JP2016128419A - Multi-layered capsule, and manufacturing method of the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a manufacturing method of a multi-layered capsule which contains two types of active pharmaceutical ingredient, and is isolated by having a multilayer structure in the capsule, and a multi-layered capsule.SOLUTION: In a multi-layered capsule, a first compartment 61 and a second compartment 62 respectively contain a first homogeneous material 51 and a second homogeneous material 52, and a barrier layer 50 isolates the first homogeneous material 51 from the second homogeneous material 52. A manufacturing method of a multi-layered capsule includes: a process of adding the first homogeneous material, the second homogeneous material, and the barrier layer 50 to an internal space of a capsule body; a process of adding the barrier layer 50 to the front or rear of the first homogeneous material; a process of attaching at least one cover body on at least one opening of a body; and the like. The multi-layered capsule includes the barrier layer arranged in the internal space of the capsule body in order to separate the first compartment 61 containing the first homogeneous material and the second compartment 62 containing the second homogeneous material 52, and the barrier layer is mineral oil and paraffin wax.SELECTED DRAWING: Figure 1C

Description

  In the manufacture of drugs, encapsulation refers to various techniques used to encapsulate drugs in a relatively stable shell known as capsules. The two main types of capsules are hard shell capsules and soft shell capsules. For example, FIG. 1A shows a typical hard shell capsule formed by a tubular body and a tubular cover body (cap) for holding the components. The tubular body is smaller than the tubular cover body, as shown, but may be larger. The capsule is in a pre-tightened state, i.e. the capsule cover body is attached to the capsule body but is easily removed therefrom, e.g. at any desired or required time for adding a filler thereto. In general, it is supplied as it is. In the process of adding the ingredients, the pre-tightened capsules are loaded into the hopper; then a predefined number of capsules are released and then the cover body is separated from the capsule body to fill the ingredients. The After filling, the cover body is returned onto the capsule body. Depending on the desired purpose under different circumstances, such as deodorization, leak prevention, and oxidation prevention, the capsules can be subjected to various drying process processes.

  There are a few capsule-adding devices on the market that can handle the addition of granule or powder, which is less problematic. However, these devices have the problem of maintaining the desired drug efficacy when processed into semi-solid or liquid components. For example, it is important to maintain a stable level of the separation surface of the initial filler in the semi-solid or liquid form so that the initial filler does not mix with the next semi-solid or liquid component. Once mixed, drug efficacy is weakened due to diffusion of drugs or interactions between drugs.

  Furthermore, if the semi-solid or liquid separation surface is foaming or not fixed, the drug on or near the separation surface dissolves separately from the rest; it is not flat, tilted Or due to the larger contact surface between layers from the foaming surface. The dissolution time of the drug is unpredictable and the expected efficacy cannot be achieved.

The present invention provides a multilayer capsule and a method for producing the multilayer capsule. The multilayer capsule of the present invention comprises at least two layers of homogeneous material and at least one barrier layer, wherein each layer of homogeneous material comprises the same or different biopharmaceutical components and is the same or different from the other layers. Has different elution forms. Multilayer capsules are in some embodiments:
A body including at least one opening and an interior space;
At least one cover body for mounting on or removing from at least one opening of the body;
A barrier layer disposed in the interior space of the body to separate the first and second compartments, the barrier layer being solid at room temperature and semi-solid or liquid at temperatures above 35 ° C.

In some embodiments, provided herein is a method of making a multi-layer capsule, the method comprising:
Providing a capsule including a body and at least one cover body, the body having an interior space and at least one opening;
An additional step of adding a first homogeneous material, a second homogeneous material, and a barrier layer to the interior space of the body, wherein the barrier layer is added before or after the first homogeneous material; and at least one opening in the body Attaching at least one cover body on the part, wherein the first and second homogeneous materials are separated by a barrier layer.

  The method of manufacturing a multilayer capsule of the present invention, in some embodiments, includes the step of adding a semi-solid or liquid form barrier layer to the body of the capsule to separate the first and second compartments. Here, the barrier layer is solid at temperatures below 35 ° C. The barrier layer comprises, in some embodiments, mineral oil and paraffin wax in a weight ratio between 0 and 4.

<Incorporation by quotation>
All publications, patents, and patent applications mentioned in this specification are to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated so that each was incorporated by reference. , Incorporated herein by reference.

  The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and by the accompanying drawings of which:

FIG. 1A shows an exemplary schematic of a prior art capsule and a capsule of the present invention. FIG. 1B shows an exemplary schematic of a prior art capsule and a capsule of the present invention. FIG. 1C shows an exemplary schematic of a prior art capsule and a capsule of the present invention. FIG. 2 shows an exemplary flow chart for the preparation of the capsule of the present invention. FIG. 3 shows an exemplary diagram for producing the multilayer capsule of the present invention. FIG. 4 shows a simplified exemplary diagram for the preparation of a single inventive multilayer capsule. FIG. 5A shows an exemplary nozzle of the present invention having a specific spread angle. FIG. 5B shows an exemplary nozzle of the present invention having a specific spread angle. FIG. 6A shows an exemplary diagram from another embodiment for producing a multilayer capsule of the present invention. FIG. 6B shows an exemplary diagram from another embodiment for producing a multilayer capsule of the present invention. FIG. 7A is an exemplary flowchart based on FIG. 6A for manufacturing a diagram. FIG. 7B is an exemplary flow chart based on FIG. 6B for producing a diagram.

  In some embodiments, the present invention provides a multilayer capsule comprising at least two layers of homogeneous material and at least one barrier layer, wherein each layer of homogeneous material is a component of the same or different biopharmaceutical ( Active ingredient (API) nutritional supplement, etc.) and has the same or different elution form as the other layers. In order to achieve the stability of the drug in the capsule and the desired drug efficacy and to ensure that the drug does not interact during the preparation of the multilayer capsule, the capsules of the present invention are further stable. In addition, it includes a barrier component composed of components that are friendly to living bodies.

  The active pharmaceutical ingredient may be a hypnotic or other non-limiting pharmaceutical ingredient such as antibiotics, zaleplon, zolpidem, such as vancomycin, teicoplanin, ramoplanin, difimicin, kanamycin, neomycin, colistin. The dietary supplement may be vitamins, amino acids, plant extracts, non-botanicals, or other non-limiting dietary supplements.

  Referring to FIGS. 1A-1C, the capsule (1) of the present invention includes at least one cover body (3) and a body (2), where the body (2) has at least one opening (4). And an internal space (5). In some embodiments, the cover body (3) has a slightly larger diameter than the body (2), whereby the cover body (3) is mounted over the opening of the body (2); The opening (4) can be closed. In some embodiments, the body (2) has an inner wall of the body (2) that separates the interior space (5) to provide a first compartment (61) and a second compartment (62) (FIG. 1C). A barrier layer (50) in contact with the substrate. In certain embodiments, the barrier layer thickness accounts for about 5% to 25% of the length of the body. The barrier layer is made from a bio-friendly material that can be dissolved, digested and / or released in the gastrointestinal tract under the gastrointestinal environment. In some embodiments, the barrier layer (50) comprises mineral oil, paraffin (paraffin wax), combinations thereof, and the like. In some embodiments, the weight ratio of mineral oil to paraffin wax is between 0 and 4, which is that the barrier layer is paraffin wax or the barrier layer is solid at room temperature or normal storage temperature. It may contain 0-80% mineral oil mixed with at least 20% wax as such. The melting point of the barrier layer is determined by the ratio of mineral oil and paraffin wax.

  Referring to FIG. 1C, the first compartment (61) and the second compartment (62) include a first homogeneous material (51) and a second homogeneous material (52), respectively, where the barrier layer (50) is Separating the first homogeneous material (51) and the second homogeneous material (52). In other words, the internal space (5) of the main body includes three additional components. In some embodiments, the first homogeneous material (51) and the second homogeneous material (52) comprise active pharmaceutical ingredients. The first or second homogeneous material can be a liquid, solid, or semi-solid at room temperature or normal storage conditions. In some embodiments, the liquid comprises a homogeneous liquid or suspension. In some embodiments, the solid comprises a solid block, microcapsule, granule, or powdered solid (eg, a powder). A semi-solid is a viscous fluid that flows relatively slowly compared to a liquid. A solid block refers to a solid that can be in semi-solid or liquid form at elevated temperatures (eg, greater than 35 ° C.). In some embodiments, the first or second homogeneous material comprises at least one heat in the form of a solid block at room temperature or normal storage temperature, and a semi-solid or liquid at a high temperature (eg, greater than 35 ° C.). Contains soluble excipients. In some embodiments, the first homogeneous material (51) has a melting point that is higher than the melting point of the barrier layer (50), and the barrier layer (50) has a melting point that is higher than the melting point of the second homogeneous material (52). Have

  Typical hot-melt excipients include, but are not limited to, polyethylene glycol (PEG), lipophilic compounds, propylene glycol fatty acid esters, optional pH sensitive polymers (such as sodium alginate or sodium carboxymethyl cellulose), polyethylene glycol esters, etc. including.

In some embodiments described herein, a method is provided for producing a multilayer capsule of the present invention, wherein the addition process is completed by a capsule filling device. The capsule filling device can be an intermittent and / or continuous drive to complete the capsule filling, to the capsule holder by a disk link, chain link, or other suitable link known in the art. Can be applied. Referring to the schematic diagrams of FIGS. 2 and 3-4, step (810) includes loading a capsule that has been pre-tightened into the hopper. Step (820) includes loading the capsule into a holder or holder block and adjusting the orientation of the capsule. A first homogeneous material under a fixed form (or shape) based on minimal contact (separation) surfaces between adjacent fillers to ensure the desired efficacy or bioavailability properties of the drug ( 51) In order to add the barrier layer (50) and the second homogeneous material (52), the capsule orientation for the filling process is preferably the same as the capsule 1 orientation as shown in FIG. The axes of the body (2) and cover body (3) are perpendicular to the horizontal plane, while the body opening (4) is in a horizontal and up position; The interface or surface of each filler will be parallel to the opening (4) under operating conditions and the adjacent filler will have a minimal contact surface (or separation surface). In some embodiments, the proper orientation of the capsule can be monitored by a sensor (eg, a laser or a visible light sensor) and can be adjusted according to the situation. For example, a laser sensor can be used to detect the forward or backward orientation of the capsule. When the capsule is inverted (ie the body (3) is at the top), the capsule is rotated to advance the orientation after passing through a means that adjusts the orientation, such as a disk that prepares the orientation. The Once the capsule is in the proper orientation position, it will remain intact after passing through the orientation adjusting disk. Step (830): Separate the cover body (3) from the body (2) to expose the opening (4). Thereafter, step (840) eliminates poor detached capsules and defective bodies. Under normal operation, the body (2) and the cover body (3) in the capsule are separated according to the situation. However, if the capsules do not separate properly, the unseparated capsules are removed by a thimble device or a thimble-like device and sent to a collection box in step (840). Further, in some embodiments, when a defective capsule (e.g., a capsule without a cover body or having a broken cover body, or a capsule without a body or having a broken body) is detected, the machine The operation is stopped until a certain capsule is removed by removal means (such as manual removal of the defective capsule). A defective capsule can be detected, for example, by two laser sensors, one for detecting the body and the other for detecting the cover body.
Only when both bodies are detected, the device moves on to the next step (ie step (850)).

  Step (850): Add the first homogeneous material (51) to the body (2) of the capsule. The addition of capsules may be continuous or parallel. The first homogeneous material (51) comprises, in some embodiments, a solid block that is semi-solid or liquid at elevated temperatures. In certain embodiments, the solid block is semi-solid or liquid at a temperature above 35 ° C. The solid block is solid when the temperature is below 35 ° C. or at room temperature and so does not mix with the next added substance (eg, barrier layer). The first homogeneous material (51) is heated to be homogeneously semi-solid or liquid with elution properties that allow it to be added to the capsule body (2) by additional means. In some embodiments, the additional means is via a nozzle. For example, if the melting point of the first homogeneous material (51) is A ° C. and the substance becomes a solid block, then step (850) is further in semi-solid or liquid form for easy addition via additional means. To raise the temperature above A ° C. to produce a first homogeneous material (51). When the first homogeneous material (51) is heated, step (855) includes cooling the first homogeneous material, for example, to a temperature below A ° C by cooling means. The cooling means is not limited to air (room temperature) in the capsule body (2), in the capsule holder or holder block, or in the liquid or semi-solid form of the first homogeneous material (51) in order to increase the curing rate of cooling. Or cold air). In certain embodiments, the cooling means comprises applying an external cooling device; for example, using cooling to cool the capsule holder such that the capsule body (2) and the first homogeneous material (51) cool. Including. On the other hand, the first homogeneous material (51) is not heated so as to have the same form during the addition and storage steps or at room temperature (eg, powder form during the addition step and at storage conditions). If it can be added directly at step 855, it is not necessary to proceed with step (855). The addition of the first homogeneous material (51) is completed after steps (850) and (855).

  Step (860) involves the barrier layer (50) to the capsule body (2) to form a first compartment (61) to which the first homogeneous material (51) is added and a second compartment (62) that has not yet been added. The process of adding is included. In certain embodiments, the amount of bio-friendly material used to prepare the barrier layer (51) comprises about 5% to about 25% of the length of the body, but is not limited to this range It is determined by the thickness. In some embodiments, the thickness of the barrier layer comprises about 5% to about 20%, about 5% to about 15%, or about 5% to about 10% of the length of the body. Further, in some embodiments, the barrier layer used herein is in a semi-solid or liquid form for easy filling. As described above, the barrier layer includes, in some embodiments, mineral oil, paraffin (or paraffin wax), combinations thereof, and the like. In certain embodiments, the weight ratio of mineral oil to paraffin wax is between 0 and 4. When the barrier layer comprises 100% paraffin wax, the barrier layer has a melting point of about 60-65 ° C. The form of such a barrier layer (100% paraffin wax) changes to a semi-solid or liquid form when heated to 60-65 ° C. The melting point of the barrier layer decreases when mineral oil is added, so the temperature required to produce a semi-solid or liquid barrier layer (51) can be below 60-65 ° C. Therefore, the temperature used in step (860) is further determined by the melting point of the barrier layer associated with the composition (eg, mineral oil and paraffin wax quantification).

  Furthermore, as previously stated, the purpose of the barrier layer (50) is to separate the first homogeneous material (51) and the second homogeneous material (52); Added after adding 51). Because the barrier layer is in semi-solid or liquid form (after being heated) so that it is added on top of the first homogeneous material (51) in solid block form, the melting point B ° C. of the barrier layer is In order to avoid remelting of the material (51), it needs to be below A ° C. (melting point of the first homogeneous material). In short, the melting point of the barrier layer (50) needs to be less than the first homogeneous material (51). The composition of the barrier layer is therefore adjusted to have a melting point less than the first homogeneous material. However, the melting point B ° C is higher than room temperature or normal storage temperature to avoid melting the barrier layer at room temperature or normal storage conditions, which loses its ability to act as a barrier and therefore mixes with other layers. Need to be expensive.

  In some embodiments, the first homogeneous material (from the additional process of the barrier layer (by direct ejection, spraying, or release from the nozzle during the addition step) resulting in a rough surface of the first homogeneous material (51). In order not to apply pressure to the surface of 51), the method or device of the present invention comprises a nozzle of the present invention, which ejects an element (eg a barrier layer) over the interior space (7) of the capsule. Spray, or release, thus reducing the pressure on the surface of the first homogeneous material (51). Referring to FIGS. 5A and 5B, the barrier layer (50) is sprayed onto the release point R of the wall (7) having a distance d from the surface of the homogeneous material. In certain embodiments, R is from about 2 mm to about 3 mm. In some embodiments, the spray angle theta is about 0 to 60 degrees. In certain embodiments, the spray angle theta is about 10 to 45 degrees. In certain embodiments, the spray angle theta is about 10-40 degrees (FIG. 5B). The spray angle theta is defined as the degree between the line L (from the nozzle spray point S to the internal space release point R) and the horizontal line from the nozzle spray point S to the internal space (7). One skilled in the art will readily recognize that the length and / or size of the nozzle of the present invention and the design of the tip or release point of the nozzle of the present invention can vary according to the specifications of the targeted capsule of the present invention. I will. The design shown in FIG. 5 is a non-limiting example.

  In some embodiments, if the step of applying pressure to the surface of the first homogeneous material (51) from the additional process of the barrier layer by direct ejection, spraying, or release from the nozzle of the present invention is not a problem, the homogeneous Conventional nozzles are used that spray directly onto the surface of the material.

  Step (865): Cooling of the barrier layer (50) to a temperature below B ° C. via a cooling means. The purpose of this step is to ensure a solid form of the barrier layer (50) to avoid mixing with the next added substance (ie, the second homogeneous material (52)). If the temperature is below B ° C, the barrier layer (50) becomes solid and has little opportunity to mix with what is next added. The cooling means is the same as in step (855). The addition of the second element (ie, barrier layer (50)) is completed after steps (860) and (865).

  Step 850: Addition of the second homogeneous material (52) to the capsule body (2). In certain embodiments, the second homogeneous material (52) is added to a solid form, such as a solid block, microcapsule, granule, or a powdered solid such as a powder (Condition 1). In certain embodiments, the second homogeneous material (52) is added in liquid or semi-solid form (condition 2). In certain embodiments, during the additional process, the homogeneous material (52) in liquid or semi-solid form remains in liquid or semi-solid form at room temperature or normal storage temperature (condition 2a). In certain embodiments, during the additional process, the homogeneous material (52) in liquid or semi-solid form becomes a solid block at room temperature or normal storage temperature (condition 2b); in short, the second homogeneous material (52) Is in the form of a semi-solid or liquid at high temperatures (eg, higher than 35 ° C.).

  For example, when adding the second homogeneous material (52) under condition 2b, if the melting point of the second homogeneous material (52) is C ° C, the step (870) further raises the temperature above C ° C. For the process. Furthermore, since the second homogeneous material (52) is added to the surface of the cured (solidified) barrier layer (50), the melting point C ° C. of the second homogeneous material (52) is that of the barrier layer (50). In order to avoid remelting, it is necessary to be lower than B ° C. (melting point of the barrier layer (50)). In short, the melting point of the second homogeneous material (52) needs to be less than the barrier layer (50). As a result, based on steps (850), (860) and (870), A ° C> B ° C> C ° C; in short, the material with the higher melting point needs to be added first. For example, a three-layer capsule containing zaleplon was prepared according to the method of the present invention. A three-layer capsule consists of two layers of homogeneous material containing zaleplon (ie, a first homogeneous material and a second homogeneous material) and one layer of the barrier that does not contain zaleplon. The barrier layer was made from paraffin wax. Both the first and second homogeneous materials are solid blocks at room temperature. The temperature for adding the first homogeneous material was 75-80 ° C., where the substance was a fluid and was easily added to the capsule. The barrier layer consisted of 100% paraffin wax requiring an additional temperature of about 60-65 ° C. The additional temperature of the second homogeneous material was 55-60 ° C. In summary, in order to reach the melting points of the first homogeneous material (51), the barrier layer (50) and the second homogeneous layer (52), steps (850), (860) and (870) are: In order to heat the barrier layer and the second homogeneous layer, a heating step is further included, the temperature range being between room temperature (eg 25 ° C.) and 80 ° C.

  Another example of producing a three-layer capsule is as follows. Vancomycin containing the first homogeneous layer (containing sodium alginate and polyethylene glycol glycerides) was first added to the body of the capsule in liquid form at high temperature. The barrier layer (including paraffin wax) was then cooled (from 70 ° C. to room temperature) and then applied over the first homogeneous material. A second homogeneous material comprising vancomycin, PEG 1500, and polyethylene glycol glycerides was then added over the barrier layer after cooling to room temperature.

  After step (870), step (875) may be selected to cool the second homogeneous material (52). In some embodiments, the second homogeneous material is cooled to room temperature or a temperature suitable for storage. The addition of the second homogeneous material (52) (ie, the third element) is completed after steps (870) and (875). Step (880) includes attaching a cover body (3) over the opening (4) of the body (2) to complete a typical inventive process for producing a multilayer capsule. Step (890) includes releasing the multilayer capsule and the capsule with incomplete filler. For example, a capsule having an incomplete filler is measured by a weight measuring device. If the weight of the capsule is not within specifications, the capsule is automatically excluded; this process is a fully filled capsule, incompletely filled, when the latter two types of capsules are excluded Identify capsules and empty capsules.

  In some embodiments, the present invention provides a bio-friendly and safe barrier layer (50) for separating the first homogeneous material (51) and the second homogeneous material (52). In certain embodiments, the first homogeneous material (51) includes one or more active pharmaceutical ingredients (API). In certain embodiments, the second homogeneous material (52) includes one or more pharmaceutically active ingredients. In certain embodiments, the first and second homogeneous materials include one or more pharmaceutically active ingredients. The barrier layer (50) may change the property of elution (melting) between layers (ie, homogeneous materials) and / or if both the first and second homogeneous materials contain APIs (same or different APIs). Preventing the API interaction between the first and second homogeneous materials. For example, without a barrier layer, the API may penetrate between layers due to concentration differences, thereby altering the desired drug effect. In addition, any other effects caused by each other of the first homogeneous material (51) and the second homogeneous material (52) can be avoided by the barrier layer (50).

  Another exemplary multi-layer capsule, and its method of preparation, is shown in FIGS. 6A and 6B, where a barrier layer (50) is first added, separating the interior space into two. Unlike the typical capsule and its method of preparation shown in FIG. 4, when the first and second homogeneous materials are introduced through the same opening (4), the body (2 ) Has openings (4) and (4 ′). Therefore, a cover body (3) mounted on the opening (4) and a cover body (3 ') mounted on the opening (4') are used. Thus, the first homogeneous material (51) is introduced through the opening (4) and the second homogeneous material (52) is introduced through the opening (4 '). Therefore, a step of adjusting the two orientations is required.

  For example, referring to the working drawings of FIGS. 7A-7B, step (910) includes placing a pre-closed capsule into a hopper. Step (920) includes separating the at least one cover body from the body (2) and removing the capsule by insufficient separation. Step (930) includes the addition of a barrier layer (50). The barrier layer may be formed directly in the internal space that connects to the internal space, or may be formed by adding to the internal space temporarily on top of a pre-placed stent (not shown in Work Drawing 6A). The main additional order is the same as previously described, where the material with the higher melting point is added first. In this example, since the barrier layer (50) is added first, the first and second homogeneous materials need to have a lower melting point than the barrier layer if they are added in a semi-solid or liquid form. Therefore, the composition (and hence the melting point) of the barrier layer (50) is predetermined in step (930) based on the melting points of the first and second homogeneous materials. The barrier layer must have a melting point that is higher than room temperature or normal storage temperature, so that the barrier layer loses its function due to separation of the layers and mixes with other layers at room temperature or storage temperature. Does not dissolve.

  Step 935: Cooling of the barrier layer (50). If a temporarily pre-installed stent is used in step (930), the stent is removed in step (935) before starting the next step. Step 940: Control of capsule orientation. This is a first orientation adjustment to make the axis of the body (2) perpendicular to the horizontal plane so as to allow the opening (4) of the body to be in a horizontal position and an upper position. (See also FIG. 6A). Step (950) includes the addition of the first homogeneous material (51); step (955) includes the cooling of the first homogeneous material (51). Step (960) includes attaching the first cover body (3) over the opening (4) of the body (2) and rotating the capsule orientation by 180 degrees (continuing FIGS. 7A-7B). . Step (965) includes the step of removing the second cover body (3 '). Regarding the step (960), the orientation adjustment is performed after the cover body (3 ′) is removed in the step (965), and then the opening (4 ′) (the opening facing the opening (4)) is moved to the horizontal position. Need to be in position. Step (970) includes the addition of a second homogeneous material (52); step (975) includes the cooling of the second homogeneous material (52). Step (980) includes attaching a second cap (3 ′) over the opening (4 ′) of the body (2); step (990) releasing the fully filled capsule. And eliminating empty or incompletely filled capsules.

  Thus, this embodiment also provides an alternative additional order of the first and second homogeneous materials. For example, if the first or second homogeneous material is a microcapsule, granule, powdered solid, semi-solid, or liquid during the addition process and at room temperature or normal storage conditions, the procedure Can be applied to the preparation of multi-layer capsules of the present invention, where, for example, the first homogeneous material (51) is added in semi-solid or liquid form and the second homogeneous material (52) is a microcapsule. Or both of the first and second homogeneous materials are added in liquid form; alternatively, both substances are added in semi-solid form. That is because the procedure does not require adding a barrier layer in the form of a semi-solid or liquid on the surface of the microcapsule, granule, powdered solid, semi-solid, or liquid layer. (Implementation is not easy).

  While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. It will now be appreciated by those skilled in the art that numerous changes, changes and substitutions can be made without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be utilized in practicing the invention. The following claims are intended to define the scope of the invention, and methods and structures within the scope of these claims and their equivalents are intended to be embraced thereby.

Claims (26)

  A multilayer capsule, wherein the multilayer capsule comprises at least two layers of homogeneous material and at least one barrier layer, wherein each layer of homogeneous material comprises components of the same or different biopharmaceuticals and other layers A multilayer capsule, characterized in that it has the same or different elution form.   The multilayer capsule according to claim 1, wherein the component of the biopharmaceutical is an active pharmaceutical ingredient or a nutritional supplement. A multilayer capsule, wherein the multilayer capsule is
A body including at least one opening and an interior space;
At least one cover body for mounting on or removing from at least one opening of the body;
A barrier layer disposed in the interior space of the body for separating the first and second compartments, the barrier layer being solid at room temperature and semi-solid or liquid at temperatures above 35 ° C. Multi-layer capsule characterized by   4. Multilayer capsule according to claim 1 or 3, characterized in that the barrier layer comprises mineral oil and paraffin wax in a weight ratio between 0 and 4.   The multilayer capsule according to claim 3, wherein the thickness of the barrier layer occupies about 5% to 25% of the length of the capsule body.   4. Multi-layer capsule according to claim 3, characterized in that the body has two openings and two cover bodies for mounting on or removing from each of the openings of the body.   The multilayer capsule according to claim 3, characterized in that the first compartment comprises a first homogeneous material and the second compartment comprises a second homogeneous material.   The multilayer according to claim 7, characterized in that the first or second homogeneous material is in the form of a solid selected from solid blocks, microcapsules, granules, and powdered solids at room temperature. capsule.   The first or second homogeneous material is in the form of a solid block, wherein the solid block is semi-solid or liquid at a temperature above 35 ° C. Multi-layer capsule.   10. Multi-layer capsule according to claim 9, characterized in that the first or second homogeneous material comprises at least one heat-soluble excipient which is semi-solid or liquid at a temperature above 35 ° C. .   8. Multi-layer capsule according to claim 7, characterized in that the first or second homogeneous material is in liquid form.   The multilayer capsule according to claim 11, wherein the liquid comprises a suspension.   The multi-layer capsule according to claim 7, characterized in that the first or second homogeneous material is in a semi-solid form at room temperature.   The multilayer capsule according to claim 9, wherein the first homogeneous material has a melting point higher than that of the barrier layer, and the barrier layer has a melting point higher than that of the second homogeneous material.   The multilayer capsule according to claim 9, wherein the barrier layer has a melting point higher than that of the first homogeneous material and the second homogeneous material. A method of producing a multilayer capsule, the method comprising:
Providing a capsule including a body and at least one cover body, the body having an interior space and at least one opening;
An additional step of adding a first homogeneous material, a second homogeneous material, and a barrier layer to the interior space of the body, wherein the barrier layer is added before or after the first homogeneous material; and at least one opening in the body Attaching at least one cover body on the part, wherein the first and second homogeneous materials are separated by a barrier layer.   Further comprising adjusting the orientation of the capsule to allow the axis of the body and at least one cover body to be perpendicular to a horizontal plane, allowing the at least one opening of the body to be in a horizontal and up position. The method of claim 16, wherein the method is characterized.   The method of claim 16, further comprising removing at least one cover body to expose at least one opening.   The method of claim 16, wherein the adding step further comprises a heating step of heating the first homogeneous material, the second homogeneous material, and the barrier layer to be in a semi-solid or liquid form.   The method according to claim 19, wherein the heating step is performed between 25 ° C. and 85 ° C.   The method of claim 19, wherein the adding step further comprises cooling the first homogeneous material, the second homogeneous material, and the barrier layer to be in the form of a solid or solid block.   The method according to claim 16, characterized in that the barrier layer comprises mineral oil and paraffin wax in a weight ratio between 0 and 4.   The method of claim 16, wherein the thickness of the barrier layer occupies about 5% to 25% of the length of the body.   Adding the barrier layer after the first homogeneous material includes spraying the barrier layer to a discharge point on the inner wall, wherein the distance between the discharge point and the top of the homogeneous material is about 2 mm to about 3 mm. The method of claim 16, wherein there is.   The step of spraying the barrier layer is performed at an angle of about 10 degrees to about 40 degrees between a line defined from the nozzle spray point to the inner wall discharge point and a horizontal line from the nozzle spray point to the inner wall. 24. The method of claim 23, wherein:   17. A method according to claim 16, characterized in that a first homogeneous material, a second homogeneous material, or a barrier layer having a higher melting point is added first.