Controlled-release formulation for oral administration comprising melatonin, and preparation method therefor

Abstract

The present invention relates to an orally administered formulation comprising melatonin 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

[0004]

Background Art

[0005] [Patent Document] Korean Patent Publication No. 10-2023-0095364

[0006]

Contents of the invention

[0007]

Technical Challenges

[0008]

Technical Solution

[0009]

Effect of the invention

[0010]

Brief description of drawings

[0011]

Best Mode for Carrying Out the Invention

[0012] In a 5% aqueous solution, it can exhibit a viscosity of about 60 to 170 mPa-s, specifically 75 to 150 mP*. According to an embodiment of the present invention, the HPC can have a molecular weight of 85,000 Daltons to 100,000 Daltons, specifically 90,000 Daltons to 98,000 Daltons. According to an embodiment of the present invention, the HPC can have a diameter through which 85% (v / v) or more passes through a 30 mesh sieve, and 99% (v / v) or more can have a diameter through which 20 mesh sieve. In one embodiment of the present invention, the shell can further include one or more pharmaceutically acceptable additives such as a swelling agent, a disintegrant, and a plasticizer. Specifically, it may further include one or more of PE0 (Polyethylene Oxides), alginic acid, carrageenan, agarose, pectin, crospovidone, sodium starch glycolate, croscarmellose sodium, propylene glycol, polyethylene glycol, triacetin, glycerin, and triethyl citrate, and more specifically, it may further include one or more of PEO, croscarmellose sodium, and PEG4000 (Polyethylene Glycol 4000), and even more specifically, it may further include PEO, but is not limited thereto. In one embodiment of the present invention, a formulation manufactured using the polymer and / or pharmaceutically acceptable additives can maintain sufficient strength to maintain its structure during the production and distribution process of the formulation for a long period of time, has excellent storage stability, and after administration, the formulation swells and adheres to the gastric mucosa to exhibit an excellent delayed-release effect. Specifically, the formulation according to embodiments of the present invention swells to the extent that it is difficult to pass through the pylorus of the stomach, adheres to the gastric mucosa, and remains in the stomach for a long period of time, thereby easily controlling the desired release of the drug.In addition, in one embodiment of the present invention, the thickness of the shell including HPC as the polymer can be easily controlled and manufactured using 3D printing, thereby easily controlling the release delay time of the drug contained in the internal space. Specifically, the shell including HPC may further include one or more of PEO, croscarmellose sodium, and PEG4000, and the shell composition has printability suitable for outputting with a 3D printer, and a formulation 3D printed with the shell composition has excellent strength for a long period of time, and can exhibit the desired delayed-release and sustained-release characteristics of the formulation after administration. In one embodiment of the present invention, the internal space may include a drug and a pharmaceutically acceptable additive. The pharmaceutically acceptable additive may include a sustained-release agent, an excipient, and a binder, and specifically, may include an excipient and a sustained-release agent, more specifically, MCC (Microcrystal 1 ine cellulose) and HPMC. The drug may be included without limitation as long as it exhibits pharmacological activity, and specifically, it may include drugs such as melatonin and caffeine that have a short half-life and thus require sustained drug release to maintain a pharmacological effect, and more specifically, it may include melatonin, but is not limited thereto. In one embodiment of the present invention, the shell may not include a drug. In one embodiment of the present invention, the shell may further include one or more drugs, and the drugs included in the shell may be the same as or different from the drugs included in the internal space, and may have the same pharmacological activity or different pharmacological activity. For example, the drug included in the shell may be included without limitation as long as it exhibits pharmacological activity, and specifically, it may include drugs such as melatonin and caffeine that have a short half-life and thus require sustained drug release to maintain a pharmacological effect.In one embodiment of the present invention, there is provided an oral administration formulation comprising a shell comprising HPC; and an internal space surrounded by the shell, wherein the internal space comprises a drug, wherein the internal space may comprise only one or more drugs or may further comprise pharmaceutically acceptable additives together with the drugs, wherein the pharmaceutically acceptable additives may be excipients, sustained-release agents, or binders. In one embodiment of the present invention, there is provided an oral administration formulation comprising a shell comprising HPC; and an internal space surrounded by the shell, wherein the internal space comprises a drug, wherein the drug may be melatonin. In one embodiment of the present invention, the drug and / or pharmaceutically acceptable additives contained in the internal space may be in the form of a solid or liquid formulation. The above "solid formulation" means that the active ingredient and / or pharmaceutically acceptable additives are in a solid or semi-solid state, and the solid formulation can be selected from tablets, powders, capsules, granules, pastes, and hydrogels, and specifically, it can be a tablet, capsule, or powder, but is not limited thereto. For example, if the drug contained in the internal space is melatonin, the internal space can be a powder containing melatonin, or a powder, tablet, or capsule containing melatonin and pharmaceutically acceptable additives. The above "liquid formulation" means that the active ingredient and / or pharmaceutically acceptable additives are in a liquid state, and the liquid formulation can be in the form of a mixture of a drug and a liquid, and the solvent can be a fat-soluble solvent, but is not limited thereto. In one embodiment of the present invention, the internal space can contain 0.1 to 20 parts by weight, specifically, about 5 to 20 parts by weight, of a pharmaceutically acceptable additive per 1 part by weight of the drug.For example, the pharmaceutically acceptable additive may be present in an amount of about 5 parts by weight, about 6 parts by weight, about 7 parts by weight, about 8 parts by weight, about 9 parts by weight, about 10 parts by weight, about 11 parts by weight, about 12 parts by weight, about 13 parts by weight, about 14 parts by weight, about 15 parts by weight, about 16 parts by weight, about 17 parts by weight, about 18 parts by weight, about 19 parts by weight, and about 20 parts by weight, based on 1 part by weight of the drug. In one embodiment of the present invention, the shell may comprise HPC in an amount of at least 60 wt% based on the weight of the entire shell. In one embodiment of the present invention, the shell may comprise HPC in an amount of from 60 wt% to 99 wt% based on the weight of the entire shell. Specifically, the shell may comprise about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt%, about 80 wt%, about 85 wt%, about 90 wt%, about 95 wt%, and about 99 wt% of HPC based on the weight of the entire shell, and more specifically, about 90 wt%. In one embodiment of the present invention, the shell may comprise 90 wt% of HPC and 10 wt% of PEO based on the weight of the entire shell; and the inner space may comprise 0.1 to 20 parts by weight of a pharmaceutically acceptable additive with respect to 1 part by weight of the drug. In one embodiment of the present invention, the shell may comprise 90 wt% of HPC and 10 wt% of PEO based on the weight of the entire shell; and the inner space may comprise 5 to 9 parts by weight of a pharmaceutically acceptable additive with respect to 1 part by weight of melatonin. In one embodiment of the present invention, the shell may comprise 90 wt% of HPC and 10 wt% of PEO based on the weight of the entire shell; and the inner space may comprise 10 to 20 wt% of melatonin, 70 to 90 wt% of excipients, and more than 0 to 20 wt% of sustained-release agent based on the weight of the entire material contained in the inner space.In one embodiment of the present invention, the shell may comprise 90 wt% HPC and 10 wt% PEO, based on the weight of the entire shell; and the internal space may comprise 4 to 19 parts by weight of excipients and more than 0 to 5 parts by weight of a sustained-release agent, based on 1 part by weight of melatonin. In one embodiment of the present invention, the shell may comprise 90 wt% HPC and 10 wt% PEO, based on the weight of the entire shell; and the internal space may comprise 7 to 9 parts by weight of excipients and more than 0 to 2 parts by weight of a sustained-release agent, based on 1 part by weight of melatonin. In one embodiment of the present invention, the shell may have a thickness of 0.5 mm to 3.0 mm, specifically, 0.7 mm to 2.0 mm. For example, about 0.7 mm, about 0.8 mm, about 0.9 mm, about.

[0013] 1.0 mm, ] 2 1.1 mm, uh] 2 1.2 mm, uh] 2 1.3 mm, uh] 2 1.4 mm, uh] 2 1.5 mm, uh] 2 1.6 mm, uh]

[0014] It can be 1.7 mm, about 1.8 mm, about 1.9 mm or about 2.0 mm, more specifically about

[0015] 0.7 mm, about 1.0 mm, about 1.5 mm, or about 2.0 mm. In one embodiment of the present invention, the shell may comprise 90 wt% HPC and 10 wt% PEO based on the weight of the entire shell; and the inner space may comprise 5 to 9 parts by weight of a pharmaceutically acceptable additive with respect to 1 part by weight of melatonin, and the thickness of the shell may be 0.7 mm to 2.0 mm. In one embodiment of the present invention, the shell may comprise 90 wt% HPC and 10 wt% PEO based on the weight of the entire shell; and 4 to 19 parts by weight of an excipient and more than 0 to 5 parts by weight of an extended-release agent with respect to 1 part by weight of melatonin, and the thickness of the shell may be 0.7 mm to 2.0 mm. In one embodiment of the present invention, the shell may comprise 90 wt% HPC and 10 wt% PEO based on the weight of the entire shell; And 7 to 9 parts by weight of excipients and more than 0 to 2 parts by weight of sustained-release agent per 1 part by weight of melatonin, and the thickness of the shell may include 0.7 mm to 2.0 mm. In one embodiment of the present invention, the oral administration formulation may be a controlled-release formulation, specifically, a delayed-release and / or sustained-release formulation. The "controlled-release" means controlling the release rate of the active ingredient of the formulation, and the release may be used interchangeably with dissolution, and in the present invention, the controlled-release means delayed-release and / or sustained-release. The "delayed-release" means that the drug of the formulation is not released in the body for a certain period of time after taking the formulation. In one embodiment of the present invention, the drug in the internal space may be released 5 hours after taking the formulation. Specifically, the drug contained in the internal space of the formulation may be released in an amount of 5% or less of the total drug weight for 5 to 12 hours after taking the formulation.For example, the drug contained in the inner space may be released in an amount of 5% or less of the total weight over a period of about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12 hours, but is not limited thereto. The "sustained release" may mean that the release of the drug of the formulation proceeds slowly over a period of time or longer. In one embodiment of the present invention, the drug may be released from 4 hours to 12 hours from the start of the release of the drug in the inner space after taking the formulation, and specifically, it may include that 85% or more of the total weight of the drug in the inner space is released from 4 hours to 12 hours. For example, the drug in the inner space may be released for about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 11 hours, and about 12 hours after the drug release initiation, and more specifically, more than 85% of the total weight may be released, but is not limited thereto. In one embodiment of the present invention, the drug may be released in an amount of 5% by weight or less of the total weight of the drug from 5 hours to 12 hours after taking the formulation. In one embodiment of the present invention, the oral administration formulation may be included such that after taking the formulation, about 5% by weight to 50% by weight of the total weight of the drug from the inner space is released from 2 hours from the release initiation, and more than 85% of the total weight of the drug from the inner space is released from 4 hours to 12 hours from the release initiation. In one embodiment of the present invention, the oral administration formulation may include a formulation in which, when the formulation is added to a test solution at 37°C and pH 1.2 in a rotating paddle device having a paddle that rotates at 50 rpm, the drug contained in the internal space of the formulation is released in an amount of 5 wt% or less of the total weight of the drug over a period of 5 to 12 hours.In one embodiment of the present invention, the oral administration formulation may include a formulation in which, when the formulation is added to a test solution at 37°C and pH 1.2 in a rotating paddle device having a paddle that rotates at 50 rpm, about 5% to 50% by weight of the total weight of the drug in the internal space is released within 2 hours from the start of release, and more than 85% by weight of the total weight of the drug is released within 4 hours to 12 hours from the start of release. In the formulation according to the present invention, since the release of the drug in the internal space is delayed by about 5 hours to 12 hours, the effect of the drug (e.g., melatonin) present in the internal space of the formulation does not appear immediately after taking the formulation, so that the drug in the internal space of the formulation is delayed-released at a desired time so that the effect of the drug can be exhibited at a desired time. Specifically, the tablet according to embodiments of the present invention does not require taking the preparation according to the time at which the medicinal effect should appear, and even when taken together with a drug that should have a rapid medicinal effect, the medicinal effect appears after a certain period of time, thereby significantly improving the convenience of taking the medication for the patient. More specifically, when the drug in the inner space of the preparation is melatonin, the preparation of the embodiment of the present invention can be effectively applied to improving jet lag. For example, according to an embodiment of the present invention, when melatonin is included in the inner space of the preparation, melatonin can exert its pharmacological effect after a certain period of time when the preparation is taken, thereby effectively preventing or treating insomnia or sleep disorders due to jet lag while improving the convenience of taking the medication for the patient. In particular, when a preparation including melatonin in the inner space is taken together with a stimulant such as caffeine, drowsiness and fatigue can be minimized immediately after taking the preparation due to the stimulant ingredient such as caffeine, and after a certain period of time, melatonin is released, allowing sufficient sleep to be achieved.In embodiments of the present invention, when the drug contained in the internal space is melatonin, the formulation can be such that 5% or less of the drug contained in the internal space of the formulation is released for 8 to 12 hours after taking the formulation in the morning. Alternatively, when the formulation is taken in the afternoon, 5% or less of the drug contained in the formulation can be released for 5 to 8 hours. In addition, the formulation of the present invention provides sustained-release properties so that the drug release continues for about 4 to 12 hours from the start of drug release, and thus can be applied to drugs with a short half-life and a rapid disappearance of drug effect, so that the drug effect can be maintained for a desired period of time. In one embodiment of the present invention, the oral administration preparation may be included without limitation as long as it is in a form that can be administered orally, and specifically, the preparation may be in a form in which a drug can be contained in an internal space that is surrounded by a shell and is distinct from the outside, and more specifically, the oral administration preparation is in the form of a capsule, and even more specifically, may be in one of a disk shape, a fillet shape, and a round shape. The "disk shape (100)" may mean a preparation having a three-dimensional shape in which the upper part (130) and the lower part (120) of the preparation are oval-shaped, and the height (123) is shorter than the long axis (121) of the upper and lower ovals, as shown in FIG. The "fillet shape (200)" may mean a preparation having a three-dimensional shape in which the upper part (230) and the lower part (200) of the preparation are rectangles with curved corners, and the height (223) is shorter than the length of the width (221) of the upper and lower rectangles, as shown in FIG. The above "round type (300)" may mean a three-dimensional shape in which the upper part (330) and the lower part (320) of the formulation are rectangles in the form of semicircles rather than straight lines, as shown in Fig. 1c, and the height (323) is shorter than the horizontal length (321) of the upper and lower rectangles.In one embodiment of the present invention, the oral administration preparation may include one manufactured using 3D printing. The 3D printing may be one of Material Extrusion, Vat Polymer Ization, 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, comprising: a shell including HPC; and an internal space surrounded by the shell, wherein the internal space includes melatonin. The melatonin may include melatonin, a pharmaceutically acceptable salt thereof, an optical isomer thereof, a hydrate or solvate thereof, or a mixture thereof. The shell can delay the release of the drug located in the internal space formed by the shell for a desired time by controlling the thickness of the shell, and the present invention can delay the release of the drug for about 5 to 12 hours. In addition, the internal space formed by the shell is an empty space, which can enable the formulation to remain in the stomach, and in order to induce the desired delayed-release time with the gastric retention properties, the shell can be manufactured in a size that can be easily administered orally without excessively increasing the thickness of the shell. In one embodiment of the present invention, the shell can further include one or more pharmaceutically acceptable additives such as a swelling agent, a disintegrating agent, and a plasticizer.Specifically, it may further include one or more of PEO, alginic acid, carrageenan, agarose, pectin, crospovidone, sodium starch glycolate, croscarmellose sodium, propylene glycol, polyethylene glycol, triacetin, glycerin, and triethyl citrate, and more specifically, it may further include one or more of PEO, croscarmellose sodium, and PEG4000, and even more specifically, it may further include PEO, but is not limited thereto. In one embodiment of the present invention, the inner space may include melatonin and a pharmaceutically acceptable additive. The pharmaceutically acceptable additive includes a sustained-release agent, an excipient, and a binder, and specifically, it may include a sustained-release agent, an excipient, and more specifically, MCC, HPMC, but is not limited thereto. In one embodiment of the present invention, the shell may not include a drug. In one embodiment of the present invention, the shell may further include one or more drugs, and the drugs contained in the shell may be the same as or different from the drugs contained in the inner space, and may have the same pharmacological activity or different pharmacological activity. For example, the drugs contained in the shell may be included without limitation as long as they exhibit pharmacological activity, and specifically, may include drugs such as melatonin and caffeine, which have a short half-life and require sustained drug release to maintain a pharmacological effect. In one embodiment of the present invention, a pharmaceutical composition comprising a shell including HPC; and an inner space surrounded by the shell, wherein the inner space includes melatonin, wherein the inner space may further include a pharmaceutically acceptable additive together with melatonin, and wherein the pharmaceutically acceptable additive may be a sustained-release agent. In one embodiment of the present invention, the drug and / or pharmaceutically acceptable additive contained in the inner space may be in the form of a solid or liquid formulation.The above solid may be selected from tablets, powders, capsules, granules, pastes, and hydrogels, and specifically, may be tablets, capsules, or powders, but is not limited thereto. The above liquid may be a fat-soluble solvent, but is not limited thereto. In one embodiment of the present invention, the inner space may contain 0.1 to 20 parts by weight of a pharmaceutically acceptable additive relative to 1 part by weight of melatonin. Specifically, it may be 5 to 9 parts by weight. In one embodiment of the present invention, the shell may contain HPC in an amount of 60 wt% or more based on the weight of the entire shell. In one embodiment of the present invention, the shell may contain HPC in an amount of 60 wt% to 99 wt% based on the weight of the entire shell. Specifically, the shell may comprise about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt%, about 80 wt%, about 85 wt%, about 90 wt%, about 95 wt%, and about 99 wt% of HPC based on the weight of the entire shell, and more specifically, about 90 wt%. In one embodiment of the present invention, the shell may comprise 90 wt% of HPC and 10 wt% of PEO based on the weight of the entire shell; and the inner space may comprise 0.1 to 20 wt% of a pharmaceutically acceptable additive relative to 1 part by weight of melatonin. In one embodiment of the present invention, the shell may comprise 90 wt% of HPC and 10 wt% of PEO based on the weight of the entire shell; and the inner space may comprise 5 to 9 wt% of a pharmaceutically acceptable additive relative to 1 part by weight of melatonin. In one embodiment of the present invention, the shell may comprise 90 wt% of HPC and 10 wt% of PEO based on the weight of the entire shell; and the inner space may comprise 10 to 20 wt% of melatonin, 70 to 90 wt% of excipients, and more than 0 to 20 wt% of sustained-release agent based on the weight of the entire material contained in the inner space.In one embodiment of the present invention, the shell may comprise 90 wt% HPC and 10 wt% PEO, based on the weight of the entire shell; and the internal space may comprise 4 to 19 wt% of excipients and more than 0 to 5 wt% of sustained-release agent, based on 1 wt% of melatonin. In one embodiment of the present invention, the shell may comprise 90 wt% HPC and 10 wt% PEO, based on the weight of the entire shell; and the internal space may comprise 7 to 9 wt% of excipients and more than 0 to 2 wt% of sustained-release agent, based on 1 wt% of melatonin. In one embodiment of the present invention, the thickness of the shell may be 0.5 mm to 3.0 mm, specifically 0.7 mm to 2.0 mm. For example, about 0.7 mm, about 0.8 mm, about 0.9 mm, about.

[0016] 1.0 mm, ] 2 1.1 mm, uh] 2 1.2 mm, uh] 2 1.3 mm, uh] 2 1.4 mm, uh] 2 1.5 mm, uh] 21.6 mm, 1.7 mm, about 1.8 mm, about 1.9 mm or about 2.0 mm, and more specifically, about 0.7 mm, about 1.0 mm, about 1.5 mm or about 2.0 mm. In one embodiment of the present invention, the shell comprises 90 wt% of HPC and 10 wt% of PEO based on the weight of the entire shell; and the inner space comprises 5 to 9 wt% of a pharmaceutically acceptable additive with respect to 1 wt% of melatonin, and the thickness of the shell is 0.7 mm to 2.0 mm. In one embodiment of the present invention, the shell comprises 90 wt% of HPC and 10 wt% of PEO based on the weight of the entire shell; And 4 to 19 parts by weight of excipients and more than 0 to 5 parts by weight of sustained-release agent per 1 part by weight of melatonin, and the thickness of the shell may be 0.7 mm to 2.0 mm. In one embodiment of the present invention, the shell may include 90 wt% of HPC and 10 wt% of PEO based on the total weight of the shell; and 7 to 9 parts by weight of excipients and more than 0 to 2 parts by weight of sustained-release agent per 1 part by weight of melatonin, and the thickness of the shell may be 0.7 mm to 2.0 mm. In one embodiment of the present invention, the pharmaceutical composition may be for controlled release, and specifically, may be for delayed release and / or sustained release. In one embodiment of the present invention, the pharmaceutical composition may include that melatonin contained in the internal space is released in an amount of 5 wt% or less of the total weight of melatonin for 5 to 12 hours after administration. In one embodiment of the present invention, the pharmaceutical composition may include a composition in which about 5% to 50% by weight of the total weight of the drug is released from the internal space within 2 hours from the start of release of melatonin after administration, and more than 85% of the total weight of melatonin is released from 4 hours to 12 hours from the start of release of melatonin in the internal space.In one embodiment of the present invention, the pharmaceutical composition may comprise, when added to a test solution at 37°C and pH 1.2 in a rotating paddle device having a paddle that rotates at 50 rpm, melatonin contained in the inner space is released in an amount of 5 wt% or less of the total weight of melatonin for 5 to 12 hours. In one embodiment of the present invention, the pharmaceutical composition may comprise, when added to a test solution at 37°C and pH 1.2 in a rotating paddle device having a paddle that rotates at 50 rpm, melatonin in the inner space is released in an amount of about 5 wt% to 50 wt% of the total weight of the drug for 2 hours from the start of release, and melatonin in the inner space is released in an amount of 85% or more of the total weight of melatonin for 4 to 12 hours. According to one embodiment of the present invention, a formulation containing melatonin in an inner space exhibits a high swelling rate under a test solution of pH 1.2, exhibits excellent physical strength, and can maintain its shape with excellent adhesiveness without the formulation being separated (Experimental Example 1, Figs. 3 to 5). According to one embodiment of the present invention, when the shell of the formulation containing melatonin in an inner space includes HPC or a mixture of HPC and PEO, when the release rate is measured under a test solution dissolution condition of pH 1.2, the release of melatonin begins after 5 hours (for example, after 8 hours or 8 hours), and the release of melatonin can continue for 4 to 11 hours from the start of the release (Experimental Example 2 and Fig. 6). According to one embodiment of the present invention, the formulation containing melatonin in an inner space can exhibit different delayed-release and sustained-release patterns by adjusting the thickness of the shell even though the shell is formed of the same material. Specifically, by adjusting the thickness of the shell, the onset of melatonin release can be set to a range of 5 to 12 hours, and the duration of melatonin release can be maintained for 4 to 11 hours (Experimental Example 3 and Fig. 7).According to one embodiment of the present invention, even if the shape of the formulation is changed, melatonin in the internal space can exhibit excellent delayed-release and sustained-release (Experimental Example 4 and FIGS. 8 and 9). The present invention provides a kit containing a formulation 1 for oral administration, which comprises a shell including HPC and an internal space surrounded by the shell, wherein the internal space includes melatonin; and formulation 2 including a drug exhibiting activity different from melatonin. In one embodiment of the present invention, formulation 1 for oral administration, which comprises a shell including HPC and an internal space surrounded by the shell, wherein the internal space includes melatonin, may be substantially the same as described above unless they are contradictory to each other. In one embodiment of the present invention, formulation 2 including a drug exhibiting activity different from melatonin in the kit may be an immediate-release formulation. As previously discussed, Formulation 1 and Formulation 2 can be administered simultaneously, and when Formulation 2 is an immediate-release formulation, when Formulation 1 and Formulation 2 are taken simultaneously in the kit, the pharmacological effect according to the drug included in Formulation 2 can appear immediately, and the pharmacological effect according to melatonin included in Formulation 2 can appear after 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 an immediate-release formulation containing a stimulant such as caffeine. According to one embodiment of the present invention, when the preparations of the kit, which are immediate-release preparations containing a stimulant such as caffeine, are taken simultaneously upon arrival in a region with a time difference, the pharmacological effect of preparation 2, which is an stimulant effect, appears immediately, thereby minimizing symptoms such as drowsiness and fatigue during the day and reducing inconvenience in activities, and during sleep time, the release of melatonin, which is a drug of preparation 1, is initiated, and melatonin is continuously released during sleep time, thereby preventing or treating sleep disorders such as insomnia caused by jet lag.In addition, Formulation 1 can control the start time of drug release by controlling the thickness of the shell of the formulation, and a patient with jet lag can take the formulation of the kit by selecting Formulation 1 having a shell thickness that indicates the desired release time of melatonin according to the time of arrival in an area where jet lag exists (for example, 10:00 AM or 4:00 PM) for the prevention or treatment of jet lag, thereby significantly improving the convenience of taking medication for the patient. The present invention provides a method for producing the oral administration formulation. The present invention relates to a method for producing an oral administration formulation using 3D printing, including the steps of (a) producing a shell composition including HPC; (b) producing a structure having an open top by melting and outputting the shell composition using a 3D printer; (c) injecting a drug into the internal space of the structure through the open top; and (d) forming a cover covering the top of the structure by melting and outputting the shell composition using a 3D printer.

[0017] 3D printing is a technology that enables the production of small quantities of various products that can be customized for each individual. It includes Material Extrusion, Vat Polymerization, Powder Bed Fusion,

[0018] There are various methods such as Material / Binding Jetting. The above 3D printing is Material Extrusion, Vat Polymerization, Powder Bed

[0019] It can be one of Fusion, Material / Binding Jetting, specifically Material

[0020] Extrusion may be, but is not limited thereto. In the step (a), the shell composition may further include a step of having a uniform particle size distribution through a mesh. For example, the mesh may be, but is not limited thereto. In the step (b), the heating temperature during melting may be, but is not limited to, 130 °C to 180 。in. In the step (b), the extrusion speed may be, but is not limited to, 2 to 10 mm / s. In the step (c), the step of injecting the drug and pharmaceutically acceptable additives into the formulation may include, but is not limited to, pausing the 3D printer for 30 to 60 seconds. The method for manufacturing a formulation according to the present invention uses a method in which the shell composition is mixed in powder form and directly fed into the silo of a 3D printer, and then melted and printed from a nozzle, rather than being manufactured into a filament, so that the manufacturing process is simple, and it has the advantage of being able to apply polymers that are not suitable for filaments and pharmaceutically acceptable additives. 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 can use relatively heat-sensitive raw materials because heat is applied only during the printing process. Therefore, it is free in the use of raw materials, and since there is no cost for manufacturing filament, there is an advantage in terms of cost. The 3D printing method can manufacture a formulation customized to the individual, taking into account the severity of the disease, the timing and dosage of the drug administration, etc. Accordingly, the present invention can provide a customized formulation so that patients suffering from jet lag can appropriately select it according to the arrival time of the jet lag area by manufacturing formulations with different shell thicknesses using a 3D printer. In one embodiment of the present invention, the shell may further include one or more pharmaceutically acceptable additives such as a swelling agent, a disintegrating agent, and a plasticizer.Specifically, it may further include one or more of PEO, alginic acid, carrageenan, agarose, pectin, crospovidone, sodium starch glycolate, croscarmellose sodium, propylene glycol, polyethylene glycol, triacetin, glycerin, and triethyl citrate, and more specifically, it may further include one or more of PEO, croscarmellose sodium, and PEG4000, and even more specifically, it may further include PEO, but is not limited thereto. In one embodiment of the present invention, a formulation manufactured using the polymer and / or a pharmaceutically acceptable additive can maintain sufficient strength for a long period of time to maintain its structure during the production and distribution process of the formulation, has excellent storage stability, and after taking the formulation, swells and adheres to the gastric mucosa to exhibit an excellent delayed-release effect. Specifically, the formulation according to the embodiments of the present invention swells to the extent that it is difficult to pass through the pylorus of the stomach, adheres to the gastric mucosa, and remains in the stomach for a long period of time, thereby easily controlling the desired release of the drug. In addition, in one embodiment of the present invention, the thickness of the shell including HPC as the polymer can be easily controlled and manufactured using 3D printing, and accordingly, the delayed release time of the drug contained in the internal space can be easily controlled. Specifically, the shell including the HPC may further include one or more of PEO, croscarmellose sodium, and PEG4000, and the shell composition has printability suitable for printing with a 3D printer, and a formulation 3D printed with the shell composition has excellent strength for a long period of time, and can exhibit the desired delayed-release and sustained-release properties of the formulation after administration. In one embodiment of the present invention, the internal space may include a drug and a pharmaceutically acceptable additive.The pharmaceutically acceptable additives include a sustained-release agent, an excipient, and a binder, and specifically, a sustained-release agent, and more specifically, MCC and HPMC may be included. 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 and caffeine, and thus requires sustained drug release to maintain a pharmacological effect, and more specifically, it may include melatonin, but is not limited thereto. In one embodiment of the present invention, the shell may not include a drug. In one embodiment of the present invention, the shell may further include one or more drugs, and the drugs included in the shell may be the same as or different from the drugs included in the inner space, and may have the same pharmacological activity or different pharmacological activity. For example, the drug included in the shell may be a drug that has a short half-life, such as melatonin and caffeine, and thus requires sustained drug release to maintain a pharmacological effect. In one embodiment of the present invention, a shell including HPC; And an internal space surrounded by the shell, wherein the internal space contains a drug, and the internal space may contain only one or more drugs or may further contain pharmaceutically acceptable additives together with the drugs, wherein the pharmaceutically acceptable additives may be excipients, binders, or sustained-release agents. In one embodiment of the present invention, there is provided an oral administration formulation comprising a shell comprising HPC; and an internal space surrounded by the shell, wherein the internal space contains a drug, wherein the drug may be melatonin. In one embodiment of the present invention, the drug and / or pharmaceutically acceptable additives contained in the internal space may be in the form of a solid or liquid formulation. The solid formulation may be selected from a tablet, a powder, a capsule, a granule, a paste, and a hydrogel, and specifically may be, but is not limited to, a tablet, a capsule, or a powder.The liquid formulation may be, but is not limited to, a lipid-soluble solvent. In one embodiment of the present invention, the inner space may contain 0.1 to 20 parts by weight of a pharmaceutically acceptable additive per 1 part by weight of the drug. Specifically, it may be about 5 to 9 parts by weight. In one embodiment of the present invention, the shell may contain HPC in an amount of 60 wt% or more based on the weight of the entire shell. In one embodiment of the present invention, the shell may contain HPC in an amount of 60 wt% to 99 wt% based on the weight of the entire shell. Specifically, the shell may contain HPC in an amount of about 60 wt%, about 65 wt%, about 70 wt%, about 75 wt%, about 80 wt%, about 85 wt%, about 90 wt%, about 95 wt%, and about 99 wt%, and more specifically, about 90 wt%. In one embodiment of the present invention, the shell may comprise 90 wt% of HPC and 10 wt% of PEO based on the weight of the entire shell; and the inner space may comprise 5 to 9 wt% of a pharmaceutically acceptable additive relative to 1 wt% of the drug. In one embodiment of the present invention, the shell may comprise 90 wt% of HPC and 10 wt% of PEO based on the weight of the entire shell; and the inner space may comprise 5 to 9 wt% of a pharmaceutically acceptable additive relative to 1 wt% of melatonin. In one embodiment of the present invention, the shell may comprise 90 wt% of HPC and 10 wt% of PEO based on the weight of the entire shell; and the inner space may comprise 10 to 20 wt% of melatonin, 70 to 90 wt% of an excipient, and more than 0 to 20 wt% of an extended-release agent based on the weight of the entire material contained in the inner space. In one embodiment of the present invention, the shell may comprise 90 wt% of HPC and 10 wt% of PEO based on the weight of the entire shell; And the inner space may contain 4 to 19 parts by weight of excipients and more than 0 to 5 parts by weight of sustained-release agent per 1 part by weight of melatonin.In one embodiment of the present invention, the shell may comprise 90 wt% of HPC and 10 wt% of PEO based on the weight of the entire shell; and the inner space may comprise 7 to 9 wt% of excipients and 0 to 2 wt% of sustained-release agent based on 1 wt% of melatonin. In one embodiment of the present invention, the thickness of the laminated shell in step (b) may be 0.5 mm to 3.0 mm, specifically 0.7 mm to 2.0 mm. For example, it may be about 0.7 mm, about 0.8 mm, about 0.9 mm, about 1.0 mm, about 1.1 mm, about 1.2 mm, about 1.3 mm, about 1.4 mm, about 1.5 mm, about 1.6 mm, about 1.7 mm, about 1.8 mm, about 1.9 mm or about 2.0 mm, and more specifically, it may be about 0.7 mm, about 1.0 mm, about 1.5 mm or about 2.0 mm. In one embodiment of the present invention, the shell may comprise 90 wt% of HPC and 10 wt% of PEO based on the weight of the entire shell; and the inner space may comprise 5 to 9 wt% of a pharmaceutically acceptable additive per 1 wt% of melatonin, and the thickness of the shell may be 0.7 mm to 2.0 mm. In one embodiment of the present invention, the shell may comprise 90 wt% of HPC and 10 wt% of PEO based on the weight of the entire shell; and the internal space may comprise 4 to 19 wt% of excipients and more than 0 to 5 wt% of sustained-release agent with respect to 1 wt% of melatonin, and the thickness of the shell may be 0.7 mm to 2.0 mm. In one embodiment of the present invention, the shell may comprise 90 wt% of HPC and 10 wt% of PEO based on the weight of the entire shell; and the internal space may comprise 7 to 9 wt% of excipients and more than 0 to 2 wt% of sustained-release agent with respect to 1 wt% of melatonin, and the thickness of the shell may be 0.7 mm to 2.0 mm.In one embodiment of the present invention, the formulation manufactured by the above manufacturing method may be a controlled-release formulation, and specifically, may be a sustained-release and / or sustained-release formulation. In one embodiment of the present invention, the formulation manufactured by the above manufacturing method may include a formulation in which the drug contained in the internal space of the formulation is released in an amount of 5 wt% or less of the total drug weight from 5 hours to 12 hours after taking the formulation. In one embodiment of the present invention, the formulation manufactured by the above manufacturing method may include a formulation in which the drug in the internal space is released in an amount of about 5 wt% to 50 wt% of the total drug weight from 2 hours from the start of release of the drug after taking the formulation, and in which 85% or more of the total drug weight of the drug in the internal space is released from 4 hours to 12 hours from the start of release. In one embodiment of the present invention, the formulation manufactured by the above manufacturing method may include a drug contained in the inner space of the formulation that is released in an amount of 5 wt% or less of the total weight of the drug for 5 to 12 hours when the formulation is added to a test solution at 37°C and pH 1.2 in a rotating paddle device having paddles that rotate at 50 rpm. In one embodiment of the present invention, the formulation manufactured by the above manufacturing method may include a drug contained in the inner space that is released in an amount of about 5 wt% to 50 wt% of the total weight of the drug for 2 hours from the start of release and more than 85% of the total weight of the drug for 4 to 12 hours from the start of release when the formulation is added to a test solution at 37°C and pH 1.2 in a rotating paddle device having paddles that rotate at 50 rpm. In one embodiment of the present invention, the preparation manufactured by the above manufacturing method may be included without limitation as long as it is in a form that can be administered orally, and specifically, the preparation for oral administration may be in the form of a capsule, and more specifically, may be in one of the forms of a disk shape, a fillet shape, or a round shape.The description of the preparation examined above can be substantially identically applied to the above manufacturing method as long as it is not contradictory. The present invention relates to a food composition for preventing or improving jet lag, comprising a shell including HPC; and an internal space surrounded by the shell, wherein the internal space includes melatonin. The term "improvement" includes all acts in which a disease is improved or beneficial by administration of the composition. The term "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 shell comprises 90 wt% of HPC and 10 wt% of PEO based on the total weight of the shell; And the inner space may contain 10 to 20 wt% of melatonin, 70 to 90 wt% of excipients, and more than 0 to 20 wt% of sustained-release agent based on the total weight of the material contained in the inner space. In one embodiment of the present invention, the shell may contain 90 wt% of HPC and 10 wt% of PEO based on the total weight of the shell; and the inner space may contain 4 to 19 wt% of excipients and more than 0 to 5 wt% of sustained-release agent with respect to 1 part by weight of melatonin. In one embodiment of the present invention, the shell may contain 90 wt% of HPC and 10 wt% of PEO based on the total weight of the shell; and the inner space may contain 7 to 9 wt% of excipients and more than 0 to 2 wt% of sustained-release agent with respect to 1 part by weight of melatonin. The descriptions of the preparation, pharmaceutical composition, and manufacturing method described above may be substantially identically 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, which comprises HPC and a pharmaceutically acceptable additive, and the pharmaceutically acceptable additive is selected from one or more of PEO, sodium croscarmellose, and PEG4000. In one embodiment of the present invention, the composition for application to the 3D printer may comprise HPC and PEO. In one embodiment of the present invention, the composition for application to the 3D printer may comprise 60% by weight or more of HPC based on the total weight of the composition. In one embodiment of the present invention, the composition for application to the 3D printer may comprise 60% to 99% by weight of HPC based on the total weight of the composition. Specifically, based on the total weight of the composition, HPC may be about 60% by weight, about 65% by weight, about 70% by weight, about 75% by weight, about 80% by weight, about 85% by weight, about 90% by weight, about 95% by weight, and about 99% by weight, and more specifically, about 90% by weight. In one embodiment of the present invention, the composition for application to the 3D printer may comprise 90% by weight of HPC and 10% by weight of PEO based on the total weight of the composition. The composition according to one embodiment of the present invention melts at a viscosity suitable for output at a heating temperature of 130 °C to 180 °C, which is the heating temperature of the nozzle part of the 3D printer, and at the time of output, the output may have an adhesive force such that the output can adhere to the bed of the 3D printer. The output produced from the composition may not cause a phenomenon in which the output separates and moves from the bed during the manufacturing process of the preparation, and the layers of the output can be stacked in the shape of the desired preparation, so that when applied to a 3D printer, the output performance and the manufacturing suitability of the preparation are significantly excellent.The oral administration preparation, pharmaceutical composition and food composition comprising the composition for application to a 3D printer according to an 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 (delayed release and sustained release) even after administration. In addition, the oral administration preparation, pharmaceutical composition and food composition comprising the composition manufactured with a 3D printer can significantly improve the convenience of patient medication by allowing the efficacy of melatonin to appear after a certain period of time even if melatonin and other active ingredients such as stimulants are taken together immediately upon arrival in a region with a time difference.

[0021] [National Research and Development Project Supporting This Invention]

[0022] [Task Unique 1415173636

[0023] [Task number 20015288

[0024] [Ministry Name] Ministry of Trade, Industry and Energy

[0025] [Name of Project Management (Specialist) Institution] Korea Institute of Industrial Technology Planning and Evaluation

[0026] [Research Project Name] Bioindustry Technology Development (R&D)

[0027] [Research Project Name] Development of Customized Dosage-Adjustable Oral Medicines Based on 3D Printing Technology

[0028] [Contribution rate] 1 / 1

[0029] [Project Implementing Organization Name] Dong-A Pharmaceutical Co., Ltd. [Research Period] April 1, 2021 – December 31, 2025

[0030] [Form for carrying out the invention] An oral administration formulation according to an embodiment of the present invention will be described in more detail with reference to the drawings below. The oral administration formulation illustrated in the drawings only illustrates one specific example of the formulation according to an embodiment of the present invention, and the present invention is not limited to the structure illustrated in the drawings. FIG. 1A, FIG. 1B, and FIG. 1C are diagrams showing the shape of a formulation according to an embodiment of the present invention. Referring to FIG. 1A, the formulation (100) is composed of a shell surrounding a lower portion (120), an upper portion (130), and an internal space (110). Here, the "internal space (110)" refers to a three-dimensional empty space formed at a predetermined thickness (dll to 13) from the outermost portions of the lower portion, upper portion, and side surfaces of the formulation (100). In addition, the "shell" refers to a structure surrounding the internal space created by stacking layers output from a 3D printer according to a preset software design. In the above diagram la, the thickness of the formulation (dll to 13) may be different from each other, and may be all the same or different. In the above diagram la, a drug may be positioned in the internal space, and the release rate of the drug in the internal space may be controlled by controlling the thickness of the shell, and a certain amount of empty space exists in the internal space, so that when the formulation of diagram la is taken, the formulation swells, and the drug may be released over a long period of time. The above description of the structure of the la formulation is substantially equally applicable to the remaining embodiments, i.e., the formulation (100), lower portion (120), upper portion (130), internal space (110), and thickness (dll to dl3) in the la formulation can also be substantially equally applied to the formulations (200, 300), lower portion (220, 320), upper portion (230, 330), internal space (210, 220), and thickness (d21 to d23, d31 to d33) in the lb formulation and the lc formulation as long as they are not contradictory to each other.The descriptions in the formulations, pharmaceutical compositions, food compositions and manufacturing methods discussed above, unless they are contradictory, can be substantially equally applied to the formulations (100, 200, 300), the lower part of the shell (120, 220, 320), the upper part of the shell (130, 230, 330), the internal space of the shell (110, 210, 220), the thickness of the shell (dll to dl3, d21 to d23, d31 to d33), the drug contained in the internal space and / or the shell, the release of the drug from the formulation, etc., as shown in FIG. 2. FIG. 2 exemplarily illustrates a method for manufacturing a formulation according to FIG. 2. Referring to FIG. 2, the formulation of the present invention comprises: (1) a step of melting and outputting a shell composition mounted on a 3D printer; (2) a step of stacking a lower part (120) of the formulation having a predetermined thickness (dll); (3) A step of forming a structure having an internal space (110) by printing only a perimeter of a certain thickness (dl2); (4) A step of temporarily stopping the printer and then loading a drug and / or a pharmaceutically acceptable additive into the internal space (110); and (5) A step of operating the printer again after loading the drug and / or the pharmaceutically acceptable additive to laminate the upper part (130) to a certain thickness (dl3). The description of FIG. 2 is also merely an example of the form of FIG. 1a, and the manufacturing method according to FIG. 2 can be substantially equally applied to the formulations according to FIG. 1b and FIG. 1c as long as they are not contradictory, and is not limited to the structure. In addition, the descriptions of the formulations, pharmaceutical compositions, food compositions, and manufacturing methods examined above can be substantially equally applied to the manufacturing method of FIG. 2 as long as they are not contradictory. Hereinafter, the following examples are presented to explain the present invention in more detail. However, the following examples are merely illustrative of the present invention, and the content of the present invention is not limited to the examples disclosed below.A shell composition for manufacturing a formulation using the compositions of Examples 1 to 3 and a 3D printer was manufactured. Specifically, a mixture of a composition according to the following Table 1 was mixed in a V-MIXER for 20 minutes at 90 rpm to manufacture a homogeneously mixed composition of Examples 1 to 3. The HPC used in this example is HPC_LF (Manufacturer: Ashland co. Ltd., Trade name: Klucel), and the HPC_LF used has a molecular weight (MW) of 95,000 Daltons, a viscosity of 75-150 mPa-s (Measurement conditions: Brookfield LVF viscometer, 25 °C, 5% aqueous solution), and a particle size of which 85% or more passes through a 30 mesh sieve and 99% or more passes through a 20 mesh sieve. In order to manufacture the formulation using the compositions of Examples 1 to 3, a self-made 3D printer was used, and the formulation was modeled using 3D printing slicer software. The 3D printing of the present invention was performed using a Screw Direct Powder One Nozzle. The compositions of Examples 1 to 3 manufactured above were put into the 3D printer, and the lower part and the side perimeter of the shell were printed according to the conditions of Table 2 below, and before printing the upper part, printing was temporarily stopped, and then a mixture of melatonin and microcrystalline cellulose was injected into the internal space. The mixture injected into the internal space was manufactured with a composition of 9 parts by weight of microcrystalline cellulose per 1 part by weight of melatonin. After the injection of the mixture of melatonin and excipients was completed, printing of the upper part of the shell was completed, thereby manufacturing the formulation.

[0031] Table 11

[0032] Table 2 Manufacturing of formulations using a 3D printer of Examples 4 to 10 The compositions of Examples 4 to 10 were manufactured with the same composition as the composition of Example 2 of Table 1 above, and the manufacturing method of the formulations was also manufactured in substantially the same manner as the manufacturing method of Examples 1 to 3, except that the output conditions of Table 3 below were used.

[0033] Table 3 <Experimental Example 1> Evaluation of physical properties of the formulation

[0034] To evaluate the physical stability of Examples 1 to 3 manufactured through 3D printing, the swelling ratio, physical strength, and adhesive strength were evaluated. Swelling ratio W evaluation Swelling ratio is based on the diagonal length of the formulation before swelling, and the ratio of the increased diagonal length of the formulation compared to before putting it into the solution is evaluated by measuring the length of the formulation after 30 minutes and 1 hour under the conditions of the dissolution test solution (pHl .2), and the results are shown in Fig. 3. As confirmed in Fig. 3, Example 1 showed the highest swelling ratio of 130% after 1 hour, and Examples 2 and 3 showed similar results at 120%. Physical strength (mm) evaluation The physical strength was measured using a Texture Analyzer (TA. XTplusC) under the conditions of detection speed 200 / s and test speed 0.5 mm / s. When a pressure of 0.65 N was applied, the depth to which the formulation was pressed was measured, and the results are shown in Fig. 4. As can be seen in Fig. 4, it was confirmed that the physical strength decreased as the content of PEO increased. In other words, Example 3, which did not contain PEO, was the hardest, and Example 1, which had a PEO content of 32 wt%, had the lowest strength. Adhesion (N) Evaluation The adhesion was measured using the same device as the physical strength measurement, and the measurement conditions were as follows. The maximum value of the (-) force applied when the formulation was detached after being adhered to the probe was measured under the conditions of a detection speed of 200 / s and a test speed of 0.5 mm / s, and the results are shown in Fig. 5. As can be seen in Fig. 5, the adhesion was the highest in Example 3, and decreased in the order of Example 2 and Example 1. That is, the adhesion increased as the content of PEO included in the shell decreased (Fig. 5). However, it was confirmed that this was not a significant difference as in the swelling ratio.

[0035] <Experimental Example 2> Evaluation of in-vitro release characteristics according to shell composition Melatonin dissolution characteristics of the formulations of Examples 1, 2, and 3 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 1.2 using a dissolution tester, and the test solution was collected at 1-hour intervals for 0 to 27 hours, and the released melatonin 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. As a result of evaluating the dissolution characteristics of the formulations of Examples 1, 2, and 3, it was confirmed that the release was delayed for a certain period of time in all three compositions, and it was also confirmed that a sustained-release characteristic in which the drug was slowly released after the initiation of release was exhibited. Specifically, as confirmed in Fig. 6, Example 1 delayed the release for up to 8 hours, and about 85% of the drug was released 9 hours after the initiation of the release of melatonin, and the release of the drug was completed after 10 hours. In addition, Example 2 delayed the release for up to 9 hours, and about 85% of the melatonin was released 11 hours after the initiation of release, and Example 3 started the release after 12 hours, and about 85% of the melatonin was released 11 hours thereafter. It was confirmed that all of the above example compositions were capable of delayed release and sustained-release of the drug.

[0036] <Experimental Example 3> Evaluation of in-vitro release characteristics according to shell thickness Formulations having the same composition as the shell composition of Example 2, but having thicknesses of 1.0 mm (Experimental Example 4) and 1.5 mm (Experimental Example 5) and having a disk shape were manufactured according to the method described above under the conditions of Table 3. The evaluation of release characteristics was performed on the formulations of Examples 2, 4, and 5, and was carried out in the same manner as in Experimental Example 2, and the results are shown in Fig. 7. As confirmed in Fig. 7, it was confirmed that the release could be delayed for 5 to 12 hours depending on the thickness of the shell. In Example 2, which had the thickest shell thickness of 2 mm, melatonin release started after 11 to 12 hours, 85% of the drug was released after 8 hours from the start of release, and release was completed after 10 hours. Example 4, in which the shell thickness was 1 mm, the drug release commenced after 5 hours and continued for 6 hours from the initiation of drug release, so that 85% of the drug was released 6 hours after the release of melatonin, and the drug release was completed 7 hours after the initiation of drug release. Example 5, in which the shell thickness was 1.5 mm, the drug release commenced after 8 to 10 hours and continued for 10 to 11 hours.

[0037] <Experimental Example 4> Evaluation of release characteristics according to the shape of the formulation Evaluation of in-vitro release characteristics according to the shape of the formulation Formulations having the same composition as the shell composition of Example 2, the same thickness of 1 mm, and each having a disk shape (Example 4), fillet shape (Example 6), and round shape (Example 7) were manufactured according to the method described above under the conditions of Table 3. The evaluation of release characteristics was performed on the formulations of Examples 4, 6, and 7, and was carried out in the same manner as in Experimental Example 2, and the results are shown in Fig. 8. As confirmed in Fig. 8, even when the shapes of the formulations were changed to fillet shape (Example 6) and round shape (Example 7) with the same composition and thickness, a release pattern similar to that of the disk shape (Example 4) was exhibited. Specifically, Examples 6 and 7 delayed the release of melatonin for up to 8 hours, and the release of melatonin lasted for up to 4.5 hours after the initiation of release. Evaluation of in vitro release characteristics according to the thickness of the round formulation Formulations having the same composition as the shell composition of Example 2 and having a thickness of 0.5 mm (Example 8), 0.7 mm (Example 9), 1.0 mm (Example 7), and 1.5 mm (Example 10) based on the upper and lower surfaces, respectively, were manufactured according to the method described above under the conditions of Table 3. The evaluation of release characteristics was performed on the formulations of Examples 7, 8, 9, and 10, and was carried out in the same manner as in Experimental Example 2, and the results are shown in Fig. 9. As confirmed in Fig. 9, when the same composition was used in the round formulation, the thickness was changed to 0.5 mm (Example 8), 0.7 mm (Example 9), 1 mm (Example 7), and 1.5 mm (Example 10), and the release characteristics were evaluated, and it was confirmed that the release was delayed by 5 to 10 hours through thickness adjustment. In addition, Examples 8 and 9, which had thin shell thicknesses of 0.5 mm and 0.7 mm, delayed the release by 5 to 6 hours, and Examples 8 and 9, which had thin shell thicknesses of 1 mm (Example 7) and 1.5 mm, delayed the release by 5 to 6 hours.As it increased to 5 mm (Example 10), the release showed a pattern of increasing to 7 hours and 10 hours.

[0038] [Description of symbols]

[0039] 100, 200, 300: Agent

[0040] 110, 210, 310: Internal space of the agent

[0041] 120, 220, 320: Bottom of the agent

[0042] 121, 221, 321: Long axis or width of the bottom surface of the agent

[0043] 122, 222, 322: Short axis or height of the bottom surface of the agent

[0044] 123, 223, 323: Height of the agent

[0045] t >〒누 HP비인STPS이 I SC TS이 :〜〜 ‘ ‘ W石 WW따 6으=OSog :- -

Claims

46 【Scope of Claims】 【 Claim 11 A formulation for oral administration, comprising: a shell including HPC; and an internal space surrounded by the shell, wherein the internal space includes a drug. 【

2. A formulation according to claim 1, wherein the shell further comprises at least one of PEO, alginic acid, carrageenan, agarose, pectin, crospovidone, sodium starch glycolate, sodium croscarmellose, propylene glycol, polyethylene glycol, triacetin, glycerin, and triethyl citrate.

3. A formulation according to claim 1 or 2, wherein the shell does not contain a drug. 【

4. In claim 1 or 2, 47 Shell is a formulation containing one or more additional drugs. 【

5. The composition according to any one of claims 1 to 4, wherein the internal space contains a drug and a pharmaceutically acceptable additive. 【

6. A formulation according to any one of claims 1 to 5, wherein the drug and / or pharmaceutically acceptable additive contained in the internal space is in a solid or liquid form. 【

7. A preparation according to claim 6, wherein the solid form is a tablet, capsule or powder. 【

8. A formulation according to any one of claims 1 to 7, wherein the internal space of the formulation contains 0.1 to 20 parts by weight of a pharmaceutically acceptable additive per 1 part by weight of the drug. 48 【A formulation according to any one of claims 1 to 8, wherein the shell contains HPC in an amount of 60 wt% to 99 wt% based on the weight of the entire shell.

10. A formulation according to claims 1 to 9, wherein the shell contains 90 wt% of HPC and 10 wt% of PEO based on the weight of the entire shell, and the internal space contains 0.1 to 20 wt% of a pharmaceutically acceptable additive per 1 wt% of the drug contained in the internal space.

11. A formulation according to claims 1 to 10, wherein the thickness of the shell is 0.7 mm to 2 mm.

12. In any one of claims 1 to 11, the drug in the internal space is released 5 hours after taking the preparation. I] I] .

13. A formulation according to any one of claims 1 to 12, wherein the drug is released in an amount of 5 wt% or less of the total weight of the drug 5 to 12 hours after taking the formulation.

14. The low-dose formulation according to any one of claims 1 to 13, wherein 5 wt% to 50 wt% of the total weight of the drug is released from the start of release of the drug in the internal space for 2 hours after taking the formulation, and 85% or more of the total weight of the drug is released from 4 hours to 12 hours after the start of release of the drug in the internal space.

15. A formulation according to any one of claims 1 to 14, wherein when the formulation is added to a test liquid at 37°C and pH 1.2 in a rotating paddle device having a paddle that rotates at 50 rpm, a drug contained in the internal space of the formulation is released in an amount of 5 wt% or less of the total weight of the drug for 5 to 12 hours.

16. A formulation according to any one of claims 1 to 15, wherein when the formulation is added to a test solution at 37°C and pH 1.2 in a rotating paddle device having a paddle that rotates at 50 rpm, 5 to 50 wt% of the total weight of the drug in the internal space is released within 2 hours from the start of release, and 85% or more of the total weight of the drug is released within 4 to 12 hours from the start of release.

17. A formulation according to any one of claims 1 to 16, wherein the pharmaceutically acceptable additives are a swelling agent, a disintegrating agent, a plasticizer, an excipient, a binder, and a sustained-release agent.

18. A formulation according to any one of claims 1 to 17, wherein the drug contained in the internal space is melatonin. 【Claim 1 is in claim 8, A formulation wherein the shell comprises 90 wt% of HPC and 10 wt% of PEO based on the weight of the entire shell; and the inner space comprises 4 to 19 wt% of excipients and 0 to 5 wt% of sustained-release agent per 1 wt% of melatonin. 【

20. A formulation according to any one of claims 1 to 19, wherein the formulation is manufactured using 3D printing. 【

21. In claim 20, 3D printing is a process that uses Material Extrusion.

22. (a) a step of preparing a shell composition comprising HPC; (b) a step of manufacturing a structure with an open top by melting and outputting the shell composition using a 3D printer; (c) a step of injecting a drug into the internal space of the structure through the open top; and (d) A method for manufacturing an oral administration formulation using 3D printing, comprising the step of forming a cover covering the upper part of the structure by melting and outputting the shell composition using a 3D printer. 52

23. A manufacturing method according to claim 22, wherein the shell composition further comprises at least one of PEO, alginic acid, carrageenan, agarose, pectin, crospovidone, sodium starch glycolate, sodium croscarmellose, propylene glycol, polyethylene glycol, triacetin, glycerin, and triethyl citrate.

24. A manufacturing method according to claim 22 or 23, wherein the shell composition does not contain a drug.

25. A manufacturing method according to claim 22 or 23, wherein the shell composition further comprises one or more drugs. 【

26. A manufacturing method according to any one of claims 22 to 25, wherein the internal space contains a drug and a pharmaceutically acceptable additive. 53

27. A manufacturing method according to any one of claims 22 to 26, wherein the drug and / or pharmaceutically acceptable additive contained in the internal space is in a solid or liquid form. 【

28. A manufacturing method according to claim 27, wherein the solid form is a tablet, capsule or powder. 【Claim 2 A manufacturing method according to any one of claims 22 to 28, wherein the internal space contains 0.1 to 20 parts by weight of a pharmaceutically acceptable additive per 1 part by weight of the drug.

30. A manufacturing method according to any one of claims 22 to 29, wherein the shell contains 60 to 100 wt% of HPC based on the weight of the entire shell. 54

31. A manufacturing method according to any one of claims 22 to 30, wherein the shell comprises 90 wt% of HPC and 10 wt% of PEO based on the weight of the entire shell; and the internal space comprises 0.1 to 20 wt% of a pharmaceutically acceptable additive per 1 wt% of the drug.

32. A manufacturing method according to any one of claims 22 to 31, wherein the thickness of the shell is 0.7 mm to 2 mm. 【

33. A manufacturing method according to any one of claims 22 to 32, wherein the pharmaceutically acceptable additive is a swelling agent, a disintegrating agent, a plasticizer, an excipient, a binder, or a sustained-release agent.

34. A manufacturing method according to any one of claims 22 to 33, wherein the drug in the internal space is melatonin.

35. 55 In claim 34, a manufacturing method wherein the shell comprises 90 wt% of HPC and 10 wt% of PEO based on the weight of the entire shell; and the internal space comprises 4 to 19 wt% of excipients and more than 0 to 5 wt% of sustained-release agent based on 1 wt% of melatonin.

36. In any one of claims 22 to 35, 3D printing is a manufacturing method that uses Material Extrusion.

37. A pharmaceutical composition for preventing or treating jet lag, comprising: a shell comprising HPC; and an inner space surrounded by the shell, wherein the inner space comprises melatonin. 【

38. A pharmaceutical composition according to claim 37, wherein the internal space further comprises one or more pharmaceutically acceptable additives. 56 【Claim 3: A pharmaceutical composition according to claim 38, wherein the pharmaceutically acceptable additives are excipients, binders, and sustained-release agents.

40. A pharmaceutical composition according to claim 39, wherein the composition comprises 90 wt% of HPC and 10 wt% of PEO based on the weight of the entire shell; and the internal space comprises 4 to 19 wt% of an excipient and more than 0 to 5 wt% of an extended-release agent per 1 wt% of melatonin.

41. A food composition for preventing or improving jet lag, comprising: a shell containing HPC; and an inner space surrounded by the shell, wherein the inner space contains melatonin.

42. In claim 41, 90 wt% of HPC and 10 wt% of PEO based on the weight of the entire shell; and 57 A food composition, wherein the inner space contains 4 to 19 parts by weight of excipients and 0 to 5 parts by weight of a sustained-release agent per 1 part by weight of melatonin.

43. A composition for application to a 3D printer, comprising HPC and a pharmaceutically acceptable additive, wherein the pharmaceutically acceptable additive is selected from one or more of PEO, alginic acid, carrageenan, agarose, pectin, crospovidone, sodium starch glycolate, sodium croscarmellose, propylene glycol, polyethylene glycol, triacetin, glycerin, and triethyl citrate.

44. A composition according to claim 43, wherein the pharmaceutically acceptable additive is PEO.

45. A composition according to claim 43 or 44, wherein the composition comprises HPC in an amount of 60 wt% to 99 wt% based on the weight of the entire composition.

46. A composition according to any one of claims 43 to 45, wherein the composition comprises 90 wt% of HPC and 10 wt% of PEO based on the weight of the entire composition.

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