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WO2025133728A1 - Formulation à libération contrôlée comprenant de la caféine, et son procédé de préparation - Google Patents

Formulation à libération contrôlée comprenant de la caféine, et son procédé de préparation Download PDF

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Publication number
WO2025133728A1
WO2025133728A1 PCT/IB2024/058380 IB2024058380W WO2025133728A1 WO 2025133728 A1 WO2025133728 A1 WO 2025133728A1 IB 2024058380 W IB2024058380 W IB 2024058380W WO 2025133728 A1 WO2025133728 A1 WO 2025133728A1
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WO
WIPO (PCT)
Prior art keywords
compartment
formulation
drug
pharmaceutically acceptable
filling density
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/IB2024/058380
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English (en)
Korean (ko)
Inventor
장봉석
김성래
박주환
이효중
박준우
성시우
김희은
윤춘희
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Dong A Pharmaceutical Co Ltd
Original Assignee
Dong A Pharmaceutical Co Ltd
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Filing date
Publication date
Application filed by Dong A Pharmaceutical Co Ltd filed Critical Dong A Pharmaceutical Co Ltd
Publication of WO2025133728A1 publication Critical patent/WO2025133728A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y10/00—Processes of additive manufacturing
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y70/00—Materials specially adapted for additive manufacturing
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B33—ADDITIVE MANUFACTURING TECHNOLOGY
    • B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
    • B33Y80/00—Products made by additive manufacturing
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A23V2200/31—Foods, ingredients or supplements having a functional effect on health having an effect on comfort perception and well-being
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2250/00—Food ingredients
    • A23V2250/20—Natural extracts
    • A23V2250/21—Plant extracts
    • A23V2250/2108—Caffeine, coffee extract
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2300/00—Processes
    • A23V2300/16—Extrusion

Definitions

  • the present invention relates to an oral administration preparation having a drug release control function 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 containing caffeine as an active ingredient for preventing or treating jet lag; and a composition for application to a 3D printer.
  • Caffeine is an alkaloid found in coffee beans, tea leaves, and kola nuts, and is used as a raw material for food and medicine. Since caffeine stimulates the sensory center of the cerebral cortex, consuming an appropriate amount of caffeine can temporarily provide an awakening effect that clears the mind and has a diuretic effect that removes waste products. Jet lag refers to various symptoms experienced when experiencing a place with a different standard time zone due to a flight, etc. Jet lag is a symptom that occurs when the time zone changes faster than the body can adapt to the change in time zone due to a flight, etc., and the sleep and wakefulness rhythm is not in harmony with the external environment. Representative symptoms include sleep disorders, headaches, fatigue, and loss of appetite.
  • Patent Document Korean Patent Publication No. 10-1757313
  • the present invention provides an oral administration preparation 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 present invention also provides a method for producing the oral administration preparation, the method comprising the steps of: (a) producing a composition comprising a drug and at least one pharmaceutically acceptable additive; (b) using a 3D printer to output the composition and laminate one of the first compartment and the second compartment; and (c) after the step (b), sequentially laminating the remaining compartments.
  • the present invention also provides 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.
  • the present invention also provides 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 present invention also provides 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 release-limiting agent.
  • the present invention can easily control the release speed of the drug by combining a compartment in which the drug is released immediately after taking the drug and a compartment in which the drug release continues for a certain period of time.
  • the drug in the formulation according to the present invention is caffeine
  • the awakening effect is exerted immediately upon arrival at a region with jet lag and ingestion of the drug, and the awakening effect can continue throughout the daytime, thereby effectively resolving fatigue due to jet lag, and since the desired duration of the awakening effect varies depending on the time of arrival at a region with jet lag, a formulation having an internal filling density can be selected accordingly, thereby having customized characteristics.
  • Fig. 1 shows a plan view of the formulation of the present invention.
  • Fig. 2 is a diagram schematically showing a method for manufacturing the formulation of the present invention.
  • Fig. 3 is a graph showing the dissolution characteristics according to the internal filling density (30%, 70%, 80%, 90%) of the formulation of the present invention.
  • Fig. 4 is a graph showing the dissolution characteristics according to the ratio of sustained-release polymers of the formulation of the present invention.
  • Figure 5 is a graph showing the dissolution characteristics according to the internal filling density (30%, 37%, 50%, 90%) of the formulation of the present invention.
  • Figure 6 is a graph showing the PK characteristics in beagle dogs according to the internal filling density (30%, 50%, 90%) of the formulation of the present invention.
  • the present invention relates to an oral administration formulation comprising two or more compartments, each of which comprises a drug and one or more pharmaceutically acceptable additives.
  • the formulation according to the present invention can comprise two or more compartments having different internal filling densities in one formulation using 3D printing, and by controlling the internal filling density, the release of the drug can be maintained immediately after administration and/or for a certain period of time, depending on the purpose. Specifically, as the internal filling density approaches 0%, the surface area of the formulation in contact with the digestive solution increases, which can induce rapid release of the drug, and as the internal filling density is adjusted to approach 100%, the surface area of the formulation in contact with the digestive solution decreases, which can induce sustained release of the drug.
  • the formulation according to the present invention can be manufactured using 3D printing, and has the advantage of being able to produce a formulation optimized with personalized ingredients and dosages, and being able to control the drug release pattern by manufacturing a formulation having geometrical features that cannot be implemented with existing manufacturing methods.
  • the compartments can be arranged in a side-by-side form, which is an arrangement form that cannot be implemented in existing formulations that were manufactured using the existing compression formulation process and could only be arranged in a layer-by-layer form, and a single A controlled-release preparation can be prepared using only the composition.
  • the drug may be included without limitation as long as it exhibits pharmacological activity, and specifically, it includes a drug such as melatonin and caffeine, which has a short half-life and thus requires sustained drug release to maintain a pharmacological effect, and more specifically, it may include caffeine, but is not limited thereto.
  • the drug includes all of a pharmaceutically acceptable salt, an optical isomer thereof, a hydrate or a solvate thereof of the drug, for example, melatonin may include melatonin, a pharmaceutically acceptable salt thereof, an optical isomer thereof, a hydrate or a solvate thereof, or a mixture thereof.
  • the infill densities of the compartments may be different from each other.
  • the infill densities of each compartment may be such that at least one pair of compartments is different from each other.
  • the formulation has three compartments, the internal filling densities of the first and second compartments 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.
  • 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.
  • 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 The first compartment or the second compartment may have the same drug and/or pharmaceutically acceptable excipients
  • the first to third compartments may all have different drugs and/or pharmaceutically acceptable excipients.
  • the " nth compartment" refers to the first compartment, the second compartment, and the third compartment in that order from the left or lower compartment in a multi-compartment preparation, and is an order arbitrarily assigned to describe two or more compartments of the preparation, and therefore the present invention is not limited to the above designation.
  • the present invention relates to an oral administration preparation 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.
  • the infill densities of the first compartment and the second compartment may be different from each other.
  • the infill 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
  • 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%, more specifically about 30%, about 50%, about 90%.
  • the first compartment is selected from an internal filling density of 25% or more and 40% or less
  • the second compartment is selected from an internal filling density of 50% or more and 100%.
  • the first compartment may have a fill density of one of 30% or 37%
  • the second compartment may have a fill density of one of 50% or 90%.
  • the first compartment may have a fill density of 30%, and the second compartment may have a fill density of 50%.
  • the first compartment may have a fill density of 30%, and the second compartment may have a fill density of 90%.
  • the oral administration formulation may be a controlled release formulation, specifically, an immediate release, delayed release and/or sustained release formulation, more specifically, an immediate release and sustained release formulation.
  • the drug included in the first compartment may be immediate-released, and the drug included in the second compartment may include delayed-release and/or sustained-release.
  • the "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, the release control means immediate-release and/or sustained-release.
  • the “immediate-release” means that the drug of the formulation is rapidly released within a certain period of time after administration.
  • the first compartment may have an internal filling density of 40% or less, and the drug included in the first compartment may include that 85% or more of the total weight of the drug included in the first compartment is released within 2 hours after administration of the formulation.
  • the "sustained-release” means that the drug of the formulation is slowly released over a certain period of time after administration. That means.
  • 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 include 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.
  • the second compartment may have an internal filling density of 90% or more, and the drug contained in the second compartment may include 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 first compartment has 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.
  • the second compartment has an inner 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 within 2 hours after administration of the formulation, and 80% or less of the total weight of the drug is released within 4 hours.
  • the second compartment has an internal filling density of 90% or more, and the second compartment of the formulation has a rotating paddle having a paddle that rotates at 50 rpm.
  • the drug included in the second compartment When added to a test solution at 37°C and pH 6.8 in the device, the drug included in the second compartment may be released such that 60% or less of the total weight of the drug included in the second compartment is released 4 hours after administration of the formulation, and 85% or less of the total weight of the drug is released 8 hours.
  • fill density refers to the degree of density when filling the internal space after outputting the outer periphery of the formulation using a 3D printer, with 0% meaning no filling and 100% meaning completely filling the interior. That is, the closer it gets to 100%, the less empty space there is inside, and any pattern that can be output can be included without limitation as a pattern for filling the interior, specifically, a grid pattern, a honeycomb pattern, a check pattern, etc.
  • the drug and the 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 sustained-release agent, an enteric agent, a plasticizer, a solubilizer, a disintegrant, a stabilizer, and a colorant, and specifically, may be a binder, an excipient, and a sustained-release agent.
  • PVP Polyvinylpyrrol idone
  • MCC Morocrystal 1 ine cel lulose
  • Poly(meth)acrylate Eudragit
  • Lactose L-HPC (Low-subs titrated hydroxypropylcelluloseose)
  • HPC Hydrophilic polymer
  • HPMC Hydrophilic polymer
  • HPMC Hydrophilic polymer
  • HPMC Hydrophilic polymer
  • the composition of the formulation including the pharmaceutically acceptable additive may have properties suitable for outputting with a 3D printer. Specifically, there is no spreading or collapsing of the layer when outputting with the composition, and the output precision outputting with the desired internal filling density is excellent.
  • the formulation manufactured with the composition has excellent strength, and can exhibit the desired immediate-release and sustained-release characteristics of the formulation after administration.
  • the formulation may include 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.
  • the formulation 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.
  • 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.
  • the formulation may contain 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 Eudragit (Poly(meth)acrylate) based on the total weight of the formulation.
  • the formulation may contain 30 wt% of caffeine, 20 wt% of PVP, 30 wt% of MCC, and 20 wt% of Eudragit.
  • 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 side-by-side form according to the present invention is different from the layer-by-layer form in which the upper part of the first compartment and the lower part of the second compartment are attached, in that the side parts of the first compartment and the second compartment are attached, so that the lower part and the upper part of the formulation in which the internal pores are exposed according to the control of the internal filling density can both come into contact with the digestive solution, and 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.
  • 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 Mater ial/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 comprises two or more compartments, each of which comprises caffeine and one
  • the present invention relates to a pharmaceutical composition for preventing or treating jet lag, comprising the pharmaceutically acceptable additives above.
  • the caffeine may include caffeine, a pharmaceutically acceptable salt thereof, an optical isomer thereof, a hydrate or solvate thereof, or a mixture thereof.
  • the internal filling densities of the compartments may be different from each other.
  • the internal filling densities of each compartment may have at least one pair of different 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 compartment or the second compartment, and the internal filling densities of the first to third compartments may all be different.
  • the drug and the pharmaceutically acceptable additive included in each compartment may be the same.
  • the drug and/or pharmaceutically acceptable excipient contained in each compartment may be different in at least one compartment from the other compartments.
  • the formulation has three compartments, the drug and/or pharmaceutically acceptable excipient of the first compartment and the second compartment may be different, the drug and/or pharmaceutically acceptable excipient of the third compartment may be the same as that of the first or second compartment, and the drug and/or pharmaceutically acceptable excipient of the first to third compartments may all be different.
  • the present invention comprises 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 excipient.
  • a pharmaceutical composition for preventing or treating jet lag comprising: a pharmaceutical composition comprising: a pharmaceutically acceptable salt, i.e., ...
  • the first compartment can include one having an internal fill density selected from 25% or more and 40% or less, and the second compartment can include one having an internal fill density selected from 50% or more and 100% or less.
  • the first compartment can include one having an internal fill density of one of 30% or 37%, and the second compartment can include one having an internal fill density of one of 50% or 90%.
  • the first compartment may have an internal filling density of 30%, and the second compartment may have an internal filling density of 50%.
  • the first compartment may have an internal filling density of 30%, and the second compartment may have an internal filling density of 90%.
  • 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.
  • the drug contained in the first compartment is immediate release, and the The drug contained in the second compartment may include delayed release and/or sustained release.
  • the first compartment has an internal filling density of 40% or less, and the drug contained in the first compartment may include 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.
  • the second compartment has an internal filling density of 50% or more and less than 90%, and the drug contained in the second compartment may include 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.
  • 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.
  • 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.
  • 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 at 37°C and pH 6.8 in a rotating paddle device having a paddle that rotates at 50 rpm, the drug contained in the second compartment is 60% or less of the total weight of the drug contained in the second compartment at 2 hours after administration of the formulation. and may include releasing not more than 80% of the total weight of the drug in 4 hours.
  • the second compartment has an inner 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, the drug contained in the second compartment may include releasing not more than 60% of the total weight of the drug contained in the second compartment in 4 hours after administration of the formulation, and releasing not more than 85% of the total weight of the drug in 8 hours.
  • the formulation according to the present invention includes compartments with differently controlled inner filling densities in one formulation, so that immediate release and sustained release can be simultaneously achieved through ingestion of one formulation.
  • the drug effect should be exerted immediately upon taking the dosage, and the corresponding drug effect should be sustained for a certain period of time
  • a formulation manufactured with an internal filling density in which the first compartment exhibits immediate-release characteristics and the second compartment exhibits sustained-release characteristics is taken, the drug in the first compartment begins to be released immediately after taking the dosage, and 85% or more of the total weight of the drug is released within 2 hours, so that the drug effect can be exerted quickly, and the drug in the second compartment begins to be released gradually after taking the dosage, and 80% of the drug is released after 4 hours or after 8 hours, so that the drug effect can be sustained for a desired period of time for patients, thereby significantly improving the convenience of taking the medication.
  • the formulation of one embodiment of the present invention can be effectively applied to improving jet lag.
  • the drug of the formulation according to the embodiment of the present invention contains caffeine
  • the rapid release of the drug proceeds immediately from the immediate release compartment, and the stimulating effect is exerted, so that the symptoms of jet lag, 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 one Since jet lag can be improved simply by taking the preparation, the convenience of taking the medicine is excellent.
  • the drug and the pharmaceutically acceptable additive included in the first compartment and the second compartment may be the same.
  • the drug and/or the pharmaceutically acceptable additive included in the first compartment and the drug and/or the pharmaceutically acceptable additive included in the second compartment may be different.
  • the pharmaceutically acceptable additive may be one or more of a binder, an excipient, a sustained-release agent, an enteric carrier, a plasticizer, a solubilizer, a disintegrant, a stabilizer, and a colorant, and specifically, it may be a binder, an excipient, and a sustained-release agent.
  • 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 hydroxypropylcelluloseose), HPC (Hydr oxypropyl cel luose), Ko 11 i don SR (Polyvinyl acetate and polyvinylpyrrolidone), HPMC (Hydr oxypr opy 1 meth y 1 ce 11 u 1 ose), and more specifically, it may be PVP, MCC, and Eudragit.
  • PVP Polyvinylpyrrolidone
  • MCC Morocrystal 1 ine cel luose
  • Poly(meth)acrylate Eudragit
  • Lactose L-HPC (Low-substance ti tuted hydroxypropylcelluloseose
  • 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.
  • 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 a pharmaceutically acceptable additive.
  • the drug and the first compartment and the second compartment may be The weight ratio of the pharmaceutically acceptable additives included in the compartment and the second compartment may be 1:19 to 1:1.
  • the pharmaceutical 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.
  • PVP Polyvinylpyrrolidone
  • MCC Microcrystalline cellulose
  • Eudragi t Poly(meth)acrylate
  • 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 pharmaceutical composition may include one manufactured using 3D printing.
  • 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.
  • the oral administration preparation may be included without limitation in a form that can be administered orally, and may be in the form of, for example, a circle, a triangle, a square, an oval, a rectangle, etc.
  • the preparation may be in the form of a tablet.
  • a preparation including caffeine may exhibit different release rates by adjusting the internal filling density even though it has the same composition.
  • the release rate of caffeine when the release rate of caffeine was measured in a dissolution test solution of pH 6.8, By changing the inner filling density, the release can be adjusted to exhibit a range of characteristics, 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 (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, when the inner filling density is set to the same 100%, 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.
  • the present invention is a composition suitable for the manufacture of a formulation for controlled release (Experimental Example 2 and Fig. 4).
  • 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 including 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.
  • the first compartment and the second compartment contain caffeine and one or more pharmaceutically acceptable additives.
  • Oral administration formulation 1 including additives may be substantially the same as those discussed above as long as they are not contradictory.
  • formulation 2 including a drug exhibiting different activity from caffeine in the kit may be a delayed-release and/or sustained-release formulation.
  • 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 taken simultaneously, the pharmacological effect of the drug included in formulation 2 appears after a certain period of time after taking the formulation, and the release of the drug progresses gradually for a certain period of time thereafter, so that the pharmacological effect can be sustained, and the pharmacological effect of caffeine included in formulation 1 appears immediately and the pharmacological effect can be sustained for a certain period of time, so that the convenience of taking the medication by the patient can be significantly improved.
  • the kit may be for preventing or treating jet lag
  • Formulation 2 may be a delayed-release and/or sustained-release formulation containing a sleep-inducing agent or a sleeping pill such as melatonin.
  • Formulation 2 when the formulations of the kit, wherein Formulation 2 is a delayed-release and/or sustained-release formulation containing a sleep-inducing agent or a sleeping pill such as melatonin, are taken simultaneously upon arrival at an area where jet lag exists, the pharmacological effect of Formulation 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 Formulation 2, which is a sleeping effect, appears after a certain period of time, so that the drug of Formulation 2 is continuously released during sleeping hours, thereby preventing or treating sleep disorders such as insomnia caused by jet lag.
  • Formulation 1 controls the internal filling density of the formulation to extend the duration of drug release.
  • the formulation 1 having an internal filling density indicating a desired caffeine release duration according to the time of arrival in an area where time difference exists (for example, 10:00 AM or 4:00 PM) for the prevention or treatment of jet lag can be taken by selecting the formulation 1 having an internal filling density indicating a desired caffeine release duration according to the time of arrival in an area where time difference exists, so as to significantly improve the convenience of taking the 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 the oral administration formulation using 3D printing, comprising the steps of: (a) producing a composition comprising at least one drug and at least one pharmaceutically acceptable additive; (b) outputting the composition using a 3D printer to laminate one compartment; and (c) sequentially laminating the remaining compartments after the step (b).
  • 3D printing is a technology that enables the production of a variety of small quantities of customized formulations, and there are various methods such as Material Extrusion, Vat Polymerization, Powder Bed Fusion, and Mater ial/Binding Jetting.
  • the 3D printing may be one of Material Extrusion, Vat Polymerization, Powder Bed Fusion, and Mater ial/Binding Jetting, and specifically, may be Material Extrusion, but is not limited thereto.
  • the composition may further include a step of having a uniform particle size distribution through a mesh.
  • the mesh may be 20 to 40 mesh, but is not limited thereto.
  • the pressure during output may be 0.4 MPa to 0.8 MPa. However, it is not limited thereto.
  • 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 composition in a powder form, adds water, manufactures it into a dough form, and then puts it directly into the silo of a 3D printer and outputs it using pressure from a nozzle, so the manufacture 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.
  • the 3D printing method used in the present invention does not have a process in which heat is applied, so it can use relatively heat-sensitive raw materials. Therefore, it is free in the use of raw materials, and since there is no cost for manufacturing filaments, there is an advantage in terms of cost.
  • the 3D printing method can manufacture a formulation customized for each individual by considering the severity of the disease, the timing and dosage of drug administration, etc. Accordingly, the present invention can provide a personalized formulation by manufacturing a formulation by including compartments with different internal filling densities in a single formulation using a 3D printer so that patients suffering from jet lag can select the appropriate formulation according to their arrival time in the jet lag area.
  • the drug may be included without limitation as long as it exhibits pharmacological activity, and specifically, it may include a drug such as melatonin or caffeine that has a short half-life and thus requires sustained drug release to maintain a pharmacological effect, and more specifically, it may include caffeine, but is not limited thereto.
  • the internal filling densities of the compartments may be different from each other. may.
  • the internal filling density of each compartment may be such that at least one pair of compartments has a different internal filling density.
  • 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.
  • the drug and the pharmaceutically acceptable excipient included in each compartment may be the same.
  • the drug and/or the pharmaceutically acceptable excipient included in each compartment may be such that at least one compartment is different from the remaining compartments.
  • the formulation has three compartments
  • the drug and/or pharmaceutically acceptable excipient of the first compartment and the second compartment may be different
  • the third compartment may have the same drug and/or pharmaceutically acceptable excipient as the first or second compartment
  • the drug and/or pharmaceutically acceptable excipient of the first to third compartments may all be different.
  • the present invention relates to a method for producing the oral administration formulation, the method comprising the steps of: (a) producing a composition comprising at least one drug and at least one pharmaceutically acceptable excipient; (b) using a 3D printer to output the composition and laminate one of the first compartment and the second compartment; and (c) after the step (b), sequentially laminating the remaining compartments.
  • the internal filling densities of the first compartment and the second compartment may be different from each other.
  • the internal filling density 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%.
  • the first compartment may include a filling density selected from 25% or more and 40% or less, and the second compartment may include a filling density selected from 50% or more and 100% or less.
  • the first compartment may include a filling density of one of 30% or 37%, and the second compartment may include a filling density of one of 50% or 90%.
  • the first compartment may include a filling density of 30%, and the second compartment may include a filling density of 50%.
  • the first compartment may include a filling density of 30%, and the second compartment may include a filling density of 90%.
  • the drug and pharmaceutically acceptable additives included in each compartment may be the same.
  • the drug and pharmaceutically acceptable additives included in the first compartment and the second compartment may be the same. In one embodiment of the present invention, the drug and/or The pharmaceutically acceptable additive 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 colorant, and specifically, may be a binder, an excipient, and a release-promoting agent.
  • 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 hydroxypropylcelluloseose), HPC (Hydr oxypropyl cel luose), Ko 11 i don SR (Polyvinyl acetate and polyvinylpyrrolidone), HPMC (Hydr oxypr opy 1 meth y 1 ce 11 u 1 ose), and more specifically, it may be PVP, MCC, and Eudragit.
  • PVP Polyvinylpyrrolidone
  • MCC Morocrystal 1 ine cel luose
  • Poly(meth)acrylate Eudragit
  • Lactose L-HPC (Low-substance ti tuted hydroxypropylcelluloseose
  • the drug may be included in an amount of 5 wt% to 50 wt% and the pharmaceutically acceptable additive in an amount of 50 wt% to 95 wt% based on the total weight of the formulation.
  • the formulation 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.
  • 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.
  • the formulation contains 10 to 50 wt% of caffeine and 15 to 30 wt% of PVP (Polyvinylpyrrolidone) based on the total weight of the formulation. % by weight, MCC (Microcrystal 1 ine cel luose) 20 wt % to 50 wt % and Eudragi t (Poly(meth)acrylate) 5 wt % to 20 wt %.
  • 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 preparation 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.
  • the drug and pharmaceutically acceptable additive included in the first compartment and the second compartment may be the same.
  • 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.
  • the pharmaceutically acceptable additive may be one or more of a binder, an excipient, a sustained-release agent, an enteric agent, a plasticizer, a solubilizer, a disintegrant, a stabilizer, and a colorant, and specifically, may be a binder, an excipient, and a sustained-release agent.
  • 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 hydroxypropylcelluloseose), HPC (Hydr oxypr opy 1 meth y 1 ce 11 u 1 ose), Ko 11 i don SR (Polyvinyl acetate and polyvinylpyrrolidone), HPMC (Hydr oxypr opy 1 meth y 1 ce 11 u 1 ose), and more specifically, it may be PVP, MCC, and Eudragit.
  • PVP Polyvinylpyrrolidone
  • MCC Morocrystal 1 ine cel luose
  • Poly(meth)acrylate Eudragit
  • Lactose L-HPC (Low-substance ti tut
  • the food 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 food composition.
  • the food composition 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.
  • 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.
  • the food composition may include a total weight of the composition. It may contain 10 to 50 wt% of caffeine, 15 to 30 wt% of PVP (Polyvinylpyrrolidone), 20 to 50 wt% of MCC (Microcrystalline cellulose), and 5 to 20 wt% of Eudragi t (Poly(meth)acrylate). Specifically, it may contain 30 wt% of caffeine, 20 wt% of PVP, 30 wt% of MCC, and 20 wt% of Eudragi t.
  • the present invention relates to a composition for application to a 3D printer, comprising caffeine and one or more pharmaceutically acceptable additives.
  • 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 colorant, and specifically, may be a binder, an excipient, and a release-promoting agent.
  • it may be at least one of PVP(Polyvinylpyrrolidone), MCC(Microcrystal 1 ine cel luose), Poly(meth)acrylate(Eudragit), Lactose, L-HPC(Low-substance thi tuted hydroxypropylcelluloseose), HPC(Hydroxypropyl cel luose), Ko 11 i don SR(Polyvinyl acetate and polyvinylpyrrolidone), HPMC (Hydr oxypr opy 1 meth y 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.
  • the pharmaceutically acceptable additive is Specifically, it can be PVP (Polyvinylpyrrolidone), MCC (Microcrystal 1 ine cel luose), and PolyGiieth)acrylate (Eudragi t).
  • the composition may contain 5 to 50 wt% of the drug and 50 to 95 wt% of the pharmaceutically acceptable additive based on the total weight of the composition.
  • 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 a pharmaceutically acceptable additive.
  • 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.
  • the composition may include 30 wt% of caffeine, 20 wt% of PVP, 30 wt% of MCC, and 20 wt% of Eudragi t.
  • the composition has a viscosity suitable for printing with a pressure applied by a 3D printer, and when printing, the printed product has an adhesive strength sufficient to adhere to the bed of the 3D printer so that the printed product can be laminated without being separated from the bed, and the printed layers do 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 are manufactured using a 3D printer. Since the laminated layers are not separated, it exhibits excellent strength, and can exhibit excellent release control function (immediate release and sustained release) even after administration.
  • the oral administration preparation, pharmaceutical composition and food composition including the composition manufactured by a 3D printer simultaneously contain immediate-release and sustained-release compartments, so that when a patient arrives at a region where there is a time difference and ingests the preparation, the drug effect appears immediately, and at the same time, the drug effect is sustained until the target time, so that the convenience of taking the medication can be significantly improved, and a preparation having a drug release duration tailored to an individual patient can be selected depending on the arrival time, so that it can provide the advantage of personalized treatment.
  • FIG. 1 is a diagram showing the shape of a formulation according to one embodiment of the present invention.
  • the formulation (100) is composed of a first compartment (110) and a second compartment (120).
  • the compartments are output with different "infill densities", and each compartment is arranged in a "side by side form”.
  • the "infill density” means the degree to which the inside of the compartment is filled.
  • the pattern when forming the infill density may include a grid pattern, a honeycomb pattern, a check pattern, etc., and is not limited to a specific pattern and may be appropriately selected and adjusted.
  • the "side-by-side configuration" in which the first compartment and the second compartment are arranged means that the contact surface where the first compartment and the second compartment are in contact with the bottom surface of the formulation that contacts the bed of the 3D printer is positioned vertically.
  • Fig. 1 are illustratively described, and can be applied without limitation to formulations including three or more compartments and formulations having shapes such as circles, triangles, squares, ovals, and rectangles.
  • the descriptions in the formulation, pharmaceutical composition, food composition, and manufacturing method examined above can be substantially equally applied to the formulation (100), the compartments (110, 120), drug release from the formulation, etc., as long as they are not contradictory to each other, as shown in Fig. 1.
  • Fig. 2 is an illustrative description of a method for manufacturing a formulation according to Fig. 1. Referring to FIG.
  • the formulation of the present invention can be manufactured through (1) a step of outputting a composition for manufacturing a formulation mounted on a 3D printer; (2) a step of laminating the first compartment (110) with a predetermined internal filling density; and (3) a step of laminating the second compartment (120) with a predetermined internal filling density.
  • the description of FIG. 2 is also only an example of the form of FIG. 1, and the manufacturing method according to FIG. 2 is not limited to the structure of FIG. 1.
  • the descriptions in the formulation, pharmaceutical composition, food composition, and manufacturing method examined above can be substantially equally applied to the manufacturing method of FIG. 2 as long as they are not contradictory to each other.
  • the following examples are presented in order to explain the present invention in more detail.
  • composition of Example 1 and Manufacturing of a Formulation Using a 3D Printer A composition for manufacturing a formulation was manufactured. Specifically, caffeine, PVP K90, MCC101, and Eudragi t RS were homogeneously mixed in the contents shown in Table 1 below and sieved through a 60 mesh sieve, and then water was added in an amount of 125 wt% of the solid content based on the total content (solid content) of the above components, to prepare a composition of Example 1 for printing.
  • Example 1 For the manufacture of a formulation using the composition of Example 1, a self-made 3D printer was used, and the formulation was modeled using Simpl i fy3D software. The 3D printing of the present invention was performed using a Mono-pump One Nozzle. The composition of Example 1 manufactured above was put into a 3D printer and the composition was output according to the conditions of Table 2 below to manufacture formulations of Examples 2 to 6.
  • 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 method (paddle method) of the dissolution test method of the Korean Pharmacopoeia.
  • 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 minute, 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.
  • 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 3 hours, and Example 5 with an internal filling density of 90% released 80% of the caffeine in the formulation after 4 hours.
  • 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.
  • 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 the sustained-release polymer, Eudragi t RS, under the same internal filling density conditions was performed on the formulations of Examples 8 to 10 and was performed 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 manufactured by using the composition of Example 1 to manufacture the formulation of Example 8, the composition of Example 6 to manufacture the formulation of Example 9, and the composition of Example 7 to manufacture the formulation of Example 10 under 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.
  • 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 contained in the formulation 6 hours after the start of the test
  • Example 10 which contained the highest sustained-release polymer content of 20%, released 85% of the caffeine contained in the formulation 6 hours after the start of the test, and ... It was confirmed that 85% of caffeine was released.
  • All of Examples 8 to 10 exhibited sustained-release properties, and it was confirmed that the formulation of Example 10, which had the highest content of Eudragi t RS, a sustained-release polymer, exhibited the longest sustained-release duration.
  • 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 the test performed on Examples 11 to 13, the formulation uniformity judgment values (AV) were 4.3 for Example 11, 2.6 for Example 12, and 3.4 for Example 13, respectively, which correspond to AV ⁇ 15 in all, indicating that the formulations are suitable.
  • Example 4 In-vitro dissolution characteristic evaluation according to internal filling density of formulation
  • the dissolution characteristic evaluation of the formulation according to the change in internal filling density was performed on the formulation showing the longest sustained release degree among the compositions of Experimental Example 2.
  • the evaluation was performed on the formulations of Examples 11 to 14, and was performed 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 formulation was the same as that of Example 7 except that the output conditions of Table 4 were used. It was manufactured by a method substantially the same as the manufacturing method of formulations 2 to 5.
  • 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.
  • 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
  • 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.
  • 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 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.
  • Example 11 with an internal filling density of 30% showed a Tmax of 1 hour
  • Example 12 with an internal filling density of 50% showed a Tmax of 2 hours
  • Example 13 with an internal filling density of 90% showed a Tmax of 3 hours. It was confirmed that as the internal filling density of the formulation increased, the Tmax was delayed, indicating that the release control trend in-vitro was similarly shown in-vivo.
  • Example 12 showed a Tmax of 106.58 hr*w/mL and Example 13 was measured as 95.27 hr*w/mL.
  • 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% confirmed that only 90% of the drug contained in the formulation was absorbed into the blood as the drug release rate was slow.

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Abstract

La présente invention concerne une formulation administrée par voie orale comprenant de la caféine en tant que principe actif et ayant une propriété de régulation de la libération de médicament, et un procédé pour la préparer à l'aide d'une impression 3D et concerne une composition pharmaceutique et une composition alimentaire, de la formulation, pour prévenir ou traiter les effets du décalage horaire, et une composition à appliquer à une imprimante 3D.
PCT/IB2024/058380 2023-12-19 2024-08-29 Formulation à libération contrôlée comprenant de la caféine, et son procédé de préparation Pending WO2025133728A1 (fr)

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KR1020230185770A KR20250095810A (ko) 2023-12-19 2023-12-19 카페인을 포함하는 방출조절용 제제 및 이의 제조방법
KR10-2023-0185770 2023-12-19

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WO2025133728A1 true WO2025133728A1 (fr) 2025-06-26

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011074015A (ja) * 2009-09-30 2011-04-14 Tomita Pharmaceutical Co Ltd 固形製剤及びその製造方法
US11304903B2 (en) * 2017-03-27 2022-04-19 Oxford University Innovation Limited Compartmentalised gel matrix and method of production
KR20230093606A (ko) * 2021-12-20 2023-06-27 포항공과대학교 산학협력단 3d 프린팅용 세포외기질 기반 하이브리드 잉크 및 이의 제조방법
KR20230131916A (ko) * 2021-01-15 2023-09-14 갈벤타 아게 박동성 방출 카페인 제제
WO2023174910A1 (fr) * 2022-03-14 2023-09-21 Sissa - Scuola Internazionale Superiore Di Studi Avanzati Dispositif d'administration de médicament à base de graphène servant à une administration par voie mucosale et transmucosale

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101757313B1 (ko) 2015-11-24 2017-07-12 신안산대학교 산학협력단 3d 프린터용 필라멘트 조성물 및 이의 압출 방법

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2011074015A (ja) * 2009-09-30 2011-04-14 Tomita Pharmaceutical Co Ltd 固形製剤及びその製造方法
US11304903B2 (en) * 2017-03-27 2022-04-19 Oxford University Innovation Limited Compartmentalised gel matrix and method of production
KR20230131916A (ko) * 2021-01-15 2023-09-14 갈벤타 아게 박동성 방출 카페인 제제
KR20230093606A (ko) * 2021-12-20 2023-06-27 포항공과대학교 산학협력단 3d 프린팅용 세포외기질 기반 하이브리드 잉크 및 이의 제조방법
WO2023174910A1 (fr) * 2022-03-14 2023-09-21 Sissa - Scuola Internazionale Superiore Di Studi Avanzati Dispositif d'administration de médicament à base de graphène servant à une administration par voie mucosale et transmucosale

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