WO2023182736A1 - Formulation composite de comprimé multicouche et son procédé de préparation - Google Patents

Formulation composite de comprimé multicouche et son procédé de préparation Download PDF

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WO2023182736A1
WO2023182736A1 PCT/KR2023/003605 KR2023003605W WO2023182736A1 WO 2023182736 A1 WO2023182736 A1 WO 2023182736A1 KR 2023003605 W KR2023003605 W KR 2023003605W WO 2023182736 A1 WO2023182736 A1 WO 2023182736A1
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acid
polymer
drug
polymerized
layer
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PCT/KR2023/003605
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English (en)
Korean (ko)
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김호준
김기역
진근우
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주식회사 위바이오트리
주식회사 씨앤팜
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Publication of WO2023182736A1 publication Critical patent/WO2023182736A1/fr

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    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • the present invention relates to a multilayer tablet combination preparation and a method for manufacturing the same.
  • niclosamide which has a strong antiviral effect against SARS-CoV-2, the virus that recently caused the COVID-19 pandemic, and docetaxel, a representative example of an anticancer drug, are representative examples of drugs with significantly poor solubility. Because the structure of the drug itself makes it difficult for patients to absorb, its use is limited. While various studies are being attempted to solve this problem, increasing the solubility and dissolution of the drug by solubilizing the drug acts as the most important factor in drug absorption.
  • oral drug delivery is one of the most preferred routes for in vivo administration of drugs, mainly due to patient convenience and manufacturability of dosage forms.
  • Recent pharmaceutical research has focused on drug delivery and absorption, which can offer distinct advantages over traditional release formulations of drugs. This has the potential to maximize efficacy while minimizing administration frequency and toxicity.
  • the gastrointestinal (GI) tract refers to the digestive tract and includes tubes such as the esophagus, stomach, small intestine, large intestine, rectum, and anus.
  • GI gastrointestinal
  • a drug lacks stability in gastric juices, causes irritation in the gastrointestinal tract, or needs to be targeted to specific areas, or because of pH changes throughout the GI tract, for drugs in oral dosage forms, formulation development may be necessary to improve drug absorption. The effect can be increased.
  • single-layer immediate-release tablets which have been commonly used as existing oral dosage forms, have a problem in that it is difficult to control the absorption of the drug immediately after oral administration due to the nature of the preparation.
  • drugs that are mainly absorbed in specific parts of the body, it is difficult to control the release, dispersion and absorption of the drug in the form of a single-layer immediate-release tablet, making oral administration difficult as it does not show the drug's effect properly. Therefore, single-layer preparations generally allow rapid absorption of the drug without specific targeting for therapeutic action, but there is a problem in that it is difficult to improve the low absorption rate of the drug.
  • the present invention relates to a multilayer tablet composite preparation for improving the bioavailability of a drug or a pharmaceutically acceptable salt thereof, comprising at least one of a drug or a pharmaceutically acceptable salt thereof, a crystallization inhibitor, and a polymer for controlling the drug release rate.
  • a drug-containing layer formed from a first mixing portion containing; and a floating layer formed of a second mixing portion containing at least one of a polymer polymerized with poly(meth)acrylate, a polymer polymer polymerized with acrylic acid, and a swellable polymer.
  • the present invention is a multilayer tablet complex that can provide more effective pharmaceutical effects by increasing the residence time in the stomach to maximize the absorption rate of the drug in the body and improving the absorption of the drug in the stomach and small intestine.
  • the purpose is to provide a manufacturing method for the preparation.
  • the present invention provides a drug-containing layer formed of a first mixing portion containing a drug or a pharmaceutically acceptable salt thereof, a crystallization inhibitor, and a polymer for controlling the drug release rate; and a floating layer formed from a second mixing portion containing at least one of a polymer polymerized with poly(meth)acrylate, a polymer polymer polymerized with acrylic acid, and a swellable polymer.
  • the present invention includes the steps of dissolving a crystallization inhibitor and a drug in an organic solvent to prepare a first dissolved product; preparing a powder of the first melt by drying the first melt; Forming a drug-containing layer using the powder of the first lysate; And preparing a multi-layer tablet forming a floating layer by compressing a second mixed portion containing at least one of a polymer polymer polymerized with poly(meth)acrylate and a polymer polymer polymerized with acrylic acid and a swellable polymer in the drug-containing layer.
  • the purpose is to provide a method for manufacturing a multi-layered tablet combination preparation comprising a.
  • the present invention provides a gastric retentive drug delivery system (GRDDS) function that can manipulate the release of API in the body to control the therapeutic efficacy of the drug, improve patient compliance, and reduce the frequency of administration through a multilayer tablet combination formulation. It has the effect of providing
  • GMDDS gastric retentive drug delivery system
  • the multilayer tablet combination preparation of the present invention can solve the problem of low drug absorption rate or gastrointestinal tract irritation, which is a problem during oral administration, and when targeting a specific area, it can be used due to changes in drug absorption rate due to pH changes throughout the GI tract. It can provide effects that can solve problems.
  • Figure 1 is a photograph of the multilayer tablet combination preparation of the present invention.
  • Figure 2 is a graph of the results of in vivo pharmacokinetic analysis for beagles.
  • Figure 3 is a graph of the results of in vivo pharmacokinetic analysis for minipigs.
  • Figure 4 is a graph of AUC values among the in vivo pharmacokinetic analysis results for minipigs.
  • Figure 5 is a graph of the results of in vivo pharmacokinetic analysis for minipigs.
  • Figure 6 is a graph of AUC values among the in vivo pharmacokinetic analysis results for minipigs.
  • Figure 7 is a graph of the results of in vivo pharmacokinetic analysis of beagles in Examples 10 and 11 and Comparative Examples 5 and 6.
  • Figure 8 is a graph of AUC values among the in vivo pharmacokinetic analysis results for beagles in Examples 10 and 11 and Comparative Examples 5 and 6.
  • Figure 9 is a photograph of a three-layer tablet manufactured by the method of Example 12 as an example of a multi-layer tablet.
  • the present invention is a first drug containing at least one of a drug or a pharmaceutically acceptable salt thereof, a crystallization inhibitor, and a polymer for controlling the drug release rate that can improve the problem of weakening the effect of the drug in the body due to lower absorption rate when administered orally.
  • a drug-containing layer formed as a mixing portion; and a second mixing portion containing at least one of a polymer polymerized with poly(meth)acrylate, a polymer polymer polymerized with acrylic acid, and a swellable polymer.
  • the second mixing portion containing at least one of a polymer polymerized with poly(meth)acrylate, a polymer polymer polymerized with acrylic acid, and a lipophilic polymer is configured to provide floatability to the multilayer tablet composite preparation.
  • the polymer obtained by polymerizing acrylic acid may be one or more types selected from carbomer copolymer type, carbomer homopolymer type, and ammonio methacrylate copolymer type (AMMONIO METHACRYLATE COPOLYMER TYPE). More specifically, the carbomer copolymer type may be a carbomer copolymer type (CARBOMER COPOLYMER TYPE (ALLYL PENTAERYTHRITOL CROSSLINKED)) in which allyl pentaerythritol is crosslinked, and the carbomer homopolymer type may be a carbomer copolymer type in which allyl pentaerythritol is crosslinked.
  • carbomer copolymer type may be a carbomer copolymer type (CARBOMER COPOLYMER TYPE (ALLYL PENTAERYTHRITOL CROSSLINKED)) in which allyl pentaerythritol is crosslinked
  • CARBOMER HOMOPOLYMER TYPE ALLYL PENTAERYTHRITOL CROSSLINKED
  • allyl sucrose cross-linked carbomer homopolymer type CARBOMER HOMOPOLYMER TYPE (ALLYL SUCROSE CROSSLINKED)
  • allyl pentaerythritol cross-linked carbomer homopolymer type It may be a polymer type (CARBOMER HOMOPOLYMER TYPE (ALLYL PENTAERYTHRITOL CROSSLINKED)).
  • the carbomer copolymer type, carbomer homopolymer type, and ammonio methacrylate copolymer type can be classified into A, B, and C, respectively. Carbomers belonging to the above are restricted. It can be used without.
  • the polymer polymer in which poly(meth)acrylate is polymerized is specifically a polymer polymer in which methacrylate is polymerized, a polymer polymer in which ethyl acrylate is polymerized, a polymer polymer in which methacrylate and ethyl acrylate are polymerized, and ethylene glycol.
  • the polymer polymer obtained by polymerizing poly(meth)acrylate is METHACRYLIC ACID - ETHYL ACRYLATE COPOLYMER) (1:1) TYPE A, METHACRYLIC ACID - ETHYL ACRYLATE COPOLYMER) (1:1) TYPE B, METHACRYLIC ACID - ETHYL ACRYLATE COPOLYMER) (1:1) TYPE C, METHACRYLIC ACID - METHYL METHACRYLATE COPOLYMER (1:1) TYPE A, METHACRYLIC ACID - METHYL METHACRYLATE COPOLYMER (1:1) TYPE B, METHACRYLIC ACID - METHYL METHACRYLATE COPOLYMER (1:1) TYPE C, METHACRYLIC ACID - METHYL METHACRYLATE COPOLYMER (1:2) TYPE A, METHACRYLIC ACID - ETHYL ACRYLATE COPOLYMER
  • the polymer polymer polymer polymerized with poly(meth)acrylate or the polymer polymer polymerized with acrylic acid each has a tap density of 0.01 g/mL to 1.0 g/mL, more preferably 0.025 g/mL to 0.7. In g/mL, it plays a role in providing floating properties to the drug-containing preparation when forming a multilayer tablet complex preparation. If the tap density range of the poly(meth)acrylate-polymerized polymer or the acrylic acid-polymerized polymer does not fall within the above-mentioned range, it will not float, or even if it floats and stays, it will sink within 30 minutes, causing initial damage. Drug release and absorption may not occur. In addition, when a floating base exceeding the above tap density range is used, a phenomenon in which the drug is not continuously released (trapping) occurs when the drug stays in the stomach, and the expected effect may not be achieved.
  • the swellable polymer can be used without limitation as long as it is a polymer that can provide floating properties to the floating layer, but includes methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, sodium carboxymethylcellulose, sodium alginate, It may be one or more selected from polyethylene oxide, pregelatinized starch, carrageenan, xanthan gum, locust bean gum, and guar gum.
  • the drug includes Niclosamide, Closantel, rafoxanide, oxyclozanide, Artesunate, Tilorone, and cyclosporine ( Cyclosporine, perhexiline maleate, loperamide, mefloquine, amodiaquine, proscillaridin, phenazopyridine, digitoxin ), penfluridol, clomiphene, toremifene, digoxin, hexachlorophene, hydroxyprogesterone, thioridazine, salinomycin ( salinomycin, quinacrine, eltrombopag, cepharanthine, ciclesonide, ceritinib (LDK378), dihydrogambogic acid ), osimertinib (AZD-9291), isopomiferin, anidulafungin (LY303366), osajin, lustrombopag, isosajin , gilteritini
  • Docetaxel Paclitaxel, Cabazitaxel, Etoposide, Topotecan, Idarubicin, Fluorouracil, and Abiraterone ), Axitinib, Bosutinib, Cabozantinib, ceritinib, dabrafenib, erlotinib, lapatinib, midostaurin Anticancer drugs such as midostaurin, neratinib, nilotinib, nintedanib, pazopanib, sonidegib, and trametinib, or ascorbic acid (Ascorbic acid), vitamin A, lipoic acid, pramipexole, allopurinol, pentoxifylline, melatonin, probucol, quercetin , transcrocetinate, acetylcysteine, nicaraven, lodoxamide, 4-n-butylresorcinol, tocopherol
  • Acid protocatechuic acid, salvianic acid, sinapic acid, tranexamic acid, valeric acid, Veratric Acid , chlorogenic acid, asiatic acid, madecasic acid, suberic acid, hyaluronic acid, ursolic acid, ascorbic acid.
  • salvianolic acid B pyridine-3-carboxylic acid, ascorbyl palmitate, ascorbyl glucoside, carnitine , pantothenic acid, biotin, folic acid, alliin, glutathione, serine, glycine, alanine, avenanthramide ), threonine, cysteine, valine, leucine, methionine, proline, phenylalanine, tyrosine, tryptophan, aspartic acid (aspartic acid), glutamic acid, asparagine, glutamine, histidine, lysine, arginine, decanal, retinaldehyde, cinnamaldehyde (cinnamaldehyde), catechin-aldehyde, coniferyl aldehyde, syringaldehyde, vanillin, edaravone, idebenone, coenzyme Q10 ), ubiquino
  • the multilayer tablet combination preparation of the present invention can be effectively applied to poorly soluble drugs among the above drugs, and more preferably may be one or more types selected from the halogenated salicylanilide series and taxane series drugs.
  • the halogenated salicylanilide-based drugs may include niclosamide, closantel, lapoxanide, and oxyclozanide
  • the taxane-based drugs include docetaxel, paclitaxel, and cabazitaxel ( Cabazitaxel), etc.
  • pharmaceutically acceptable salts refer to salts commonly used in the pharmaceutical industry, for example, inorganic ionic salts made of calcium, potassium, sodium and magnesium, hydrochloric acid, nitric acid, phosphoric acid, bromic acid, and iodine.
  • Inorganic acid salts prepared from acids, perchloric acid, sulfuric acid, etc.; Acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid.
  • Organic acid salts made from acids, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc.; Sulfonic acid salts made from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, etc.; Amino acid salts made from glycine, arginine, lysine, etc.; and amine salts prepared from trimethylamine, triethylamine, ammonia, pyridine, picoline, etc., but the types of salts meant in the present invention are not limited by these salts listed.
  • the multilayer tablet combination preparation of the present invention is within the scope of the present invention if the drug-containing layer and the floating layer are formed in two or more layers, and changes or substitutions in the stacking order or coating method are within the scope of the present invention. It is self-evident and falls within the scope of the present invention.
  • the multilayer tablet combination preparation of the present invention may further include an intermediate layer between the drug-containing layer and the floating layer, or may further include a third layer laminated on top and/or below the drug-containing layer and the floating layer.
  • Figure 9 is a floating layer - drug-containing layer - floating layer, which is formed in the form of a three-layer multilayer tablet with floating layers formed on the top and bottom of the drug-containing layer, respectively.
  • the intermediate layer and/or the third layer may be formed of the same or different components as the drug-containing layer or floating layer listed in the present invention.
  • the combination preparation in the present invention can be used without limitation as long as it is formulated for oral administration. Specifically, it may mean tablets, capsules, granules, etc., and if the tablet form consists of two or more layers, it falls within the scope of the present invention. Specifically, the tablets include orally disintegrating tablets, chewable tablets, effervescent tablets, dispersion tablets, dissolving tablets, etc., and the granules may refer to forms such as hard capsules and soft capsules.
  • the tablets in the present invention are made by homogenizing the drug (or main ingredient) with additives such as excipients, binders, and disintegrants, and then compression molding them as is, or by adding the main ingredient and lubricant to pre-made granules to homogenize them.
  • Compression molding method add additives such as excipients, binders, and disintegrants to the main ingredients to make them homogeneous; add water or a solution containing the binder to form granules in an appropriate manner; then add a lubricant, mix, and compression mold. This may mean manufacturing by adding additives such as excipients, binders, and disintegrants to the powder and mixing it evenly, then moistening it with a solvent and molding it into a certain shape, or putting it in a certain mold and then drying it.
  • combination preparation of the present invention is within the scope of the present invention in addition to the multi-layered tablet form.
  • the first mixing part and/or the second mixing part of the multilayer tablet combination preparation may further include a metal hydroxide or metal oxide.
  • the metal hydroxide may be a compound represented by Formula 1 or 2, and the metal oxide may be represented by Formula 3.
  • M 2+ is a divalent metal cation selected from the group consisting of Mg 2+ , Ni 2+ , Cu 2+ , Co 2+ and Zn 2+
  • M 3+ is Al 3+
  • Fe 3 + is a trivalent metal cation selected from the group consisting of V 3+ , Ti 3+ , Mn 3+ and Ga 3+
  • x is a number ranging from 0 to 10
  • m is a number ranging from 0 to 20.
  • A is an anion selected from the group consisting of CO 3 2- , NO 3 - , Br - , Cl - , SO 4 2- , HPO 4 2- and F -
  • n is the charge number of anion A.
  • n is a number ranging from 0.5 to 5
  • z is a number ranging from 0 to 5
  • y is a positive number greater than or equal to 0.
  • M 2+ is a divalent metal cation selected from the group consisting of Mg 2+ , Ni 2+ , Cu 2+ , Co 2+ and Zn 2+ , and x has a range of 0 to 2 number
  • A is an anion selected from the group consisting of CO 3 2- , NO 3- , Br- , Cl-, SO 4 2- , HPO 4 2- and F-
  • n is the charge number of anion A
  • n is a number in the range of 0 to 2
  • z is a number in the range of 0 to 1
  • y is a positive number of 0 or more than 0.
  • M 2+ is Mg 2+ , Ni 2+ , Cu 2+ or Zn 2+
  • x is a number ranging from 0 to 2
  • A is CO 3 2- , NO 3 - , Br - , Cl - , SO 4 2- , HPO 4 2- or F -
  • n is the charge number of anion A
  • n is a number ranging from 0 to 2
  • z is 0 to 1. It is a number with a range below, and y is 0 or a positive number greater than 0.
  • a crystallization inhibitor may refer to a polymer that can delay the return of a compound to its crystalline form when dissolved in a solvent, etc., so as to maintain the amorphous or non-crystalline form of each compound when the drug is dissolved in a solvent.
  • the crystallization inhibitor includes polyvinyl pyrrolidone-based compounds, poloxamer-based compounds, cellulose-based compounds, polyethylene glycol-based compounds, polyoxyethylene sorbitan fatty acid esters compounds, and lecithin-based compounds. ) compounds, fatty acid compounds, glycerol fatty acid esters compounds, sorbitan fatty acid esters compounds, oils, sodium dodecyl sulfate, sodium stearyl puma It may be sodium stearyl fumarate, stearic acid, lauric acid, and carrageenan.
  • polyvinyl pyrrolidone-based compounds include polyvinylpyrrolidone K10 (MW 8000-10,000), polyvinylpyrrolidone K12 (MW 11,000-12,000), polyvinylpyrrolidone K15 (MW 14,000-18,000), and polyvinylpyrrolidone K17 (MW 14,000-18,000).
  • MW means molecular weight.
  • the poloxamer-based compounds include poloxamer 101, poloxamer 105, poloxamer 105 benzoate, poloxamer 108, poloxamer 122, poloxamer 123, poloxamer 124, poloxamer 181, and poloxamer 182.
  • the weight average molecular weight of the poloxamer-based compound described above may be 5,000 to 500,000.
  • the cellulose-based compounds include hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose, hydroxypropylcellulose (HPC), carboxymethylcellulose (CMC), and ethyl cellulose ( It may be one or more selected from the group consisting of ethylcellulose (EC), methylcellulose (MC), and cellulose acetate (CA).
  • HPMC hydroxypropyl methylcellulose
  • HPC hydroxypropyl methylcellulose
  • HPC hydroxypropylcellulose
  • CMC carboxymethylcellulose
  • ethyl cellulose It may be one or more selected from the group consisting of ethylcellulose (EC), methylcellulose (MC), and cellulose acetate (CA).
  • the weight average molecular weight of the above-mentioned cellulose-based compound may be 5,000 to 500,000.
  • polyethylene glycol-based compounds include polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 500, polyethylene glycol 1000, polyethylene glycol 1400, and polyethylene glycol 1500.
  • the weight average molecular weight of the above-described polyethylene glycol-based compound may be 5,000 to 500,000.
  • Tween surfactant is an ester bonded form of fatty acid and ethylene oxide. More specifically, polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan monopalmitate (Tween 40), polyoxyethylene glycol sorbitan monostearate (polyethylene glycol sorbitan) monostearate; Tween 60), Tween65, polyoxyethylene sorbitan monooleate (Tween80), and polyoxyethylene sorbitan trioleate (Tween85).
  • the lecithin-based compound refers to lecithin and its derivatives, including phospholipids, phosphatidyl choline, mixed phospholipids, sodium cholate, and hydroxylase. It may be hydroxylated phospholipids, hydroxylated lecithin, etc.
  • the fatty acid-based compounds include butyric acid, caproic acid, caprylic acid, capric acid, stearic acid, and lauric acid.
  • oleic acid myristoleic acid, palmitoic acid, oleic acid, linoleic acid, ⁇ -linolenic acid, ⁇ -linolenic acid, gadoleic acid, eicosadienoic acid, eicosapentanoic acid, arachidoic acid, erucic acid, docosadienoic acid, docostrienoic acid, docosapentaenoic acid, docosahexaenoic acid, It may be adrenic acid, nervonic acid, etc.
  • glycerol fatty acid esters include polyglycerol fatty acid esters, polyglycerol polyricinoleate, polyoxyethyleneglycerol triricinoleate, and cremophor EL. It may be, etc.
  • the sorbitan fatty acid ester may be sorbitan monolaurate (Span 20), sorbitan monooleate (Span 80), etc.
  • oils may be soybean, MCT oil (Medium-Chain Triglyceride), caster oil, etc. It is preferable that the above-mentioned crystallization inhibitor is further included because it can improve the solubility and dispersibility of the drug.
  • the polymer for controlling the drug release rate is a substance that can help control the drug release rate when formulating a drug, and includes calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, ethyl cellulose, polyethylene oxide, and leucostvine gum.
  • Guar gum, Bofill polyvinyl acetate, polyvinylpyrrolidone-polyvinyl acrylate copolymer, polyvinyl alcohol-polyethylene glycol copolymer, polyvinylpyrrolidone-polyvinylacetate copolymer, bentonite, hectorite, Carrageenan, It may be Ceratonia, Cetostearyl alcohol, hydroxypropyl starch, magnesium aluminum silicate, polydextrose, poly(methyl vinyl ether/maleic anhydrose), propylene glycol alginate, and saponate. .
  • the first mixing part and/or the second mixing part of the present invention may further include one or more compounds selected from the group consisting of an enteric coating agent, a foam generator, and a swelling excipient.
  • the enteric coating refers to a material that coats the drug so that the drug is released when it passes through the intestinal tract instead of being released in the stomach.
  • Enteric coating can be used to select the area in the intestine where the drug is released.
  • the bioavailability varies over time depending on the pH of each area in the intestine, especially in the stomach due to recrystallization by gastric juice. Absorption of the drug is significantly reduced.
  • the use of an enteric coating agent may be desirable in that it is possible to select an optimized formulation for drugs with different absorption rates depending on the pH of the organ by suppressing recrystallization of the drug in the stomach using an enteric coating agent.
  • the enteric coating agent may be hydroxypropyl-methyl cellulose phthalate, zein, shellac, etc.
  • the bubble generator may be sodium carbonate, sodium bicarbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and citric acid.
  • the bubble generator may be used to form a floating layer by being included in the second mixing part with the polymer polymer polymerized with the poly(meth)acrylate of the present invention and the polymer polymer polymerized with acrylic acid.
  • the swelling excipients include carboxymethyl cellulose, natural cellulose, pectin, hyaluronic acid, polyacrylate, polyethylene oxide, polypropylene oxide, monosaccharides, methacrylic acid-ethyl acrylate copolymers, shellacs, and carbopolymers (carbomer, carboxyvinyl polymer). ) and polyvinyl alcohol, hydroxypropyl methyl cellulose phthalate-based compounds, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methyl acetate succinate, carboxymethyl cellulose, carboxymethyl ethyl cellulose.
  • cellulose acetate phthalate compounds hydroxypropyl cellulose compounds, ethyl cellulose compounds, methylcellulose compounds, polyvinyl acetate phthalate, silicon dioxide, calcium silicate, lactose, starch, lactose, mannitol, kaolin inorganic salt, powdered sugar. , powdered cellulose derivatives, microcrystalline cellulose, etc.
  • the combination preparation of the present invention is formulated in the form of film coating, semi-permeable membrane coating, water-insoluble coating, tablet, double tablet, stomach retention tablet, etc. using a coating agent, the blood concentration of the drug is very high. Since it has been confirmed, a coating layer may be further included in that the formation of the coating agent may be helpful for effects such as improving the solubility of the drug.
  • the combination preparation of the present invention may additionally contain ingredients that do not increase medicinal efficacy but are commonly used in pharmaceutical combination preparations to improve smell, taste, vision, etc.
  • the multilayer tablet combination preparation of the present invention may additionally contain pharmaceutically acceptable additives.
  • Pharmaceutically acceptable additives may be, for example, excipients, lubricants, binders, and disintegrants.
  • pharmaceutically acceptable additives may be, for example, starch, gelatinized starch, microcrystalline cellulose, lactose, povidone, colloidal silicone, etc.
  • Dioxide calcium hydrogen phosphate, lactose, mannitol, taffy, gum arabic, pregelatinized starch, corn starch, powdered cellulose, hydroxypropyl cellulose, Opadry, sodium starch glycolate, carnauba lead, synthetic aluminum silicate, stearic acid, magnesium stearate. , aluminum stearate, calcium stearate, white sugar, dextrose, sorbitol, and talc, but are not limited thereto.
  • the present invention includes the steps of dissolving a crystallization inhibitor and a drug in an organic solvent to prepare a first dissolved product; preparing a powder of the first melt by drying the first melt; Forming a drug-containing layer using the powder of the first lysate; And manufacturing a multilayer tablet that forms a floating layer by compressing a second mixing portion containing at least one of a polymer polymer polymerized with poly(meth)acrylate and a polymer polymer polymerized with acrylic acid in the drug-containing layer. , provides a method for manufacturing a multilayer tablet combination preparation.
  • the present term includes the steps of dissolving a crystallization inhibitor and a drug in an organic solvent to prepare a first dissolved product; Dissolving one or more of magnesium oxide, hydrotalcite, and magnesium hydroxide in the first melt; preparing a powder of the first melt by drying the first melt; Forming a drug-containing layer using the powder of the first lysate; And manufacturing a multilayer tablet that forms a floating layer by compressing a second mixed portion containing at least one of a polymer polymer polymerized with poly(meth)acrylate and a polymer polymer polymerized with acrylic acid in the drug-containing layer.
  • a method for manufacturing a multilayer tablet combination preparation is provided.
  • the present invention includes the steps of dissolving a crystallization inhibitor and a drug in an organic solvent to prepare a first dissolved product; preparing a powder of the first melt by drying the first melt; Preparing a mixture by mixing one or more of magnesium oxide, hydrotalcite, and magnesium hydroxide into the powder; Forming a drug-containing layer using the mixture; And manufacturing a multilayer tablet that forms a floating layer by compressing a second mixing portion containing at least one of a polymer polymer polymerized with poly(meth)acrylate and a polymer polymer polymerized with acrylic acid in the drug-containing layer. , provides a method for manufacturing a multilayer tablet combination preparation.
  • the organic solvent may be one or more selected from ethanol, methanol, propanol, butanol, and acetonitrile, and any organic solvent may be used without limitation. However, in terms of improving reactivity, an anhydrous organic solvent may be more preferable, and anhydrous ethanol may be most preferable.
  • water can be further included in the organic solvent or water can be used as needed.
  • any conventional method of tableting a two-layer tablet can be used without limitation. More specifically, a tablet press can be used.
  • the tableting method includes first forming a drug-containing layer in a first mixing section to form a multilayer tablet; Securing space for forming a floating layer on the drug-containing layer; forming a floating layer on the drug-containing layer; And it may include the step of applying tableting pressure to the floating layer.
  • the expression of the first lysate, drug-containing layer, and floating layer in the above production method is an arbitrary order, and the order of preparing the first lysate, drug-containing layer, and floating layer may be changed or replaced, and such substitution or order may be performed. Changes to are obvious to those skilled in the art and fall within the scope of the present invention.
  • the drug-containing layer may be formed from the first mixing part, and the floating layer may be formed from the second mixing part.
  • the step may include filling the first mixture into the container of the tablet press and then pre-compressing the filled first mixture. Filling at this time allows the first mixing part to freely fall into the container, and can create a space for filling the second mixing part through preload.
  • a floating layer is formed with a second mixing portion thereon, and the second mixing portion can also be formed by freely falling on the drug-containing layer.
  • a drug-containing layer may be formed in a tablet press using the second mixing unit, and a floating layer may be formed on the drug-containing layer using the first mixing unit.
  • the multilayer tablet composite preparation may further include the step of dry mixing the first dissolved powder with one or more metal oxides or metal hydroxides selected from Formulas 1 to 3. More preferably, the at least one metal oxide or metal hydroxide selected from Formulas 1 to 3 may be magnesium oxide (MgO).
  • MgO magnesium oxide
  • the ratio of the drug-containing layer and the floating layer in the multilayer tablet combination preparation may be 1:9 to 9:1 by weight, and more specifically, 2:8 to 8:2.
  • the multilayer tablet combination preparation of the present invention contains 0.1 to 40% by weight of the drug or a pharmaceutically acceptable salt thereof, 0.2 to 80% by weight of a crystallization inhibitor, and 0.5 to 0.5% by weight of a swellable polymer when the total weight of the first mixing portion is 100% by weight. It may contain 80% by weight.
  • the multilayer tablet composite preparation may further include 0.1 to 40% by weight of one or more types selected from the group consisting of compounds represented by Formulas 1 to 3, and may be selected from the group consisting of enteric coating agents, foam generators, and swellable excipients. It may further include 1 to 30% by weight of one or more selected substances.
  • the multilayer tablet composite preparation of the present invention contains 80% of at least one of a polymer polymerized with poly(meth)acrylate, a polymer polymer polymerized with acrylic acid, and a swellable polymer when the total weight of the second mixing portion is 100% by weight. It may contain from 100% by weight.
  • the multilayer tablet combination preparation of the present invention may be for anti-inflammatory, antiviral, and/or anticancer purposes.
  • anti-inflammatory means having the effect of alleviating inflammatory reactions caused by infectious, traumatic, endogenous, inflammatory, degenerative, or autoimmune causes. This includes diseases such as ulcerative colitis, inflammatory disease, Crohn's disease, and viral enteritis.
  • antiviral use refers to malaria infection or Epstein Barr Virus (EBV), hepatitis B virus, hepatitis C virus, HIV, HTLV 1, and Varicella that have an antiviral effect and cause viral diseases.
  • -Corona viruses and/or variants thereof such as Varicella-Zoster Virus (VZV), Human Papilloma Virus (HPV), SARS-CoV and/or SARS-CoV2 More specifically, regarding viruses such as omicron, rhinovirus, adenovirus, RS virus, parainfluenza virus, RS virus, etc., which cause colds or respiratory diseases, and other retroviruses. It means that it has a virus proliferation inhibitory effect and antibiotic function.
  • VZV Varicella-Zoster Virus
  • HPV Human Papilloma Virus
  • SARS-CoV SARS-CoV2
  • viruses such as omicron, rhinovirus, adenovirus, RS virus, parainfluenza virus,
  • anticancer use mainly means having anticancer activity by acting directly on DNA to block the replication, transcription, and translation processes of DNA, or by interfering with the synthesis of nucleic acid precursors in the metabolic pathway and inhibiting cell division.
  • fibrosarcoma myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, and lymphatic vessels.
  • Lymphangiosarcoma lymphangioendothelioma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer (pancreatic cancer), breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma (sweat gland carcinoma), sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, Renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms tumor, cervical cancer (cervical cancer), testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma (astrocytoma), medullob
  • the multilayer tablet combination preparation of the present invention can be administered at a dose of 0.001 mg/kg to 500 mg/kg, once to eight times a day, and depending on the course, once to three times a day, once to three times a day. It can be administered once, 1 to 3 times in 4 days, or 1 to 3 times in 5 days.
  • the multilayer tablet combination preparation of the present invention can be optimized for administration by oral administration (oral administration).
  • Example 5 Preparation of multilayer tablet (Na-alginate ratio - 5% in first mixing part)
  • the first mixing part is prepared by dry mixing dried NIC-PVP, 1.629 g of MgO, and 0.368 g of alginate-Na.
  • Example 6 Preparation of multilayer tablet (Na-alginate ratio control, 2.5% in first mixing part)
  • the first mixing part is prepared by dry mixing dried NIC-PVP, 2.786 g of MgO, and 0.25 g of alginate-Na.
  • the second mixing part is manufactured using carbomer (947). A drug layer is formed with 0.225 g of the first mixing part, and a floating layer is formed with 0.15 g of the second mixing part, and a multi-layer tablet composite preparation is tableted.
  • Example 7 Preparation of multilayer tablet (Na-alginate ratio control, 7.5% in first mixing part)
  • Example 8 Manufacture of multilayer tablet (Na-alginate ratio - 5% in first mixing part)
  • Example 9 Manufacture of multilayer tablet (Na-alginate ratio - 5% in first mixing part)
  • the first mixing section is manufactured by ball milling dried NIC-PVP, 1.629 g of MgO, and 0.368 g of alginate-Na.
  • the second mixing part was prepared by dry mixing 0.5 g of carbomer 71G and 0.3 g of sodium carbonate, then adding 0.2 g of carbomer 974P and dry mixing. After filling 0.225 g of the first mixing portion into the container of the tablet press, the filled drug-containing layer is pre-compressed. After the drug-containing layer is formed, 0.15 g of the second mixing portion is freely dropped and compressed into tablets to form a floating layer thereon.
  • the filled drug-containing layer is pre-compressed to form a drug-containing layer.
  • 0.2 g of the second mixing portion is allowed to fall freely and is compressed into tablets to prepare a multi-layer tablet.
  • the second mixing section is prepared by mixing 42.75 g of carbomer 71G and 42.75 g of Na(CO 3 ) 2 , adding 19.5 g of carbomer974P, mixing, and then adding and mixing 5 g of magnesium stearate as a lubricant.
  • the filled drug-containing layer is pre-compressed to form a drug-containing layer.
  • 0.2 g of the second mixing portion is allowed to fall freely and is compressed into tablets to prepare a multi-layer tablet.
  • the filled floating layer After filling 0.3 g of the second mixing portion into the container of the tablet press, the filled floating layer is pre-compressed to form a floating layer. After filling 0.3 g of the first mixing portion on top of the floating layer into the container of the tablet press, the filled drug-containing layer is pre-compressed to form a drug-containing layer. To form a third layer with the same ingredients as the second mixing portion on top of the drug-containing layer, 0.1 g of the second mixing portion is allowed to fall freely and is compressed into a tablet to prepare a multilayer tablet.
  • a first mixing part was prepared by mixing 5 g of dried NIC-PVP, 2 g of MgO, and 0.368 g of sodium alginate. A single-layer tablet is compressed using 0.4 g of the first mixing portion.
  • the first mixing part is prepared by dry mixing the dried NIC-PVP powder, 2.714 g of MgO, and 0.5 g of xantan gum. A single-layer tablet is compressed using 0.4 mg of the first mixing portion.
  • compositions of Examples 1 to 4 and Comparative Examples 1 and 2 were each administered once a day at a dose of 40 mg/kg.
  • Experimental Example 2 In-vivo pharmacokinetic analysis of the compositions of Examples, Reference Examples, and Comparative Examples (minipig) The in-vivo pharmacokinetic analysis was conducted using the compositions of Examples 5 to 9 and Comparative Example 3 using minipigs. Plasma drug concentration information was obtained by single oral administration to pigs.
  • compositions of Examples 5 to 9 and Comparative Example 3 were administered at a dose of 500 mg per animal once a day.
  • Example 9 AUC(last) 797.14 969.22 Cmax 144.16 162.20 Tmax 5.00 2.00 t 1/2 5.26 2.69 * AUC: ng ⁇ h/mL, C max : ng/mL, T max & t 1/2 : h
  • Experimental Example 3 In-vivo pharmacokinetic analysis of the compositions of Examples and Comparative Examples (Beagle) In-vivo pharmacokinetic analysis was performed using the compositions of Examples 10 and 11 and Comparative Examples 5 and 6. It has been done. Plasma drug concentration information was obtained by single oral administration of the compositions of Examples 10 and 11 and Comparative Examples 5 and 6 to beagles.
  • compositions of Examples 10 and 11 and Comparative Examples 5 and 6 were each administered at a dose of 50 mg/kg once a day.
  • the reason for increasing the sustained release of the drug through multilayer tablets as in the example is that if the Cmax of the drug in the blood is high, the probability of exposure to toxicity increases, so by increasing the sustained release of the drug by adjusting the AUC and tmax values, the drug's sustained release in the blood is increased. This is to maintain the concentration in the therapeutic window to maximize its functional role. From the results in Tables 10 and 11 below and Figures 7 and 8, when Cmax is increased by formulating into a multilayer tablet, the AUC and tmax values are also appropriately It was confirmed that the toxicity of the drug was reduced by increasing the dose, but the effect of the drug was sustainable.
  • multilayer tablets have the advantage of reducing the number of doses compared to single-layer tablets.
  • the drug is continued to be administered when the blood concentration of the drug drops.
  • the blood concentration of the drug decreases. It can be seen that the concentration preservation effect in Examples 10 and 11 is significantly superior to that in Comparative Example 6 at the point where .

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Abstract

La présente invention concerne une formulation composite de comprimé multicouche et son procédé de préparation, ainsi qu'un type de formulation qui peut améliorer la biodisponibilité de médicaments et son procédé de préparation.
PCT/KR2023/003605 2022-03-21 2023-03-17 Formulation composite de comprimé multicouche et son procédé de préparation WO2023182736A1 (fr)

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KR20130025459A (ko) * 2011-08-31 2013-03-12 부산대학교 산학협력단 경구투여용 서방성 다층정제
KR20130115257A (ko) * 2010-09-30 2013-10-21 시오노기세이야쿠가부시키가이샤 난용성 약물의 용해성 개선 제제
KR20130120118A (ko) * 2012-04-25 2013-11-04 (주)비씨월드제약 이중층 구조를 갖는 위체류성 서방성 제제
KR20180114515A (ko) * 2017-04-10 2018-10-18 성균관대학교산학협력단 다공성 위체류층을 포함하는 서방성 제제 및 이의 제조방법
KR20210105761A (ko) * 2020-02-19 2021-08-27 한국프라임제약주식회사 콜린알포세레이트를 주성분으로 하는 서방성 제제

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100869330B1 (ko) * 2007-06-13 2008-11-18 조선대학교산학협력단 트리메톡시플라본을 유효성분으로 함유하는 항암제의활성 증진제
KR20130115257A (ko) * 2010-09-30 2013-10-21 시오노기세이야쿠가부시키가이샤 난용성 약물의 용해성 개선 제제
KR20130025459A (ko) * 2011-08-31 2013-03-12 부산대학교 산학협력단 경구투여용 서방성 다층정제
KR20130120118A (ko) * 2012-04-25 2013-11-04 (주)비씨월드제약 이중층 구조를 갖는 위체류성 서방성 제제
KR20180114515A (ko) * 2017-04-10 2018-10-18 성균관대학교산학협력단 다공성 위체류층을 포함하는 서방성 제제 및 이의 제조방법
KR20210105761A (ko) * 2020-02-19 2021-08-27 한국프라임제약주식회사 콜린알포세레이트를 주성분으로 하는 서방성 제제

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