WO2023182736A1 - Multi-layered tablet composite formulation and preparation method therefor - Google Patents

Multi-layered tablet composite formulation and preparation method therefor 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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French (fr)
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/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, 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
    • A61K9/2086Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/16Amides, e.g. hydroxamic acids
    • A61K31/165Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167Amides, 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2009Inorganic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/2027Organic 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

The present invention relates to a multi-layered tablet composite formulation and a preparation method therefor and, to a formulation type which can improve the bioavailability of drugs and a preparation method therefor.

Description

다층정 복합제제 및 이의 제조방법Multilayer tablet combination preparation and method for manufacturing same
본 발명은 다층정 복합제제 및 이의 제조방법에 대한 것이다. The present invention relates to a multilayer tablet combination preparation and a method for manufacturing the same.
약물의 경구 투여 제형 개발에서 있어서 약물의 생체 이용률을 높이기 위해 용출 및 용해도의 개선이 점점 더 중요해지고 있다. 특히, 최근 COVID-19 대유행을 불러온 바이러스인 SARS-CoV-2에 대해 강력한 항바이러스 효과를 가진 니클로사마이드 및 항암제의 대표예인 도세탁셀은 용해도가 현저히 떨어지는 약물의 대표적인 예시이다. 이는 약물 자체의 구조로 인해 환자가 흡수하기 어렵기 때문에 그 사용에 제약을 받고 있는 실정이다. 이를 해결하기 위해 다양한 연구가 시도되는 가운데 약물의 가용화에 의한 약물의 용해도 및 용출의 증가는 약물의 흡수에 가장 중요한 요소로 작용된다. In the development of oral drug formulations, improving dissolution and solubility is becoming increasingly important to increase drug bioavailability. In particular, 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.
또한, 다양한 약물 전달 시스템 중에서 경구 약물 전달은 주로 환자의 편의성과 제형의 제조 가능성으로 인해 약물의 체내 투여에 가장 선호되는 경로 중 하나이다. 최근 제약 연구는 약물의 기존 방출 제형에 비해 확실한 이점을 제공할 수 있는 약물 전달 및 흡수에 초점을 맞추고 있다. 이는 투여 빈도와 독성을 최소화하면서 효능을 최대화할 가능성이 있다.Additionally, among various drug delivery systems, 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.
특히 약물의 경구용 투여시 낮은 흡수력으로 인해 위장(GI) 관에서 약물의 흡수가 국소적으로 작용할 수 있는데 장내에서 흡수될 수 있는 효과적인 방법으로 다층정 제제의 개발의 중요성이 대두되고 있다. 통상적으로 위상(GI)관 은 소화관을 의미하는 것으로 식도, 위, 소장, 대장, 직장 및 항문 등의 관을 의미한다. 예를 들어 약물이 위액에서 안정성이 부족하거나 위장관에 자극을 일으키거나 특정 부위를 표적으로 해야 하는 경우, GI 관 전체에 걸쳐 pH 변화가 있기 때문에 경구 투여 형태의 약물의 경우 제제 개발을 통해 약물 흡수의 효과를 높일 수 있다.In particular, due to the low absorption capacity of drugs when administered orally, absorption of drugs may occur locally in the gastrointestinal (GI) tract, and the importance of developing multilayer tablet formulations as an effective method for absorption in the intestine is emerging. Typically, the gastrointestinal (GI) tract refers to the digestive tract and includes tubes such as the esophagus, stomach, small intestine, large intestine, rectum, and anus. For example, if 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.
뿐만 아니라 약물의 가용화를 위해 고분자를 활용하여 용해도를 향상시키고자 하는 시도가 계속되어 왔다. 이에 Contribution to the Improvement of an Oral Formulation of Niclosamide, an Antihelmintic Drug Candidate for Repurposing in SARS-CoV-2 and Other Viruses(Eduardo Jose Barbosa 외 5인 공저)등의 논문에서도 니클로사마이드와 같은 약물의 용해도를 향상시키기 위해 고분자 물질을 사용하는 것에 대해 개시하고 있다. 개시된 논문 등에서도 고분자 물질을 이용할 경우 니클로사마이드의 용해도를 개선할 수 있음을 개시하고 있으나, 향상된 용해도의 범위가 니클로사마이드의 실질적인 체내 흡수율을 향상시키고, 이의 항바이러스 효과를 실질적으로 나타낼 수 있을 정도로 유의미한 효과를 달성하지 못했다는 점에서 여전히 문제가 있다. In addition, attempts to improve solubility by using polymers to solubilize drugs have continued. Accordingly, papers such as Contribution to the Improvement of an Oral Formulation of Niclosamide, an Antihelmintic Drug Candidate for Repurposing in SARS-CoV-2 and Other Viruses (co-authored by Eduardo Jose Barbosa and 5 others) also showed that the solubility of drugs such as niclosamide was improved. It discloses the use of polymer materials to do this. Although the disclosed papers and the like disclose that the solubility of niclosamide can be improved when polymer materials are used, the improved solubility range can improve the actual absorption rate of niclosamide in the body and substantially demonstrate its antiviral effect. There is still a problem in that it has not achieved a significant effect.
또한, 기존 경구제형으로 일반적으로 사용해오던 단층형의 속방정은 제제의 특성상 경구투여 직후 약물의 흡수력을 조절하기 어려운 문제가 있엇다. 특히, 체내의 특정 부위에서 주로 흡수되는 약물의 경우 단층형의 속방정 형태로는 약물의 방출, 체내 분산 및 흡수에 대한 조절이 어려워 약물의 효과를 제대로 나타내지 못하여 경구 투여를 어렵게 만들었다. 따라서, 단층형 제제는 일반적으로 치료작용에 대한 특별한 표적화 없이 약물의 빠른 흡수가 일어날 수 있지만 약물에는 낮은 흡수율 문제를 개선시키기 어렵다는 문제가 있다. In addition, 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. In particular, in the case of 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.
[선행기술][Prior art]
Contribution to the Improvement of an Oral Formulation of Niclosamide, an Antihelmintic Drug Candidate for Repurposing in SARS-CoV-2 and Other Viruses(Eduardo Jose Barbosa 외 5인 공저)Contribution to the Improvement of an Oral Formulation of Niclosamide, an Antihelmintic Drug Candidate for Repurposing in SARS-CoV-2 and Other Viruses (co-authored by Eduardo Jose Barbosa and 5 others)
본 발명은 약물 또는 이의 약학적으로 허용가능한 염의 생체 이용율을 향상시키기 위한 다층정 복합제제에 대한 것으로, 약물 또는 이의 약학적으로 허용되는 염과, 결정화 억제제 및 약물 방출 속도 제어용 고분자 중 1종 이상을 포함하는 제1 혼합부로 형성된 약물 포함층; 및 폴리(메타)크릴레이트가 중합된 고분자 중합체 및 아크릴산이 중합된 고분자 중합체 및 팽윤성 고분자 중 1종 이상을 포함하는 제2 혼합부로 형성된 부유층을 포함하는 다층정 복합제제를 제공한다. 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.
또한 본 발명은 체내 흡수율 향상을 위해 약물의 흡수율을 최대화할 수 있도록 위에서의 체류 시간을 증가시키고, 위 및 소장에서의 약물의 흡수도를 향상시켜 보다 효과적으로 약학적 효과를 제공할 수 있는 다층정 복합제제의 제조방법을 제공하는 것을 목적으로 한다. In addition, 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.
본 발명은 약물 또는 이의 약학적으로 허용되는 염과, 결정화 억제제 및 약물 방출 속도 제어용 고분자 중 1종 이상을 포함하는 제1 혼합부로 형성된 약물 포함층; 및 폴리(메타)크릴레이트가 중합된 고분자 중합체, 아크릴산이 중합된 고분자 중합체 및 팽윤성 고분자 중 1종 이상을 포함하는 제2 혼합부로 형성된 부유층을 포함하는 다층정 복합제제를 제공한다. 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.
또한, 본 발명은 유기용매에 결정화 억제제 및 약물을 용해시켜 제1 용해물을 제조하는 단계; 상기 제1 용해물을 건조하여 제1 용해물의 파우더를 제조하는 단계; 상기 제1 용해물의 파우더를 이용하여 약물 포함층을 형성하는 단계; 및 상기 약물 포함층에 폴리(메타)크릴레이트가 중합된 고분자 중합체 및 아크릴산이 중합된 고분자 중합체 및 팽윤성 고분자 중 1종 이상을 포함하는 제2 혼합부를 타정하여 부유층을 형성하는 다층정을 제조하는 단계를 포함하는, 다층정 복합제제의 제조방법을 제공하는 것을 목적으로 한다. In addition, 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.
본 발명은 다층정 복합제제를 통해 약물에 의한 치료 효능을 제어하고, 환자의 순응도를 개선하고, 투여 빈도를 줄이기 위해 신체에서 API의 방출을 조작할 수 있는 위체류 약물 전달 시스템(GRDDS) 기능을 제공하는 효과를 갖는다. 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
또한, 본 발명의 다층정 복합제제는 경구 투여시의 문제인 약물의 흡수율 저하 또는 위장관 자극 문제를 해결 가능하며, 특정 부위를 표적으로 할 경우 GI 관 전체에 걸쳐 pH 변화에 따른 약물의 흡수율 변화에 따른 문제를 해결 가능한 효과를 제공 가능하다. In addition, 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.
도 1은 본 발명의 다층정 복합제제에 대한 사진이다. Figure 1 is a photograph of the multilayer tablet combination preparation of the present invention.
도 2는 비글에 대한 생체 내 약물동태 분석 결과에 대한 그래프이다. Figure 2 is a graph of the results of in vivo pharmacokinetic analysis for beagles.
도 3은 미니피그에 대한 생체 내 약물동태 분석 결과에 대한 그래프이다. 도 4는 미니피그에 대한 생체 내 약물동태 분석 결과 중 AUC 값에 대한 그래프 이다. 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.
도 5는 미니피그에 대한 생체 내 약물동태 분석 결과에 대한 그래프이다.Figure 5 is a graph of the results of in vivo pharmacokinetic analysis for minipigs.
도 6은 미니피그에 대한 생체 내 약물동태 분석 결과 중 AUC 값에 대한 그래프 이다. Figure 6 is a graph of AUC values among the in vivo pharmacokinetic analysis results for minipigs.
도 7은 실시예 10, 11 및 비교예 5 및 6의 비글에 대한 생체 내 약물동태 분석 결과에 대한 그래프이다. 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.
도 8은 실시예 10, 11 및 비교예 5 및 6의 비글에 대한 생체 내 약물동태 분석 결과 중 AUC 값에 대한 그래프이다. 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.
도 9는 다층정 형태의 일예로, 실시예 12의 방법으로 제조된 3층정 형태에 대한 사진이다. 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.
본 발명은 경구 투여시 더 낮은 흡수율로 인해 약물이 갖는 효과의 체내 발현 약화문제를 개선 가능한 약물 또는 이의 약학적으로 허용되는 염과 결정화 억제제 및 약물 방출 속도 제어용 고분자 중 1종 이상을 포함하는 제1 혼합부로 형성된 약물 포함층; 및 폴리(메타)크릴레이트가 중합된 고분자 중합체 및 아크릴산이 중합된 고분자 중합체 및 팽윤성 고분자 중 1종이상을 포함하는 제2 혼합부로 형성된 부유층을 포함하는 다층정 복합제제를 제공한다.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.
본 발명에서 폴리(메타)크릴레이트가 중합된 고분자 중합체 및 아크릴산이 중합된 고분자 중합체 및 패윤성 고분자 중 1종 이상을 포함하는 제2 혼합부는 다층정 복합제제에 부유성을 부여하기 위한 구성이다. In the present invention, 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.
상기 아크릴산이 중합된 고분자 중합체는 카보머 코폴리머 타입, 카보머 호모폴리머 타입 및 암모니오 메타크릴레이트 코폴리머 타입(AMMONIO METHACRYLATE COPOLYMER TYPE)에서 선택되는 1종 이상일 수 있다. 보다 구체적으로, 상기 카보머 코폴리머 타입은 알릴 펜타에리스리톨이 가교결합된 카보머 코폴리머 타입(CARBOMER COPOLYMER TYPE (ALLYL PENTAERYTHRITOL CROSSLINKED)) 일 수 있으며, 상기 카보머 호모폴리머 타입은 알릴 펜타에리스리톨이 가교결합된 카보머 호모폴리머 타입(CARBOMER HOMOPOLYMER TYPE (ALLYL PENTAERYTHRITOL CROSSLINKED)) 또는 알릴 수크로스가 가교결합된 카보머 호모폴리머 타입(CARBOMER HOMOPOLYMER TYPE (ALLYL SUCROSE CROSSLINKED)), 알릴 펜타에리스리톨이 가교결합된 카보머 호모폴리머 타입(CARBOMER HOMOPOLYMER TYPE (ALLYL PENTAERYTHRITOL CROSSLINKED))일 수 있다. 상기 카보머 코폴리머 타입, 카보머 호모폴리머 타입 및 암모니오 메타크릴레이트 코폴리머 타입(AMMONIO METHACRYLATE COPOLYMER TYPE)은 각각 A,B,C로 그 종류가 분류될 수 있으며, 상기에 속하는 카보머라면 제한없이 사용가능하다. 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 HOMOPOLYMER TYPE (ALLYL PENTAERYTHRITOL CROSSLINKED) or 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 (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.
상기 폴리(메타)크릴레이트가 중합된 고분자 중합체는 구체적으로 메타크릴레이트가 중합된 고분자 중합체, 에틸아크릴레이트가 중합된 고분자 중합체, 메타크릴레이트와 에틸아크릴레이트가 중합된 고분자 중합체, 에틸렌글라이콜이 중합된 고분자 중합체, 메타크릴엑시드와 메틸메타크릴레이트가 중합된 고분자 중합체, 에틸렌글라이콜이 중합된 고분자 중합체, 암모늄 메타크릴레이트가 중합된 고분자 중합체, 다이메틸아미노에틸과 메타크릴레이트과 부틸 메타크릴레이트가 중합된 고분자 중합체에서 선택되는 1 종 이상일 수 있다. 보다 구체적으로 상기 폴리(메타)크릴레이트가 중합된 고분자 중합체는 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 - METHYL METHACRYLATE COPOLYMER (1:2) TYPE B, METHACRYLIC ACID - METHYL METHACRYLATE COPOLYMER (1:2) TYPE C, ETHYL ACRYLATE AND METHYL METHACRYLATE COPOLYMER (2:1; 600000 MW) TYPE A, ETHYL ACRYLATE AND METHYL METHACRYLATE COPOLYMER (2:1; 600000 MW) TYPE B, ETHYL ACRYLATE AND METHYL METHACRYLATE COPOLYMER (2:1; 600000 MW) TYPE C, AMMONIO METHACRYLATE COPOLYMER TYPE A, AMMONIO METHACRYLATE COPOLYMER TYPE B, AMMONIO METHACRYLATE COPOLYMER TYPE C, DIMETHYLAMINOETHYL METHACRYLATE - BUTYL METHACRYLATE - METHYL METHACRYLATE COPOLYMER TYPE A, DIMETHYLAMINOETHYL METHACRYLATE - BUTYL METHACRYLATE - METHYL METHACRYLATE COPOLYMER TYPE B 및 DIMETHYLAMINOETHYL METHACRYLATE - BUTYL METHACRYLATE - METHYL METHACRYLATE COPOLYMER TYPE C에서 선택되는 1종 이상일 수 있다. 상기 폴리(메타)크릴레이트가 중합된 고분자 중합체는 보다 구체적으로 유드라짓(Eudragit) 계열 고분자 중합체가 바람직할 수 있다. 상기 유드라짓 계열 고분자 종류는 하기 표 1에 나열하였다. 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. This polymer polymer, a polymer polymer polymerized with methacryl acid and methyl methacrylate, a polymer polymer polymerized with ethylene glycol, a polymer polymer polymerized with ammonium methacrylate, dimethylaminoethyl, methacrylate, and butyl methacrylate. It may be one or more types selected from polymers in which crylate is polymerized. More specifically, 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 - METHYL METHACRYLATE COPOLYMER (1:2) TYPE B, METHACRYLIC ACID - METHYL METHACRYLATE COPOLYMER (1:2) TYPE C, ETHYL ACRYLATE AND METHYL METHACRYLATE COPOLYMER (2:1; 600000 MW) TYPE A, ETHYL ACRYLATE AND METHYL METHACRYLATE COPOLYMER (2:1; 600000 MW) TYPE B, ETHYL ACRYLATE AND METHYL METHACRYLATE COPOLYMER (2:1; 600000 MW) TYPE C, AMMONIO METHACRYLATE COPOLY MER TYPE A, AMMONIO METHACRYLATE COPOLYMER TYPE B, AMMONIO METHACRYLATE COPOLYMER TYPE C, DIMETHYLAMINOETHYL METHACRYLATE - BUTYL METHACRYLATE - METHYL METHACRYLATE COPOLYMER TYPE A, DIMETHYLAMINOETHYL METHACRYLATE - BUTYL METHACRYLATE - METHYL METHACRYL ATE COPOLYMER TYPE B and DIMETHYLAMINOETHYL METHACRYLATE - BUTYL METHACRYLATE - METHYL METHACRYLATE COPOLYMER TYPE C There may be one or more types selected. The polymer obtained by polymerizing the poly(meth)acrylate may be more specifically a Eudragit-based polymer. The types of Eudragit series polymers are listed in Table 1 below.
상품명product name IUPAC 명칭IUPAC name
Eudragit RL 100
Eudragit RL PO
Eudragit RL 30 D
Eudragit RL 12.5
Eudragit RL 100
Eudragit RL PO
Eudragit RL 30 D
Eudragit RL 12.5
Poly(ethyl acrylate-co-methyl methacrylate-co-trimethyl ammonioethyl methacrylate chloride)1:2:0.2 (AMMONIO METHACRYLATE COPOLYMER TYPE A)Poly(ethyl acrylate-co-methyl methacrylate-co-trimethyl ammonioethyl methacrylate chloride)1:2:0.2 (AMMONIO METHACRYLATE COPOLYMER TYPE A)
Eudragit RS 100
Eudragit RS PO
Eudragit RS 30 D
Eudragit RS 12.5
Eudragit RS 100
Eudragit RS PO
Eudragit RS 30 D
Eudragit RS 12.5
Poly(ethyl acrylate-co-methyl methacrylate-co-trimethyl ammonioethyl methacrylate chloride)1:2:0.1(AMMONIO METHACRYLATE COPOLYMER TYPE B)Poly(ethyl acrylate-co-methyl methacrylate-co-trimethyl ammonioethyl methacrylate chloride)1:2:0.1(AMMONIO METHACRYLATE COPOLYMER TYPE B)
Eudragit NE 30D
Eudragit NE 40D
Eudragit NM 30D
Eudragit NE 30D
Eudragit NE 40D
Eudragit NM 30D
(ETHYL ACRYLATE AND METHYL METHACRYLATE COPOLYMER(2:1;75000)(ETHYL ACRYLATE AND METHYL METHACRYLATE COPOLYMER(2:1;75000)
Eudragit L 30D-55
Eudragit L 100-55

Eudragit L 100/ 12.5
Eudragit L 30D-55
Eudragit L 100-55

Eudragit L 100/ 12.5
Poly(methacrylic acid-co-methyl methacrylate)1:1 (METHACRYLIC ACID-ETHYL ACRYLATE COPOLYMER (1:1) TYPE A)
METHACRYLIC ACID-ETHYL ACRYLATE COPOLYMER (1:1)
Poly(methacrylic acid-co-methyl methacrylate)1:1 (METHACRYLIC ACID-ETHYL ACRYLATE COPOLYMER (1:1) TYPE A)
METHACRYLIC ACID-ETHYL ACRYLATE COPOLYMER (1:1)
Eudragit S 100Eudragit S 12.5Eudragit S 100Eudragit S 12.5 Poly(methacrylic acid-co-methyl methacrylate)1:2 (METHACRYLIC ACID-ETHYL ACRYLATE COPOLYMER (1:2))Poly(methacrylic acid-co-methyl methacrylate)1:2 (METHACRYLIC ACID-ETHYL ACRYLATE COPOLYMER (1:2))
Eudragit L 30D-55Eudragit L 100-55Eudragit L 30D-55Eudragit L 100-55 Poly(methacrylic acid-co-ethyl methacrylate)1:1Poly(methacrylic acid-co-ethyl methacrylate)1:1
Eudragit E 100Eudragit E 12.5
Eudragit E PO
Eudragit E 100Eudragit E 12.5
Eudragit E PO
Poly(buthylmethacrylate-co-(2-dimetnylaminoethyl) methacralte-co-methyl methacrylate)1:2:1 (DEMETHYLAMINOETHYL METHACRYLATE-BUTHYL METHACRYLATE-METHYL METHACRYLATE COPOLYMER)Poly(buthylmethacrylate-co-(2-dimetnylaminoethyl) methacralte-co-methyl methacrylate)1:2:1 (DEMETHYLAMINOETHYL METHACRYLATE-BUTHYL METHACRYLATE-METHYL METHACRYLATE COPOLYMER)
또한, 상기 폴리(메타)크릴레이트가 중합된 고분자 중합체 또는 아크릴산이 중합된 고분자 중합체는 각각 탭 밀도(tap density)가 0.01g/mL 내지 1.0g/mL, 보다 바람직하게는 0.025g/mL 내지 0.7g/ mL 로, 다층정 복합제제를 형성하였을 때 약물을 포함하는 제제에 부유성을 부여하는 역할을 한다. 만약 상기 폴리(메타)크릴레이트가 중합된 고분자 중합체 또는 아크릴산이 중합된 고분자 중합체의 탭 밀도 범위가 상술한 범위에 속하지 않을 경우 부유가 이루어지지 않거나, 부유및 체류가 되더라도 30분내에 가라앉게 되어 초기 약물 방출 및 흡수가 나타나지 않을 수 있다. 또한 상기 탭 밀도 범위를 초과는 부유성 기제를 사용할 경우 약물의 위 체류시 약물이 지속적으로 방출되지 못하고(trapping)는 현상이 발생하여 기대하는 효과가 나타나지 않을 수 있다.In addition, the 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.
본 발명에서 팽윤성 고분자는 부유층에 부유성을 부여할 수 있는 고분자라면 제한없이 사용가능하나, 메틸셀룰로오스, 히드록시프로필메틸셀룰로오스, 히드록시프로필셀룰로오스, 히드록시에틸셀룰로오스, 카복시메틸셀룰로오스나트륨, 알긴산 나트륨, 폴리에틸렌 옥사이드, 전호화전분, 카라기난, 잔탄 검, 로커스트 빈 검 및 구아 검등에서 선택되는 1종이상일 수 있다. In the present invention, 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.
본 발명에서 상기 약물은 니클로사마이드(Niclosamide), 클로산텔(Closantel), 라폭사니드(rafoxanide), 옥시클로나자이드(oxyclozanide), 아테수네이트(Artesunate), 틸로론(Tilorone), 시클로스포린(Cyclosporine), 퍼헥실린 말레산염(perhexiline maleate), 로페라미드(loperamide), 메플로퀸(mefloquine), 아모디아퀸(amodiaquine), 프로스킬라리딘(proscillaridin), 페나조피리딘(phenazopyridine), 디기톡신(digitoxin), 펜플루디올(penfluridol), 클로미펜(clomiphene), 토레미펜(toremifene), 디곡신(digoxin), 헥사클로로펜(hexachlorophene), 히드록시프로게스테론(hydroxyprogesterone), 티오리다진(thioridazine), 살리노마이신(salinomycin), 퀸아크린(quinacrine), 엘트롬보팍(eltrombopag), 세파란틴(cepharanthine), 시클레소니드(ciclesonide), , 세리티닙(ceritinib(LDK378)), 디하이드로감보그산(dihydrogambogic acid), 오시머티닙(osimertinib(AZD-9291)), 이소포미페린(isopomiferin), 아니둘라펀진(anidulafungin(LY303366)), 오사진(osajin), 루스트롬보팍(lusutrombopag), 이소오사진(isoosajin), 길테리티닙(gilteritinib), 베르바민(berbamine), 에바스틴(ebastine), 테트란드린(tetrandrine), 아베마시클립(abemaciclib(USAN)), 이바카프토어(ivacaftor), 바제독시펜(bazedoxifene), 메퀴타진(mequitazine), 트리파라놀(triparanol), 드로록시펜(droloxifene), 드로네다론(dronedarone), 클로로퀸(chloroquine), 히드록시클로로퀸(hydroxychloroquine), 로피나비어(lopinavir), 파비피라비르(favipiravir) 및 아타자나비어(atazanavir), 덱사메타손(dexamethasone) 등에서 선택되는 1종 이상의 심혈관계 치료제, 항생제, 말라리아 치료제, 진통제로 항바이러스제로 사용 가능한 약물일 수 있다. 또한, 도세탁셀(Docetaxel), 파클리탁셀(Paclitaxel), 카바지탁셀(Cabazitaxel), 에토포시드(Etoposide), 토포테칸(Topotecan), 이다루비신(Idarubicin), 플루로우라실(Fluorouracil), 아비라테론(Abiraterone), 악시티닙(Axitinib), 보수티닙(Bosutinib), 카보잔티닙(Cabozantinib), 세리티닙(ceritinib), 다브라페닙(dabrafenib), 에를로티닙(erlotinib), 라파티닙(lapatinib), 미도스타우린(midostaurin), 네라티닙(neratinib), 닐로티닙(nilotinib), 닌테다닙(nintedanib), 파조파닙(pazopanib), 소니데집(sonidegib), 트라메티닙(trametinib) 등의 항암제 이거나, 아스코빅산(Ascorbic acid), vitamin A, 리포산(lipoic acid), 프라미펙솔(pramipexole), 알로푸리놀(allopurinol), 펜톡시필린(pentoxifylline), 멜라토닌(melatonin), 프로부콜(probucol), 쿼세틴(quercetin), 트랜스크로세티네이트(transcrocetinate), 아세틸시스테인(acetylcysteine), 니카라벤(nicaraven), 로독사마이드(lodoxamide), 4-n-부틸레조르시놀(4-n-butylresorcinol), 토코페롤(tocopherol), 바쿠치올(bakuchiol), (+)-카테킨((+)-catechin), 커큐민(curcumin), 히드록시티로솔(hydroxytyrosol), 파이톨(phytol), 레조르시올(resorcinol), 카르타민(carthamine), 루테올린(luteolin), 코릴라진(corilagin), 레스베라트롤(resveratrol), 레티놀(retinol), 루틴(rutin), 히드로퀴논(hydroquinone), 아시아티코사이드(asiaticoside), 마데카소사이드(madecassoside), 진세노사이드(ginsenoside), 보르네올(borneol), 디오스메틴(diosmetin), 아스파라신(aspalathin), 유지놀(eugenol), 망고스틴(mangostin), 펠라르고니딘(pelargonidin), 시아니딘(cyaniding), 델피니딘(delphinidin), 피오니딘(peonidin), 페튜니딘(petunidin), 말비딘(malvidin), 루테인(lutein), 퀘르세틴(quercetin), 아데노신(adenosine), 팔미트산 아스코빌(ascorbyl palmitate), 아스코빌글루코사이드(ascorbyl glucoside), 피리독신(pyridoxine), 티아민(thiamine), 사포닌(saponin), 세코이졸라릭이레시놀(secoisolariciresinol), 마타이레시놀(matairesinol), 피노이레시놀(pinoresinol), 메드이레시놀(medioresinol), 라릭이레시놀(lariciresinol), 시린가레시놀(syringaresinol), 알티제닌(artigenin), 엔테로락톤(enterolactone), 엔테로디올(enterodiol), 아라키돈산(arachidonic acid), 아비에트산(abietic acid), 아브시스산(abscisic acid), 알파리포산(α-lipoic acid), 아젤라익산(azelaic acid), 카페인산(caffeic acid), 히드록시벤조산(hydroxybenzoic acid), 프로토카테츄산(protocatechuic acid), 엘라그산(ellagic Acid), 페룰산(ferulic acid), 펄빅산(fulvic acid), 올레오놀산(oleanolic acid), 페놀산(phenolic acid), 히드록시신남산(hydroxycinnamic acid), 바닐릭산(vanillic Acid), 프로토카테츄산(protocatechuic acid), 살비아닉산(salvianic acid), 시냅픽 애시드(sinapic acid), 트라넥사민산(tranexamic acid), 발레르산(valeric acid), 베라트르산(Veratric Acid), 클로로겐산(chlorogenic acid), 아시아틱애시드(asiatic acid), 마데카식애시드(madecasic acid), 수베르산(suberic acid), 히알루론산(hyaluronic acid), 우르솔산(ursolic acid), 아스코브 산(ascorbic acid), 살비아논산 B(salvianolic acid B), 피리딘-3-카복시산(pyridine-3-carboxylic acid), 아스코빌팔미테이트(ascorbyl palmitate), 아스코빌글루코시드(ascorbyl glucoside), 카르니틴(carnitine), 판토텐산(pantothenic acid), 비오틴(biotin), 폴산(folic acid), 알리인(alliin), 글루타티온(glutathione), 세린(serine), 글리신(glycine), 알라닌(alanine), 아베난티라미드(avenanthramide), 트레오닌(threonine), 시스테인(cysteine), 발린(valine), 류신(leucine), 메티오닌(methionine), 프롤린(proline), 페닐알라닌(phenylalanine), 티로신(tyrosine), 트립토판(tryptophan), 아스파트산(aspartic acid), 글루탐산(glutamic acid), 아스파라긴(asparagine), 글루타민(glutamine), 히스티딘(histidine), 리신(lysine), 아르기닌(arginine), 데칸알(decanal), 레틴알데히드(retinaldehyde), 신남알데히드(cinnamaldehyde), 카테킨-알데히드(catechin-aldehyde), 코니페릴 알데히드(coniferyl aldehyde), 시링알데히드(syringaldehyde), 바닐린(vanillin), 이다라본(edaravone), 이데베논(idebenone), 코엔자임 큐10(coenzyme Q10), 유비퀴논(ubiquinone), 미토큐(mitoQ), 아스타잔틴(astaxanthin), 카페인(caffeine), 파라크산틴(paraxanthine), 테오필린(theophylline), 마타이레시놀(matairesinol), 파이시온(physcion), 프로파페논(propafenone), 쿠마린(coumarin), 제니스테인(genistein), 챨콘(chalcone), 나린제닌(naringenin), 베르제닌(bergenin), 아멘토플라본(amentoflavone), 비오카닌 A(Biochanin A), 리보플라빈(riboflavin), 세사민(Sesamin)등을 들 수 있다. 덱스트란 황산(dextran sulfate), 황산철(ferrous sulfate), 페룰릭 애시드-4-0-설페이트(ferulic acid-4-O-sulfate), 아스코빌 설페이트(ascorbyl sulfate) 등의 항염증, 항산화제 중에서 선택되는 1종 이상 일 수 있다. In the present invention, 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 , gilteritinib, berbamine, ebastine, tetradrine, abemaciclib (USAN), ivacaftor, bazedoxifene ), mequitazine, triparanol, droloxifene, dronedarone, chloroquine, hydroxychloroquine, lopinavir, favipyra It may be one or more types of drugs selected from favipiravir, atazanavir, dexamethasone, etc., that can be used as antiviral drugs, antibiotics, malaria drugs, painkillers, etc. Additionally, 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, Bakuchiol, (+)-catechin, curcumin, hydroxytyrosol, phytol, resorcinol, carthamine ), luteolin, corilagin, resveratrol, retinol, rutin, hydroquinone, asiaticoside, madecassoside, gin Ginsenoside, borneol, diosmetin, aspalathin, eugenol, mangostin, pelargonidin, cyanidin, Delphinidin, peonidin, petunidin, malvidin, lutein, quercetin, adenosine, ascorbyl palmitate, Ascorbyl glucoside, pyridoxine, thiamine, saponin, secoisolariciresinol, matairesinol, pinoresinol, medire Medioresinol, lariciresinol, syringaresinol, artigenin, enterolactone, enterodiol, arachidonic acid, abietic acid ( abietic acid, abscisic acid, α-lipoic acid, azelaic acid, caffeic acid, hydroxybenzoic acid, protocatechuic acid , ellagic acid, ferulic acid, fulvic acid, oleanolic acid, phenolic acid, hydroxycinnamic acid, vanillic acid. 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. 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 ), ubiquinone, mitoQ, astaxanthin, caffeine, paraxanthine, theophylline, matairesinol, physcion , propafenone, coumarin, genistein, chalcone, naringenin, bergenin, amentoflavone, Biochanin A , riboflavin, sesamin, etc. Among anti-inflammatory and antioxidant agents such as dextran sulfate, ferrous sulfate, ferulic acid-4-O-sulfate, and ascorbyl sulfate, There may be one or more types selected.
본 발명의 다층정 복합제제는 보다 바람직하게 상기 약물 중 난용성 약물에 효과적으로 적용될 수 있으며, 더욱 바람직하게는 할로겐화된 살리실 아닐리드계열 및 탁센 계열 약물에서 선택되는 1종 이상일 수 있다. 상기 할로겐화된 살리실 아닐리드 계열 약물은 니클로사마이드(niclosamide), 클로산텔, 라폭사니드 및 옥시클로자니드 등 일 수 있으며, 상기 탁센 계역 약물은 도세탁셀(docetaxel), 파클리탁셀(paclitaxel) 및 카바지탁셀(Cabazitaxel) 등 일 수 있다.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, and the taxane-based drugs include docetaxel, paclitaxel, and cabazitaxel ( Cabazitaxel), etc.
본 발명에서 약학적으로 허용되는 염은 의약업계에서 통상적으로 사용되는 염을 의미하며, 예를 들어 칼슘, 포타슘, 소듐 및 마그네슘 등으로 제조된 무기이온염, 염산, 질산, 인산, 브롬산, 요오드산, 과염소산 및 황산 등으로 제조된 무기산염; 아세트산, 트라이플루오로아세트산, 시트르산, 말레인산, 숙신산, 옥살산, 벤조산, 타르타르산, 푸마르산, 만데르산, 프로피온산, 젖산, 글리콜산, 글루콘산, 갈락투론산, 글루탐산, 글루타르산, 글루쿠론산, 아스파르트산, 아스코르브산, 카본산, 바닐릭산, 하이드로 아이오딕산 등으로 제조된 유기산염; 메탄설폰산, 에탄설폰산, 벤젠설폰산, p-톨루엔설폰산 및 나프탈렌설폰산 등으로 제조된 설폰산염; 글리신, 아르기닌, 라이신 등으로 제조된 아미노산염; 및 트리메틸아민, 트라이에틸아민, 암모니아, 피리딘, 피콜린 등으로 제조된 아민염 등이 있으나, 열거된 이들 염에 의해 본 발명에서 의미하는 염의 종류가 한정되는 것은 아니다. In the present invention, 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.
본 발명의 다층정 복합제제는 약물을 포함하는 약물 포함층과 부유층이 2층 또는 그 이상으로 형성되는 것이라면 본 발명의 범위 내에 속하는 것이며, 이들의 적층 순서 또는 코팅 방식의 변경 또는 치환은 통상의 기술자에 자명하며, 본 발명의 범위에 해당한다.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.
구체적으로, 본 발명의 다층정 복합제제는 약물 포함층 및 부유층 사이에 중간층을 더 포함하거나, 약물 포함층 및 부유층 상부 및/또는 하부에 적층되는 제3의 층을 더 포함하는 것일 수 있다. 일실시예로 도 9는 부유층-약물 포함층-부유층으로 약물 포함층의 상부 및 하부 각각 부유층이 형성된 3층의 다층정 형태로 형성된 것이다. 상기 중간층 및/또는 제3의 층은 본 발명에서 나열된 약물 포함층 또는 부유층과 동일 또는 상이한 성분으로 형성될 수 있다. Specifically, 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. In one embodiment, 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.
본 발명에서의 복합제제는 경구 복용 방식으로 제형화되는 것이라면 제한없이 이용가능하다. 구체적으로 정제(Tablet), 캡슐제(capsules), 과립제(Granules)등을 의미할 수 있으며, 상기 정제형태가 2층 이상을 구성하는 것이라면 본 발명의 범위에 속하는 것이다. 구체적으로, 상기 정제는 구강붕해정, 추어블정, 발포정, 분산정,용해정등을 포함하며, 상기 과립제는 경질캡슐제와 연질캡슐제 등의 형태를 의미할 수 있다. 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.
또한, 본발명에서의 정제는 약물(또는 주성분 이라 함)에 부형제, 결합제, 붕해제 등의 첨가제를 넣어 균질하게 한 것을 그대로 압축 성형하거나 미리 만든 과립에 주성분과 활택제 등을 넣어 균질하게 한 후 압축성형하는 방법, 주성분에 부형제,결합제, 붕해제 등의 첨가제를 넣어 균질하게 한 것에 물 또는 결합제를 함유하는 용액을 넣어 적절한 방법으로 입상으로 만든 다음 활택제 등을 넣어 섞고 압축성형하는 방법 및 주 서분에 부형제 또는 결합제, 붕해제 등의 첨가제를 넣어 고르게 섞은 것을 용매로 습윤시켜 일정한 형상으로 성형하거나 일정한 틀에 넣어 성형한 다음 건조하는 방법 등으로 제조하는 것을 의미할 수 있다. In addition, 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.
또한, 본 발명의 복합제제는 다층정 형태이외에도 통상의 기술자에게 자명한 범위로의 정제형태 변경은 본 발명의 범위에 속함은 자명하다. 예를들어, 고분자 화합물 등을 이용하여 얇게 코팅한 필름 코팅정, 나정에 당류 또는 당알코올을 함유하는 코팅제로 코팅한 당의정, 내핵정을 조성이 다른 외층으로 피복하여 제조한 유핵정 등으로의 설계변경은 본 발명의 복합제제의 범위에 속하는 것이다. In addition, it is obvious that the combination preparation of the present invention is within the scope of the present invention in addition to the multi-layered tablet form. For example, design of film-coated tablets thinly coated using polymer compounds, sugar-coated tablets coated with a coating containing sugars or sugar alcohols on uncoated tablets, and press-coated tablets manufactured by coating the inner core tablet with an outer layer of different composition. Changes are within the scope of the combination preparation of the present invention.
본 발명에서 다층정 복합제제 중 제1 혼합부 및/또는 제2 혼합부는 금속 수산화물 또는 금속 산화물을 더 포함하는 것일 수 있다. 상기 금속 수산화물은 화학식 1 또는 2로 표시되는 화합물일 수 있으며, 상기 금속 산화물은 화학식 3으로 표시되는 것일 수 있다. 상기 화학식 1 내지 3에 속하는 화합물 중 마그네슘 옥사이드(MgO), 하이드로 탈사이트(Mg6Al2CO3(OH)16·4H2O; Mg2Al1CO0.5(OH)4·nH2O; Mg2.56Al1CO0.5(OH)7.12·0.12H2O; Mg2.41Al1CO0.5(OH)6.82·0.12H2O; Mg0.74Al0.26(OH)2Cl0.24·0.58H2O), 마그네슘 하이드록사이드(Mg(OH)2) 또는 이들의 혼합물을 포함하는 것이 약물의 용해도 개선에 가장 효과적이라는 점에서 바람직할 수 있다.In the present invention, 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. Among the compounds belonging to the formulas 1 to 3, magnesium oxide (MgO), hydrotalcite (Mg 6 Al 2 CO 3 (OH) 16 ·4H 2 O; Mg 2 Al 1 CO 0.5 (OH) 4 ·nH 2 O; Mg 2.56 Al 1 CO 0.5 (OH) 7.12 ·0.12H 2 O; Mg 2.41 Al 1 CO 0.5 (OH) 6.82 ·0.12H 2 O; Mg 0.74 Al 0.26 (OH) 2 Cl 0.24 ·0.58H 2 O), magnesium hyde It may be preferable to include oxide (Mg(OH) 2 ) or a mixture thereof because it is most effective in improving the solubility of the drug.
[화학식 1][Formula 1]
[(M2+ (10-x)M3+ x(OH)m)((An-)z)]yH2O[(M 2+ (10-x) M 3+ x (OH) m )((A n- ) z )]yH 2 O
(상기 화학식 1에서, M2+은 Mg2+, Ni2+, Cu2+, Co2+ 및 Zn2+로 이루어진 군 중에서 선택된 2가 금속 양이온이며, M3+는 Al3+, Fe3+, V3+, Ti3+ , Mn3+ 및 Ga3+로 이루어진 군 중에서 선택된 3가 금속 양이온이며, x는 0초과 10미만의 범위를 갖는 수이며, m은 0초과 20이하의 범위를 갖는 수이며, A는 CO3 2- , NO3 - , Br- , Cl- , SO4 2- , HPO4 2- 및 F- 로 이루어진 군에서 선택되는 음이온이며, n은 음이온 A의 전하수이며, n은 0.5이상 5이하의 범위를 갖는 수이고, z는 0이상 5이하의 범위를 갖는 수이고, y는 0 또는 0 이상의 양수이다.)(In Formula 1, 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 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, and m is a number ranging from 0 to 20. is a number, and 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 - , and 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, and y is a positive number greater than or equal to 0.)
[화학식 2][Formula 2]
[(M2+(OH)2-x)((An-)z)]yH2O[(M 2+ (OH) 2-x )((A n- ) z )]yH 2 O
(상기 화학식 2에서, M2+은 Mg2+, Ni2+, Cu2+, Co2+ 및 Zn2+로 이루어진 군 중에서 선택된 2가 금속 양이온이며, x는 0이상 2미만의 범위를 갖는 수이며, A는 CO3 2- , NO3 - , Br- , Cl- , SO4 2- , HPO4 2- 및 F- 로 이루어진 군에서 선택되는 음이온 이며, n은 음이온 A의 전하수이며, n은 0이상 2이하의 범위를 갖는 수이고, z는 0 이상 1이하의 범위를 갖는 수이고, y는 0 또는 0 이상의 양수이다.)(In Formula 2, 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, and y is a positive number of 0 or more than 0.)
[화학식 3][Formula 3]
[(M2+(O)2-x)((An-)z)]yH2O[(M 2+ (O) 2-x )((A n- ) z )]yH 2 O
(상기 화학식 3에서, M2+은 Mg2+, Ni2+, Cu2+ 또는 Zn2+이며, x는 0이상 2 미만의 범위를 갖는 수이며, A는 CO3 2- , NO3 - , Br-, Cl-, SO4 2- , HPO4 2- 또는 F-의 음이온이며, n은 음이온 A의 전하수이며, n은 0이상 2이하의 범위를 갖는 수이고, z는 0이상 1이하을 범위를 갖는 수이고, y는 0 또는 0 이상의 양수이다.)(In Formula 3, M 2+ is Mg 2+ , Ni 2+ , Cu 2+ or Zn 2+ , x is a number ranging from 0 to 2, and 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, and z is 0 to 1. It is a number with a range below, and y is 0 or a positive number greater than 0.)
본 발명에서 결정화 억제제란 약물이 용매에 용해될 때 각 화합물의 무정형 또는 비결정형을 유지시키도록 용매 등에 용해된 상태에서 화합물이 결정형으로 되돌아 가는 것을 지연시킬 수 있는 고분자를 의미할 수 있다. 상기 결정화 억제제에 약물을 로딩(loading) 시켜 약물의 결정화 시간을 지연시킴에 따라 체내에서 약물의 용해성을 상승시킴으로써 약물의 혈중 농도를 높일 수 있는 효과를 얻을 수 있다. In the present invention, 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. By delaying the crystallization time of the drug by loading the drug into the crystallization inhibitor, the solubility of the drug in the body can be increased, thereby increasing the blood concentration of the drug.
구체적으로 상기 결정화 억제제는 폴리비닐 피롤리돈계 화합물, 폴록사머계 화합물, 셀룰로오스계 화합물, 폴리에틸렌 글라이콜계 화합물, 폴리옥시에틸렌 소르비탄 지방산 에스터계((polyoxyethylene sorbitan fatty acid esters) 화합물, 레시틴계(lecithin) 화합물, 지방산계 화합물, 글리세롤 지방산 에스터계(glycerol fatty acid esters) 화합물, 소르비탄 지방산 에스터계(sorbitan fatty acid esters)화합물, 오일류, 소디엄 도데실 설페이트(sodium dodecyl sulfate), 소디엄 스테아릴 퓨마레이트(sodium stearyl fumarate), 스테아릴산(stearic acid), 라이릴산(lauric acid) 및 카라기난(carrageenan) 일 수 있다. Specifically, 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.
또한, 상기 폴리비닐 피롤리돈계 화합물은 polyvinylpyrrolidone K10(MW 8000~10,000), polyvinylpyrrolidone K12(MW 11,000~12,000), polyvinylpyrrolidone K15(MW 14,000~18,000), polyvinylpyrrolidone K17(MW 14,000~18,000), polyvinylpyrrolidone K18(MW 14,000~18,000), polyvinylpyrrolidone K25(MW 20,00~25,000), polyvinylpyrrolidone K30(MW30,00~40,000), polyvinylpyrrolidone K60(MW 50,00~60,000) 및 polyvinylpyrrolidone K90(MW80,00~90,000)으로 이루어진 군에서 선택되는 1종 이상일 수 있다. 상기에서 MW란 molecular weight 으로 분자량을 의미한다. In addition, the 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). 000), polyvinylpyrrolidone K18 (MW 14,000~18,000), polyvinylpyrrolidone K25(MW 20,00~25,000), polyvinylpyrrolidone K30(MW30,00~40,000), polyvinylpyrrolidone K60(MW 50,00~60,000) and polyvinylpyrrolidone K90(MW80,00~90,00) 00) In a group consisting of There may be one or more types selected. In the above, MW means molecular weight.
또한, 상기 폴록사머계 화합물은 폴록사머계 화합물은 폴록사머 101, 폴록사머 105, 폴록사머 105 벤조에이트, 폴록사머 108, 폴록사머 122, 폴록사머 123, 폴록사머 124, 폴록사머 181, 폴록사머 182, 폴록사머 182 디벤조에이트, 폴록사머 183, 폴록사머 184, 폴록사머 185, 폴록사머 188, 폴록사머 212, 폴록사머 215, 폴록사머 217, 폴록사머 231, 폴록사머 234, 폴록사머 235, 폴록사머 237, 폴록사머 238, 폴록사머 282, 폴록사머 284, 폴록사머 288, 폴록사머 331, 폴록사머 333, 폴록사머 334, 폴록사머 335, 폴록사머 338, 폴록사머 401, 폴록사머 402, 폴록사머 403 및 폴록사머 407등으로 이루어진 군에서 선택되는 1종이상일 수 있으며, 폴록사머 407이 보다 바람직할 수 있다. 상술한 폴록사머계 화합물의 중량 평균 분자량은 5,000 내지 500,000일 수 있다.In addition, 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. , poloxamer 182 dibenzoate, poloxamer 183, poloxamer 184, poloxamer 185, poloxamer 188, poloxamer 212, poloxamer 215, poloxamer 217, poloxamer 231, poloxamer 234, poloxamer 235, poloxamer 237, Poloxamer 238, Poloxamer 282, Poloxamer 284, Poloxamer 288, Poloxamer 331, Poloxamer 333, Poloxamer 334, Poloxamer 335, Poloxamer 338, Poloxamer 401, Poloxamer 402, Poloxamer 403 and It may be one or more types selected from the group consisting of poloxamer 407, etc., and poloxamer 407 may be more preferable. The weight average molecular weight of the poloxamer-based compound described above may be 5,000 to 500,000.
또한, 상기 셀룰로오스계 화합물은 하이드록프로필 메틸셀룰로오스(hydroxypropyl methylcellulose;HPMC), 하이드록시에틸 셀룰로오스(hydroxyethyl cellulose), 하이드록시프로필 셀룰로오스(hydroxypropylcellulose;HPC), 카복시메틸 셀룰로오스(carboxymethylcellulose;CMC), 에틸 셀룰로오스(ethylcellulose;EC) , 메틸셀룰로오스(methylcellulose : MC) 및 셀룰로오스 아세테이트(cellulose acetate;CA)로 이루어진 군에서 선택되는 1종 이상일 수 있다. 상술한 셀룰로오스계 화합물의 중량 평균 분자량은 5,000 내지 500,000일 수 있다.In addition, 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). The weight average molecular weight of the above-mentioned cellulose-based compound may be 5,000 to 500,000.
또한, 상기 폴리에틸렌 글라이콜계 화합물은 폴리에틸렌 글라이콜 200, 폴리에틸렌 글라이콜300, 폴리에틸렌 글라이콜 400, 폴리에틸렌 글라이콜 500, 폴리에틸렌 글라이콜 1000, 폴리에틸렌 글라이콜 1400, 폴리에틸렌 글라이콜 1500, 폴리에틸렌 글라이콜 4000, 폴리에틸렌 글라이콜 8000, 폴리에틸렌 글라이콜 10000 및 메톡시 폴리에틸렌 글라이콜 550으로 이루어진 군에서 선택되는 1종 이상일 수 있다. 상술한 폴리에틸렌 글라이콜계 화합물의 중량 평균 분자량은 5,000 내지 500,000일 수 있다.In addition, the 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. , polyethylene glycol 4000, polyethylene glycol 8000, polyethylene glycol 10000, and methoxy polyethylene glycol 550. The weight average molecular weight of the above-described polyethylene glycol-based compound may be 5,000 to 500,000.
상기 폴레옥시에틸렌 소르비탄 지방산 에스터계의 경우 상업적으로 판매되는 Tween계 계면활성제가 가장 대표적이며, 지방산과 에틸렌옥사이드가 에스테르 결합된 형태를 취한다. 보다 구체적으로, 폴리옥시에틸렌 소르비탄 모노아우레이트(Polyoxyethylene sorbitan monolaurate; Tween 20, 폴리옥시에틸렌 소르비탄 모노팔미테이트 (polyoxyethylene sorbitan monopalmitate; Tween 40), 폴리옥시에틸렌 글리콜 소르비탄 모노스테아레이트(polyethylene glycol sorbitan monostearate; Tween 60), Tween65, 폴리옥시에틸렌 소르비탄 모노올레이트(polyoxyethylene sorbitan monooleate; Tween80) 및 폴리옥시에틸렌 소르비탄 트리올레이트(polyoxyethylene sorbitan trioleate; Tween85)등일 수 있다. In the case of the polyoxyethylene sorbitan fatty acid ester system, the most representative commercially available 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).
또한, 상기 레시틴계 화합물은 레시틴 및 이의 유도체에 대한 물질로, 포스포리피드(phospholipids), 포스파티딜 콜린(phosphatidyl choline), 복합 포스포리피드(mixed phospholipids), 소디엄 콜레이트(sodium cholate), 하이드록실레이티드 포스포리피드(hydroxylated phospholipids), 및 하이드록실레이티드 레시틴(hydroxylated lecithin)등일 수 있다. In addition, 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.
또한, 상기 지방산계 화합물은 부티르산(butyric acid), 카프로익산(caproic acid), 카프릴릭산(caprylic acid), 카프릭산(capric acid), 스테아릭산(stearic acid), 라우릴산(lauric acid), 올레산(oleic acid), 미리스톨레인산(myristoleic acid), 팔미토일산(pamitoleic acid), 올레인산(oleic acid), 리놀레인산(linoleic aicd), 알파리놀레닌산(α-linolenic acid), 감마리놀레닌산(γ-linolenic acid), 가돌레인산(gadoleic acid), 에이코사디에노인산(eicosadienoic acid), 에이코사펜타에노인산(eicosapentanoic acid), 아라키도닌산(arachidoic acid), 에루신산(erucic acid), 도코사디에노인산(docosadienoic acid), 도코사트리에노인산(docostrienoic acid), 도코사펜타에노인산(docosapentaenoic acid), 도코사헥사에노인산(docosahexaenoic acid), 아드레닌산(adrenic acid), 넬보닌산(nervonic acid) 등일 수 있다. In addition, 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, α-linolenic acid, γ-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.
또한, 상기 글리세롤 지방산 에스터는 폴리그리세롤 지방산 에스터(polyglycerol fatty acid esters), 폴리글리세롤 폴리리시놀리에이트(polyglycerol polyricinoleate), 폴리옥시에틸렌글리세롤 트리리시놀리에이트(polyoxyethyleneglycerol triricinoleate), 크레모포 EL(cremophor EL)등일 수 있다. In addition, the glycerol fatty acid esters include polyglycerol fatty acid esters, polyglycerol polyricinoleate, polyoxyethyleneglycerol triricinoleate, and cremophor EL. It may be, etc.
또한, 상기 소르비탄 지방산 에스터는 소르비탄 모노아우레이트(sorbitan monolaurate;Span 20), 소르비탄 모노올리에이트(sorbitan monooleate;Span 80)등일 수 있다.Additionally, the sorbitan fatty acid ester may be sorbitan monolaurate (Span 20), sorbitan monooleate (Span 80), etc.
또한, 상기 오일류는 소이빈 (soybean), MCT oil(Medium-Chain Triglyceride), 캐스터 오일(caster oil) 등일 수 있다. 상술한 결정화 억제제를 더 포함할 경우 약물의 용해도 및 분산성을 향상시킬 수 있다는 점에서 바람직하다. Additionally, the 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.
상기 약물 방출 속도 제어용 고분자는 약물을 제형화 함에 있어 약물 방출 속도를 조절하는데 도움을 줄 수 있는 물질들로, 카복시메틸셀룰로오즈칼슘, 카복시메틸셀룰로오즈나트륨, 메틸셀룰로오즈, 에틸셀룰로오즈, 폴리에틸렌옥사이드, 루코스트빈검, 구아검, 크산탄검(Xanthan gum), 아카시아검, 트라가칸트검(Tragacanth gum), 알긴산, 알긴산나트륨, 알긴산칼슘, 알긴산암모늄, 아가(Agar), 젤라틴, 폴리메타메틸아크릴레이트, 폴리카르보필, 폴리비닐아세테이트, 폴리비닐피롤리돈-폴리비닐아크릴레이트 공중합제, 폴리비닐알콜-폴리에틸렌글리콜 공중합제, 폴리비닐피롤리돈-폴리비닐아세테이트 공중합체, 벤토나이트, 헥토라이트, 카라기난(Carrageenan), 세라토니아(Ceratonia), 세토스테아릴알콜(Cetostearyl alcohol), 하이드록시프로필전분, 마그네슘 알루미늄 실리케이트, 폴리덱스트로오즈, 폴리(메틸비닐에테르/말레익안하이드로스), 프로필렌글리콜알지네이트 및 사포네이트 등일 수 있다.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. .
본 발명의 제1 혼합부 및/또는 제2 혼합부는 장용 코팅제, 기포발생제 및 팽윤성 부형제 중 1 종이상의 화합물을 더 포함하는 것일 수 있다. 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.
본 발명에서 상기 장용 코팅제(Enteric coating)는 약물이 위에서 방출되지 않고 장관을 통과할 때 방출되도록 약물을 코팅하는 물질을 의미한다. 장용 코팅제를 이용하여 약물이 방출되는 장 내 부위를 선택할 수 있으며, 특히 니클로사마이드의 경우 장 내 부위별 pH에 따라 생체 이용율이 시간별로 다르게 나타나는데, 특히 위(stomach)에서 위액에 의한 재결정화로 인해 약물의 흡수가 현저히 떨어지게된다. 이에, 장용 코팅제를 이용하여 위에서의 약물의 재결정화를 억제하여 장기의 pH 별로 흡수율이 다른 약물에 대한 최적화된 제형을 선택할 수 있다는 점에서 장용 코팅제의 이용이 바람직할 수 있다. 구체적으로 상기 장용 코팅제는 히드록시프로필메틸셀룰로오즈 프탈레이트(hydroxypropyl- methyl cellulose phthalate), 제인(zein), 쉘락(shellac)등일 수 있다. In the present invention, 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. In particular, in the case of niclosamide, 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. Accordingly, 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. Specifically, the enteric coating agent may be hydroxypropyl-methyl cellulose phthalate, zein, shellac, etc.
상기 기포발생제는 탄산나트륨, 탄산수소나트륨, 중탄산나트륨, 탄산칼륨, 중탄산칼륨 및 시트르산등 일 수 있다. 상기 기포발생제는 본 발명의 폴리(메타)크릴레이트가 중합된 고분자 중합체 및 아크릴산이 중합된 고분자 중합체와 제2 혼합부에 포함되어 부유층을 형성되는 사용될 수 있다. 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.
상기 팽윤성 부형제는 카르복시메틸셀룰로오스, 천연셀룰로오스, 펙틴, 히알루론산, 폴리아크릴레이드, 폴리에틸렌옥사이드, 폴리프로필렌옥사이드, 단당류, 메타크릴산-아크릴산에틸공중합체류, 쉘락류, 카보폴류(카보머, 카복시비닐폴리머) 및 폴리비닐알코올이며, 하이드록시프로필메틸셀룰로오스프탈레이트계 화합물, 셀룰로오스아세테이트프탈레이트, 셀룰로오스아세테이트숙시네이트, 하이드록시프로필메틸셀룰로오스아세테이트숙시네이트, 하이드록시프로필메틸아세테이트숙시네이트, 카르복시메틸셀룰로오스, 카르복시메틸에틸셀룰로오스, 셀룰로오스아세테이트프탈레이트계 화합물, 하이드록시프로필셀룰로오스계 화합물, 에틸셀룰로오스계 화합물, 메틸셀룰로오스계 화합물, 폴리비닐아세테이트프탈레이트, 이산화규소, 규산 칼슘, 유당, 전분, 락토오스, 만니톨, 카올린 무기염, 분말화 당, 분말화 셀루로오스 유도체 및 미결정셀룰로오스 등일 수 있다. 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.
본 발명의 복합제제는 코팅제 등을 이용하여 필름 코팅, 반투막코팅, 수불용성 코팅, 타블렛, 이중정(tablet), 위 체류정(tablet)등의 형태로 제형화 시켰을 때 약물의 혈중 농도가 매우 높게 나타남을 확인하였으므로, 코팅제의 형성이 약물의 용해도 향상 등의 효과에 도움이 될 수 있다는 점에서 코팅층을 더 포함할 수 있다. When 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.
또한, 본 발명의 복합제제는 약효를 증가시키지는 않으나 약학적 복합제제에 통상 사용되어 냄새, 맛, 시각 등을 향상시킬 수 있는 성분을 추가로 포함할 수 있다. 또한, 본 발명의 다층정 복합제제는 약학적으로 허용 가능한 첨가제를 추가적으로 포함할 수 있다. 약학적으로 허용 가능한 첨가제는 예컨대, 부형제, 활택제, 결합제 및 붕해제 등일 수 있으며, 구체적으로, 약학적으로 허용 가능한 첨가제는 예컨대, 전분, 젤라틴화 전분, 미결정셀룰로오스, 유당, 포비돈, 콜로이달실리콘디옥사이드, 인산수소칼슘, 락토스, 만니톨, 엿, 아라비아고무, 전호화 전분, 옥수수전분, 분말셀룰로오스, 히드록시프로필셀룰로오스, 오파드라이, 전분글리콜산나트륨, 카르나우바납, 합성규산알루미늄, 스테아린산, 스테아린산마그네슘, 스테아린산알루미늄, 스테아린산칼슘, 백당, 덱스트로스, 소르비톨 및 탈크 등이 있으나, 이를 한정하지 않는다. In addition, 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. In addition, 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. Specifically, 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.
본 발명은 유기용매에 결정화 억제제 및 약물을 용해시켜 제1 용해물을 제조하는 단계; 상기 제1 용해물을 건조하여 제1 용해물의 파우더를 제조하는 단계; 상기 제1 용해물의 파우더를 이용하여 약물 포함층을 형성하는 단계; 및 상기 약물 포함층에 폴리(메타)크릴레이트가 중합된 고분자 중합체 및 아크릴산이 중합된 고분자 중합체 중 1종 이상을 포함하는 제2 혼합부를 타정하여 부유층을 형성하는 다층정을 제조하는 단계를 포함하는, 다층정 복합제제의 제조방법을 제공한다. 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.
또한, 본 말명은 유기용매에 결정화 억제제 및 약물을 용해시켜 제1 용해물을 제조하는 단계; 상기 제1 용해물에 마그네슘 옥사이드, 하이드로 탈사이트 및 마그네슘 하이드록사이드 중 1종 이상을 용해하는 단계; 상기 제1 용해물을 건조하여 제1 용해물의 파우더를 제조하는 단계; 상기 제1 용해물의 파우더를 이용하여 약물 포함층을 형성하는 단계; 및 상기 약물 포함층에 폴리(메타)크릴레이트가 중합된 고분자 중합체 및 아크릴산이 중합된 고분자 중합체 중 1종 이상을 포함하는 제2 혼합부를 타정하여 부유층을 형성하는 다층정을 제조하는 단계 포함하는, 다층정 복합제제의 제조방법을 제공한다.In addition, 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.
또한, 본 발명은 유기용매에 결정화 억제제 및 약물을 용해시켜 제1 용해물을 제조하는 단계; 상기 제1 용해물을 건조하여 제1 용해물의 파우더를 제조하는 단계; 상기 파우더에 마그네슘 옥사이드, 하이드로 탈사이트 및 마그네슘 하이드록사이드 중 1종 이상을 넣어 혼합 하여 혼합물을 제조하는 단계; 상기 혼합물을 이용하여 약물 포함층을 형성하는 단계; 및 상기 약물 포함층에 폴리(메타)크릴레이트가 중합된 고분자 중합체 및 아크릴산이 중합된 고분자 중합체 중 1종 이상을 포함하는 제2 혼합부를 타정하여 부유층을 형성하는 다층정을 제조하는 단계를 포함하는, 다층정 복합제제의 제조방법을 제공한다. In addition, 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.
상기 유기용매는 에탄올, 메탄올, 프로판올, 부탄올 및 아세토 나이트릴에서 선택되는 1종 이상일 수 있으며, 유기용매라면 제한없이 이용 가능하다. 다만, 반응성을 향상시키는 측면에서 무수 유기용매가 더욱 바람직할 수 있으며, 무수 에탄올이 가장 바람직할 수 있다. 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.
본 발명의 제조방법에서는 필요에 따라 유기용매에 물을 더 포함시키거나, 물을 이용할 수 있다. In the production method of the present invention, water can be further included in the organic solvent or water can be used as needed.
상기 타정하는 방법의 경우 통상적으로 2층정을 타정하는 방법이라면 제한하지 않고 사용될 수 있다. 보다 구체적으로 타정기를 이용할 수 있다. 상기 타정하는 방법은 다층정의 형성을 위해 먼저 제1 혼합부로 약물 포함층을 형성하는 단계; 상기 약물 포함층 상에 부유층의 형성을 위한 공간을 확보하는 단계; 상기 약물 포함층 상에 부유층을 형성하는 단계; 및 상기 부유층에 대하여 타정압을 가하여 타정하는 단계를 포함할 수 있다. 상기 제조방법의 제1 용해물, 약물 포함층 및 부유층의 표현은 임의적으로 순서를 지정한 것으로 상기 제1 용해물, 약물 포함층 및 부유층을 제조하는 순서는 변경 또는 치환 될 수 있으며, 이런 치환 또는 순서의 변경은 통상의 기술자에 자명하며, 본 발명의 범위에 해당한다.In the case of the above tableting method, 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.
일 실시예에서, 약물 포함층은 상기 제1 혼합부로 형성하고, 상기 부유층은 제2 혼합부로 형성할 수 있다. 약물 포함층을 형성하는 단계에서, 제1 혼합부를 타정기의 용기에 충진시킨 후 충진된 제1 혼합물을 예압(pre-compression)하는 단계를 포함할 수 있다. 이때의 충진은 제1 혼합부가 용기로 자유낙하할 수 있도록 하며, 예압을 통해 제2 혼합부를 충진 할 수 있는 공간을 만들어줄 수 있다. 약물 포함층이 형성된 후, 그 위에 제2 혼합부로 부유층을 형성하고, 제2 혼합부 또한 약물 포함층 상에 자유낙하됨으로써 형성될 수 있다. 다른 실시예에서, 제2 혼합부로 타정기에서 약물 포함층을 형성하고, 제1 혼합부로 약물 포함층 상에 부유층을 형성할 수 있다.In one embodiment, the drug-containing layer may be formed from the first mixing part, and the floating layer may be formed from the second mixing part. In the step of forming the drug-containing layer, 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. After the drug-containing layer is formed, 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. In another embodiment, 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.
본 발명에서 상기 다층정 복합제제는 제1 용해물의 파우더에 화학식 1 내지 3에서 선택되는 1종 이상의 금속 산화물 또는 금속 수산화물과 건식 혼합하는 단계를 더 포함하는 것일 수 있다. 상기 화학식 1 내지 3에서 선택되는 1종 이상의 금속 산화물 또는 금속 수산화물은 보다 바람직하게 마그네슘 옥사이드(MgO)일 수 있다. 상기 마그네슘 옥사이드를 혼합할 경우 약물의 용해도가 현저히 개선되는 효과를 얻을 수 있으며, 이로 인해 목적하는 생체 이용율 향상효과를 얻을 수 있다는 점에서 바람직하다. In the present invention, 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). When mixing the magnesium oxide, the solubility of the drug can be significantly improved, which is desirable in that the desired bioavailability improvement effect can be obtained.
본 발명에서, 상기 다층정 복합제제에서의 약물 포함층 및 부유층이 차지하는 비율은 중량비로 1:9 내지 9:1일 수 있으며, 보다 구체적으로는 2:8 내지 8:2 일 수 있다. In the present invention, 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.
본 발명의 다층정 복합제제는 상기 제1 혼합부 총 중량을 100중량 %로 하였을 때, 약물 또는 이의 약학적으로 허용가능한 염 0.1 내지 40 중량%, 결정화 억제제 0.2 내지 80중량%, 팽윤성 고분자 0.5 내지 80중량%을 포함할 수 있다. 상기 다층정 복합제제는 또한 화학식 1 내지 3으로 표시되는 화합물로 이루어진 군에서 선택되는 1종 이상을 0.1 내지 40중량%를 더 포함할 수 있으며, 장용 코팅제, 기포발생제 및 팽윤성 부형제로 이루어진 군에서 선택되는 1 종이상의 물질 1 내지 30중량%를 더 포함할 수 있다. 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.
본 발명의 다층정 복합제제는 상기 제2 혼합부 총 중량을 100 중량%로 하였을 때, 폴리(메타)크릴레이트가 중합된 고분자 중합체, 아크릴산이 중합된 고분자 중합체 및 팽윤성 고분자 중 1종 이상을 80 내지 100중량%로 포함할 수 있다. 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.
본 발명의 다층정 복합제제는 항염증용, 항바이러스용 및/또는 항암용일 수 있다. The multilayer tablet combination preparation of the present invention may be for anti-inflammatory, antiviral, and/or anticancer purposes.
본 발명에서 항염증용이란, 감염성, 외상성, 내인성, 염증성, 퇴행성 또는 자가면역성에 의한 염증성 반응을 완화시킬 수 있는 효과를 갖는 것을 의미한다. 이는 궤양성 대장염, 염증창자질환(inflammatory disease), 크론병, 바이러스성 장염과 같은 질환을 포함한다. In the present invention, 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.
본 발명에서 항바이러스용이란, 항바이러스 효과를 갖는 것으로 바이러스성 질환을 일으키는 말라리아 감염 또는 엡스타인 바르 바이러스(Epstein Barr Virus; EBV), B형 간염 바이러스, C형 간염 바이러스, HIV, HTLV 1, 바리셀라-조스터 바이러스(Varicella-Zoster Virus; VZV), 인간 파필로마 바이러스(Human Papilloma Virus; HPV), SARS-CoV 및/또는 SARS-CoV2 등의 코로나 바이러스(Corona virus) 및/또는 이의 변이체(variant) 보다 구체적으로 오미크론(omicron), 감기 또는 호흡기 질환의 원인이 되는 리노바이러스(rhinovirus), 아데노 바이러스, RS 바이러스, 파라인플루엔자 바이러스, RS 바이러스 등에 의한 감염증, 기타 레트로바이러스 (retrovirus)등의 바이러스에 대하여 바이러스 증식 억제 효과 및 항생기능을 갖는 것을 의미한다. In the present invention, 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.
또한, 본 발명에서의 항암용이란 의미는 주로 DNA에 직접 작용하여 DNA의 복제, 전사, 번역과정을 차단하거나 대사경로에 핵산 전구체의 합성을 방해하고 세포분열을 저해함으로써 항암활성을 갖는 것을 의미한다. 구체적으로 섬유육종(fibrosarcoma), 점액육종(myxosarcoma), 지방육종(liposarcoma), 연골육종(chondrosarcoma), 골육종(osteogenic sarcoma), 골육종(chordoma), 맥관육종(angiosarcoma), 내피 육종(endotheliosarcoma), 림프관육종(lymphangiosarcoma), 림프관내피육종 (lymphangioendotheliosarcoma), 윤활막종(synovioma), 중피종(mesothelioma), 유윙 종양(Ewing's tumor), 평활근육종(leiomyosarcoma), 횡문근육종(rhabdomyosarcoma), 대장암종(colon carcinoma), 췌장암(pancreatic cancer), 유방암(breast cancer), 난소암(ovarian cancer), 전립선암(prostate cancer), 편평세포암종(squamous cell carcinoma), 기저세포암종(basal cell carcinoma), 샘암종 (adenocarcinoma), 한선암종(sweat gland carcinoma), 피지샘암종(sebaceous gland carcinoma), 유두암종(papillary carcinoma), 유두모양샘암종(papillary adenocarcinoma), 낭샘암종 (cystadenocarcinoma), 속질암종(medullary carcinoma), 기관지유래암종(bronchogenic carcinoma), 신세포암종(renal cell carcinoma), 간암(hepatoma), 담관암종(bile duct carcinoma), 융모막암종 (choriocarcinoma), 정상피종(seminoma), 배아암종(embryonal carcinoma), 빌름 종양(Wilms tumor), 자궁경부암(cervical cancer), 고환암(testicular tumor), 폐암종(lung carcinoma), 소세포폐암종(small cell lung carcinoma), 방광암종(bladder carcinoma), 상피내암종(epithelial carcinoma), 신경교종 (glioma), 별아교세포종(astrocytoma), 속질모세포종(medulloblastoma), 머리인두종 (craniopharyngioma), 뇌실막세포종(ependymoma), 송과체종(pinealoma), 혈관모세포종(hemangioblastoma), 청신경종(acoustic neuroma), 희소돌기아교세포종(oligodendroglioma), 수막종(meningioma), 멜라닌종(melanoma), 신경모세포종(neuroblastoma) 및 망막모세포종(retinoblastoma)을 포함하는 암, 및 유방, 전립선, 신장, 방광, 또는결장 조직에서 생성된 암종 (carcinoma); 지방세포 종양, 예컨대 지방종(lipoma), 섬유지방종(fibrolipoma), 지방모세포종(lipoblastoma), 지방종증(lipomatosis), 히베모마(hibemoma), 혈관종(hemangioma), 및/또는 지방육 종(liposarcoma)과 같은 지방조직에서 나타나는 종양성 질환에 대하여 치료 효과를 갖는 것을 의미한다. In addition, in the present invention, 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. . Specifically, 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), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma cancer, including meningioma, melanoma, neuroblastoma, and retinoblastoma, and carcinoma produced in breast, prostate, kidney, bladder, or colon tissue; Adipocyte tumors, such as lipoma, fibrolipoma, lipoblastoma, lipomatosis, hibemoma, hemangioma, and/or liposarcoma. It means that it has a therapeutic effect on neoplastic diseases that occur in adipose tissue.
본 발명의 다층정 복합제제는 0.001mg/kg 내지 500mg/kg의 용량으로, 1일 1회 내지 8회 투여될 수 있으며, 경과 진행에 따라 2일 1회 내지 3회, 3일 1회 내지 3회, 4일 1회 내지 3회, 5일 1회 내지 3회 등으로 조절하여 투여할 수 있다. 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.
본 발명의 다층정 복합제제는 경구 복용(경구 투여)하여 투여하는 방법에 최적화 될 수 있다. The multilayer tablet combination preparation of the present invention can be optimized for administration by oral administration (oral administration).
실시예 1: 다층정의 제조Example 1: Preparation of multilayer tablet
둥근바닥플라스크에 PVP 4g을 무수 에탄올 50mL에 녹인 용액에 Niclosamide 1g을 용액에 넣고 1시간 정도 교반 후, 건조를 한다. 건조된 NIC-PVP 5g과 MgO 2g을 건식 혼합한다(제1 혼합부). 제2 혼합부는 카보머(carbomer(947)을 이용하여 제조한다. 다층정 타정을 위해 상기 제1 제1 혼합부 0.225g으로 약물층, 제2 혼합부 0.15g으로 부유층을 형성하여 다층정 복합제제를 타정한다.In a round bottom flask, add 1g of Niclosamide to a solution of 4g of PVP in 50mL of absolute ethanol, stir for about 1 hour, and then dry. 5 g of dried NIC-PVP and 2 g of MgO are dry mixed (first mixing section). The second mixing part is manufactured using carbomer (947). For tableting of multi-layer tablets, 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 to form a multi-layer tablet composite preparation. .
상기 실시예 1의 방법으로 타정된 다층정은 도 1에 나타내었다. The multilayer tablet tableted by the method of Example 1 is shown in Figure 1.
실시예 2: 다층정의 제조Example 2: Preparation of multilayer tablet
둥근바닥플라스크에 PVP 4g을 무수 에탄올 50mL에 녹인 용액에 Niclosamide 1g을 용액에 넣고 1시간 정도 교반 후, 건조를 한다. 건조된 NIC-PVP 5g과 MgO 2g, alginate-Na 0.368g을 건식 혼합하여 제 1 혼합부를 형성한다. 제2 혼합부는 카보머(carbomer(947)을 이용하여 제조한다. 다층정 타정을 위해 제1 혼합부 0.225g으로 약물층, 제2 혼합부 0.15g으로 부유층을 형성하여 다층정 복합제제를 타정한다.In a round bottom flask, add 1g of Niclosamide to a solution of 4g of PVP in 50mL of absolute ethanol, stir for about 1 hour, and then dry. 5 g of dried NIC-PVP, 2 g of MgO, and 0.368 g of alginate-Na are dry mixed to form a first mixing section. The second mixing part is manufactured using carbomer (947). For tableting of multi-layered tablets, 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 to form a multi-layer tablet composite preparation. .
실시예 3: 다층정의 제조Example 3: Preparation of multilayer tablet
둥근바닥플라스크에 PVP 4g을 무수 에탄올 50mL에 녹인 용액에 Niclosamide 1g을 용액에 넣고 1시간 정도 교반 후, 건조를 한다. 건조된 NIC-PVP 5g과 MgO 2g, xantan gum 0.368g을 건식 혼합하여 제1 혼합부를 형성한다. 제2 혼합부는 카보머(carbomer(947)을 이용하여 제조한다. 다층정 타정을 위해 제1 혼합부 0.225g으로 약물층, 제2 혼합부 0.15g으로 부유층을 형성하여 다층정 복합제제를 타정한다.In a round bottom flask, add 1g of Niclosamide to a solution of 4g of PVP in 50mL of absolute ethanol, stir for about 1 hour, and then dry. 5 g of dried NIC-PVP, 2 g of MgO, and 0.368 g of xantan gum are dry mixed to form a first mixing section. The second mixing part is manufactured using carbomer (947). For tableting of multi-layered tablets, 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 to form a multi-layer tablet composite preparation. .
실시예 4: 다층정의 제조Example 4: Preparation of multilayer tablet
둥근바닥플라스크에 PVP 4g을 무수 에탄올 50mL에 녹인 용액에 Niclosamide 1g을 용액에 넣고 1시간 정도 교반 후, 건조를 한다. 건조된 NIC-PVP 5g과 MgO 2g, chitosan 0.368g을 건식 혼합하여 제1 혼합부를 형성한다. 제2 혼합부는 카보머(carbomer(947)을 이용하여 제조한다. 다층정 타정을 위해 제1 혼합부 0.225g으로 약물층, 제2 혼합부 0.15g으로 부유층을 형성하여 다층정 복합제제를 타정한다.In a round bottom flask, add 1g of Niclosamide to a solution of 4g of PVP in 50mL of absolute ethanol, stir for about 1 hour, and then dry. 5 g of dried NIC-PVP, 2 g of MgO, and 0.368 g of chitosan are dry mixed to form a first mixing section. The second mixing part is manufactured using carbomer (947). For tableting of multi-layered tablets, 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 to form a multi-layer tablet composite preparation. .
실시예 5: 다층정의 제조 (Na-alginate 비율 - 제1 혼합부에 5%)Example 5: Preparation of multilayer tablet (Na-alginate ratio - 5% in first mixing part)
둥근바닥플라스크에 PVP 3.257g을 무수 에탄올 20mL에 녹인 용액에 Niclosamide 0.814g을 용액에 넣고 1시간 정도 교반 후, 건조를 한다. 건조된 NIC-PVP와 MgO 1.629g, alginate-Na 0.368g을 건식 혼합하여 제1 혼합부를 제조한다.Add 0.814 g of Niclosamide to a solution of 3.257 g of PVP dissolved in 20 mL of absolute ethanol in a round bottom flask, stir for about 1 hour, and then dry. The first mixing part is prepared by dry mixing dried NIC-PVP, 1.629 g of MgO, and 0.368 g of alginate-Na.
제 2 혼합부는 카보머 1.5g, 미결정셀룰로오스 5.7g, 콜리돈 에스알 20.0g, 구연산 1.25g 및 중탄산나트륨 4.3g을 달아 20분간 혼합한 후 스테아르산마그네슘 0.6g을 투입하여 5분간 혼합하여 제2혼합부를 제조 한다. 상기 제1 혼합부 0.225g으로 약물층, 제2 혼합부 0.2g으로 부유층을 형성하여 다층정 복합제제를 타정한다.In the second mixing section, 1.5 g of carbomer, 5.7 g of microcrystalline cellulose, 20.0 g of Kollidon SR, 1.25 g of citric acid, and 4.3 g of sodium bicarbonate were weighed and mixed for 20 minutes, then 0.6 g of magnesium stearate was added and mixed for 5 minutes for the second mixing. Manufacture wealth. A drug layer is formed with 0.225 g of the first mixing portion and a floating layer is formed with 0.2 g of the second mixing portion, and a multi-layered tablet combination preparation is tableted.
실시예 6: 다층정의 제조 (Na-alginate 비율 조절, 제1 혼합부에 2.5%)Example 6: Preparation of multilayer tablet (Na-alginate ratio control, 2.5% in first mixing part)
둥근바닥플라스크에 PVP 5.571을 무수 에탄올 24mL에 녹인 용액에 Niclosamide 1.393g을 용액에 넣고 1시간 정도 교반 후, 건조를 한다. 건조된 NIC-PVP와 MgO 2.786g, alginate-Na 0.25g을 건식 혼합하여 제1 혼합부를 제조한다. 제2 혼합부는 카보머(carbomer(947)을 이용하여 제조한다. 상기 제1 혼합부 0.225g으로 약물층, 제2 혼합부 0.15g으로 부유층을 형성하여 다층정 복합제제를 타정한다. Add 1.393 g of Niclosamide to a solution of PVP 5.571 dissolved in 24 mL of absolute ethanol in a round bottom flask, stir for about 1 hour, and dry. 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.
실시예 7: 다층정의 제조 (Na-alginate 비율 조절, 제1 혼합부에 7.5%)Example 7: Preparation of multilayer tablet (Na-alginate ratio control, 7.5% in first mixing part)
둥근바닥플라스크에 PVP 5.286을 무수 에탄올 24mL에 녹인 용액에 Niclosamide 1.321g을 용액에 넣고 1시간 정도 교반 후, 건조를 한다. 건조된 NIC-PVP와 MgO 2.643g, alginate-Na 0.75g을 건식 혼합하여 제1 혼합부를 형성한다. 제2 혼합부는 카보머(carbomer(947)을 이용하여 제조한다. 상기 제1 혼합부 0.225g으로 약물층, 제2 혼합부 0.15g으로 부유층을 형성하여 다층정 복합제제를 타정한다.Add 1.321 g of Niclosamide to a solution of PVP 5.286 dissolved in 24 mL of absolute ethanol in a round bottom flask, stir for about 1 hour, and dry. Dried NIC-PVP, 2.643 g of MgO, and 0.75 g of alginate-Na are dry mixed to form a first mixing section. 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.
실시예8. 다층정의 제조 (Na-alginate 비율 - 제1 혼합부에 5%)Example 8. Manufacture of multilayer tablet (Na-alginate ratio - 5% in first mixing part)
둥근바닥플라스크에 PVP 3.257g을 무수 에탄올 20mL에 녹인 용액에 Niclosamide 0.814g을 용액에 넣고 1시간 정도 교반 후, 건조를 한다. 건조된 NIC-PVP와 MgO 1.629g, alginate-Na 0.368g을 볼 밀링 하여 제1 혼합부를 제조한다. 제2 혼합부는 carbomer 974P를 이용하여 제조하였다. 제1 혼합부 0.225g을 타정기의 용기에 충진 시킨 후 충진된 약물 포함층을 예압(pre-compression) 한다. 약물 포함층이 형성된 후, 그 위에 부유층 형성을 위해 제2 혼합부 0.15g을 자유낙하 하여 타정을 한다.Add 0.814 g of Niclosamide to a solution of 3.257 g of PVP dissolved in 20 mL of absolute ethanol in a round bottom flask, stir for about 1 hour, and then dry. 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 using carbomer 974P. 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.
실시예9. 다층정의 제조 (Na-alginate 비율 - 제1 혼합부에 5%)Example 9. Manufacture of multilayer tablet (Na-alginate ratio - 5% in first mixing part)
둥근바닥플라스크에 PVP 3.257g을 무수 에탄올 20mL에 녹인 용액에 Niclosamide 0.814g을 용액에 넣고 1시간 정도 교반 후, 건조를 한다. 건조된 NIC-PVP와 MgO 1.629g, alginate-Na 0.368g을 볼 밀링 하여 제1 혼합부를 제조한다. 제2 혼합부는 carbomer 71G 0.5g과 탄산나트륨 0.3g을 건식 혼합 후, carbomer 974P 0.2g을 더하여 건식 혼합하여 제조하였다. 제1 혼합부 0.225g을 타정기의 용기에 충진 시킨 후 충진된 약물 포함층을 예압(pre-compression) 한다. 약물 포함층이 형성된 후, 그 위에 부유층 형성을 위해 제2 혼합부 0.15g을 자유낙하 하여 타정을 한다.Add 0.814 g of Niclosamide to a solution of 3.257 g of PVP dissolved in 20 mL of absolute ethanol in a round bottom flask, stir for about 1 hour, and then dry. 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.
실시예 10. 다층정의 제조Example 10. Preparation of multilayer tablet
둥근바닥플라스크에 PVP 4g을 무수 에탄올 50mL에 녹인 용액에 Docetaxel 1g을 용액에 1시간 교반 후, HPMC(6mPas) 0.9g과 poloxamer 407 0.9g을 넣고 1시간 교반 후 용액을 회전증발 농축기를 통해 용매를 완전히 제거하여 파우더를 수득하여 제1 혼합부를 제조한다. 제2 혼합부는 carbomer 71G 42.75g과 Na(CO3)2 42.75g을 혼합 후, carbomer974P 19.5g을 넣고 혼합한 후 활택제로 스테아린산 마그네슘 5g을 넣고 혼합하여 제조한다. 제1 혼합부 0.3g을 타정기의 용기에 충진 시킨 후 충진된 약물 포함층을 예압(pre-compression)하여 약물 포함층을 형성한다. 상기 약물 포함층 상부에 부유층 형성을 위해 제2 혼합부 0.2g 을 자유낙하 시켜 타정하여 다층정을 제조한다. In a round-bottomed flask, 4 g of PVP was dissolved in 50 mL of absolute ethanol, and 1 g of Docetaxel was stirred for 1 hour. Then, 0.9 g of HPMC (6 mPas) and 0.9 g of poloxamer 407 were added and stirred for 1 hour, and the solvent was removed through a rotary evaporator. Completely remove to obtain powder to prepare the first mixing part. 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. After filling 0.3 g of the first mixing portion into the container of the tablet press, the filled drug-containing layer is pre-compressed to form a drug-containing layer. To form a floating layer on top of the 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.
실시예 11. 다층정의 제조Example 11. Preparation of multilayer tablet
둥근바닥플라스크에 PVP 4g을 무수 에탄올 50mL에 녹인 용액에 Docetaxel 1g을 용액에 1시간 교반 후, HPMC(6mPas) 0.9g과 poloxamer 407 0.9g을 넣고 1시간 교반 후 용액을 회전증발 농축기를 통해 용매를 완전히 제거하여 Docetaxel-PVP-HPMC 파우더를 제조한다. 상기 Docetaxel-PVP-HPMC 파우더에 MgO 2g을 넣고 잘 섞은 후 흰색의 파우더를 수득하여 제1 혼합부를 형성한다. 제2 혼합부는 carbomer 71G 42.75g과 Na(CO3)2 42.75g을 혼합 후, carbomer974P 19.5g을 넣고 혼합한 후 활택제로 스테아린산 마그네슘 5g을 넣고 혼합하여 제조한다. 상기 제1 혼합부 0.3g을 타정기의 용기에 충진 시킨 후 충진된 약물 포함층을 예압(pre-compression) 하여 약물 포함층을 형성한다. 상기 약물 포함층 상부에 부유층 형성을 위해 제2 혼합부 0.2g 을 자유낙하 시켜 타정하여 다층정을 제조한다.In a round-bottomed flask, 4 g of PVP was dissolved in 50 mL of absolute ethanol, and 1 g of Docetaxel was stirred for 1 hour. Then, 0.9 g of HPMC (6 mPas) and 0.9 g of poloxamer 407 were added and stirred for 1 hour, and the solvent was removed through a rotary evaporator. Docetaxel-PVP-HPMC powder is prepared by completely removing it. 2g of MgO was added to the Docetaxel-PVP-HPMC powder and mixed well to obtain a white powder to form the first mixing section. 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. After filling 0.3 g of the first mixing portion into the container of the tablet press, the filled drug-containing layer is pre-compressed to form a drug-containing layer. To form a floating layer on top of the 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.
실시예 12. 다층정의 제조 Example 12. Preparation of multilayer tablet
둥근바닥플라스크에 PVP 3.257g을 무수 에탄올 20mL에 녹인 용액에 Niclosamide 0.814g을 용액에 넣고 1시간 정도 교반 후, 건조를 한다. 건조된 NIC-PVP와 MgO 1.629g, alginate-Na 0.368g을 건식 교반 하여 제1 혼합부를 제조한다. 제2 혼합부는 carbomer 974P 5.76g과 탄산나트륨 3.84g을 건식 혼합 후, 활택제로 스테아린산 마그네슘 0.4g 더하여 건식 혼합하여 제조하였다.Add 0.814 g of Niclosamide to a solution of 3.257 g of PVP dissolved in 20 mL of absolute ethanol in a round bottom flask, stir for about 1 hour, and then dry. The first mixing part was prepared by dry stirring dried NIC-PVP, 1.629 g of MgO, and 0.368 g of alginate-Na. The second mixing part was prepared by dry mixing 5.76 g of carbomer 974P and 3.84 g of sodium carbonate, then adding 0.4 g of magnesium stearate as a lubricant.
상기 제2 혼합부 0.3g 을 타정기의 용기에 충진 시킨 후 충진된 부유층을 예압(pre-compression) 하여 부유층을 형성한다. 상기 부유층 상부에 제1 혼합부 0.3g을 타정기의 용기에 충진 시킨 후 충진된 약물 포함층을 예압(pre-compression) 하여 약물 포함층을 형성한다. 상기 약물 포함층 상부에 다시 제2 혼합부와 동일한 성분으로 제3의 층 형성을 위해 제2 혼합부 0.1g 을 자유낙하 시켜 타정하여 다층정을 제조한다.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.
비교예 1: 단층정의 제조 Comparative Example 1: Manufacture of single-layer crystal
둥근바닥플라스크에 PVP 4g을 무수 에탄올 50mL에 녹인 용액에 Niclosamide 1g을 용액에 넣고 1시간 정도 교반 후, 건조를 한다. 건조된 NIC-PVP 5g과 MgO 2g을 건식 혼합하여 제1 혼합부를 제조하였다. 상기 제1 혼합부 0.4g으로 단층정을 타정 한다.In a round bottom flask, add 1g of Niclosamide to a solution of 4g of PVP in 50mL of absolute ethanol, stir for about 1 hour, and then dry. The first mixing part was prepared by dry mixing 5 g of dried NIC-PVP and 2 g of MgO. A single-layer tablet is compressed using 0.4 g of the first mixing portion.
비교예 2: 단층정의 제조 Comparative Example 2: Manufacture of single layer crystal
둥근바닥플라스크에 PVP 4g을 무수 에탄올 50mL에 녹인 용액에 Niclosamide 1g을 용액에 넣고 1시간 정도 교반 후, 건조를 한다. 건조된 NIC-PVP 5g과 MgO 2g, 소듐알지네이트 0.368g을 혼합하여 제1 혼합부를 제조하였다. 상기 제1 혼합부 0.4g으로 단층정을 타정 한다.In a round bottom flask, add 1g of Niclosamide to a solution of 4g of PVP in 50mL of absolute ethanol, stir for about 1 hour, and then dry. 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.
비교예 3. Comparative Example 3.
Yomesan(Niclosamide 원료)Yomesan (Niclosamide raw material)
비교예 4. 단층정의 제조Comparative Example 4. Manufacture of single layer crystal
둥근바닥플라스크에 PVP 5.429g을 무수 에탄올 26mL에 녹인 용액에 Niclosamide 1.357g을 용액에 넣고 1시간 정도 교반 후 건조시켜 NIC-PVP파우더를 형성한다. 상기 건조된 NIC-PVP 파우더와 MgO 2.714g, xantan gum 0.5g을 건식 혼합하여 제1 혼합부를 제조한다. 상기 제1 혼합부 0.4mg으로 단층정을 타정 한다.Add 1.357 g of Niclosamide to a solution of 5.429 g of PVP in 26 mL of absolute ethanol in a round bottom flask, stir for about 1 hour, and dry to form NIC-PVP powder. 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.
비교예 5. Comparative Example 5.
DOCETAXEL 원료DOCETAXEL raw materials
비교예 6. 단층정의 제조Comparative Example 6. Manufacture of single-layer crystal
둥근바닥플라스크에 PVP 4g을 무수 에탄올 50mL에 녹인 용액에 Docetaxel 1g을 용액에 1시간 교반 후, HPMC(6mPas) 0.9g과 poloxamer 407 0.9g을 넣고 1시간 교반 후 용액을 회전증발 농축기를 통해 용매를 완전히 제거한다. Docetaxel-PVP-HPMC 파우더에 MgO 2g을 넣고 잘 섞은 후 흰색의 파우더를 수득하여 단층정을 제조한다. In a round-bottomed flask, 4 g of PVP was dissolved in 50 mL of absolute ethanol, and 1 g of Docetaxel was stirred for 1 hour. Then, 0.9 g of HPMC (6 mPas) and 0.9 g of poloxamer 407 were added and stirred for 1 hour, and the solvent was removed through a rotary evaporator. Remove it completely. Add 2g of MgO to Docetaxel-PVP-HPMC powder and mix well to obtain a white powder to prepare a single-layer tablet.
실험예 1: 실시예 및 비교예 조성물의 생체 내(in-vivo) 약물동태(pharmacokinetic) 분석 (비글)Experimental Example 1: In-vivo pharmacokinetic analysis of Example and Comparative Example compositions (Beagle)
생체 내 약물동태 분석은 실시예 1 내지 4 및 비교예 1 및 2의 조성물을 이용하여 수행되었다. 상기 실시예 1 내지 4 및 비교예 1 및 2의 조성물을 비글에 단일 경구 투여하여 혈장 약물 농도 정보를 획득하였다. In vivo pharmacokinetic analysis was performed using the compositions of Examples 1 to 4 and Comparative Examples 1 and 2. Plasma drug concentration information was obtained by single oral administration of the compositions of Examples 1 to 4 and Comparative Examples 1 and 2 to beagles.
또한, 상기 실시예 1 내지 4 및 비교예 1 및 2의 조성물을 각각 40mg/kg 용량으로 1일 1회 투여하였다. In addition, the 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.
상기 분석에서 실시예 1 내지 4 및 비교예 1 및 2의 결과는 도 2 에 나타내었다. 도 2의 그래프는 비글의 혈장내 NIC 농도를 시간에 따라 나타낸 것이다. 구체적인 약물동태 파라미터는 하기 표 2 및 3에 기재하였다. The results of Examples 1 to 4 and Comparative Examples 1 and 2 in the above analysis are shown in Figure 2. The graph in Figure 2 shows the concentration of NIC in the plasma of a beagle over time. Specific pharmacokinetic parameters are listed in Tables 2 and 3 below.
구체적으로, 니클로사마이드의 체내 흡수에 있어서 분산과 용해도는 흡수에 큰 영향을 미친다. 단층정의 경우 폴리비닐 피롤리딘(PVP)의 점성에 의해 체내에서 잘 분산되지 못하고 뭉쳐져 소화기관 내 임의의 한곳에 머무르다가 흡수 효율이 높은 부위에서 흡수 되지 못하고 장을 통해 소화될 수 있는데 이 경우 그 기능적 요인을 상실하게 되는 문제가 발생할 수 있다. 한편, 하기 실험결과로부터 단층정 형태인 비교예 1 및 2 대비 다층정 형태인 실시예 1 내지 4에서 혈중 용해도가 현저히 우수함을 확인할 수 있으며, 다층정으로 제제화 된 본 발명의 다층정 복합제제가 단층정 보다 더 약효를 증가시킬 수 있음을 알 수 있다. Specifically, in the absorption of niclosamide into the body, dispersion and solubility have a significant impact on absorption. In the case of single-layer tablets, due to the viscosity of polyvinyl pyrrolidine (PVP), they cannot be dispersed well in the body and clump up and stay in one random place in the digestive tract. They may not be absorbed in areas with high absorption efficiency and may be digested through the intestines. In this case, their functional Problems may arise where factors are lost. Meanwhile, from the following experimental results, it can be seen that the blood solubility of Examples 1 to 4, which are in the form of a multilayer tablet, is significantly superior to that of Comparative Examples 1 and 2, which are in the form of a single-layer tablet, and that the multi-layered tablet combination preparation of the present invention formulated as a multi-layer tablet is a single-layer tablet. It can be seen that the efficacy of the drug can be further increased.
TimeTime Niclosamide PONiclosamide PO
hh 실시예 1Example 1 실시예 2Example 2 실시예 3Example 3 실시예 4Example 4 비교예 1Comparative Example 1 비교예 2Comparative Example 2
00 NDN.D. NDN.D. NDN.D. NDN.D. NDN.D. NDN.D.
0.250.25 508.099 508.099 7342.375 7342.375 109.297 109.297 177.727 177.727 63.575 63.575 21.784 21.784
0.50.5 531.638 531.638 -- 255.752 255.752 148.463 148.463 33.273 33.273 20.461 20.461
1One 174.577 174.577 -- 230.912 230.912 42.451 42.451 38.443 38.443 56.084 56.084
22 62.644 62.644 -- 101.790 101.790 66.608 66.608 16.888 16.888 18.727 18.727
44 40.895 40.895 -- 5.646 5.646 21.636 21.636 5.818 5.818 11.356 11.356
66 18.629 18.629 -- 4.952 4.952 1.402 1.402 4.524 4.524 13.117 13.117
88 2.272 2.272 -- 1.874 1.874 1.073 1.073 3.243 3.243 3.012 3.012
PK ParametersPK Parameters Niclosamide PONiclosamide PO
실시예 1Example 1 실시예 2Example 2 실시예 3Example 3 실시예 4Example 4 비교예 1Comparative Example 1 비교예 2Comparative Example 2
AUC(last)AUC(last) 672.61 672.61 NDN.D. 472.17 472.17 279.01 279.01 106.46 106.46 135.23 135.23
AUC(inf)AUC(inf) 676.33 676.33 NDN.D. 474.83 474.83 280.59 280.59 128.66 128.66 144.22 144.22
CmaxCmax 531.64 531.64 NDN.D. 255.75 255.75 177.73 177.73 63.58 63.58 56.08 56.08
TmaxTmax 0.50 0.50 NDN.D. 0.50 0.50 0.25 0.25 0.25 0.25 1.00 1.00
t1/2 t 1/2 1.14 1.14 NDN.D. 0.99 0.99 1.03 1.03 4.74 4.74 2.07 2.07
* AUC: ng·h/mL, Cmax: ng/mL, Tmax & t1/2: h
** ND: Not detected
* AUC: ng·h/mL, C max : ng/mL, T max & t 1/2 : h
** ND: Not detected
실험예 2: 실시예, 참조예 및 비교예 조성물의 생체 내(in-vivo) 약물동태(pharmacokinetic) 분석 (미니피그)생체 내 약물동태 분석은 실시예 5 내지 9 및 비교예 3의 조성물을 미니피그에 단일 경구 투여하여 혈장 약물 농도 정보를 획득하였다. 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.
또한, 상기 실시예 5 내지 9 및 비교예 3의 조성물을 각각 1마리당 500mg용량으로 1일 1회 투여하였다. In addition, the compositions of Examples 5 to 9 and Comparative Example 3 were administered at a dose of 500 mg per animal once a day.
상기 분석에서 실시예 5 내지 9 및 비교예 3의 투여 결과는 도 3 및 5에 나타내었다. 구체적인 약물동태 파라미터는 하기 표 4 내지 7에 기재하였다. 테스트한 조성물과 AUC의 관계는 도 4 및 6에 나타내었다. In the above analysis, the administration results of Examples 5 to 9 and Comparative Example 3 are shown in Figures 3 and 5. Specific pharmacokinetic parameters are listed in Tables 4 to 7 below. The relationship between tested compositions and AUC is shown in Figures 4 and 6.
하기 표 4 내지 7 및 도 3 내지 6에서 확인할 수 있듯이, 제형화한 니클로사마이드가 제형화 되지 않은 니클로사마이드인 Yomesan(비교예 3) 보다 우수한 생체 이용율을 나타냄을 확인하였다. 이에 더하여, 다층정 복합제제로 제형화된 실시예 5 및 6은 위산을 다량 분비하는 미니피그의 체내에서도 단층정제 형태인 비교예 4보다 현저히 우수한 생체 이용율을 나타냄을 확인할 수 있었다. 이에, 다층정 중 부유층에 부유가능한 고분자 물질을 이용하여 다층정제화 한 본 발명이 약물의 생체 이용율 개선에 단층정에 대비하여 현저한 효과를 가짐을 확인하였다. As can be seen in Tables 4 to 7 and Figures 3 to 6 below, it was confirmed that the formulated niclosamide exhibited superior bioavailability than the unformulated niclosamide, Yomesan (Comparative Example 3). In addition, it was confirmed that Examples 5 and 6, which were formulated as a multilayer tablet composite preparation, showed significantly better bioavailability than Comparative Example 4, which was in the form of a single-layer tablet, even in the body of minipigs that secreted a large amount of gastric acid. Accordingly, it was confirmed that the present invention, which is a multi-layer tablet using a polymer material that can float in the floating layer of the multi-layer tablet, has a significant effect in improving the bioavailability of the drug compared to a single-layer tablet.
Time Time Niclosamide PO 500 mg/head , Mini pig
 
Niclosamide PO 500 mg/head, Mini pig
hh Yomesan(비교예 3)Yomesan (Comparative Example 3) 실시예 5Example 5 비교예 4Comparative Example 4
00 NDN.D. NDN.D. NDN.D.
0.250.25 BQLBQL 264.89264.89 10.22810.228
0.50.5 BQLBQL 204.328204.328 21.35421.354
1One BQLBQL 218.438218.438 57.12257.122
22 BQLBQL 158.881158.881 115.243115.243
44 0.883 0.883 59.559.5 72.02972.029
66 1.941 1.941 60.03860.038 15.65115.651
88 4.119 4.119 22.79422.794 12.81912.819
1212 2.600 2.600 7.1347.134 10.53510.535
* Data are represented as the mean concentration(n=2)* Data are represented as the mean concentration (n=2)
* Plasma concentration: ng/mL * Plasma concentration: ng/mL
* ND: not detected, BQL: below quantitative limit(< 0.5 ng/mL)* ND: not detected, BQL: below quantitative limit (< 0.5 ng/mL)
PK ParametersPK Parameters Niclosamide PO 500 mg , Mini pigNiclosamide PO 500 mg, Mini pig
Yomesan(비교예 3)Yomesan (Comparative Example 3) 실시예 5Example 5 비교예 4Comparative Example 4
AUC(last)AUC(last) 19.0619.06 866.72866.72 461.16461.16
CmaxCmax 4.74.7 264.89264.89 115.24115.24
TmaxTmax 77 0.250.25 22
t1/2 t 1/2 NCNC 2.32.3 10.9110.91
* AUC: ng·h/mL, Cmax: ng/mL, Tmax & t1/2: h* AUC: ng·h/mL, C max : ng/mL, T max & t 1/2 : h
TimeTime Niclosamide PO 500mg/KG , Mini pigNiclosamide PO 500mg/KG, Mini pig
hh 실시예 6Example 6 실시예7Example 7
00 NDN.D. NDN.D.
0.250.25 109.623109.623 426.233426.233
0.50.5 148.505148.505 566.735566.735
1One 296.118296.118 465.922465.922
22 439.962439.962 249.543249.543
44 601.514601.514 168.13168.13
66 142.451142.451 100.691100.691
88 148.161148.161 73.27473.274
1212 90.85790.857 37.87337.873
* Data are represented as the mean concentration(n=2)* Data are represented as the mean concentration (n=2)
* Plasma concentration: ng/mL* Plasma concentration: ng/mL
* ND: not detected* ND: not detected
PK ParametersPK Parameters Niclosamide PONiclosamide PO
실시예 6Example 6 실시예 7Example 7
AUC(last)AUC(last) 3079.253079.25 1876.041876.04
CmaxCmax 601.51601.51 589.43589.43
Tmax Tmax 44 2.252.25
t1/2 t 1/2 4.084.08 2.642.64
* AUC: ng·h/mL, Cmax: ng/mL, Tmax & t1/2: h* AUC: ng·h/mL, C max : ng/mL, T max & t 1/2 : h
** NC: Not calculated** NC: Not calculated
TimeTime Niclosamide PONiclosamide PO
hh 실시예 8Example 8 실시예 9Example 9
00 0.347 0.347 0.135 0.135
0.250.25 33.983 33.983 71.806 71.806
0.50.5 38.652 38.652 108.317 108.317
1One 73.577 73.577 123.827 123.827
22 108.398 108.398 162.198 162.198
44 89.723 89.723 86.587 86.587
66 54.142 54.142 81.489 81.489
88 69.751 69.751 66.325 66.325
1212 29.686 29.686 19.674 19.674
* Data are represented as the mean concentration(n=2)
* Plasma concentration: ng/mL
* Data are represented as the mean concentration (n=2)
* Plasma concentration: ng/mL
PK ParametersPK Parameters Niclosamide PONiclosamide PO
실시예 8Example 8 실시예 9Example 9
AUC(last)AUC(last) 797.14 797.14 969.22 969.22
CmaxCmax 144.16 144.16 162.20 162.20
TmaxTmax 5.00 5.00 2.00 2.00
t1/2 t 1/2 5.26 5.26 2.69 2.69
* AUC: ng·h/mL, Cmax: ng/mL, Tmax & t1/2: h* AUC: ng·h/mL, C max : ng/mL, T max & t 1/2 : h
실험예 3: 실시예 및 비교예 조성물의 생체 내(in-vivo) 약물동태(pharmacokinetic) 분석 (비글)생체 내 약물동태 분석은 실시예 10, 11 및 비교예 5 및 6의 조성물을 이용하여 수행되었다. 상기 실시예 10, 11 및 비교예 5 및 6의 조성물을 비글에 단일 경구 투여하여 혈장 약물 농도 정보를 획득하였다. 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.
또한, 상기 실시예 10, 11 및 비교예 5 및 6의 조성물을 각각 50mg/kg 용량으로 1일 1회 투여하였다. In addition, the 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.
상기 분석에서 실시예 10, 11 및 비교예 5 및 6의 결과는 도 7 및 8에 나타내었다. 도 7의 그래프는 비글의 혈장내 도세탁셀의 농도를 시간에 따라 나타낸 것이다. 구체적인 약물동태 파라미터는 하기 표 10 및 11에 기재하였다. The results of Examples 10 and 11 and Comparative Examples 5 and 6 in the above analysis are shown in Figures 7 and 8. The graph in Figure 7 shows the concentration of docetaxel in the plasma of a beagle over time. Specific pharmacokinetic parameters are listed in Tables 10 and 11 below.
실시예와 같이 다층정을 통해 약물의 서방성을 증대 시킨 이유는, 약물의 혈중 Cmax가 높으면 독성에 노출될 확률이 높아지므로 AUC 및 tmax 값의 조정을 통해 약물의 서방성을 증가 시킴으로써 약물의 혈중농도를 therapeutic window에서 유지시켜 그 기능적 역할을 극대화할 수 있도록 하기 위함인데, 하기 표 10 및 표 11, 도 7 및 도 8의 결과로부터 다층정으로 제형화 시킴으로써 Cmax가 높아지는 경우 AUC 및 tmax 값도 적절히 증가시켜 약물의 독성을 줄이되 약물의 효과가 지속 가능함을 확인하였다. 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.
또한, 다층정은 단층정 대비 복용 횟수를 줄일 수 있는 장점이 있는데, 이는 약물의 효과를 지속시키기 위해 약물의 혈중농도가 떨어지는 시점에서 약을 계속 투여 하게 되는데 다층정으로 제형화 시킬경우 약물의 혈중 농도가 떨어지는 시점이 비교예 6에 대비하여 실시예 10 및 11에서의 농도 보전 효과가 현저히 우수함을 확인할 수 있다. In addition, multilayer tablets have the advantage of reducing the number of doses compared to single-layer tablets. In order to maintain the effect of the drug, the drug is continued to be administered when the blood concentration of the drug drops. When formulated as a multilayer tablet, 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 .
Time Time Docetaxel PO 50 mg/kgDocetaxel PO 50 mg/kg
hh 비교예 5Comparative Example 5 비교예 6Comparative Example 6 실시예 10Example 10 실시예 11Example 11
00 NDN.D. NDN.D. NDN.D. NDN.D.
0.250.25 0.239 0.239 53.817 53.817 30.618 30.618 28.525 28.525
0.50.5 0.219 0.219 94.890 94.890 39.726 39.726 42.683 42.683
1One 0.243 0.243 29.472 29.472 82.114 82.114 92.837 92.837
22 0.140 0.140 28.140 28.140 58.857 58.857 153.311 153.311
44 0.621 0.621 12.834 12.834 23.556 23.556 31.102 31.102
66 0.675 0.675 9.781 9.781 8.745 8.745 12.258 12.258
88 0.222 0.222 14.757 14.757 11.547 11.547 19.080 19.080
* Data are represented as the mean concentration(n=2)
* Plasma concentration: ng/mL
* ND: not detected
* Data are represented as the mean concentration (n=2)
* Plasma concentration: ng/mL
* ND: not detected
PK ParametersPK Parameters Docetaxel PO 50 mg/kgDocetaxel PO 50 mg/kg
비교예 5Comparative Example 5 비교예 6Comparative Example 6 실시예 10Example 10 실시예 11Example 11
AUC(last)AUC(last) 1.86 1.86 173.34 173.34 248.57 248.57 428.53 428.53
CmaxCmax 0.50 0.50 112.98 112.98 82.49 82.49 162.15 162.15
TmaxTmax 3.50 3.50 0.38 0.38 0.75 0.75 1.50 1.50
t1/2 t 1/2 NCNC 3.46 3.46 2.89 2.89 1.89 1.89
* AUC: ng·h/mL, Cmax: ng/mL, Tmax & t1/2: h* AUC: ng·h/mL, C max : ng/mL, T max & t 1/2 : h

Claims (14)

  1. 약물 또는 이의 약학적으로 허용되는 염과, 결정화 억제제 및 약물 방출 속도 제어용 고분자 중 1종 이상을 포함하는 제1 혼합부로 형성된 약물 포함층; 및A drug-containing layer formed of a first mixing portion including a drug or a pharmaceutically acceptable salt thereof, a crystallization inhibitor, and a polymer for controlling the drug release rate; and
    폴리(메타)크릴레이트가 중합된 고분자 중합체, 아크릴산이 중합된 고분자 중합체, 및 팽윤성 고분자 중 1종 이상을 포함하는 제2 혼합부로 형성된 부유층을 포함하는, 다층정 복합제제. A multilayer tablet composite formulation comprising 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.
  2. 청구항 1에 있어서,In claim 1,
    상기 폴리(메타)크릴레이트가 중합된 고분자 중합체, 아크릴산이 중합된 고분자 중합체 및 팽윤성 고분자에서 선택되는 1종 이상의 고분자 중합체는 탭 밀도(tap density)가 0.01g/mL 내지 1.0g/mL인 것인, 다층정 복합제제. At least one polymer selected from the group consisting of a polymer polymerized with poly(meth)acrylate, a polymer polymer polymerized with acrylic acid, and a swellable polymer has a tap density of 0.01 g/mL to 1.0 g/mL. , Multilayer tablet combination preparation.
  3. 청구항 1에 있어서, In claim 1,
    상기 제1 혼합부는 하기 화학식 1 내지 3 표시되는 화합물로 이루어진 군에서 선택되는 1종 이상의 화합물을 더 포함하는 것인, 다층정 복합제제. The first mixing part is a multi-layered tablet combination preparation further comprising at least one compound selected from the group consisting of compounds represented by the following formulas 1 to 3.
    [화학식 1][Formula 1]
    [(M2+ (10-x)M3+ x(OH)m)((An-)z)]yH2O[(M 2+ (10-x) M 3+ x (OH) m )((A n- ) z )]yH 2 O
    (상기 화학식 1에서, M2+은 Mg2+, Ni2+, Cu2+, Co2+ 및 Zn2+로 이루어진 군 중에서 선택된 2가 금속 양이온이며,(In Formula 1, M 2+ is a divalent metal cation selected from the group consisting of Mg 2+ , Ni 2+ , Cu 2+ , Co 2+ and Zn 2+ ,
    M3+는 Al3+, Fe3+, V3+, Ti3+ , Mn3+ 및 Ga3+로 이루어진 군 중에서 선택된 3가 금속 양이온이며, M 3+ is a trivalent metal cation selected from the group consisting of Al 3+ , Fe 3+ , V 3+ , Ti 3+ , Mn 3+ and Ga 3+ ,
    x는 0초과 10미만의 범위를 갖는 수이며, x is a number in the range between 0 and 10,
    m은 0초과 20이하의 범위를 갖는 수이며, m is a number ranging from 0 to 20,
    A는 CO3 2- , NO3 - , Br- , Cl- , SO4 2- , HPO4 2- 및 F- 로 이루어진 군에서 선택되는 음이온이며, 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- ,
    n은 음이온 A의 전하수이며, n is the charge of anion A,
    n은 0.5이상 5이하의 범위를 갖는 수이고, z는 0이상 5이하의 범위를 갖는 수이고,n is a number ranging from 0.5 to 5, z is a number ranging from 0 to 5,
    y는 0 또는 0 이상의 양수이다..)y is 0 or a positive number greater than 0.)
    [화학식 2][Formula 2]
    [(M2+(OH)2-x)((An-)z)]yH2O[(M 2+ (OH) 2-x )((A n- ) z )]yH 2 O
    (상기 화학식 2에서, (In Formula 2 above,
    M2+은 Mg2+, Ni2+, Cu2+, Co2+ 및 Zn2+로 이루어진 군 중에서 선택된 2가 금속 양이온이며, M 2+ is a divalent metal cation selected from the group consisting of Mg 2+ , Ni 2+ , Cu 2+ , Co 2+ and Zn 2+ ,
    x는 0이상 2미만의 범위를 갖는 수이며, x is a number ranging from 0 to 2,
    A는 CO3 2- , NO3 - , Br- , Cl- , SO4 2- , HPO4 2- 및 F- 로 이루어진 군에서 선택되는 음이온 이며,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- ,
    n은 음이온 A의 전하수이며, n은 0이상 2이하의 범위를 갖는 수이고, n is the charge number of anion A, n is a number ranging from 0 to 2,
    z는 0 이상 1이하의 범위를 갖는 수이고,z is a number ranging from 0 to 1,
    y는 0 또는 0 이상의 양수이다..)y is 0 or a positive number greater than 0.)
    [화학식 3][Formula 3]
    [(M2+(O)2-x)((An-)z)]yH2O[(M 2+ (O) 2-x )((A n- ) z )]yH 2 O
    (상기 화학식 3에서,(In Formula 3 above,
    M2+은 Mg2+, Ni2+, Cu2+ 또는 Zn2+이며, M 2+ is Mg 2+ , Ni 2+ , Cu 2+ or Zn 2+ ,
    x는 0이상 2 미만의 범위를 갖는 수이며, x is a number ranging from 0 to 2,
    A는 CO3 2- , NO3 - , Br-, Cl-, SO4 2- , HPO4 2- 또는 F-의 음이온이며, A is an anion of CO 3 2- , NO 3- , Br- , Cl- , SO 4 2- , HPO 4 2- or F- ,
    n은 음이온 A의 전하수이며, n은 0이상 2이하의 범위를 갖는 수이고, n is the charge number of anion A, n is a number ranging from 0 to 2,
    z는 0이상 1이하을 범위를 갖는 수이고, z is a number ranging from 0 to 1,
    y는 0 또는 0 이상의 양수이다..)y is 0 or a positive number greater than 0.)
  4. 청구항 3에 있어서, In claim 3,
    상기 화학식 1 내지 3으로 표시되는 화합물은 마그네슘 옥사이드, 하이드로탈사이트 및 마그네슘 하이드록사이드에서 선택되는 1종 이상인 것인, 다층정 복합제제.The compound represented by Formulas 1 to 3 is one or more selected from magnesium oxide, hydrotalcite, and magnesium hydroxide, a multilayer tablet combination preparation.
  5. 청구항 1에 있어서, In claim 1,
    상기 제1 혼합부 또는 제2 혼합부는 장용코팅제, 기포발생제 및 팽윤성 부형제 중 1 종이상의 화합물을 더 포함하는 것인, 다층정 복합제제.The first mixing part or the second mixing part further includes one or more compounds selected from the group consisting of an enteric coating agent, a foam generator, and a swelling excipient.
  6. 청구항 1에 있어서,In claim 1,
    상기 아크릴산이 중합된 고분자 중합체는 카보머 코폴리머 타입, 카보머 호모폴리머 타입 및 암모니오 메타크릴레이트 코폴리머 타입(AMMONIO METHACRYLATE COPOLYMER TYPE)에서 선택되는 1종 이상인 것인, 다층정 복합제제. The high molecular weight polymer obtained by polymerizing acrylic acid is at least one selected from the group consisting of carbomer copolymer type, carbomer homopolymer type, and ammonio methacrylate copolymer type (AMMONIO METHACRYLATE COPOLYMER TYPE), a multi-layered tablet combination preparation.
  7. 청구항 1에 있어서, In claim 1,
    상기 폴리(메타)크릴레이트가 중합된 고분자 중합체는 메타크릴레이트가 중합된 고분자 중합체, 에틸아크릴레이트가 중합된 고분자 중합체, 메타크릴레이트와 에틸아크릴레이트가 중합된 고분자 중합체, 에틸렌글라이콜이 중합된 고분자 중합체, 메타크릴엑시드와 메틸메타크릴레이트가 중합된 고분자 중합체, 에틸렌글라이콜이 중합된 고분자 중합체, 암모늄 메타크릴레이트가 중합된 고분자 중합체, 다이메틸아미노에틸과 메타크릴레이트-부틸 메타크릴레이트가 중합된 고분자 중합체에서 선택되는 1 종 이상인 것인, 다층정 복합제제.The polymer polymer in which poly(meth)acrylate is polymerized is 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 is polymerized. polymer polymer, polymer polymer polymerized with methacrylic acid and methyl methacrylate, polymer polymer polymerized with ethylene glycol, polymer polymer polymerized with ammonium methacrylate, dimethylaminoethyl and methacrylate-butyl methacrylate. A multi-layered tablet combination preparation, wherein the rate is one or more selected from polymerized polymers.
  8. 청구항 1에 있어서, In claim 1,
    상기 약물은 니클로사마이드(Niclosamide), 클로산텔(Closantel), 라폭사니드(rafoxanide), 옥시클로나자이드(oxyclozanide), 아테수네이트(Artesunate), 틸로론(Tilorone), 시클로스포린(Cyclosporine), 퍼헥실린 말레산염(perhexiline maleate), 로페라미드(loperamide), 메플로퀸(mefloquine), 아모디아퀸(amodiaquine), 프로스킬라리딘(proscillaridin), 페나조피리딘(phenazopyridine), 디기톡신(digitoxin), 펜플루디올(penfluridol), 클로미펜(clomiphene), 토레미펜(toremifene), 디곡신(digoxin), 헥사클로로펜(hexachlorophene), 히드록시프로게스테론(hydroxyprogesterone), 티오리다진(thioridazine), 살리노마이신(salinomycin), 퀸아크린(quinacrine), 엘트롬보팍(eltrombopag), 세파란틴(cepharanthine), 시클레소니드(ciclesonide), , 세리티닙(ceritinib(LDK378)), 디하이드로감보그산(dihydrogambogic acid), 오시머티닙(osimertinib(AZD-9291)), 이소포미페린(isopomiferin), 아니둘라펀진(anidulafungin(LY303366)), 오사진(osajin), 루스트롬보팍(lusutrombopag), 이소오사진(isoosajin), 길테리티닙(gilteritinib), 베르바민(berbamine), 에바스틴(ebastine), 테트란드린(tetrandrine), 아베마시클립(abemaciclib(USAN)), 이바카프토어(ivacaftor), 바제독시펜(bazedoxifene), 메퀴타진(mequitazine), 트리파라놀(triparanol), 드로록시펜(droloxifene), 드로네다론(dronedarone), 클로로퀸(chloroquine), 히드록시클로로퀸(hydroxychloroquine), 로피나비어(lopinavir), 파비피라비르(favipiravir), 아타자나비어(atazanavir), 덱사메타손(dexamethasone), 도세탁셀(Docetaxel), 파클리탁셀(Paclitaxel), 카바지탁셀(Cabazitaxel), 에토포시드(Etoposide), 토포테칸(Topotecan), 이다루비신(Idarubicin), 플루로우라실(Fluorouracil), 아비라테론(Abiraterone), 악시티닙(Axitinib), 보수티닙(Bosutinib), 카보잔티닙(Cabozantinib), 세리티닙(ceritinib), 다브라페닙(dabrafenib), 에를로티닙(erlotinib), 라파티닙(lapatinib), 미도스타우린(midostaurin), 네라티닙(neratinib), 닐로티닙(nilotinib), 닌테다닙(nintedanib), 파조파닙(pazopanib), 소니데집(sonidegib), 트라메티닙(trametinib), 아스코빅산(Ascorbic acid), vitamin A, 리포산(lipoic acid), 프라미펙솔(pramipexole), 알로푸리놀(allopurinol), 펜톡시필린(pentoxifylline), 멜라토닌(melatonin), 프로부콜(probucol), 쿼세틴(quercetin), 트랜스크로세티네이트 (transcrocetinate), 아세틸시스테인(acetylcysteine), 니카라벤(nicaraven), 로독사마이드(lodoxamide), 4-n-부틸레조르시놀(4-n-butylresorcinol), 토코페롤(tocopherol), 바쿠치올(bakuchiol), (+)-카테킨((+)-catechin), 커큐민(curcumin), 히드록시티로솔(hydroxytyrosol), 파이톨(phytol), 레조르시올(resorcinol), 카르타민(carthamine), 루테올린(luteolin), 코릴라진(corilagin), 레스베라트롤(resveratrol), 레티놀(retinol), 루틴(rutin), 히드로퀴논(hydroquinone), 아시아티코사이드(asiaticoside), 마데카소사이드(madecassoside), 진세노사이드(ginsenoside), 보르네올(borneol), 디오스메틴(diosmetin), 아스파라신(aspalathin), 유지놀(eugenol), 망고스틴(mangostin), 펠라르고니딘(pelargonidin), 시아니딘(cyaniding), 델피니딘(delphinidin), 피오니딘(peonidin), 페튜니딘(petunidin), 말비딘(malvidin), 루테인(lutein), 퀘르세틴(quercetin), 아데노신(adenosine), 팔미트산 아스코빌(ascorbyl palmitate), 아스코빌글루코사이드(ascorbyl glucoside), 피리독신(pyridoxine), 티아민(thiamine), 사포닌(saponin), 세코이졸라릭이레시놀(secoisolariciresinol), 마타이레시놀(matairesinol), 피노이레시놀(pinoresinol), 메드이레시놀(medioresinol), 라릭이레시놀 (lariciresinol), 시린가레시놀(syringaresinol), 알티제닌(artigenin), 엔테로락톤(enterolactone), 엔테로디올(enterodiol), 아라키돈산(arachidonic acid), 아비에트산(abietic acid), 아브시스산(abscisic acid), 알파리포산(α-lipoic acid), 아젤라익산(azelaic acid), 카페인산(caffeic acid), 히드록시벤조산(hydroxybenzoic acid), 프로토카테츄산(protocatechuic acid), 엘라그산(ellagic Acid), 페룰산(ferulic acid), 펄빅산(fulvic acid), 올레오놀산(oleanolic acid), 페놀산(phenolic acid), 히드록시신남산(hydroxycinnamic acid), 바닐릭산(vanillic Acid), 프로토카테츄산(protocatechuic acid), 살비아닉산(salvianic acid), 시냅픽 애시드(sinapic acid), 트라넥사민산(tranexamic acid), 발레르산(valeric acid), 베라트르산(Veratric Acid), 클로로겐산(chlorogenic acid), 아시아틱애시드(asiatic acid), 마데카식애시드(madecasic acid), 수베르산(suberic acid), 히알루론산(hyaluronic acid), 우르솔산(ursolic acid), 아스코브 산(ascorbic acid), 살비아논산 B(salvianolic acid B), 피리딘-3-카복시산(pyridine-3-carboxylic acid), 아스코빌팔미테이트(ascorbyl palmitate), 아스코빌글루코시드(ascorbyl glucoside), 카르니틴(carnitine), 판토텐산(pantothenic acid), 비오틴(biotin), 폴산(folic acid), 알리인(alliin), 글루타티온(glutathione), 세린(serine), 글리신(glycine), 알라닌(alanine), 아베난티라미드(avenanthramide), 트레오닌(threonine), 시스테인(cysteine), 발린(valine), 류신(leucine), 메티오닌(methionine), 프롤린(proline), 페닐알라닌(phenylalanine), 티로신(tyrosine), 트립토판(tryptophan), 아스파트산(aspartic acid), 글루탐산(glutamic acid), 아스파라긴(asparagine), 글루타민(glutamine), 히스티딘(histidine), 리신(lysine), 아르기닌(arginine), 데칸알(decanal), 레틴알데히드(retinaldehyde), 신남알데히드(cinnamaldehyde), 카테킨-알데히드(catechin-aldehyde), 코니페릴 알데히드(coniferyl aldehyde), 시링알데히드(syringaldehyde), 바닐린(vanillin), 이다라본(edaravone), 이데베논(idebenone), 코엔자임 큐10(coenzyme Q10), 유비퀴논(ubiquinone), 미토큐(mitoQ), 아스타잔틴(astaxanthin), 카페인(caffeine), 파라크산틴(paraxanthine), 테오필린(theophylline), 마타이레시놀(matairesinol), 파이시온(physcion), 프로파페논(propafenone), 쿠마린(coumarin), 제니스테인(genistein), 챨콘(chalcone), 나린제닌(naringenin), 베르제닌(bergenin), 아멘토플라본(amentoflavone), 비오카닌 A(Biochanin A), 리보플라빈(riboflavin), 세사민(Sesamin)등을 들 수 있다. 덱스트란 황산(dextran sulfate), 황산철(ferrous sulfate), 페룰릭 애시드-4-0-설페이트(ferulic acid-4-O-sulfate) 및 아스코빌 설페이트(ascorbyl sulfate)로 이루어진 군에서 선택되는 1종 이상인 것인, 다층정 복합제제.The drugs include Niclosamide, Closantel, rafoxanide, oxyclozanide, Artesunate, Tilorone, Cyclosporine, perhexiline maleate, loperamide, mefloquine, amodiaquine, proscillaridin, phenazopyridine, digitoxin, fen penfluridol, clomiphene, toremifene, digoxin, hexachlorophene, hydroxyprogesterone, thioridazine, salinomycin, Quinacrine, eltrombopag, cepharanthine, ciclesonide, ceritinib (LDK378), dihydrogambogic acid, Ossi osimertinib (AZD-9291), isopomiferin, anidulafungin (LY303366), osajin, lustrombopag, isosajin, Gilteri gilteritinib, berbamine, ebastine, tetradrine, abemaciclib (USAN), ivacaftor, bazedoxifene, mequi Mequitazine, triparanol, droloxifene, dronedarone, chloroquine, hydroxychloroquine, lopinavir, favipiravir ), atazanavir, dexamethasone, Docetaxel, Paclitaxel, Cabazitaxel, Etoposide, Topotecan, Idarubicin, Fluorouracil, Abiraterone, Axitinib, Bosutinib, Cabozantinib, ceritinib, dabrafenib, Erloti erlotinib, lapatinib, midostaurin, neratinib, nilotinib, nintedanib, pazopanib, sonidegib, trad Trametinib, Ascorbic acid, vitamin A, lipoic acid, pramipexole, allopurinol, pentoxifylline, melatonin, probucol (probucol), quercetin, transcrocetinate, acetylcysteine, nicaraven, lodoxamide, 4-n-butylresorcinol (4-n- butylresorcinol, tocopherol, bakuchiol, (+)-catechin, curcumin, hydroxytyrosol, phytol, resorciol (resorcinol), carthamine, luteolin, corilagin, resveratrol, retinol, rutin, hydroquinone, asiaticoside, Madecassoside, ginsenoside, borneol, diosmetin, aspalathin, eugenol, mangostin, pelargonidin ), cyanidin, delphinidin, peonidin, petunidin, malvidin, lutein, quercetin, adenosine, palmit Acid ascorbyl palmitate, ascorbyl glucoside, pyridoxine, thiamine, saponin, secoisolariciresinol, matairesinol, pinoyre Pinoresinol, medioresinol, lariciresinol, syringaresinol, artigenin, enterolactone, enterodiol, arachidonic acid ( arachidonic acid, abietic acid, abscisic acid, α-lipoic acid, azelaic acid, caffeic acid, hydroxybenzoic acid , protocatechuic acid, ellagic acid, ferulic acid, fulvic acid, oleanolic acid, phenolic acid, hydroxycinnamic acid ( hydroxycinnamic acid, vanillic 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. acid), ascorbic acid, salvianolic acid B, pyridine-3-carboxylic acid, ascorbyl palmitate, ascorbyl glucoside ( 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, glutamic acid, asparagine, glutamine, histidine, lysine, arginine, decanal, Retinaldehyde, cinnamaldehyde, catechin-aldehyde, coniferyl aldehyde, syringaldehyde, vanillin, edaravone, idebenone ), coenzyme Q10, ubiquinone, mitoQ, astaxanthin, caffeine, paraxanthine, theophylline, matairesinol ( matairesinol, physcion, propafenone, coumarin, genistein, chalcone, naringenin, bergenin, amentoflavone, Examples include Biochanin A, riboflavin, and Sesamin. One selected from the group consisting of dextran sulfate, ferrous sulfate, ferulic acid-4-O-sulfate and ascorbyl sulfate The above is a multilayer tablet combination preparation.
  9. 청구항 1에 있어서, In claim 1,
    상기 약물은 할로겐화된 살리실 아닐리드계 화합물 및 탁센 계 화합물로 이루어진 군에서 선택 되는 1종 이상인 것인, 다층정 복합제제. The drug is a multilayer tablet combination preparation, wherein the drug is at least one selected from the group consisting of halogenated salicylanilide-based compounds and taxane-based compounds.
  10. 청구항 9에 있어서, In claim 9,
    상기 할로겐화된 살리실 아닐리드계는 니클로사마이드(niclosamide), 클로산텔, 라폭사니드 및 옥시클로자니드에서 선택되는 1종 이상이며, The halogenated salicylanilide group is at least one selected from niclosamide, closantel, rapoxanide, and oxyclozanide,
    상기 탁센 계는 도세탁셀(docetaxel), 파클리탁셀(paclitaxel) 및 카바지탁셀(Cabazitaxel)에서 선택 되는 1종 이상인 것인, 다층정 복합제제. A multilayer tablet combination preparation, wherein the taxane series is one or more types selected from docetaxel, paclitaxel, and cabazitaxel.
  11. 청구항 1에 있어서, In claim 1,
    상기 다층정 복합제제는 상기 약물 포함층 및 부유층 사이에 중간층을 더 포함하는 것인, 다층정 복합제제. The multilayer tablet combination preparation further includes an intermediate layer between the drug-containing layer and the floating layer.
  12. 청구항 1에 있어서, In claim 1,
    상기 결정화 억제제는 폴리비닐 피롤리돈계 화합물, 폴록사머계 화합물, 셀룰로오스계 화합물, 폴리에틸렌 글라이콜계 화합물, 폴리옥시에틸렌 소르비탄 지방산 에스터계((polyoxyethylene sorbitan fatty acid esters) 화합물, 레시틴계(lecithin) 화합물, 지방산계 화합물, 글리세롤 지방산 에스터계(glycerol fatty acid esters) 화합물, 소르비탄 지방산 에스터계(sorbitan fatty acid esters)화합물, 오일류, 소디엄 도데실 설페이트(sodium dodecyl sulfate), 소디엄 스테아릴 퓨마레이트(sodium stearyl fumarate), 스테아릴산(stearic acid), 라이릴산(lauric acid) 및 카라기난(carrageenan)에서 선택되는 1종 이상인 것인, 다층정 복합제제. The crystallization inhibitors include polyvinyl pyrrolidone-based compounds, poloxamer-based compounds, cellulose-based compounds, polyethylene glycol-based compounds, polyoxyethylene sorbitan fatty acid esters compounds, and lecithin compounds. , fatty acid compounds, glycerol fatty acid esters compounds, sorbitan fatty acid esters compounds, oils, sodium dodecyl sulfate, sodium stearyl fumarate ( A multi-layered tablet combination preparation comprising at least one selected from sodium stearyl fumarate, stearic acid, lauric acid, and carrageenan.
  13. 청구항 1에 있어서, In claim 1,
    상기 약물 방출 속도 제어용 고분자는 카복시메틸셀룰로오즈칼슘, 카복시메틸셀룰로오즈나트륨, 메틸셀룰로오즈, 에틸셀룰로오즈, 폴리에틸렌옥사이드, 루코스트빈검, 구아검, 크산탄검(Xanthan gum), 아카시아검, 트라가칸트검(Tragacanth gum), 알긴산, 알긴산나트륨, 알긴산칼슘, 알긴산암모늄, 아가(Agar), 젤라틴, 폴리메타메틸아크릴레이트, 폴리카르보필, 폴리비닐아세테이트, 폴리비닐피롤리돈-폴리비닐아크릴레이트 공중합제, 폴리비닐알콜-폴리에틸렌글리콜 공중합제, 폴리비닐피롤리돈-폴리비닐아세테이트 공중합체, 벤토나이트, 헥토라이트, 카라기난(Carrageenan), 세라토니아(Ceratonia), 세토스테아릴알콜(Cetostearyl alcohol), 하이드록시프로필전분, 마그네슘 알루미늄 실리케이트, 폴리덱스트로오즈, 폴리(메틸비닐에테르/말레익안하이드로스), 프로필렌글리콜알지네이트 및 사포네이트에서 선택 되는 1종 이상인 것인, 다층정 복합제제. The polymer for controlling the drug release rate includes calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, ethyl cellulose, polyethylene oxide, leucostean gum, guar gum, xanthan gum, acacia gum, and tragacanth gum. gum), alginic acid, sodium alginate, calcium alginate, ammonium alginate, agar, gelatin, polymethmethyl acrylate, polycarbophil, polyvinyl acetate, polyvinylpyrrolidone-polyvinyl acrylate copolymer, polyvinyl Alcohol-polyethylene glycol copolymer, polyvinylpyrrolidone-polyvinylacetate copolymer, bentonite, hectorite, Carrageenan, Ceratonia, Cetostearyl alcohol, hydroxypropyl starch, magnesium A multilayer tablet composite preparation comprising at least one selected from aluminum silicate, polydextrose, poly(methyl vinyl ether/maleic anhydrose), propylene glycol alginate, and saponate.
  14. 유기용매에 결정화 억제제 및 약물을 용해시켜 제1 용해물을 제조하는 단계; 상기 제1 용해물을 건조하여 제1 용해물의 파우더를 제조하는 단계; 상기 제1 용해물의 파우더를 이용하여 약물 포함층을 형성하는 단계; 및 상기 약물 포함층에 폴리(메타)크릴레이트가 중합된 고분자 중합체, 아크릴산이 중합된 고분자 중합체 및 팽윤성 고분자 중 1종 이상을 포함하는 제2 혼합부를 타정하여 부유층을 형성하는 단계를 포함하는, 다층정 복합제제의 제조 방법. Preparing a first dissolved product by dissolving a crystallization inhibitor and a drug in an organic solvent; 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 forming a floating layer by compressing a second mixed portion containing at least one of a polymer polymer polymerized with poly(meth)acrylate, a polymer polymer polymerized with acrylic acid, and a swellable polymer in the drug-containing layer, thereby forming a floating layer. Method for manufacturing tablet combination preparation.
PCT/KR2023/003605 2022-03-21 2023-03-17 Multi-layered tablet composite formulation and preparation method therefor WO2023182736A1 (en)

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KR100869330B1 (en) * 2007-06-13 2008-11-18 조선대학교산학협력단 Anticancer activity enhancer containing trimethoxyflavone as an effective ingredient
KR20130025459A (en) * 2011-08-31 2013-03-12 부산대학교 산학협력단 Sustained release multilayer tablet
KR20130115257A (en) * 2010-09-30 2013-10-21 시오노기세이야쿠가부시키가이샤 Preparation for improving sollubility of poorly soluble drug
KR20130120118A (en) * 2012-04-25 2013-11-04 (주)비씨월드제약 Gastroretentive sustained release formulation with bilayer structure
KR20180114515A (en) * 2017-04-10 2018-10-18 성균관대학교산학협력단 Sustained ralease preparation comprising porous gastric retentive layer and method for producing thereof
KR20210105761A (en) * 2020-02-19 2021-08-27 한국프라임제약주식회사 A sustained release dosage form comprising choline alphoscerate as an active ingredient

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KR100869330B1 (en) * 2007-06-13 2008-11-18 조선대학교산학협력단 Anticancer activity enhancer containing trimethoxyflavone as an effective ingredient
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