filled with European Pharmacopeia test media pH

[0296] 6.8.

[0297] 3. A third bowl of the dissolution bath was filled with European Pharmacopeia test media pH 7.4.

[0298] The round discs with a diameter of 18 mm were cut from a film. A bottle with a closing lid having a circular opening in the center of the lid wherein the lid was constructed such as to accommodate the round disc of the film in the circular opening and thereby closing this opening with the film, thereby the lid itself was closed and can be used to close the bottle with a conventional screw type closing mechanism.

[0299] Once the round disc of a film was accommodated in a I id, the lid was screwed open a bottle, thereby closing the bottle.

[0300] In any of the piercing tests the time from the start of the submersion until the bottle was completely filled when a film had been pierced by this media within the test time was measured.

[0301] Table 4 summarizes the components of the films that were tested.

[0302] (I) Piercing test in acidic media A bottle containing in the lid the respective film to be tested was submerged for 2 h into the acidic media in the first bowl of the dissolution bath.

[0303] Tested were at least 12 bottles for each film.

[0304] The threshold for passing was when a minimum of 80% of the bottles did not open within the 2 h of the test.

[0305] Results are given in Table 5:

[0306] All three mono-layered films 20-1 A, 20-1 B and 20-1 C showed no acid resistance, all bottles were pierced within the 2 h test time.

[0307] (II) Piercing test at pH 6.8

[0308] A bottle containing in the lid the respective film to be tested was submerged for 1 h into the media of pH 6.8 in the second bowl of the dissolution bath. Tested were at least 8 bottles for each film.

[0309] The threshold for passing was when a minimum of 60% of the bottles did not open within the 1 h of the test. Results are given in Table 6, the piercing time is the average piercing time of all bottles:

[0310] All bottles with the three mono-layered films 20-1 A, 20-1 B and 20-1 C were pierced within the 1 h test time.

[0311] All bottles with the film 20-2 B 3 were pierced within the 1 h test time.

[0312] All bottles with the three double-layered films 20-2 A 9, 20-2 B 9 and 20-2 C 9 were pierced within the 1 h test time. (III) Piercing test at pH 7.4

[0313] A bottle containing in the lid the respective film to be tested was submerged for 1 h into the media of pH 7.4 in the third bowl of the dissolution bath.

[0314] Tested were at least 8 bottles for each film.

[0315] The threshold for passing was when all bottles opened within the 1 h of the test. Results are given in Table 7 , the piercing time is the average piercing time of all bottles:

[0316] (IV) Piercing test in the three media acidic, pH 6.8 and pH 7.4 consecutively A bottle containing in the lid the respective film to be tested was submerged

[0317] 1. at first for 2 h into the acid media in the first bowl of the dissolution bath; then

[0318] 2. thereafter for 1 h into the media of pH 6.8 in the second bowl of the dissolution bath; then

[0319] 3. thereafter for 1 h into the media of pH 7.4 in the third bowl of the dissolution bath.

[0320] Tested were at least 8 bottles for each film. All bottles showed no piercing in the first submersion in acidic media.

[0321] Only those bottles which were not pierced in the second submersion underwent the third submersion. Results are given in Table 8.

[0322] The threshold for passing the second submersion was when a minimum of 80% of the bottles did not open within the 1 h of the test. The piercing time is the average piercing time of the bottles in the third submersion.

[0323]

[0324] All the bottles with the films 20-2 B 3 were pierced in the second submersion within the test time, so no bottle with a film 20-2 B 3 was left to undergo the third submersion at pH 7.4.

[0325] Film 20-2 A 3 and film 20-2 C 3 a passed.

[0326] Discussion of the results:

[0327] • Film 20-2 B 3 (HPMC): all discs opened already in 2. submersion within the 1 h test time at pH

[0328] 6.8

[0329] • Film 20-2 A 3 (HPMC - pectin LA): The second submersion gives a pass. The third submersion gives a pass. It was unexpected that the opening time in the third submersion (32.5 min) was comparable to the opening time in the isolated test (III) at pH 7.4 (29 min)

[0330] • Film 20-2 C 3 a (HPMC - pullulan): The second submersion gives a pass. The third submersion gives a pass. It was unexpected that the opening time in the third submersion was shorter than the opening time of the films 20-2 A (HPMC - pectin LA). It was unexpected that the opening time in the third submersion (25.5 min) was shorter than the opening time in the isolated test (III) at pH 7.4 (40.5 min).

[0331] • All three polymers HPMC, pectin LA and pullulan individually are deemed to readily dissolve at pH 6.8 if exposed directly, i.e., in a single layer film, which is exposed to a medium with pH 6.8. The isolated test (II) at pH 6.8 shows that the addition of pectin LA or pullulan to HPMC actually reduces the piercing time of the respective monolayered films (20-1 A, 20-1 B and 20-1 C a and the isolated test (II)).

[0332] It was unexpected that the addition of pectin LA or pullulan to HPMC in the first layer would have an influence on the piercing time at pH 6.8 in a double layered film, where only the second layer is exposed to medium with pH 6.8 (isolated test (II)).

[0333] Also unexpected, that is contrary to the decrease of piercing time observed for the monolayered film in the isolated test (II), was that this influence results in an increase of the resistance against medium with pH 6.8, i.e., does not decrease the resistance, in the double layered films. The increase of piercing time is so effective, that HPMC alone in the first layer does not survive at all in the medium with pH 6.8 (both isolated test (II) and second submersion in test (IV)), whereas the addition of pectin LA or pullulan to the HPMC results in a pass in the medium with pH 6.8 (both isolated test (II) and second submersion in test (IV)).

Claims

CLAIMS1. A hard capsule shell, the wall of the hard capsule shell comprises two layers, a first layer and a second layer, the first layer comprises a first polymer and a second polymer; the first polymer is hydroxypropylmethylcellulose (HPMC) and the second polymer is pullulan, low methoxyl pectin (pectin LM) or a mixture thereof; the second layer comprises ethyl cellulose (EC) and sodium alginate (SA), the two layers are prepared consecutively in a double dipping process, the double dipping process prepares at first the first layer on a mold pin by dip molding in a first dip molding step and thereafter the second layer onto the first layer by a dip molding said mold pin in a second dip molding step without removal of the the first layer from the mold pin before the application of the second layer onto the first layer in the second dip molding step.

2. The hard capsule shell according to claim 1, wherein the HPMC is selected from the group ofHPMC 2910 containing about 7.0 to 12.0% hydroxypropoxy group and about 28.0 to 30.0% methoxy group,HPMC 2906 containing about 4.0 to 7.5% hydroxypropoxy group and about 27.0 to 30.0% methoxy group,HPMC 2208 containing about 4.0 to 12.0% of hydroxypropoxy group and about 19.0 to 24.0% of methoxy group,HPMC 1828 containing about 23.0 to 32.0% hydroxypropy group and about 16.5 to 20.0% methoxy group, and mixtures thereof.

3. The hard capsule shell according to claim 1 or 2, wherein the HPMC is HPMC 2906.

4. The hard capsule shell according to one or more of claims 1 to 3, wherein the amount of HPMC in the first layer is at least 50 wt%, at least 55 wt%, at least 60 wt%, at least 65 wt% or at least 70 wt%, with a higher amount being more preferable over a lower amount; the wt% are base on the dry weight of the first layer.

5. The hard capsule shell according to one or more of claims 1 to 4, wherein the amount of pectin LM in the first layer is at least 5 wt%, at least 7 wt%, at least 8 wt% or at least 9 wt%, with a higher amount being more preferable over a lower amount; and / or the amount of pectin LM in the first layer is not more than 19 wt%, than 18 wt%, than 17 wt%, than 16 wt%, than 15 wt%, than 14 wt% or than 13 wt%, with a lower limit being more preferable over a higher limit; and / or the amount of pectin LM in the first layer is from 5 to 19 wt%, from 6 to 18 wt%, from 7 to 17 wt%, from 8 to 16 wt%, from 8 to 15 wt% or from 9 to 14 wt%, with a narrower range being more preferable over a broader range; the wt% are base on the dry weight of the first layer.

6. The hard capsule shell according to one or more of claims 1 to 5, wherein the amount of pullulan in the first layer is at least 5 wt%, at least 7 wt%, at least 8 wt% or at least 9 wt%, with a higher amount being more preferable over a lower amount; and / or the amount of pullulan in the first layer is not more than 30 wt%, than 28 wt%, than 26 wt%, than 24 wt%, than 23 wt%, than 22 wt% or than 21 wt%, with a lower limit being more preferable over a higher limit; and / or the amount of pullulan in the first layer is from 5 to 30 wt%, from 7 to 28 wt%, from 7 to 26 wt%, from 7 to 24 wt% or from 8 to 23 wt%, with a narrower range being more preferable over a broader range; the wt% are base on the dry weight of the first layer.

7. The hard capsule shell according to one or more of claims 1 to 6, wherein the amount of ethyl cellulose in the second layer is at least 50 wt%, at least 52.5 wt%, at least 55 wt%, at least 57.5 wt% or at least 60 wt%, with a higher amount being more preferable over a lower amount; the wt% are base on the dry weight of the second layer.

8. The hard capsule shell according to one or more of claims 1 to 7 , wherein the amount of sodium alginate in the second layer is at least 2 wt%, at least 2.5 wt% or at least 3 wt%, with a higher amount being more preferable over a lower amount; and / or the amount of sodium alginate in the second layer is not more than 9.5 wt%, than 9 wt%, than 8.5 wt%, than 8 wt%, than 7.5 wt%, than 7 wt%, than 6.5 wt%, than 6 wt%, than 5.5 wt%, than 5wt%, than 4.5 wt%, than 4 wt% or than 3.5 wt%, with a lower limit being more preferable over a higher limit; and / or the amount of sodium alginate in the second layer is from 2 to 9.5 wt%, 2 to 9 wt%, 2 to 8.5 wt%, from 2 to 8 wt%, from 2 to 7.5 wt%, from 2 to 7.5 wt%, 2 to 7 wt%, 2 to 6.5 wt%, 2 to 6 wt%, 2 to 5.5 wt%, 2 to 5 wt%, 2 to 4.5 wt%, 2 to 4 wt%, 2 to 3.5 wt% or 2.5 to 3.5 wt%, with a narrower range being more preferable over a broader range; the wt% are base on the dry weight of the second layer.

9. The hard capsule shell according to one or more of claims 1 to 8, wherein the second layer comprises one or more plasticizer; preferably, a plasticizer is selected from the group dibutyl sebacate (DBS), triethyl citrate (TEC), Acetyl triethylcitrate (ATEC), glycerin, sorbitol, mannitol, trehalose, vegetable oil, a medium chain triglyceride, a triacetin, a phthalate, a phytosterol, a propylene glycol, a polysorbate and a polyethylene glycol; more preferably, a plasticizer is selected from the group of dibutyl sebacate (DBS), triethyl citrate (TEC) and Acetyl triethylcitrate (ATEC); even more preferably, the plasticizer is dibutyl sebacate (DBS).

10. The hard capsule shell according to one or more of claims 1 to 9, wherein the thickness of the second layer is at least 10, 15, 20 or 25 micrometer, with a larger value being more preferred than a smaller value; and / or the thickness of the second layer is from 10 to 40, from 15 to 35, from 20 to 35 micrometer, with a more narrow range preferred over a broader range.

11. The hard capsule shell according to one or more of claims 1 to 10, wherein the hard capsule shell contains an active ingredient, the active ingredient is selected from the group of active pharmaceutical ingredient, pharmaceutical dosage form, medicament, live biotherapeutic product, nutritional product and mixtures thereof; preferably, the hard capsule shell contains the active ingredient in form of a formulation, wherein the formulation comprises the active ingredient; the formulation can be a liquid or a solid formulation, a solid formulation can have the form of a powder, a granulate, nanoparticles, a caplet or a tablet.

12. The use of a hard capsule shell for filling with the active ingredient; with the hard capsule shell as defined in claims 1 to 10, and with the active ingredient as defined in claim 11; preferably the use of a hard capsule shell for oral intake.

13. A method for preparation of a hard capsule shell by a dip molding process, the dip molding process comprises a first dip molding step and a second dip molding step, the second dip molding step is done after the first dip molding step; in the first dip molding step a mold pin is dipped a into first aqueous mixture and then withdrawn from the first aqueous mixture, the first aqueous mixture comprises the first polymer, the second polymer and water, after the withdrawal from the first aqueous mixture a first polymer film forms on a mold pin, in the second dip molding step the mold pin, with the first polymer film from the first dip molding step on it, is dipped into a second aqueous mixture and then withdrawn from the second aqueous mixture, the second aqueous mixture comprises the ethyl cellulose, the sodium alginate and water, after the withdrawal from the second aqueous mixture a second polymer film forms on the first polymer film which is on the mold pin, with the hard capsule shell as defined in claims 1 to 10.

14. A hard capsule shell obtainable by a dip molding process with the hard capsule shell as defined in claims 1 to 10; with the dip molding process as defined in claim 13.

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