Controlled-release formulation comprising caffeine, and preparation method therefor

Abstract

The present invention relates to an orally administered formulation comprising caffeine as an active ingredient and having a drug-release controlling property, and a method for preparing same by using 3D printing and relates to a pharmaceutical composition and a food composition, of the formulation, for preventing or treating jet lag, and a composition to be applied to a 3D printer.

Description

[0001] Description of the Invention

[0002]

Title of invention

[0003] [Technical Field] The present invention relates to an oral dosage form having a drug release control function and having a structure in which compartments having a specific internal filling density are arranged side by side; a method for manufacturing the same using 3D printing; and a pharmaceutical composition and food composition for preventing or treating jet lag containing caffeine as an active ingredient; and a composition for application to a 3D printer.

[0004]

Background Technology

[0005] [Prior Art Literature]

[0006] [Patent Document] Korean Patent Publication No. 10-1757313

[0007]

Contents of the invention

[0008]

Technical Challenges

[0009]

Technical Solution

[0010]

Effect of the invention

[0011]

Brief description of the drawings

[0012]

Best Mode for Carrying Out the Invention

[0013] The density may be selected from about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, more specifically about 30%, about 37%, about 50%, about 90%, and even more specifically about 30%, about 50%, about 90%. In one embodiment of the present invention, the first compartment may comprise one having an internal fill density selected from 25% or more and 40% or less, and the second compartment may comprise one having an internal fill density selected from 50% or more and 100% or less. In one embodiment of the present invention, the first compartment may comprise one having an internal fill density of either 30% or 37%, and the second compartment may comprise one having an internal fill density of either 50% or 90%. In one embodiment of the present invention, the first compartment may have an internal fill density of 30%, and the second compartment may have an internal fill density of 50%. In one embodiment of the present invention, the first compartment may have an internal fill density of 30%, and the second compartment may have an internal fill density of 90%. In one embodiment of the present invention, the oral administration formulation may be a controlled-release formulation, specifically, an immediate-release, delayed-release and / or sustained-release formulation, and more specifically, an immediate-release and sustained-release formulation. In one embodiment of the present invention, the drug contained in the first compartment may be immediate-release, and the drug contained in the second compartment may include a delayed-release and / or sustained-release formulation. The above "release control" means controlling the release rate of the active ingredient of the formulation, and release and dissolution may be used interchangeably, and in the present invention, release control means immediate release and / or sustained release. The above "immediate release" means that the drug of the formulation is quickly released within a certain period of time after administration. In one embodiment of the present invention, the first compartment may have an internal filling density of 40% or less, and the drug contained in the first compartment may be released at 85% or more of the total weight of the drug contained in the first compartment within 2 hours after administration of the formulation.The above "sustained release" means that the drug of the formulation is slowly released over a certain period of time after administration. In one embodiment of the present invention, the second compartment may have an internal filling density of 50% or more and less than 90%, and the drug contained in the second compartment may be released such that 60% or less of the total weight of the drug contained in the second compartment is released at 2 hours after administration of the formulation, and 80% or less of the total weight of the drug is released at 4 hours. In one embodiment of the present invention, the second compartment may have an internal filling density of 90% or more, and the drug contained in the second compartment may be released such that 60% or less of the total weight of the drug contained in the second compartment is released at 4 hours after administration of the formulation, and 85% or less of the total weight of the drug is released at 8 hours. In one embodiment of the present invention, the first compartment may have an inner filling density of 40% or less, and when the first compartment of the formulation is added to a test solution at 37°C and pH 6.8 in a rotating paddle device having paddles that rotate at 50 rpm, the drug contained in the first compartment may be released such that 85% or more of the total weight of the drug contained in the first compartment is released within 2 hours after administration of the formulation. In one embodiment of the present invention, the second compartment may have an inner filling density of 50% or more but less than 90%, and when the second compartment of the formulation is added to a test solution at 37°C and pH 6.8 in a rotating paddle device having paddles that rotate at 50 rpm, the drug contained in the second compartment may be released such that 60% or less of the total weight of the drug contained in the second compartment is released within 2 hours after administration of the formulation, and 80% or less of the total weight of the drug is released within 4 hours. In one embodiment of the present invention, the second compartment has an internal filling density of 90% or more, and the second compartment of the formulation is heated at 37°C and pH 6 in a rotating paddle device having paddles that rotate at 50 rpm.When added to the test solution of 8, the drug contained in the second compartment may be released such that 60% or less of the total weight of the drug contained in the second compartment is released at 4 hours after administration of the formulation, and 85% or less of the total weight of the drug is released at 8 hours. In the present specification, "infill density" refers to the degree of density when filling the internal space after printing the outer rim of the formulation using a 3D printer, where 0% means not filling, and 100% means completely filling the interior. That is, as it approaches 100%, the internal empty space decreases, and as a pattern for filling the interior, any printable pattern may be included without limitation, specifically, a grid pattern, a honeycomb pattern, a checkered pattern, etc. In one embodiment of the present invention, the drug and pharmaceutically acceptable additives contained in the first compartment and the second compartment may be the same. In one embodiment of the present invention, the drug and / or pharmaceutically acceptable additive included in the first compartment and the drug and / or pharmaceutically acceptable additive included in the second compartment may be different. In one embodiment of the present invention, the pharmaceutically acceptable additive may be one or more of a binder, an excipient, a release-promoting agent, an enteric agent, a plasticizer, a solubilizing agent, a disintegrating agent, a stabilizer, and a coloring agent, and specifically, may be a binder, an excipient, and a release-promoting agent.More specifically, it may be at least one of PVP (Polyvinylpyrrolidone), MCC (Microcrystal 1 ine cel luose), Poly(meth)acrylate (Eudragit), Lactose, L-HPC (Low-substituted hydroxypropylcelulose), HPC (Hydroxypropyl cel luose), Ko 11 i don SR (Polyvinyl acetate and polyvinylpyrrolidone), HPMC (Hydr oxypropyl 1 meth 1 ce 11 u 1 ose), and more specifically, it may be PVP, MCC, Eudragit. The composition of the preparation including the pharmaceutically acceptable additive may have properties suitable for printing with a 3D printer. Specifically, there is no spreading or collapsing of the layer when printing with the composition, and the printing precision is excellent in printing with the desired internal filling density. In addition, the formulation manufactured with the above composition has excellent strength and can exhibit the desired immediate-release and sustained-release characteristics of the formulation after administration. In one embodiment of the present invention, the formulation may include 5 wt% to 50 wt% of the drug and 50 wt% to 95 wt% of the pharmaceutically acceptable additive based on the total weight of the formulation. For example, the formulation may include about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt% of the drug and about 95 wt%, about 90 wt%, about 85 wt%, about 80 wt%, about 75 wt%, about 70 wt%, about 65 wt%, about 60 wt%, about 55 wt%, about 50 wt% of the pharmaceutically acceptable additive.In one embodiment of the present invention, the weight ratio of the drug included in the first compartment and the second compartment of the formulation and the pharmaceutically acceptable excipient included in the first compartment and the second compartment may be 1:19 to 1:1. In one embodiment of the present invention, the formulation may include 10 wt% to 50 wt% of caffeine, 15 wt% to 30 wt% of PVP (Polyvinylpyrrolidone), 20 wt% to 50 wt% of MCC (Microcrystal 1 ine cel luose), and 5 wt% to 20 wt% of Eudragit (Poly(meth)acrylate) based on the total weight of the formulation. Specifically, the formulation may include 30 wt% of caffeine, 20 wt% of PVP, 30 wt% of MCC, and 20 wt% of Eudragit. In one embodiment of the present invention, the compartments may be arranged in a side-by-side or layer-by-layer form, and specifically, may be arranged in a side-by-side form. Unlike the layer-by-layer form in which the upper part of the first compartment and the lower part of the second compartment are attached, the side-by-side form according to the present invention is such that the lower part and the upper part of the formulation in which the side parts of the first and second compartments are attached and the internal pores are exposed according to the control of the internal filling density can both come into contact with the digestive solution, so that it is easy to control the release rate of the drug by controlling the internal filling density. The "side-by-side" form means that the contact surface of each compartment is vertical to the bottom surface of the formulation. The "layer-by-layer" form means that the contact surface of each compartment is horizontal to the bottom surface of the formulation. In one embodiment of the present invention, the oral administration formulation may include one manufactured using 3D printing.The above 3D printing may be one of Material Extrusion, Vat Polymerization, Powder Bed Fusion, and Material / Binding Jetting, and specifically, may be Material Extrusion, but is not limited thereto. The present invention provides a pharmaceutical composition or food composition of the oral administration preparation. The present invention relates to a pharmaceutical composition for preventing or treating jet lag, which comprises two or more compartments, each of which comprises caffeine and one or more pharmaceutically acceptable additives. The caffeine may comprise caffeine, a pharmaceutically acceptable salt thereof, an optical isomer thereof, a hydrate or solvate thereof, or a mixture thereof. In one embodiment of the present invention, the internal filling densities of the compartments may be different from each other. In one embodiment of the present invention, when the preparation comprises three or more compartments, the internal filling densities of each compartment may be such that at least one pair of compartments is different from each other. For example, if the formulation has three compartments, the internal filling densities of the first compartment and the second compartment are different, the third compartment may have the same internal filling density as the first or second compartment, or the internal filling densities of the first to third compartments may all be different. In one embodiment of the present invention, the drug and pharmaceutically acceptable excipients included in each compartment may be the same. In one embodiment of the present invention, the drug and / or pharmaceutically acceptable excipients included in each compartment may be different in at least one compartment from the remaining compartments.For example, when the formulation has three compartments, the drugs and / or pharmaceutically acceptable excipients of the first compartment and the second compartment are different, the third compartment may have the same drugs and / or pharmaceutically acceptable excipients as the first compartment or the second compartment, and the drugs and / or pharmaceutically acceptable excipients of the first to third compartments may all be different. The present invention relates to a pharmaceutical composition for preventing or treating jet lag, comprising a first compartment and a second compartment, wherein the first compartment and the second compartment each comprise at least one drug and at least one pharmaceutically acceptable excipient. In one embodiment of the present invention, the internal filling densities of the first compartment and the second compartment may be different from each other. In one embodiment of the present invention, the internal filling densities of the first compartment and the second compartment may be selected from 25% to 100%. Specifically, about 25%, about 30%, about 35%, about 37%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about.

[0014] The density may be selected from about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, more specifically about 30%, about 37%, about 50%, about 90%, and even more specifically about 30%, about 50%, about 90%. In one embodiment of the present invention, the first compartment may comprise one having an internal fill density selected from 25% or more and 40% or less, and the second compartment may comprise one having an internal fill density selected from 50% or more and 100% or less. In one embodiment of the present invention, the first compartment may comprise one having an internal fill density of either 30% or 37%, and the second compartment may comprise one having an internal fill density of either 50% or 90%. In one embodiment of the present invention, the first compartment may have a fill density of 30%, and the second compartment may have a fill density of 50%. In one embodiment of the present invention, the first compartment may have a fill density of 30%, and the second compartment may have a fill density of 90%. In one embodiment of the present invention, the pharmaceutical composition may be for controlled release, specifically for immediate release, delayed release and / or sustained release, more specifically for immediate release and sustained release. In one embodiment of the present invention, the drug contained in the first compartment may be immediate release, and the drug contained in the second compartment may be delayed release and / or sustained release. In one embodiment of the present invention, the first compartment may have a fill density of 40% or less, and the drug contained in the first compartment may be released such that 85% or more of the total weight of the drug contained in the first compartment is released within 2 hours after administration of the formulation. In one embodiment of the present invention, the second compartment may have an internal filling density of 50% or more and less than 90%, and the drug contained in the second compartment may be released at 60% or less of the total weight of the drug contained in the second compartment at 2 hours after administration of the formulation, and at 80% or less of the total weight of the drug at 4 hours.In one embodiment of the present invention, the second compartment may have an internal filling density of 90% or more, and the drug contained in the second compartment may be released such that 60% or less of the total weight of the drug contained in the second compartment is released within 4 hours after administration of the formulation, and 85% or less of the total weight of the drug is released within 8 hours. In one embodiment of the present invention, the first compartment may have an internal filling density of 40% or less, and when the first compartment of the formulation is added to a test solution at 37°C and pH 6.8 in a rotating paddle device having paddles that rotate at 50 rpm, the drug contained in the first compartment may be released such that 85% or more of the total weight of the drug contained in the first compartment is released within 2 hours after administration of the formulation. In one embodiment of the present invention, the second compartment may have an internal filling density of 50% or more and less than 90%, and when the second compartment of the formulation is added to a test solution at 37°C and pH 6.8 in a rotating paddle device having paddles that rotate at 50 rpm, the drug contained in the second compartment may be released such that 60% or less of the total weight of the drug contained in the second compartment is released at 2 hours after administration of the formulation, and 80% or less of the total weight of the drug is released at 4 hours. In one embodiment of the present invention, the second compartment may have an internal filling density of 90% or more, and when the second compartment of the formulation is added to a test solution at 37°C and pH 6.8 in a rotating paddle device having paddles that rotate at 50 rpm, the drug contained in the second compartment may be released such that 60% or less of the total weight of the drug contained in the second compartment is released at 4 hours after administration of the formulation, and 85% or less of the total weight of the drug is released at 8 hours. The formulation according to the present invention includes compartments with different internal filling densities in one formulation, so that rapid release and sustained release can be achieved simultaneously through the intake of one formulation.Specifically, when the drug effect must be exerted immediately upon taking the dosage form and the corresponding drug effect must be sustained for a certain period of time, if the first compartment is manufactured with an internal filling density exhibiting immediate-release characteristics and the second compartment is manufactured with a sustained-release characteristic, the drug in the first compartment begins to be released immediately after taking the dosage form, and more than 85% of the total weight of the drug is released within 2 hours, so that the drug effect can be exerted quickly, and the second compartment begins to be slowly released from the time of taking the drug, so that 80% of the drug is released after 4 hours or after 8 hours, so that the drug effect can be sustained for a desired time for patients, thereby significantly improving the convenience of taking the medication. More specifically, when the drug of the above-mentioned dosage form is caffeine, the dosage form of one embodiment of the present invention can be effectively applied to improve jet lag. For example, when the drug of the formulation according to an embodiment of the present invention contains caffeine, when the formulation is taken, rapid release of the drug occurs immediately from the immediate release compartment, and a stimulating effect is exerted, so that jet lag symptoms such as fatigue experienced upon arrival at a jet lag area are effectively prevented or treated, and the sustained release compartment can maintain the drug effect until the patient's sleeping time, so that jet lag can be improved by taking only one formulation, thereby providing excellent convenience in taking the medication. In one embodiment of the present invention, the drug and pharmaceutically acceptable additive included in the first compartment and the second compartment may be the same. In one embodiment of the present invention, the drug and / or pharmaceutically acceptable additive included in the first compartment and the drug and / or pharmaceutically acceptable additive included in the second compartment may be different. In one embodiment of the present invention, the pharmaceutically acceptable additive may be one or more of a binder, an excipient, a release-promoting agent, an enteric agent, a plasticizer, a solubilizing agent, a disintegrating agent, a stabilizer, and a coloring agent, and specifically, may be a binder, an excipient, and a release-promoting agent.More specifically, it may be at least one of PVP (Polyvinylpyrrolidone), MCC (Microcrystal 1 ine cel luose), Poly(meth)acrylate (Eudragit), Lactose, L-HPC (Low-substituted hydroxypropylcelulose), HPC (Hydroxypropyl cel luose), Ko 11 i don SR (Polyvinyl acetate and polyvinylpyrrolidone), HPMC (Hydr oxypropyl 1 meth 1 ce 11 u 1 ose), and more specifically, it may be PVP, MCC, Eudragit. In one embodiment of the present invention, the pharmaceutical composition may include 5 wt% to 50 wt% of the drug and 50 wt% to 95 wt% of the pharmaceutically acceptable additive based on the total weight of the pharmaceutical composition. For example, it may include about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt% of the drug and about 95 wt%, about 90 wt%, about 85 wt%, about 80 wt%, about 75 wt%, about 70 wt%, about 65 wt%, about 60 wt%, about 55 wt%, about 50 wt% of the pharmaceutically acceptable additive. In one embodiment of the present invention, the weight ratio of the drug included in the first compartment and the second compartment and the pharmaceutically acceptable additive included in the first compartment and the second compartment may be from 1:19 to 1:1.In one embodiment of the present invention, the pharmaceutical composition may contain 10 wt% to 50 wt% of caffeine, 15 wt% to 30 wt% of PVP (Polyvinylpyrrolidone), 20 wt% to 50 wt% of MCC (Microcrystalline cellulose), and 5 wt% to 20 wt% of Eudragi t (Poly(meth)acrylate), based on the total weight of the composition. Specifically, it may contain 30 wt% of caffeine, 20 wt% of PVP, 30 wt% of MCC, and 20 wt% of Eudragi t. In one embodiment of the present invention, the compartments may be arranged in a side-by-side or layer-by-layer form, and specifically, may be arranged in a side-by-side form. In one embodiment of the present invention, the pharmaceutical composition may include one manufactured using 3D printing. The above 3D printing may be one of Material Extrusion, Vat Polymerization, Powder Bed Fusion, and Material / Binding Jetting, and specifically, may be Material Extrusion, but is not limited thereto. In one embodiment of the present invention, the oral administration formulation may be in any shape that can be administered orally, and may be, for example, in a shape such as a circle, a triangle, a square, an oval, a rectangle, etc. Specifically, it may be in the form of a tablet. According to one embodiment of the present invention, formulations containing caffeine may exhibit different release rates by adjusting the internal filling density even though they have the same composition. Specifically, pH 6.When the dissolution rate of caffeine was measured in the dissolution test solution of 8, the release can be adjusted to exhibit a range from immediate-release characteristics in which more than 85% of the total drug weight is released within 2 hours to sustained-release characteristics in which the drug is released for up to 8 hours by changing the inner filling density (Experimental Examples 1 and 4 and Figs. 3 and 5). This can be confirmed by the similar release pattern trend shown in the PK test results in beagle dogs (Experimental Example 5 and Fig. 6). According to one embodiment of the present invention, it can be confirmed that the release rate of the drug in the formulation can be controlled by adjusting the content of the sustained-release polymer when the inner filling density is kept the same at 100%. Specifically, as the content of the sustained-release polymer increases to 20 wt% based on the total weight of the formulation, the degree of sustained-release of the drug is prolonged, and the range of release rate control according to the inner filling density widens, confirming that the composition is suitable for the manufacture of a formulation for controlled-release (Experimental Example 2 and Fig. 4). According to one embodiment of the present invention, when the caffeine content uniformity of the preparation containing caffeine was measured according to the Preparation Uniformity Test Method among the General Test Methods of the Korean Pharmacopoeia, the AV value was less than 15, indicating that the main ingredient content of the prepared preparation could be uniform (Experimental Example 3). The present invention provides a kit comprising: a preparation 1 for oral administration, which comprises a first compartment and a second compartment, wherein the first compartment and the second compartment contain caffeine and one or more pharmaceutically acceptable additives; and a preparation 2 containing a drug exhibiting a different activity from caffeine. In one embodiment of the present invention, the preparation 1 for oral administration, which comprises the first compartment and the second compartment, wherein the first compartment and the second compartment contain caffeine and one or more pharmaceutically acceptable additives, may be substantially the same as described above, as long as they are not contradictory to each other.In one embodiment of the present invention, Formulation 2 containing a drug having a different activity from caffeine in the kit may be a delayed-release and / or sustained-release formulation. As previously discussed, Formulation 1 and Formulation 2 may be administered simultaneously, and when Formulation 2 is a delayed-release and / or sustained-release formulation, when Formulation 1 and Formulation 2 in the kit are administered simultaneously, the pharmacological effect of the drug contained in Formulation 2 appears after a certain period of time after administration, and the release of the drug proceeds gradually for a certain period of time thereafter, so that the pharmacological effect may be sustained, and the pharmacological effect of caffeine contained in Formulation 1 may appear immediately and the pharmacological effect may be sustained for a certain period of time, thereby significantly improving the convenience of taking the medication for the patient. In one embodiment of the present invention, the kit may be for preventing or treating jet lag, and wherein Formulation 2 may be a delayed-release and / or sustained-release formulation containing a sleep inducer or a sleeping pill such as melatonin. According to one embodiment of the present invention, when the preparations of the kit, which are delayed-release and / or sustained-release preparations containing a sleep-inducing agent or a sleeping pill such as melatonin, are taken simultaneously upon arrival in a region with a time difference, the pharmacological effect of Preparation 1, which is an awakening effect, appears immediately, thereby minimizing symptoms such as drowsiness and fatigue during the day, thereby reducing inconvenience in activities, and the pharmacological effect of Preparation 2, which is a sleeping effect, appears after a certain period of time, so that the drug of Preparation 2 is continuously released during the sleeping period, thereby preventing or treating sleep disorders such as insomnia caused by jet lag. In addition, Preparation 1 can control the duration of drug release by controlling the internal filling density of the preparation, and a patient with jet lag can select Preparation 1 having an internal filling density that exhibits a desired duration of caffeine release according to the time of arrival in a region with a time difference (for example, 10:00 a.m. or 4:00 p.m.) in order to prevent or treat jet lag, and take the preparations of the kit, thereby significantly improving the convenience of taking medication for the patient.The present invention provides a method for manufacturing the oral administration formulation. The present invention relates to a method for manufacturing the oral administration formulation using 3D printing, the method comprising the steps of: (a) manufacturing a composition comprising at least one drug and at least one pharmaceutically acceptable additive; (b) printing the composition using a 3D printer to laminate one compartment; and (c) sequentially laminating the remaining compartments after step (b).

[0015] 3D printing is a technology that enables small-batch, multi-variety production of customized formulations, and there are various methods such as Material Extrusion, Vat Polymerization, Powder Bed Fusion, and Material / Binding Jetting. The 3D printing may be one of Material Extrusion, Vat Polymerization, Powder Bed Fusion, and Material / Binding Jetting, and specifically, may be Material Extrusion, but is not limited thereto. In the step (a), the composition may further include a step of having a uniform particle size distribution through a mesh. For example, the mesh may be 20 to 40 mesh, but is not limited thereto. In the step (b), the pressure during output may be 0.4 MPa to 0.8 MPa, but is not limited thereto. In the step (b), the extrusion speed may be 1800 to 4600 mm / s, but is not limited thereto. The method for manufacturing a formulation according to the present invention does not manufacture the composition into a filament, but mixes the powder-type composition, adds water to manufacture it into a dough-type composition, and then directly puts it into the silo of a 3D printer and prints it using pressure from a nozzle. Therefore, the manufacturing of the formulation is simple, and there is an advantage in that polymers that are not suitable for filaments and pharmaceutically acceptable additives can be applied. In addition, compared to the FDM method that uses a filament that requires at least two heat treatments, the 3D printing method used in the present invention does not involve a heat application process, so it can use relatively heat-sensitive raw materials. Therefore, there is freedom in the use of raw materials, and there is an advantage in cost because there is no need for filament manufacturing costs. The 3D printing method can manufacture a formulation customized to the individual by taking into account the severity of the disease, the timing and dosage of drug administration, etc.Accordingly, the present invention can provide a personalized formulation that can be appropriately selected according to the arrival time of a jet lag region for patients suffering from jet lag by manufacturing a formulation that includes compartments with different internal filling densities using a 3D printer. In one embodiment of the present invention, the drug may be included without limitation as long as it exhibits pharmacological activity, and specifically, it includes a drug that has a short half-life such as melatonin, caffeine, etc. and thus requires sustained drug release to maintain a pharmacological effect, and more specifically, it may include caffeine, but is not limited thereto. In one embodiment of the present invention, the internal filling densities of the compartments may be different from each other. In one embodiment of the present invention, when the formulation includes three or more compartments, the internal filling densities of each compartment may be such that at least one pair has different compartments. For example, when the formulation has three compartments, the internal filling densities of the first compartment and the second compartment are different, the third compartment may have the same internal filling density as the first or second compartment, and the internal filling densities of the first to third compartments may all be different. In one embodiment of the present invention, the drug and pharmaceutically acceptable excipients included in each compartment may be the same. In one embodiment of the present invention, the drug and / or pharmaceutically acceptable excipients included in each compartment may be different in at least one compartment from the other compartments. For example, when the formulation has three compartments, the drug and / or pharmaceutically acceptable excipients of the first and second compartments are different, the third compartment may have the same drug and / or pharmaceutically acceptable excipients as the first or second compartment, and the drug and / or pharmaceutically acceptable excipients of the first to third compartments may all be different.The present invention relates to a method for manufacturing the oral administration formulation, comprising the steps of: (a) manufacturing a composition comprising at least one drug and at least one pharmaceutically acceptable additive; (b) using a 3D printer to output the composition and laminate one of a first compartment and a second compartment; and (c) after step (b), sequentially laminating the remaining compartments. In one embodiment of the present invention, the internal filling densities of the first compartment and the second compartment may be different from each other. In one embodiment of the present invention, the internal filling densities of the first compartment and the second compartment may be selected from 25% to 100%. Specifically, it may be selected from about 25%, about 30%, about 35%, about 37%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, more specifically about 30%, about 37%, about 50%, about 90%, and even more specifically about 30%, about 50%, about 90%. In one embodiment of the present invention, the first compartment may include one in which the internal filling density is selected from 25% or more and 40% or less, and the second compartment may include one in which the internal filling density is selected from 50% or more and 100% or less. In one embodiment of the present invention, the first compartment may have an internal fill density of one of 30% or 37%, and the second compartment may have an internal fill density of one of 50% or 90%. In one embodiment of the present invention, the first compartment may have an internal fill density of 30%, and the second compartment may have an internal fill density of 50%. In one embodiment of the present invention, the first compartment may have an internal fill density of 30%, and the second compartment may have an internal fill density of 90%.In one embodiment of the present invention, the drug and pharmaceutically acceptable additive included in each compartment may be the same. In one embodiment of the present invention, the drug and pharmaceutically acceptable additive included in the first compartment and the second compartment may be the same. In one embodiment of the present invention, the drug and / or pharmaceutically acceptable additive included in the first compartment and the drug and / or pharmaceutically acceptable additive included in the second compartment may be different. In one embodiment of the present invention, the pharmaceutically acceptable additive may be one or more of a binder, an excipient, a release-promoting agent, an enteric agent, a plasticizer, a solubilizing agent, a disintegrating agent, a stabilizer, and a coloring agent, and specifically, may be a binder, an excipient, and a release-promoting agent. More specifically, it may be at least one of PVP (Polyvinylpyrrolidone), MCC (Microcrystal 1 ine cel luose), Poly(meth)acrylate (Eudragit), Lactose, L-HPC (Low-substituted hydroxypropylcelulose), HPC (Hydroxypropyl cel luose), Ko 11 i don SR (Polyvinyl acetate and polyvinylpyrrolidone), HPMC (Hydr oxypropyl 1 meth 1 ce 11 u 1 ose), and more specifically, it may be PVP, MCC, Eudragit. In one embodiment of the present invention, the drug may be included in an amount of 5 wt% to 50 wt% and a pharmaceutically acceptable additive in an amount of 50 wt% to 95 wt% based on the total weight of the formulation.For example, it may include about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt% of the drug and about 95 wt%, about 90 wt%, about 85 wt%, about 80 wt%, about 75 wt%, about 70 wt%, about 65 wt%, about 60 wt%, about 55 wt%, about 50 wt% of the pharmaceutically acceptable additive. In one embodiment of the present invention, the weight ratio of the drug included in the first compartment and the second compartment of the formulation and the pharmaceutically acceptable additive included in the first compartment and the second compartment may be from 1:19 to 1:1. In one embodiment of the present invention, the formulation may contain 10 wt% to 50 wt% of caffeine, 15 wt% to 30 wt% of PVP (Polyvinylpyrrolidone), 20 wt% to 50 wt% of MCC (Microcrystal 1 ine cel luose), and 5 wt% to 20 wt% of Eudragi t (Poly(meth)acrylate), based on the total weight of the formulation. Specifically, it may contain 30 wt% of caffeine, 20 wt% of PVP, 30 wt% of MCC, and 20 wt% of Eudragi t. In one embodiment of the present invention, the compartments may be arranged in a side-by-side or layer-by-layer form, and specifically, may be arranged in a side-by-side form. The description of the formulation described above may be substantially identically applied to the manufacturing method, unless contradictory. The present invention relates to a food composition for preventing or improving jet lag, comprising a first compartment and a second compartment, wherein the first compartment and the second compartment each comprise at least one drug and at least one pharmaceutically acceptable additive.The above "improvement" includes all acts in which a disease is improved or beneficial by administration of the above composition. The above "food" includes dairy products including meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, ice cream, various soups, beverages, tea, drinks, alcoholic beverages, vitamin complexes, health functional foods, health foods, and health supplements, and includes all foods in the conventional sense. In one embodiment of the present invention, the drug and pharmaceutically acceptable additive included in the first compartment and the second compartment may be the same. In one embodiment of the present invention, the drug and / or pharmaceutically acceptable additive included in the first compartment and the drug and / or pharmaceutically acceptable additive included in the second compartment may be different. In one embodiment of the present invention, the pharmaceutically acceptable additive may be one or more of a binder, an excipient, a release-promoting agent, an enteric agent, a plasticizer, a solubilizing agent, a disintegrating agent, a stabilizer, and a coloring agent, and specifically, may be a binder, an excipient, and a release-promoting agent. More specifically, it may be one or more of PVP (Polyvinylpyrrolidone), MCC (Microcrystal 1 ine cel luose), Poly(meth)acrylate (Eudragit), Lactose, L-HPC (Low-substance ti tuted hydroxypropylcelulose), HPC (Hydroxypropyl cel luose), Ko 11 i don SR (Polyvinyl acetate and polyvinylpyrrolidone), HPMC (Hydr oxypr opy 1 meth t hy 1 ce 11 u 1 ose), and more specifically, it may be PVP, MCC, Eudragit.In one embodiment of the present invention, the food composition may comprise 5 wt% to 50 wt% of the drug and 50 wt% to 95 wt% of the pharmaceutically acceptable additive based on the total weight of the food composition. For example, the food composition may comprise about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt% of the drug and about 95 wt%, about 90 wt%, about 85 wt%, about 80 wt%, about 75 wt%, about 70 wt%, about 65 wt%, about 60 wt%, about 55 wt%, about 50 wt% of the pharmaceutically acceptable additive. In one embodiment of the present invention, the weight ratio of the drug included in the first compartment and the second compartment and the pharmaceutically acceptable additive included in the first compartment and the second compartment may be 1:19 to 1:1. In one embodiment of the present invention, the food composition may include 10 wt% to 50 wt% of caffeine, 15 wt% to 30 wt% of PVP (Polyvinylpyrrolidone), 20 wt% to 50 wt% of MCC (Microcrystalline cellulose), and 5 wt% to 20 wt% of Eudragi t (Poly(meth)acrylate) based on the total weight of the composition. Specifically, it may include 30 wt% of caffeine, 20 wt% of PVP, 30 wt% of MCC, and 20 wt% of Eudragi t. The descriptions of the preparation, pharmaceutical composition, and manufacturing method described above may be substantially equally applied to the food composition of the present invention as long as they are not contradictory. The present invention relates to a composition for application to a 3D printer, comprising caffeine and one or more pharmaceutically acceptable additives.In one embodiment of the present invention, the pharmaceutically acceptable additive may be one or more of a binder, an excipient, a release-promoting agent, an enteric agent, a plasticizer, a solubilizing agent, a disintegrating agent, a stabilizer, and a coloring agent, and specifically, may be a binder, an excipient, and a release-promoting agent. More specifically, it may be at least one of PVP (Polyvinylpyrrolidone), MCC (Microcrystal 1 ine cel luose), Poly(meth)acrylate (Eudragit), Lactose, L-HPC (Low-substance ti tuted hydroxypropylcelulose), HPC (Hydroxypropyl cel luose), Ko 11 i don SR (Polyvinyl acetate and polyvinylpyrrolidone), HPMC (Hydr oxypr opy 1 meth t hy 1 ce 11 u 1 ose), and more specifically, it may be PVP, MCC, Eudragit. The present invention relates to a composition for application to a 3D printer, comprising caffeine and at least one pharmaceutically acceptable additive, wherein the pharmaceutically acceptable additive is at least one of a binder, an excipient, and a sustained-release agent. In one embodiment of the present invention, the pharmaceutically acceptable additive may be specifically PVP (Polyvinylpyrrolidone), MCC (Microcrystal 1 ine cel luose), PolyGiieth)acrylate (Eudragi t). In one embodiment of the present invention, the composition may contain 5 wt% to 50 wt% of the drug and 50 wt% to 95 wt% of the pharmaceutically acceptable additive based on the total weight of the composition.For example, it may comprise about 5 wt%, about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt% of the drug and about 95 wt%, about 90 wt%, about 85 wt%, about 80 wt%, about 75 wt%, about 70 wt%, about 65 wt%, about 60 wt%, about 55 wt%, about 50 wt% of a pharmaceutically acceptable additive. In one embodiment of the present invention, the composition may include 10 wt% to 50 wt% of caffeine, 15 wt% to 30 wt% of PVP (Polyvinylpyrrolidone), 20 wt% to 50 wt% of MCC (Microcrystal 1 ine cel luose), and 5 wt% to 20 wt% of Eudragi t (Poly(meth)acrylate) based on the total weight of the composition. Specifically, the composition may include 30 wt% of caffeine, 20 wt% of PVP, 30 wt% of MCC, and 20 wt% of Eudragi t. According to one embodiment of the present invention, the composition has a viscosity suitable for printing with the pressure applied by a 3D printer, and when printing, the printed product has an adhesive strength that can adhere to the bed of the 3D printer so that the printed product can be stacked without being separated from the bed, and the printed layer does not collapse or spread, so that excellent printing precision can be achieved. The oral administration preparation, pharmaceutical composition and food composition comprising a composition for application to a 3D printer according to one embodiment of the present invention exhibit excellent strength because the laminated layers do not separate when manufactured with a 3D printer, and can exhibit excellent release control function (immediate release and sustained release) even after administration.In addition, the oral administration preparation, pharmaceutical composition and food composition including the composition manufactured by a 3D printer can include both immediate-release and sustained-release compartments so that the drug effect appears immediately when the patient arrives at a time difference area and ingests the preparation, and at the same time, the drug effect lasts for a desired period of time, thereby significantly improving the convenience of taking the medication. In addition, the preparation having a compartment with a drug release duration tailored to the individual patient can be selected depending on the arrival time, thereby providing the advantage of personalized treatment.

[0016] [National Research and Development Project Supporting This Invention]

[0017] [Task Unique 1415173636

[0018] [Task number 20015288

[0019] [Ministry Name] Ministry of Trade, Industry and Energy

[0020] [Name of Project Management (Specialist) Institution] Korea Institute of Industrial Technology Planning and Evaluation

[0021] [Research Project Name] Bioindustry Technology Development (R&D)

[0022] [Research Project Name] Development of Customized Dosage-Adjustable Oral Medicines Based on 3D Printing Technology

[0023] [Contribution rate] 1 / 1

[0024] [Name of the project performing organization] Dong-A Pharmaceutical Co., Ltd.

[0025] [Research Period] April 1, 2021 - December 31, 2025

[0026]

Form for Embodiment of the Invention

[0027] [Table 1]

[0028] [Table 2]

[0029] <Experimental Example 1> Evaluation of Za-v / 'ro dissolution characteristics according to the internal filling density of the formulation The caffeine dissolution characteristics of the formulations of Examples 2 to 5 of the present invention were evaluated as follows. The dissolution characteristic evaluation was performed according to the 2nd dissolution test method (paddle method) of the Korean Pharmacopoeia. As the dissolution conditions, the formulation was added to 500 mL of a solution adjusted to pH 6.8 using a dissolution tester, and test solutions were collected after 0 minutes, 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, and 12 hours, and the released caffeine content was measured using HPLC. At this time, the temperature of the test solution was maintained at 37°C ± 0.5°C, the rotation speed of the paddle was 50 rpm, and a sinker was not used. The results of the dissolution characteristic evaluation of Examples 2 to 5 are shown in FIG. 3. As a result of the dissolution test evaluation of Examples 2 to 5, Example 2 with an internal filling density of 30% released 80% of the caffeine in the formulation 30 minutes after the start of the test, Example 3 with an internal filling density of 70% released 80% of the caffeine in the formulation after 2 hours, Example 4 with an internal filling density of 80% released 80% of the caffeine in the formulation after 3 hours, and Example 5 with an internal filling density of 90% released 80% of the caffeine in the formulation after 4 hours. It was confirmed that the release pattern according to the internal filling density can be controlled when a single composition was used. Compositions of Examples 6 and 7 and Preparation of Formulations Using a 3D Printer Compositions of Examples 6 and 7 were prepared according to the compositions and contents of Table 3 below in the same manner as the method for preparing the composition of Example 1.

[0030] [Table 3]

[0031] [Table 4]

[0032]

[0033] <Experimental Example 2> In-vitro dissolution characteristic evaluation according to the ratio of sustained-release polymer The dissolution characteristic evaluation of the formulation according to the ratio of Eudragi t RS, a sustained-release polymer, under the same internal filling density conditions was performed on the formulations of Examples 8 to 10, and was carried out in the same manner as in Experimental Example 1, and the results are shown in Fig. 4. The formulations of Examples 8 to 10 were prepared by using the composition of Example 1 to prepare the formulation of Example 8, the composition of Example 6 to prepare the formulation of Example 9, and the composition of Example 7 to prepare the formulation of Example 10 under the conditions of Table 4. The preparation method of the formulations was substantially the same as the preparation method of the formulations of Examples 2 to 5, except that the output conditions of Table 4 were used. As a result of the dissolution test evaluation of Examples 8 to 10, Example 8, which contained 10% of the sustained-release polymer Eudragi t RS, released 85% of the caffeine contained in the formulation 6 hours after the start of the test, Example 9, which contained the lowest sustained-release polymer content of 5%, released 85% of the caffeine after 4 hours, and Example 10, which contained the highest sustained-release polymer content of 20%, released 85% of the caffeine after more than 12 hours. All of Examples 8 to 10 exhibited sustained-release, and it was confirmed that the formulation of Example 10, which contained the highest content of the sustained-release polymer Eudragi t RS, showed the longest sustained-release period.

[0034] <Experimental Example 3> Evaluation of the uniformity of the formulation content

[0035] A content uniformity test was performed to evaluate the uniformity of the main ingredient content between individual formulations for the formulations of Examples 11 to 13 manufactured through 3D printing. The content uniformity test measures the main ingredient content and evaluates whether the content is within the allowable range, and is evaluated as suitable when the formulation uniformity judgment value (AV) is less than 15. The content uniformity test of the formulation was performed according to 61. Formulation Uniformity Test Method of the General Test Methods of the Korean Pharmacopoeia. As a result of performing the test on Examples 11 to 13, the formulation uniformity judgment value (AV) was 4.3 for Example 11, 2.6 for Example 12, and 3.4 for Example 13, respectively, corresponding to AV < 15 in all, indicating that the formulations were suitable.

[0036] <Experimental Example 4> In-vitro dissolution characteristics evaluation according to internal filling density of formulation The dissolution characteristics of the formulation according to the change in internal filling density were evaluated in the formulation that showed the longest sustained-release degree among the formulations of Experimental Example 2. This was performed on the formulations of Examples 11 to 14, and was carried out in the same manner as in Experimental Example 1, and the results are shown in Fig. 5. The formulations of Examples 11 to 14 were manufactured using the composition of Example 7 according to the conditions of Table 4. The manufacturing method of the formulations was substantially the same as the manufacturing method of the formulations of Examples 2 to 5, except that the output conditions of Table 4 were used. As a result of the dissolution test evaluation of Examples 11 to 14, Examples 11 and 14, which had internal filling densities of 30% and 37%, respectively, both released about 60% of the caffeine 30 minutes after the start of the test, and more than 85% of the total weight of caffeine was released after 2 hours. Meanwhile, Example 12, which had an internal filling density of 50%, released 60% of the caffeine 2 hours after the start of the test, and more than 80% of the caffeine was released after 4 hours, and Example 13, which had an internal filling density of 90%, released 60% of the caffeine 4 hours after the start of the test, and more than 80% of the drug was released after 8 hours.

[0037] <Experimental Example 5> PK (Pharmacokinetics) evaluation of formulation in beagle dogs The drug release behavior in beagle dogs was confirmed for the formulations of Examples 11 to 13 of the present invention, and the experiment was conducted as follows. The formulations of Examples 11 to 13, each having a caffeine dosage of 75 to 150 mg / g, were orally administered to 18 beagle dogs (male) aged 14 to 16 months and weighing an average of 9.9 to 12.5 kg. After oral administration, the blood caffeine concentration was measured at intervals of 0 minute, 15 minutes, 30 minutes, 1 hour, 1 hour 30 minutes, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, and 24 hours. The PK test results are shown in Fig. 6. As a result of the PK test of Examples 11 to 13 above, Example 11 with an internal filling density of 30% is T m Example 12, where the ax was 1 hour, the internal filling density was 50%, and Example 13, where the internal filling density was 90%, showed 2 hours and 3 hours, respectively. As the internal filling density of the formulation increased, the Tmax was delayed, confirming that the release control trend in vitro was similarly observed in vivo. When the AUCiast of Examples 12 and 13 was compared, Example 12 was measured to be 106.58 hr*w / mL and Example 13 was measured to be 95.27 hr*w / mL. Compared to Example 12, where the internal filling density was 50% and the drug contained in the formulation was completely absorbed, Example 13, where the internal filling density was 90%, showed that only 90% of the drug contained in the formulation was absorbed into the blood as the drug release rate was slowed.

[0038] [Explanation of the symbol]

[0039] 100: Preparation

[0040] 110: Section 1

[0041] 120: Section 2

Claims

38 【Scope of Claims】 【 Claim 11 An oral dosage form comprising a first compartment and a second compartment, wherein each of the first compartment and the second compartment comprises at least one drug and at least one pharmaceutically acceptable additive. 【

2. A formulation according to claim 1, wherein the infill densities of the first compartment and the second compartment are different from each other. 【

3. A formulation according to claim 1 or 2, wherein the internal filling density of the first compartment and the second compartment is selected from 25% to 100%. 【

4. A formulation according to any one of claims 1 to 3, wherein the first compartment is selected from an internal filling density of 25% or more and 40% or less, and the second compartment is selected from an internal filling density of 50% or more and 100% or less. 【

5. A formulation according to any one of claims 1 to 4, wherein the first compartment has an internal fill density of either 30% or 37%, and the second compartment has an internal fill density of either 50% or 90%. 【

6. A formulation according to any one of claims 1 to 5, wherein the first compartment has an internal filling density of 30% and the second compartment has an internal filling density of 50%. 【

7. A formulation according to any one of claims 1 to 5, wherein the first compartment has an internal filling density of 30% and the second compartment has an internal filling density of 90%. 【

8. A formulation according to any one of claims 1 to 7, wherein the first compartment and the second compartment are manufactured using the same drug and the same pharmaceutically acceptable excipient. 【A preparation according to any one of claims 1 to 8, wherein the first compartment and the second compartment are manufactured using at least one different substance including the drug and / or pharmaceutically acceptable excipient.

10. A formulation according to any one of claims 1 to 9, wherein the drug contained in the first compartment is immediate-released, and the drug contained in the second compartment is delayed-released and / or sustained-released.

11. In any one of claims 1 to 10, the first compartment has an internal filling density of 40% or less. A formulation wherein the drug contained in the first compartment releases more than 85% of the total weight of the drug contained in the first compartment within 2 hours after administration of the formulation. 【

12. A formulation according to any one of claims 1 to 11, wherein the second compartment has an internal filling density of 50% or more and less than 90%, and the drug contained in the second compartment releases 60% or less of the total weight of the drug contained in the second compartment at 2 hours after administration of the formulation, and 80% or less of the total weight of the drug is released at 4 hours.

13. A formulation according to any one of claims 1 to 11, wherein the second compartment has an internal filling density of 90% or more, and the drug contained in the second compartment releases 60% or less of the total weight of the drug contained in the second compartment at 4 hours after administration of the formulation, and 85% or less of the total weight of the drug is released at 8 hours.

14. A formulation according to any one of claims 1 to 13, wherein the first compartment has an internal filling density of 40% or less, and when the first compartment of the formulation is added to a test solution at 37°C and pH 6.8 in a rotating paddle device having paddles that rotate at 50 rpm, the drug contained in the first compartment releases 85% or more of the total weight of the drug contained in the first compartment within 2 hours after administration of the formulation.

15. A formulation according to any one of claims 1 to 14, wherein the second compartment has an internal filling density of 50% or more and less than 90%, and when the second compartment of the formulation is added to a test solution of 37°C and pH 6.8 in a rotating paddle device having paddles that rotate at 50 rpm, 60% or less of the total weight of the drug contained in the second compartment is released at 2 hours after administration of the formulation, and 80% or less of the total weight of the drug is released at 4 hours.

16. A formulation according to any one of claims 1 to 14, wherein the second compartment has an internal filling density of 90% or more, and when the second compartment of the formulation is added to a test solution of 37°C and pH 6.8 in a rotating paddle device having paddles that rotate at 50 rpm, 60% or less of the total weight of the drug contained in the second compartment is released at 4 hours after administration of the formulation, and 85% or less of the total weight of the drug is released at 8 hours. 【

17. A formulation according to any one of claims 1 to 16, comprising 5 to 50 wt% of the drug and 50 to 95 wt% of the pharmaceutically acceptable additive based on the total weight of the formulation.

18. In any one of claims 1 to 17, a drug contained in the first compartment and the second compartment of the formulation and a pharmaceutical composition contained in the first compartment and the second compartment The weight ratio of the pharmaceutically acceptable excipients included is from 1:19 to 1:

1. 【Claim 1 A formulation according to any one of claims 1 to 18, wherein the pharmaceutically acceptable additives of the first compartment and the second compartment are at least one of a binder, an excipient, and a sustained-release agent. 【

20. A formulation according to any one of claims 1 to 19, wherein the drug contained in the first compartment and the second compartment is caffeine. 【

21. A formulation according to any one of claims 1 to 20, comprising 10 to 50 wt% of caffeine, 15 to 30 wt% of PVP (Polyvinylpyrrolidone), 20 to 50 wt% of MCC (Microcrystal 1 ine cel lulose), and 5 to 20 wt% of Eudragi t (Poly(meth)acrylate) based on the total weight of the formulation. 【

22. A formulation according to claim 21, comprising 30 wt% of caffeine, 20 wt% of PVP, 30 wt% of MCC, and 20 wt% of Eudragi t based on the total weight of the formulation. 【

23. In any one of claims 1 to 22, the first compartment and the second compartment are in a side-by-side form. 43 The one that is deployed, the preparation.

24. A formulation according to any one of claims 1 to 23, wherein the formulation is manufactured using 3D printing. 【

25. In claim 24, 3D printing is a manufacturing method that uses Material Extrusion. 【

26. A method for manufacturing a formulation according to any one of claims 1 to 25, said method comprising: (a) preparing a composition comprising one or more drugs and one or more pharmaceutically acceptable excipients; (b) a step of printing the composition using a 3D printer to laminate one of the first compartment and the second compartment; and (c) A method for manufacturing an oral administration preparation using 3D printing, comprising a step of sequentially stacking the remaining sections after step (b). 【

27. ​​A manufacturing method according to claim 26, wherein the internal filling densities of the first compartment and the second compartment are different from each other. 【

28. In claim 26 or 27, the internal filling density of the first compartment and the second compartment is from 25% to 100%.

44. Manufacturing method to be selected. 【Claim 2 A manufacturing method according to any one of claims 26 to 28, wherein the first compartment is selected from an internal filling density of 25% or more and 40% or less, and the second compartment is selected from an internal filling density of 50% or more and 100% or less.

30. A manufacturing method according to any one of claims 26 to 29, wherein the first compartment has an internal fill density of either 30% or 37%, and the second compartment has an internal fill density of either 50% or 90%.

31. A manufacturing method according to any one of claims 26 to 30, wherein the first compartment has an internal filling density of 30% and the second compartment has an internal filling density of 50%. 【

32. A manufacturing method according to any one of claims 26 to 31, wherein the first compartment has an internal filling density of 30% and the second compartment has an internal filling density of 90%. 【

33. A manufacturing method according to any one of claims 26 to 31, wherein the drug and pharmaceutically acceptable excipients contained in the first compartment and the second compartment are the same. 45

34. A manufacturing method according to any one of claims 26 to 33, wherein the drug and / or pharmaceutically acceptable additive included in the first compartment and the drug and / or pharmaceutically acceptable additive included in the second compartment are different.

35. A manufacturing method according to any one of claims 26 to 34, comprising 5 to 50 wt% of the drug and 50 to 95 wt% of the pharmaceutically acceptable additive based on the total weight of the formulation.

36. A manufacturing method according to any one of claims 26 to 35, wherein the weight ratio of the drug contained in the first compartment and the second compartment of the formulation and the pharmaceutically acceptable additive contained in the first compartment and the second compartment is 1:19 to 1:

1. 【

37. A manufacturing method according to any one of claims 26 to 36, wherein the pharmaceutically acceptable additives of the first compartment and the second compartment are at least one of a binder, an excipient, and a sustained-release agent. 【

38. A manufacturing method according to any one of claims 26 to 37, wherein the drug included in the first compartment and the second compartment is caffeine. 【Claim 3 A method for manufacturing a pharmaceutical composition according to any one of claims 26 to 38, wherein the composition of step (a) comprises 10 to 50 wt% of caffeine, 15 to 30 wt% of PVP, 20 to 50 wt% of MCC, and 5 to 20 wt% of Eudragit based on the total weight of the composition.

40. A manufacturing method according to claim 39, wherein the composition of step (a) comprises 30 wt% of caffeine, 20 wt% of PVP, 30 wt% of MCC, and 20 wt% of Eudragit based on the total weight of the composition.

41. A manufacturing method according to any one of claims 26 to 40, wherein the first compartment and the second compartment are arranged in a side-by-side configuration.

42. A pharmaceutical composition for preventing or treating jet lag, comprising a first compartment and a second compartment, wherein the first compartment and the second compartment each comprise at least one drug and at least one pharmaceutically acceptable additive.

43. A pharmaceutical composition according to claim 42, wherein the pharmaceutically acceptable additives of the first compartment and the second compartment are at least one of a binder, an excipient, and a sustained-release agent.

44. 47 A pharmaceutical composition according to claim 43, comprising 30 wt% of caffeine, 20 wt% of PVP, 30 wt% of MCC, and 20 wt% of Eudragit based on the total weight of the composition.

45. A food composition for preventing or improving jet lag, comprising a first compartment and a second compartment, wherein the first compartment and the second compartment each contain at least one drug and at least one pharmaceutically acceptable additive.

46. A food composition according to claim 45, comprising 30 wt% of caffeine, 20 wt% of PVP, 30 wt% of MCC, and 20 wt% of Eudragit based on the total weight of the composition.

47. A composition for application to a 3D printer, comprising caffeine and one or more pharmaceutically acceptable additives, wherein the pharmaceutically acceptable additives are one or more of a binder, an excipient, and a release-promoting agent. 【

48. A composition according to claim 47, wherein the composition comprises 30 wt% of caffeine, 20 wt% of PVP, 30 wt% of MCC, and 20 wt% of Eudragit based on the total weight of the composition.

Images