WO2018124497A1 - Pharmaceutical composite preparation containing dapagliflozin l-proline and antidiabetic agent - Google Patents

Pharmaceutical composite preparation containing dapagliflozin l-proline and antidiabetic agent Download PDF

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WO2018124497A1
WO2018124497A1 PCT/KR2017/013690 KR2017013690W WO2018124497A1 WO 2018124497 A1 WO2018124497 A1 WO 2018124497A1 KR 2017013690 W KR2017013690 W KR 2017013690W WO 2018124497 A1 WO2018124497 A1 WO 2018124497A1
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dapagliflozin
proline
pharmaceutical
formulation
pharmaceutically acceptable
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PCT/KR2017/013690
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French (fr)
Korean (ko)
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권세호
탁진욱
김진철
김용일
박재현
우종수
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한미약품 주식회사
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer

Definitions

  • the present invention is directed to a pharmaceutical combination formulation comprising dapagliflozin L-proline and one or more antidiabetic agents.
  • the present invention provides a pharmaceutical complex preparation further comprising metformin and / or DPP-IV inhibitor in dapagliflozin L-proline, and has a high bioavailability in combination with excellent content uniformity and dissolution properties. will be.
  • Diabetes is one of the leading causes of adult death worldwide, and the number of diabetic patients is increasing rapidly with the increase in the obese population, characterized by hyperglycemia due to excessive glucose production and peripheral insulin resistance.
  • Plasma glucose is usually filtered in the renal glomeruli and actively resorbed in the proximal tubule.
  • SGLT-2 is believed to be the major transporter involved in the resorption of glucose at this site.
  • SGLT-2 sodium-glucose linked transporter 2
  • Dapagliflozin (2S, 3R, 4R, 5S, 6R) -2- [4-chloro-3- (4-ethoxybenzyl) phenyl] -6- (hydr, one of the SGLT-2 inhibitors Oxymethyl) tetrahydro-2H-pyran-3,4,5-triol) is a compound of Formula 1, and is disclosed in US Pat. No. 6,515,117.
  • Korean Patent No. 1493102 discloses (S) -propylene glycol (PG), (R) -PG, EtOH, ethylene glycol (EG), 1: 2 L-proline, 1: 1 L-proline, 1: 1 Crystal structures of dapagliflozin, including L-proline hemihydrate, and 1: 1 L-phenylalanine, are disclosed.
  • Diabetes is a chronic disease, and its condition is complicated, so the symptoms of the disease often progress with various complications. Therefore, it is necessary to select the most appropriate drug at the time of the individual patient, and when the individual drugs are used alone, sufficient effects may not be obtained depending on the symptoms. Due to various problems such as the appearance of side effects, the choice is often difficult in the clinical field. Therefore, in connection with the preparation for the treatment of diabetes mellitus, diabetes-related diseases and diabetic complications, a method of concurrently administering two or more drugs with different mechanisms has been proposed, rather than one drug alone. However, when manufacturing a combination formulation of two or more drugs, it is necessary to consider various factors such as the interaction of two or more drugs, the dissolution rate of individual drugs, and the content uniformity, which is why the preparation of the combination formulation is not easy. .
  • the present inventors seek to improve the patient's medication compliance by providing a combination formulation of dapagliflozin L-proline and an anti-diabetic agent, and to improve the effects through the administration of a combination formulation with various mechanisms and to reduce side effects.
  • the present invention provides a complex formulation further comprising metformin and / or DPP-IV inhibitor in dapagliflozin L-proline, and the present inventors have excellent dissolution rate and content uniformity to provide optimal bioavailability.
  • the present invention has been completed.
  • An object of the present invention is to provide a formulation that minimizes side effects while increasing medication compliance and increasing the effect of the patient by providing a complex formulation of therapeutic agents for diabetes with a variety of mechanisms of action. In addition, it increases the bioavailability by improving the dissolution properties and content uniformity of the individual active ingredients in the complex formulation.
  • the present invention provides a pharmaceutical combination formulation comprising dapagliflozin L-proline, and one or more antidiabetic agents.
  • Dapagliflozin L-proline may comprise 5-20 mg as dapagliflozin.
  • the antidiabetic agent is an alpha-glucosidase inhibitor, a biguanide drug, an insulin secretagogue, an insulin sensitizer, a cannabinoid receptor-1 antagonist 1 antagonist), DPP-IV inhibitor, and the like.
  • the antidiabetic agent may be metformin or a pharmaceutically acceptable salt thereof, wherein dapagliflozin L-proline is 0.1% by weight to 10% relative to metformin and its pharmaceutically acceptable salts as dapagliflozin It may be included in weight percent.
  • the antidiabetic agent may be a DPP-IV inhibitor or a pharmaceutically acceptable salt thereof, wherein dapagliflozin L-proline is dapagliflozin as the DPP-IV inhibitor and a pharmaceutically acceptable salt thereof. It may be included in 5 to 1,000% by weight relative to.
  • the DPP-IV inhibitor may be selected from the group consisting of cytagliptin, chanagliptin, saxagliptin, linagliptin, anagliptin, allogliptin and gemigliptin.
  • the pharmaceutical combination formulations provided herein may comprise a first granule comprising one or more antidiabetic agents, and dapagliflozin L-proline.
  • the first granules may comprise one or more polymers.
  • Polymers include hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), low-substituted hydroxypropyl cellulose (HPC-L), tablet shellac, methacrylate polymer, acrylate copolymer, natural gum, Guar gum, tragacanta, acacia gum, locust bean gum, xanthan gum and the like can be used, and preferably HPMC 2208, HPMC 2910, HPC-L or locust bean gum can be used, but is not limited thereto.
  • the pharmaceutical combination formulation provided in the present invention comprises a first granule comprising one or more antidiabetic agents, and a core layer comprising one or more glidants and / or dapagliflozin L-proline; And it may include a coating layer for coating the core layer.
  • the coating layer weight may be 1 to 20% by weight with respect to the core layer weight.
  • silicon dioxide magnesium salt of stearic acid, zinc salt, magnesium aluminum silicate, talc and the like may be used, and preferably silicon dioxide or magnesium stearate may be used, but is not limited thereto.
  • the first granules may comprise one or more polymers.
  • the coating layer is dapagliflozin L-proline, metformin, citagliptin, bilagliptin, saxagliptin, linagliptin, anagliptin, allogliptin, gemigliptin and pharmaceutically acceptable salts thereof It may include one or more active ingredients selected from the group consisting of.
  • oral dosage form may be a tablet or capsule.
  • the pharmaceutical complex preparation comprising dapagliflozin L-proline and an antidiabetic agent according to the present invention has a very good content uniformity and dissolution rate, and thus has an excellent absorption rate in vivo, thus leading to diabetes, diabetes-related diseases and diabetic complications. It can be used as a prophylactic or therapeutic agent.
  • Figure 1 shows the results of the content uniformity test of dapagliflozin L-proline in Examples 1 to 3.
  • Figure 2 shows the results of the content uniformity test of dapagliflozin L-proline in Examples 4 to 7.
  • FIG 3 shows the results of the content uniformity test of dapagliflozin L-proline in Examples 8 to 11.
  • Figure 4 shows the results of the content uniformity test of dapagliflozin L-proline in Examples 12 to 15.
  • Figure 5 shows the metformin dissolution rate test results in Examples 1-3.
  • Figure 6 shows the metformin dissolution rate test results in Examples 8-11.
  • Figure 7 shows the metformin dissolution rate test results in Examples 12 to 15.
  • Dapagliflozin L-proline an SGLT-2 inhibitor for the prevention or treatment of diabetes mellitus, diabetes-related diseases and diabetic complications, improves insulin sensitivity and improves diabetes sensitivity by increasing glucose excretion in urine without significant gastrointestinal side effects. By delaying the plasma glucose can be normalized.
  • Dapagliflozin L-proline that can be used in the present invention is a crystalline complex of formula (2).
  • the dapagliflozin L-proline of the present invention may be a 1: 2 crystalline complex.
  • Metformin is a biguanide antihyperglycemic agent used to treat insulin-independent diabetes mellitus (type II, non-insulin dependent diabetes mellitus, NIDDM). Metformin increases sensitivity to insulin in peripheral tissues, inhibits the absorption of sugar in the gastrointestinal tract, and reduces blood sugar production in the liver. Metformin does not promote the secretion of insulin, reduces the amount of insulin in the blood, and also protects blood vessels. It is also suitable for use in patients with obesity or hyperlipidemia, or for those whose dietary control is difficult to control because it reduces body fat and does not cause hypoglycemia.
  • the pharmaceutically acceptable salt of metformin usable in the present invention may be selected from the group consisting of hydrochloride, succinate, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate, but is not limited thereto.
  • DPP-IV inhibitors serve to cleave GLP-1, which stimulates glucose-dependent insulin secretion from pancreatic ⁇ -cells and increases the pancreatic ⁇ -cell population.
  • the DPP-VI inhibitor usable in the present invention is in the group consisting of cytagliptin, bilagliptin, saxagliptin, linagliptin, anagliptin, allogliptin, gemigliptin and pharmaceutically acceptable salts thereof It may be selected, but is not limited thereto.
  • Examples of pharmaceutically acceptable salts of DPP-VI inhibitors include salts with alkali metals (eg, lithium, sodium and potassium); Salts with alkaline earth metals (eg calcium and magnesium); Salts with zinc or aluminum; Organic bases (eg ammonia, choline, diethanolamine, lysine, ethylenediamine, t-butylamine, t-octylamine, tris (hydroxymethyl) aminomethane, N-methyl-glucosamine, triethanolamine and dehydro Salts with abiethylamine); Salts with inorganic acids (eg, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid); Salts with organic acids (eg, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulf
  • Dapagliflozin L-proline in the pharmaceutical combination formulation of the present invention may be included as 5 to 20 mg as dapagliflozin.
  • Dapagliflozin L-proline is dapagliflozin, and may be included in an amount of 0.1% to 10% by weight relative to metformin and its pharmaceutically acceptable salts.
  • dapagliflozin L-proline is dapagliflozin, and may be included in the amount of 5% to 1,000% by weight, preferably 5% to It may be included in 500% by weight.
  • the pharmaceutical complex preparations of the present invention may be prepared by adding conventional pharmaceutically acceptable carriers, excipients, binders, disintegrants, and the like, and include conventional formulations such as tablets, capsules, beads, beadlets, granules, It may be formulated as a preparation for oral administration such as pills, troches, solutions, suspensions, or parenteral administration.
  • Excipients that may be added to the present invention include, but are not limited to, lactose, starch, cellulose, dextrin, microcrystalline cellulose, potassium dihydrogen phosphate, calcium carbonate, sugars, and the like.
  • the binder may be, but is not limited to, polyvinylpyrrolidone derivatives such as povidone and copovidone, methylcellulose, ethylcellulose, cellulose derivatives such as carboxymethylcellulose sodium, starch, gelatin, and the like.
  • Disintegrants include crospovidone, pregelatinized starch, corn starch, methylcellulose, hydroxypropylmethylcellulose, sodium starch glyconate, croscarmellose sodium, low-substituted hydroxypropylcellulose, sodium starch glycolate, starch, starch Gelatinized starch, alginic acid or its sodium salt, and the like, but is not limited thereto.
  • the pharmaceutical formulation of the present invention may further include a pH adjusting agent, suspending agent, preservative, flavoring agent, colorant, sweetener, adsorbent and the like as necessary.
  • a pH adjusting agent suspending agent, preservative, flavoring agent, colorant, sweetener, adsorbent and the like.
  • the content of such additives is not particularly limited in the present invention and may be appropriately adjusted as necessary.
  • the tablet is prepared by combining the purified water in metformin or a pharmaceutically acceptable salt thereof, and then preparing the first granules; Preparing final granules by mixing dapagliflozin L-proline and a pharmaceutically acceptable additive with the prepared first granules; And tableting the final granules with tablets.
  • the tablet is prepared by mixing the DPP-IV inhibitor and the pharmaceutically acceptable additive to prepare a first granule; Preparing final granules by mixing dapagliflozin L-proline and a pharmaceutically acceptable additive with the prepared first granules; And tableting the final granules with tablets.
  • the pharmaceutical formulation of the present invention is a composite tablet
  • the pharmaceutical formulation of the present invention is a composite tablet, metformin or a pharmaceutically acceptable salt thereof, and put into purified water to the DPP-IV inhibitor, then sizing and preparing the first granules; Preparing a final granule by mixing a lubricant and a pharmaceutically acceptable additive with the prepared first granules; Tableting the final granules into tablets; And it can be prepared by the step of coating with a coating solution containing dapagliflozin L-proline in the compressed tablet.
  • the pharmaceutical formulation of the present invention is a composite tablet
  • the granules may be prepared by conventional wet granulation or dry granulation methods known in the art.
  • the tablet may be prepared by a direct tableting method, and may be tableted using a tableting machine, which is commonly used for tableting, for example, a rotary tableting machine.
  • metformin hydrochloride was mixed with HPMC2208, HPMC2910, and locust bean gum, combined with purified water, and then granulated in a 20 mesh sieve to prepare primary granules.
  • Dapagliflozin L-proline, microcrystalline cellulose, silicon dioxide, crospovidone, and magnesium stearate were added to the prepared primary granules and mixed to prepare final granules.
  • the final granules were compressed using a rotary tablet press (GRC-18, Sejong Machinery, Korea) to contain 15.6 mg (10 mg as dapagliflozin) as dapagliflozin L-proline in one tablet.
  • GRC-18 Sejong Machinery, Korea
  • a composite tablet containing pagliflozin L-proline was prepared.
  • Example 1 Example 2
  • Example 3 Wet granules Metformin hydrochloride 250 500 1000 HPMC 2208 67.5 135 270 HPMC 2910 2 4 8 Locust Bean Sword 10 20 40 mix Dapagliflozin L-Proline 15.6 15.6 15.6 Microtubule cellulose 25 50 100 Silicon dioxide 8 8 8 Crospovidone 5 10 20
  • Magnesium stearate 4 8 16 Total weight 387.1 750.6 1477.6 % Weight of dapagliflozin to metformin hydrochloride 4 % 2 % One %
  • citagliptin or linagliptin is mixed with microcrystalline cellulose, lactose and HPC-L, and then compacted using a roller compactor (TF-1-A60, Freund vector, USA) and sieved through a 20 mesh sieve. Primary dry granules were prepared.
  • Dapagliflozin L-proline, microcrystalline cellulose, lactose, crospovidone and magnesium stearate were added to the prepared primary granules and mixed to prepare final granules.
  • the final granules were compressed using a rotary tablet press (GRC-18, Sejong Machinery, Korea) to contain 15.6 mg (10 mg as dapagliflozin) as dapagliflozin L-proline in one tablet.
  • GRC-18 Sejong Machinery, Korea
  • a composite tablet containing pagliflozin L-proline was prepared.
  • Example 4 Example 5
  • Example 6 Example 7 Dry granules Cytagliptin 50 100 - - Linagliptin - - 5 10
  • Microtubule cellulose 80 160 80 160 Lactose 25 50 25 50 HPC-L 5 10
  • 10 mix Dapagliflozin L-Proline 15.6 15.6 15.6 Lactose 20
  • 20 40 Microcrystalline cellulose 10
  • Crospovidone 10 20
  • Magnesium stearate 3 6 3 6 Total weight 218.6 421.6 173.6 331.6 Dapagliflozin Weight (%) for DPP-IV Inhibitor 20% 10% 200% 100%
  • metformin hydrochloride was mixed with HPMC2208, HPMC2910, and locust bean gum, combined with purified water, and then granulated in a 20 mesh sieve to prepare primary granules.
  • the final granules were prepared by adding and mixing silicon dioxide and magnesium stearate to the prepared primary granules.
  • the final granules were compressed using a rotary tablet press (GRC-18, Sejong Machinery, Korea).
  • the tablets containing dapagliflozin L-proline and Kollicaot IR, PVP (K-30) and PEG 6000 is mixed with a coating solution (SFC-30F, Sejong Pharmatech, Korea), Combination tablets containing 15.6 mg of dapagliflozin L-proline (10 mg as dapagliflozin) were prepared.
  • Example 8 Example 9
  • Example 10 Example 11 Wet granules Metformin hydrochloride 500 500 1000 1000 HPMC 2208 135 135 270 270 HPMC 2910 4 4 8 8 Locust Bean Sword 20 20 40 40 mix Silicon dioxide 7 7 14 14 14 Magnesium stearate 15 15 30 30 Core weight 681 681 1362 1362 Drug coating part Dapagliflozin L-Proline 15.6 15.6 15.6 15.6 Kollicoat IR 80 10 20 5 PVP (K-30) 4 2 4 2 PEG 6000 8 4 8 4 Coating weight 107.6 31.6 47.6 26.6 Total weight 788.6 712.6 1409.6 1388.6 Coating weight to core weight (%) 15.8% 4.6% 3.5% 2.0%
  • Metformin hydrochloride was mixed with cytagliptin, HPMC2208, HPMC2910, and locust bean gum, combined with purified water, and then granulated in a 20 mesh sieve to prepare primary granules.
  • the final granules were prepared by adding and mixing silicon dioxide and magnesium stearate to the prepared primary granules.
  • the final granules were compressed using a rotary tablet press (GRC-18, Sejong Machinery, Korea).
  • Example 12 Wet granules Metformin hydrochloride 500 1000 Cytagliptin 50 100 HPMC 2208 135 270 HPMC 2910 4 8 Locust Bean Sword 20 40 mix Silicon dioxide 7 14 Magnesium stearate 15 30 Core weight 731 1462 Drug coating part Dapagliflozin L-Proline 15.6 15.6 Kollicoat IR 10 20 PVP (K-30) 2 4 PEG 6000 4 8 Coating weight 31.6 47.6 Total weight 762.6 1509.6 Dapagliflozin Weight (%) to Metformin Hydrochloride 2 % One % Dapagliflozin Weight (%) with respect to cytagliptin 20% 10% Coating weight (%) relative to core weight 4.3% 3.3%
  • metformin hydrochloride was mixed with HPMC2208, HPMC2910, and locust bean gum, combined with purified water, and then granulated in a 20 mesh sieve to prepare primary granules.
  • Dapagliflozin L-proline and microcrystalline cellulose, silicon dioxide, crospovidone and magnesium stearate were added to the prepared primary granules and mixed to prepare final granules.
  • the final granules were compressed using a rotary tablet press (GRC-18, Sejong Machinery, Korea).
  • the tableted tablet containing linagliptin and coated with Kollicoat IR, PVP (K-30) and PEG 6000 were coated using a coating machine (SFC-30F, Sejong Pharmatech, Korea), dapagliflozin A combination tablet containing 15.6 mg (10 mg as dapagliflozin) of L-proline was prepared.
  • Example 14 Example 15 Wet granules Metformin hydrochloride 500 1000 HPMC 2208 135 270 HPMC 2910 4 8 Locust Bean Sword 20 40 mix Dapagliflozin L-Proline 15.6 15.6 Microtubule cellulose 50 100 Silicon dioxide 8 8 Crospovidone 10 20 Magnesium stearate 8 16 Tablet weight 750.6 1477.6 Drug coating part Linagliptin 10 10 Kollicoat IR 10 20 PVP (K-30) 2 4 PEG 6000 4 8 Coating weight 26 42 Total weight 776.6 1519.6
  • Example 1 Example 2
  • Example 3 Average(%) 99.4 100.3 98.9 Deviation 1.0 0.5 0.3 Judgment 2.4 1.3 0.8 fitness fitness fitness
  • Example 4 Example 5
  • Example 6 Example 7 Average(%) 99.4 98.9 100.1 100.4 Deviation 0.5 0.4 0.8 0.8 Judgment 1.2 0.9 1.8 1.8 fitness fitness fitness fitness
  • Example 8 Example 9 Example 10 Example 11 Average(%) 100.3 100.1 99.8 99.5 Deviation 0.3 0.6 0.6 0.8 Judgment 0.8 1.4 1.5 1.8 fitness fitness fitness fitness
  • Example 12 Example 13
  • Example 14 Example 15 Average(%) 101.3 100.4 100.4 100.8 Deviation 0.3 0.5 0.4 0.3 Judgment 0.8 1.2 1.0 0.8 fitness fitness fitness fitness
  • Example 2 Example 3 0 0 0 0 0.5 9 10 10 One 19 20 19 2 37 39 36 3 49 51 47 4 61 64 60 6 70 69 65
  • Example 11 Example 11 0 0 0 0 0 0.5 4 10 14 16 One 7 18 23 27 2 13 35 41 44 3 17 48 52 56 4 22 58 61 65 6 30 67 70 78
  • Example 12 Example 13
  • Example 14 Example 15 0 0 0 0 0 0.5 8 9 6 8 One 17 21 18 21 2 37 37 39 41 3 49 53 50 51 4 61 64 62 62 6 70 69 67 69

Abstract

The present invention relates to a pharmaceutical composite preparation containing dapagliflozin L-proline and at least one antidiabetic agent. Specifically, the present invention provides a pharmaceutical composite preparation containing dapagliflozin L-proline and additionally, metformin and/or a DPP-IV inhibitor, and relates to a composite preparation having excellent content uniformity and elution properties and high bioavailability.

Description

다파글리플로진 L-프롤린과 항당뇨병제를 포함하는 약제학적 복합 제제Pharmaceutical combination formulation comprising dapagliflozin L-proline and antidiabetic agents
본 발명은 다파글리플로진 L-프롤린과 하나 이상의 항당뇨병제를 포함하는 약제학적 복합 제제에 대한 것이다. 구체적으로, 다파글리플로진 L-프롤린에 메트포르민 및/또는 DPP-IV 억제제를 추가로 포함하는 약제학적 복합 제제를 제공하며, 우수한 함량균일성 및 용출특성을 가지며 생체이용율이 높은 복합 제제에 관한 것이다.The present invention is directed to a pharmaceutical combination formulation comprising dapagliflozin L-proline and one or more antidiabetic agents. Specifically, the present invention provides a pharmaceutical complex preparation further comprising metformin and / or DPP-IV inhibitor in dapagliflozin L-proline, and has a high bioavailability in combination with excellent content uniformity and dissolution properties. will be.
전 세계적으로 당뇨병은 성인 사망의 중요한 원인의 하나가 되고 있고, 비만 인구의 증가에 따라 당뇨환자의 수도 급격하게 늘어나고 있으며, 이는 과도한 글루코스 생성 및 말초 인슐린 저항성으로 인한 과혈당증을 특징으로 한다. 혈장 글루코스는 통상적으로 신장 사구체에서 여과되고, 근위 세관에서 능동적으로 재흡수된다. SGLT-2는 이 부위에서 글루코스의 재흡수에 관여하는 주요 수송자로 판단된다.Diabetes is one of the leading causes of adult death worldwide, and the number of diabetic patients is increasing rapidly with the increase in the obese population, characterized by hyperglycemia due to excessive glucose production and peripheral insulin resistance. Plasma glucose is usually filtered in the renal glomeruli and actively resorbed in the proximal tubule. SGLT-2 is believed to be the major transporter involved in the resorption of glucose at this site.
따라서 당뇨병 환자에서 SGLT-2(Sodium-Glucose linked transporter 2)의 선택적 억제는 유의한 위장 부작용 없이 소변 중의 글루코스 배출을 증대시켜서 인슐린 민감성을 개선시키고 당뇨병 합병증의 발병을 지연시킴으로써 혈장 글루코스를 정상화시킬 수 있다. 이에, SGLT-2 억제제는 당뇨병, 당뇨병 관련 질환 및 당뇨병성 합병증의 예방 또는 치료제로 주목 받고 있다.Thus, selective suppression of sodium-glucose linked transporter 2 (SGLT-2) in diabetics can normalize plasma glucose by increasing glucose excretion in urine without significant gastrointestinal side effects, thereby improving insulin sensitivity and delaying the onset of diabetic complications. . Therefore, SGLT-2 inhibitors are attracting attention as a prophylactic or therapeutic agent for diabetes, diabetes-related diseases and diabetic complications.
SGLT-2 억제제 중 하나인 다파글리플로진(Dapagliflozin, (2S,3R,4R,5S,6R)-2-[4-클로로-3-(4-에톡시벤질)페닐]-6-(히드록시메틸)테트라히드로-2H-피란-3,4,5-트리올)은 하기 화학식 1의 화합물로서, 미국특허 제6,515,117 호에 개시되어 있다.Dapagliflozin, (2S, 3R, 4R, 5S, 6R) -2- [4-chloro-3- (4-ethoxybenzyl) phenyl] -6- (hydr, one of the SGLT-2 inhibitors Oxymethyl) tetrahydro-2H-pyran-3,4,5-triol) is a compound of Formula 1, and is disclosed in US Pat. No. 6,515,117.
[화학식 1][Formula 1]
Figure PCTKR2017013690-appb-I000001
Figure PCTKR2017013690-appb-I000001
또한, 대한민국 등록특허 제1493102호에는 (S)-프로필렌 글리콜(PG), (R)-PG, EtOH, 에틸렌 글리콜(EG), 1:2 L-프롤린, 1:1 L-프롤린, 1:1 L-프롤린 반수화물, 및 1:1 L-페닐알라닌을 포함하는 다파글리플로진의 결정 구조물들이 개시되어 있다.In addition, Korean Patent No. 1493102 discloses (S) -propylene glycol (PG), (R) -PG, EtOH, ethylene glycol (EG), 1: 2 L-proline, 1: 1 L-proline, 1: 1 Crystal structures of dapagliflozin, including L-proline hemihydrate, and 1: 1 L-phenylalanine, are disclosed.
당뇨병은 만성질환으로서 그 병태가 복잡하기 때문에, 병의 증상이 다종의 합병증을 동반하면서 진행되는 경우가 많다. 따라서 개개의 환자의 그때의 병상에 가장 적합한 약제를 선택할 필요가 있으며, 개개의 약제를 단독으로 사용하는 경우 증상에 따라 충분한 효과가 얻어지지 않는 경우도 있고, 또한 투여량의 증대나 투여의 장기화에 따른 부작용의 발현 등 여러 가지 문제로 인해 임상 현장에서는 그 선택이 곤란한 경우가 많다. 따라서 당뇨병, 당뇨병 관련 질환 및 당뇨병성 합병증의 치료용 제제와 관련하여 한가지 약물을 단독으로 투여하기 보다는 상이한 기전을 가진 2 이상의 약물을 병용 투여하는 방안이 제시되고 있다. 그러나, 2 이상의 약물을 혼합한 복합 제제를 제조할 때, 2 이상의 약물의 상호작용, 개별 약물의 용출률, 함량균일성 등 여러가지 요소를 고려해야 하므로, 복합 제제의 제조가 용이하지 않은 이유가 여기에 있다.Diabetes is a chronic disease, and its condition is complicated, so the symptoms of the disease often progress with various complications. Therefore, it is necessary to select the most appropriate drug at the time of the individual patient, and when the individual drugs are used alone, sufficient effects may not be obtained depending on the symptoms. Due to various problems such as the appearance of side effects, the choice is often difficult in the clinical field. Therefore, in connection with the preparation for the treatment of diabetes mellitus, diabetes-related diseases and diabetic complications, a method of concurrently administering two or more drugs with different mechanisms has been proposed, rather than one drug alone. However, when manufacturing a combination formulation of two or more drugs, it is necessary to consider various factors such as the interaction of two or more drugs, the dissolution rate of individual drugs, and the content uniformity, which is why the preparation of the combination formulation is not easy. .
본 발명자들은 다파글리플로진 L-프롤린과 항당뇨병제의 복합 제제를 제공함으로써 환자의 복약순응도를 향상시키고, 다양한 기전을 가진 복합 제제의 투여를 통한 효과를 향상시키고 부작용을 감소시키고자 한다. 특히, 본 발명은 다파글리플로진 L-프롤린에 메트포르민 및/또는 DPP-IV 억제제를 추가로 포함하는 복합 제제를 제공하며, 본 발명자들은 우수한 용출률 및 함량균일성을 갖도록 하여 최적의 생체내 이용율을 갖는 약제학적 복합 제제를 제공하고자 연구하였고, 그 결과 본 발명을 완성하였다.The present inventors seek to improve the patient's medication compliance by providing a combination formulation of dapagliflozin L-proline and an anti-diabetic agent, and to improve the effects through the administration of a combination formulation with various mechanisms and to reduce side effects. In particular, the present invention provides a complex formulation further comprising metformin and / or DPP-IV inhibitor in dapagliflozin L-proline, and the present inventors have excellent dissolution rate and content uniformity to provide optimal bioavailability. To provide a pharmaceutical combination formulation having a result, the present invention has been completed.
본 발명의 목적은 다양한 작용기전을 갖는 당뇨병 치료제들의 복합 제제를 제공함으로써 환자의 복약순응도를 높이고 효과를 증대시키면서 부작용을 최소화하는 제제를 제공하고자 한다. 또한, 복합 제제에서 개개의 활성성분의 용출특성 및 함량균일성을 향상시켜 생체내 이용율을 높인다. An object of the present invention is to provide a formulation that minimizes side effects while increasing medication compliance and increasing the effect of the patient by providing a complex formulation of therapeutic agents for diabetes with a variety of mechanisms of action. In addition, it increases the bioavailability by improving the dissolution properties and content uniformity of the individual active ingredients in the complex formulation.
따라서, 본 발명은 다파글리플로진 L-프롤린, 및 하나 이상의 항당뇨병제를 포함하는 약제학적 복합 제제를 제공한다. Accordingly, the present invention provides a pharmaceutical combination formulation comprising dapagliflozin L-proline, and one or more antidiabetic agents.
다파글리플로진 L-프롤린은 다파글리플로진으로서 5 내지 20 mg을 포함할 수 있다.Dapagliflozin L-proline may comprise 5-20 mg as dapagliflozin.
상기 항당뇨병제는 알파-글루코시다제 억제제(α-glucosidase inhibitor), 비구아니드 약물(Biguanide), 인슐린 분비 촉진제(insulin secretagogue), 인슐린 감작제(insulin sensitizer), 카나비노이드 수용체-1 길항제(cannabinoid receptor 1 antagonist), DPP-IV 억제제 등일 수 있다.The antidiabetic agent is an alpha-glucosidase inhibitor, a biguanide drug, an insulin secretagogue, an insulin sensitizer, a cannabinoid receptor-1 antagonist 1 antagonist), DPP-IV inhibitor, and the like.
특히, 상기 항당뇨병제는 메트포르민 또는 그의 약제학적으로 허용가능한 염일 수 있고, 이때 다파글리플로진 L-프롤린은 다파글리플로진으로서 메트포르민 및 그의 약제학상 허용가능한 염에 대하여 0.1 중량% 내지 10 중량%로 포함될 수 있다.In particular, the antidiabetic agent may be metformin or a pharmaceutically acceptable salt thereof, wherein dapagliflozin L-proline is 0.1% by weight to 10% relative to metformin and its pharmaceutically acceptable salts as dapagliflozin It may be included in weight percent.
또한, 상기 항당뇨병제는 DPP-IV 억제제 또는 그의 약제학적으로 허용가능한 염일 수 있고, 이때 다파글리플로진 L-프롤린은 다파글리플로진으로서 상기 DPP-IV 억제제 및 그의 약제학상 허용가능한 염에 대하여 5 내지 1,000 중량%로 포함될 수 있다.In addition, the antidiabetic agent may be a DPP-IV inhibitor or a pharmaceutically acceptable salt thereof, wherein dapagliflozin L-proline is dapagliflozin as the DPP-IV inhibitor and a pharmaceutically acceptable salt thereof. It may be included in 5 to 1,000% by weight relative to.
DPP-IV 억제제는 시타글립틴, 빌다글립틴, 삭사글립틴, 리나글립틴, 아나글립틴, 알로글립틴 및 제미글립틴으로 이루어진 군에서 선택될 수 있다.The DPP-IV inhibitor may be selected from the group consisting of cytagliptin, bildagliptin, saxagliptin, linagliptin, anagliptin, allogliptin and gemigliptin.
본 발명에서 제공하는 약제학적 복합 제제는 하나 이상의 항당뇨병제를 포함하는 제1 과립, 및 다파글리플로진 L-프롤린을 포함할 수 있다.The pharmaceutical combination formulations provided herein may comprise a first granule comprising one or more antidiabetic agents, and dapagliflozin L-proline.
상기 제1 과립은 하나 이상의 고분자중합체를 포함할 수 있다. 고분자중합체로는 하이드록시프로필메틸셀룰로오스(HPMC), 하이드록시프로필셀룰로오스(HPC), 저치환도 하이드록시프로필셀룰로오스(HPC-L), 정제 쉘락, 메타아크릴레이트중합체, 아크릴레이트공중합체, 천연검, 구아검, 트라가칸타, 아카시아검, 로커스트빈검, 잔탄검 등이 사용될 수 있고, 바람직하게 HPMC 2208, HPMC 2910, HPC-L 또는 로커스트빈검을 사용할 수 있으며, 이에 한정되지 않는다.The first granules may comprise one or more polymers. Polymers include hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), low-substituted hydroxypropyl cellulose (HPC-L), tablet shellac, methacrylate polymer, acrylate copolymer, natural gum, Guar gum, tragacanta, acacia gum, locust bean gum, xanthan gum and the like can be used, and preferably HPMC 2208, HPMC 2910, HPC-L or locust bean gum can be used, but is not limited thereto.
또한, 본 발명에서 제공하는 약제학적 복합 제제는 하나 이상의 항당뇨병제를 포함하는 제1 과립, 및 하나 이상의 활택제 및/또는 다파글리플로진 L-프롤린을 포함하는 코어층; 및 상기 코어층을 코팅하는 코팅층을 포함할 수 있다.In addition, the pharmaceutical combination formulation provided in the present invention comprises a first granule comprising one or more antidiabetic agents, and a core layer comprising one or more glidants and / or dapagliflozin L-proline; And it may include a coating layer for coating the core layer.
상기 코팅층 중량은 상기 코어층 중량에 대하여 바람직하게 1 내지 20 중량%일 수 있다.The coating layer weight may be 1 to 20% by weight with respect to the core layer weight.
활택제로는 이산화규소, 스테아르산의 마그네슘염, 아연염, 마그네슘 알루미늄실리케이트, 탈크 등이 사용될 수 있고 바람직하게 이산화규소 또는 스테아르산 마그네슘을 사용할 수 있으나, 이에 한정되는 것은 아니다.As the lubricant, silicon dioxide, magnesium salt of stearic acid, zinc salt, magnesium aluminum silicate, talc and the like may be used, and preferably silicon dioxide or magnesium stearate may be used, but is not limited thereto.
상기 제1 과립은 하나 이상의 고분자중합체를 포함할 수 있다. The first granules may comprise one or more polymers.
상기 코팅층은 다파글리플로진 L-프롤린, 메트포르민, 시타글립틴, 빌다글립틴, 삭사글립틴, 리나글립틴, 아나글립틴, 알로글립틴, 제미글립틴 및 그의 약제학적으로 허용가능한 염으로 이루어진 군에서 선택된 하나 이상의 활성성분을 포함할 수 있다.The coating layer is dapagliflozin L-proline, metformin, citagliptin, bilagliptin, saxagliptin, linagliptin, anagliptin, allogliptin, gemigliptin and pharmaceutically acceptable salts thereof It may include one or more active ingredients selected from the group consisting of.
또한 본 발명에서 제공하는 약제학적 복합 제제는 경구투여 형태로 제형화될 수 있으며, 경구투여 형태는 정제 또는 캡슐제일 수 있다.In addition, the pharmaceutical combination preparation provided in the present invention may be formulated in an oral dosage form, oral dosage form may be a tablet or capsule.
본 발명에 따른 다파글리플로진 L-프롤린 및 항당뇨병제를 포함하는 약제학적 복합 제제는 매우 우수한 함량균일성 및 용출률을 가지며, 따라서 생체내 흡수율이 뛰어나므로 당뇨병, 당뇨병 관련 질환 및 당뇨병성 합병증의 예방 또는 치료제로 활용될 수 있다.The pharmaceutical complex preparation comprising dapagliflozin L-proline and an antidiabetic agent according to the present invention has a very good content uniformity and dissolution rate, and thus has an excellent absorption rate in vivo, thus leading to diabetes, diabetes-related diseases and diabetic complications. It can be used as a prophylactic or therapeutic agent.
도 1은 실시예 1 내지 3에서 다파글리플로진 L-프롤린의 함량균일성시험 결과를 나타낸 것이다.Figure 1 shows the results of the content uniformity test of dapagliflozin L-proline in Examples 1 to 3.
도 2는 실시예 4 내지 7에서 다파글리플로진 L-프롤린의 함량균일성시험 결과를 나타낸 것이다.Figure 2 shows the results of the content uniformity test of dapagliflozin L-proline in Examples 4 to 7.
도 3은 실시예 8 내지 11에서 다파글리플로진 L-프롤린의 함량균일성시험 결과를 나타낸 것이다.Figure 3 shows the results of the content uniformity test of dapagliflozin L-proline in Examples 8 to 11.
도 4은 실시예 12 내지 15에서 다파글리플로진 L-프롤린의 함량균일성시험 결과를 나타낸 것이다.Figure 4 shows the results of the content uniformity test of dapagliflozin L-proline in Examples 12 to 15.
도 5는 실시예 1 내지 3에서 메트포르민 용출률 시험 결과를 나타낸 것이다.Figure 5 shows the metformin dissolution rate test results in Examples 1-3.
도 6는 실시예 8 내지 11에서 메트포르민 용출률 시험 결과를 나타낸 것이다.Figure 6 shows the metformin dissolution rate test results in Examples 8-11.
도 7는 실시예 12 내지 15에서 메트포르민 용출률 시험 결과를 나타낸 것이다.Figure 7 shows the metformin dissolution rate test results in Examples 12 to 15.
당뇨병, 당뇨병 관련 질환 및 당뇨병성 합병증의 예방 또는 치료를 위한 SGLT-2 억제제인 다파글리플로진 L-프롤린은 유의한 위장 부작용 없이 소변 중의 글루코스 배출을 증대시켜서 인슐린 민감성을 개선시키고 당뇨병 합병증의 발병을 지연시킴으로써 혈장 글루코스를 정상화시킬 수 있다.Dapagliflozin L-proline, an SGLT-2 inhibitor for the prevention or treatment of diabetes mellitus, diabetes-related diseases and diabetic complications, improves insulin sensitivity and improves diabetes sensitivity by increasing glucose excretion in urine without significant gastrointestinal side effects. By delaying the plasma glucose can be normalized.
본 발명에서 사용 가능한 다파글리플로진 L-프롤린은 하기 화학식 2의 결정질 복합체이다.Dapagliflozin L-proline that can be used in the present invention is a crystalline complex of formula (2).
[화학식 2][Formula 2]
Figure PCTKR2017013690-appb-I000002
Figure PCTKR2017013690-appb-I000002
(상기 화학식 2에서, x는 1 또는 2이고, y는 0 내지 1이다)(In Formula 2, x is 1 or 2, y is 0 to 1)
바람직하게, 본 발명의 다파글리플로진 L-프롤린은 1:2 결정질 복합체일 수 있다.Preferably, the dapagliflozin L-proline of the present invention may be a 1: 2 crystalline complex.
메트포르민은 인슐린 비의존성 진성당뇨병(type II, non-insulin dependent diabetes mellitus, NIDDM)을 치료하는데 사용되는 비구아나이드계 항 고혈당제이다. 메트포르민은 말초조직에서 인슐린에 대한 감도를 증가하고 위장관에서 당분의 흡수를 억제하며 간장에서 혈당의 생성을 감소시킨다. 메트포르민은 인슐린의 분비를 촉진하지 않으며 혈액 중의 인슐린양을 감소시키는 작용이 있고 혈관을 보호하는 작용도 있다. 또한 체내 지방을 감소시키고 저혈당 등을 초래하지 않으므로, 비만 또는 고지혈증을 갖는 환자들, 또는 음식 조절로 이상적인 혈당조절이 어려운 환자들에게 사용하기 적당한 약물이다.Metformin is a biguanide antihyperglycemic agent used to treat insulin-independent diabetes mellitus (type II, non-insulin dependent diabetes mellitus, NIDDM). Metformin increases sensitivity to insulin in peripheral tissues, inhibits the absorption of sugar in the gastrointestinal tract, and reduces blood sugar production in the liver. Metformin does not promote the secretion of insulin, reduces the amount of insulin in the blood, and also protects blood vessels. It is also suitable for use in patients with obesity or hyperlipidemia, or for those whose dietary control is difficult to control because it reduces body fat and does not cause hypoglycemia.
본 발명에서 사용 가능한 메트포르민의 약제학적으로 허용되는 염은 염산염, 숙신산염, 푸마르산염, 메탄설폰산염, 벤젠설폰산염, 톨루엔설폰산염으로 이루어진 군 중에서 선택될 수 있으나, 이에 한정되는 것은 아니다.The pharmaceutically acceptable salt of metformin usable in the present invention may be selected from the group consisting of hydrochloride, succinate, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate, but is not limited thereto.
또한, DPP-IV 억제제는 췌장 β-세포로부터의 글루코스-의존적 인슐린 분비를 자극하고 췌장 β-세포 집단을 증가시키는 GLP-1을 절단시키는 역할을 한다.In addition, DPP-IV inhibitors serve to cleave GLP-1, which stimulates glucose-dependent insulin secretion from pancreatic β-cells and increases the pancreatic β-cell population.
또한 본 발명에서 사용 가능한 DPP-VI 억제제는 시타글립틴, 빌다글립틴, 삭사글립틴, 리나글립틴, 아나글립틴, 알로글립틴, 제미글립틴 및 그의 약제학적으로 허용가능한 염으로 이루어진 군에서 선택될 수 있으나, 이에 한정되는 것은 아니다.In addition, the DPP-VI inhibitor usable in the present invention is in the group consisting of cytagliptin, bilagliptin, saxagliptin, linagliptin, anagliptin, allogliptin, gemigliptin and pharmaceutically acceptable salts thereof It may be selected, but is not limited thereto.
DPP-VI 억제제의 제약상 허용되는 염의 예로는 알칼리 금속(예를 들어, 리튬, 나트륨 및 칼륨)과의 염; 알칼리 토금속(예를 들어, 칼슘 및 마그네슘)과의 염; 아연 또는 알루미늄과의 염; 유기 염기(예를 들어, 암모니아, 콜린, 디에탄올아민, 리신, 에틸렌디아민, t-부틸아민, t-옥틸아민, 트리스(히드록시메틸) 아미노메탄, N-메틸-글루코사민, 트리에탄올아민 및 데히드로아비에틸아민)와의 염; 무기산(예를 들어, 염산, 브롬화수소산, 요오드화수소산, 황산, 질산 및 인산)과의 염; 유기산(예를 들어, 포름산, 아세트산, 프로피온 산, 옥살산, 말론산, 숙신산, 푸마르산, 말레산, 락트산, 말산, 타르타르산, 시트르산, 메탄술폰산, 에탄술폰산및 벤젠술폰산)과의 염; 및 산성 아미노산(예를 들어, 아스파르트산 및 글루탐산)과의 염 등이 포함된다.Examples of pharmaceutically acceptable salts of DPP-VI inhibitors include salts with alkali metals (eg, lithium, sodium and potassium); Salts with alkaline earth metals (eg calcium and magnesium); Salts with zinc or aluminum; Organic bases (eg ammonia, choline, diethanolamine, lysine, ethylenediamine, t-butylamine, t-octylamine, tris (hydroxymethyl) aminomethane, N-methyl-glucosamine, triethanolamine and dehydro Salts with abiethylamine); Salts with inorganic acids (eg, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid); Salts with organic acids (eg, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid and benzenesulfonic acid); And salts with acidic amino acids (eg, aspartic acid and glutamic acid), and the like.
본 발명의 약제학적 복합 제제에서 다파글리플로진 L-프롤린은 다파글리플로진으로서 5 내지 20 mg으로 포함될 수 있다. 다파글리플로진 L-프롤린은 다파글리플로진으로서, 메트포르민 및 그의 제약상 허용가능한 염에 대하여 0.1 중량% 내지 10 중량%로 포함될 수 있다. 또한, 다파글리플로진 L-프롤린은 다파글리플로진으로서, DPP-IV 억제제 및 그의 제약상 허용가능한 염에 대하여 5 중량% 내지 1,000 중량%로 포함될 수 있으며, 바람직하게는 5 중량% 내지 500 중량%로 포함될 수 있다.Dapagliflozin L-proline in the pharmaceutical combination formulation of the present invention may be included as 5 to 20 mg as dapagliflozin. Dapagliflozin L-proline is dapagliflozin, and may be included in an amount of 0.1% to 10% by weight relative to metformin and its pharmaceutically acceptable salts. In addition, dapagliflozin L-proline is dapagliflozin, and may be included in the amount of 5% to 1,000% by weight, preferably 5% to It may be included in 500% by weight.
본 발명의 약제학적 복합 제제는 통상의 약제학적으로 허용 가능한 담체, 부형제, 결합제, 붕해제 등을 첨가하여, 약제학적 분야에서 통상적인 제제, 예를 들면 정제, 캅셀제, 비드, 비들렛, 과립, 환제, 트로키제, 액제, 현탁제 등의 경구투여용 제제 또는 비경구투여용 제제로 제제화될 수 있다.The pharmaceutical complex preparations of the present invention may be prepared by adding conventional pharmaceutically acceptable carriers, excipients, binders, disintegrants, and the like, and include conventional formulations such as tablets, capsules, beads, beadlets, granules, It may be formulated as a preparation for oral administration such as pills, troches, solutions, suspensions, or parenteral administration.
본 발명에 첨가될 수 있는 부형제는 락토오스, 전분, 셀락토오스, 덱스트린, 미결정셀룰로오스, 인산일수소칼륨, 탄산칼슘, 당류 등이 있으나, 이에 한정되는 것은 아니다.Excipients that may be added to the present invention include, but are not limited to, lactose, starch, cellulose, dextrin, microcrystalline cellulose, potassium dihydrogen phosphate, calcium carbonate, sugars, and the like.
결합제로는 포비돈, 코포비돈과 같은 폴리비닐피롤리돈 유도체, 메칠셀룰로오스, 에칠셀룰로오스, 카르복시메칠셀룰로오스 나트륨과 같은 셀룰오로스 유도체, 전분, 젤라틴 등이 될 수 있으나, 이에 한정되는 것은 아니다.The binder may be, but is not limited to, polyvinylpyrrolidone derivatives such as povidone and copovidone, methylcellulose, ethylcellulose, cellulose derivatives such as carboxymethylcellulose sodium, starch, gelatin, and the like.
붕해제로는 크로스포비돈, 전호화전분, 옥수수전분, 메틸셀룰로오스, 히드록시프로필메틸셀룰로오스, 전분 글리콘산 나트륨, 크로스카르멜로즈 나트륨, 저치환도히드록시프로필셀룰로오스, 나트륨 전분 글리콜레이트, 전분, 전호화전분, 알긴산 또는 그의 나트륨 염 등이 될 수 있으나, 이에 한정되는 것은 아니다.Disintegrants include crospovidone, pregelatinized starch, corn starch, methylcellulose, hydroxypropylmethylcellulose, sodium starch glyconate, croscarmellose sodium, low-substituted hydroxypropylcellulose, sodium starch glycolate, starch, starch Gelatinized starch, alginic acid or its sodium salt, and the like, but is not limited thereto.
이 밖에도, 본 발명의 약제학적 제제는 필요에 따라 pH 조절제, 현탁화제, 보존제, 착향제, 착색제, 감미제, 흡착제 등을 더 포함할 수 있다. 이러한 첨가제의 함량은 본 발명에서 특별히 제한되지 않고 필요에 따라 적절히 조절될 수 있다.In addition, the pharmaceutical formulation of the present invention may further include a pH adjusting agent, suspending agent, preservative, flavoring agent, colorant, sweetener, adsorbent and the like as necessary. The content of such additives is not particularly limited in the present invention and may be appropriately adjusted as necessary.
본 발명의 약제학적 제제가 복합정제일 경우, 상기 정제는 메트포르민 또는 그의 약제학적으로 허용되는 염에 정제수를 넣어 연합한 후 정립하여 제1 과립을 제조하는 단계; 제조된 제1 과립에 다파글리플로진 L-프롤린 및 약제학적으로 허용 가능한 첨가제를 혼합하여 최종과립을 제조하는 단계; 및 최종과립을 정제로 타정하는 단계로 제조될 수 있다.When the pharmaceutical formulation of the present invention is a composite tablet, the tablet is prepared by combining the purified water in metformin or a pharmaceutically acceptable salt thereof, and then preparing the first granules; Preparing final granules by mixing dapagliflozin L-proline and a pharmaceutically acceptable additive with the prepared first granules; And tableting the final granules with tablets.
또한, 본 발명의 약제학적 제제가 복합정제일 경우, 상기 정제는 DPP-IV 억제제 및 약제학적으로 허용가능한 첨가제를 혼합한 후 정립하여 제1 과립을 제조하는 단계; 제조된 제1 과립에 다파글리플로진 L-프롤린 및 약제학적으로 허용 가능한 첨가제를 혼합하여 최종과립을 제조하는 단계; 및 최종과립을 정제로 타정하는 단계로 제조될 수 있다.In addition, when the pharmaceutical formulation of the present invention is a composite tablet, the tablet is prepared by mixing the DPP-IV inhibitor and the pharmaceutically acceptable additive to prepare a first granule; Preparing final granules by mixing dapagliflozin L-proline and a pharmaceutically acceptable additive with the prepared first granules; And tableting the final granules with tablets.
또한, 본 발명의 약제학적 제제가 복합정제일 경우, 메트포르민 또는 그의 약제학적으로 허용되는 염에 정제수를 넣어 연합한 후 정립하여 제1 과립을 제조하는 단계; 제조된 제1 과립에 활택제 및 약제학적으로 허용가능한 첨가제를 혼합하여 최종과립을 제조하는 단계; 최종과립을 정제로 타정하는 단계; 및 타정된 정제에 다파글리플로진 L-프롤린를 포함하는 코팅액으로 코팅하는 단계로 제조될 수 있다.In addition, when the pharmaceutical formulation of the present invention is a composite tablet, the step of preparing the first granules by combining the purified water into metformin or a pharmaceutically acceptable salt thereof and then sizing; Preparing a final granule by mixing a lubricant and a pharmaceutically acceptable additive with the prepared first granules; Tableting the final granules into tablets; And it can be prepared by the step of coating with a coating solution containing dapagliflozin L-proline in the compressed tablet.
또한, 본 발명의 약제학적 제제가 복합정제일 경우, 메트포르민 또는 그의 약제학적으로 허용되는 염, 및 DPP-IV 억제제에 정제수를 넣어 연합한 후 정립하여 제1 과립을 제조하는 단계; 제조된 제1 과립에 활택제 및 약제학적으로 허용가능한 첨가제를 혼합하여 최종과립을 제조하는 단계; 최종과립을 정제로 타정하는 단계; 및 타정된 정제에 다파글리플로진 L-프롤린을 포함하는 코팅액으로 코팅하는 단계로 제조될 수 있다.In addition, when the pharmaceutical formulation of the present invention is a composite tablet, metformin or a pharmaceutically acceptable salt thereof, and put into purified water to the DPP-IV inhibitor, then sizing and preparing the first granules; Preparing a final granule by mixing a lubricant and a pharmaceutically acceptable additive with the prepared first granules; Tableting the final granules into tablets; And it can be prepared by the step of coating with a coating solution containing dapagliflozin L-proline in the compressed tablet.
또한, 본 발명의 약제학적 제제가 복합정제일 경우, 메트포르민 또는 그의 약제학적으로 허용되는 염에 정제수를 넣어 연합한 후 정립하여 제1 과립을 제조하는 단계; 제조된 제1 과립에 활택제 및 다파글리플로진 L-프롤린을 혼합하여 최종과립을 제조하는 단계; 최종과립을 정제로 타정하는 단계; 및 타정된 정제에 DPP-IV 억제제를 포함하는 코팅액으로 코팅하는 단계로 제조될 수 있다.In addition, when the pharmaceutical formulation of the present invention is a composite tablet, the step of preparing the first granules by combining the purified water into metformin or a pharmaceutically acceptable salt thereof and then sizing; Preparing a final granule by mixing a lubricant and dapagliflozin L-proline to the prepared first granules; Tableting the final granules into tablets; And it can be prepared by coating with a coating solution comprising a DPP-IV inhibitor in the compressed tablet.
이때 상기 과립은 당업계에 공지된 통상적인 습식과립법 또는 건식과립법에 의하여 제조될 수 있다. 또한, 상기 정제는 직접 타정법에 의하여 제조될 수 있으며, 타정을 위해서는 통상적으로 사용되는 타정기, 예를 들어 로타리 타정기를 이용하여 타정할 수 있다.In this case, the granules may be prepared by conventional wet granulation or dry granulation methods known in the art. In addition, the tablet may be prepared by a direct tableting method, and may be tableted using a tableting machine, which is commonly used for tableting, for example, a rotary tableting machine.
이와 같은 제조방법에 의하여 정제를 제조할 경우, 타정의 효율성을 증가시켜, 일정한 정제 경도의 확보와 캡핑 및 라미네이팅과 같은 불량을 방지하여 생산성 개선의 효과를 확보할 수 있어 바람직하다.In the case of manufacturing tablets by such a manufacturing method, it is preferable to increase the efficiency of tableting, thereby securing a certain tablet hardness and preventing defects such as capping and laminating to secure the effect of productivity improvement.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 본 발명을 보다 구체적으로 설명하기 위한 것으로 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다.Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are intended to illustrate the present invention in more detail, and the scope of the present invention is not limited by these examples.
[실시예]EXAMPLE
실시예 1 내지 3 : 다파글리플로진 L-프롤린과 메트포르민 염산염의 복합 정제Examples 1-3: Combined Purification of Dapagliflozin L-Proline and Metformin Hydrochloride
하기 표 1의 조성으로 다파글리플로진과 L-프롤린 1:2 결정질복합체 (한미정밀, 한국)를 포함하는 정제를 제조하였다. To prepare a tablet comprising dapagliflozin and L-proline 1: 2 crystalline complex (Hanmi Precision, Korea) in the composition of Table 1.
구체적으로, 메트포르민 염산염을 HPMC2208, HPMC2910 및 로커스트빈검과 혼합한 후, 정제수를 넣어 연합한 뒤, 20 메쉬 체로 정립하여 1차 과립을 제조하였다. Specifically, metformin hydrochloride was mixed with HPMC2208, HPMC2910, and locust bean gum, combined with purified water, and then granulated in a 20 mesh sieve to prepare primary granules.
제조된 1차 과립에 다파글리플로진 L-프롤린, 미결정셀룰로오스, 이산화규소, 크로스포비돈, 및 스테아르산 마그네슘을 가하고 혼합하여 최종과립을 제조하였다.Dapagliflozin L-proline, microcrystalline cellulose, silicon dioxide, crospovidone, and magnesium stearate were added to the prepared primary granules and mixed to prepare final granules.
상기 최종 과립을 로타리 타정기(GRC-18, 세종기계, 한국)를 이용하여 타정하여, 1정에 다파글리플로진 L-프롤린으로서 15.6 mg(다파글리플로진으로서 10 mg)을 포함하는 다파글리플로진 L-프롤린이 함유된 복합정제를 제조하였다.The final granules were compressed using a rotary tablet press (GRC-18, Sejong Machinery, Korea) to contain 15.6 mg (10 mg as dapagliflozin) as dapagliflozin L-proline in one tablet. A composite tablet containing pagliflozin L-proline was prepared.
구성 성분Composition 함량 (mg)Content (mg)
실시예1Example 1 실시예2Example 2 실시예3Example 3
습식과립Wet granules 메트포르민 염산염Metformin hydrochloride 250250 500500 10001000
HPMC 2208HPMC 2208 67.567.5 135135 270270
HPMC 2910HPMC 2910 22 44 88
로커스트빈검Locust Bean Sword 1010 2020 4040
혼합mix 다파글리플로진 L-프롤린Dapagliflozin L-Proline 15.615.6 15.615.6 15.615.6
미결절셀룰로오스Microtubule cellulose 2525 5050 100100
이산화규소Silicon dioxide 88 88 88
크로스포비돈Crospovidone 55 1010 2020
스테아르산 마그네슘Magnesium stearate 44 88 1616
총 중량Total weight 387.1387.1 750.6750.6 1477.61477.6
메트포르민염산염에 대한 다파글리플로진의 중량(%)% Weight of dapagliflozin to metformin hydrochloride 4 %4 % 2 %2 % 1 %One %
실시예 4 내지 7 : 다파글리플로진 L-프롤린과 DPP-IV 억제제의 복합 정제Examples 4-7 Combination Tablets of Dapagliflozin L-Proline and DPP-IV Inhibitor
하기 표 2의 조성으로 다파글리플로진 1:2 결정질복합체(한미정밀, 한국)을 포함하는 정제를 제조하였다. To prepare a tablet comprising a dapagliflozin 1: 2 crystalline complex (Hanmi Precision, Korea) in the composition of Table 2.
구체적으로, 시타글립틴 또는 리나글립틴을 미결정셀룰로오스, 락토오스 및 HPC-L과 혼합한 후, 롤러컴팩터(TF-1-A60, Freund vector, 미국)를 이용하여 컴팩팅 후 20 메쉬 체로 체과하여 1차 건식과립을 제조하였다.Specifically, citagliptin or linagliptin is mixed with microcrystalline cellulose, lactose and HPC-L, and then compacted using a roller compactor (TF-1-A60, Freund vector, USA) and sieved through a 20 mesh sieve. Primary dry granules were prepared.
제조된 1차 과립에 다파글리플로진 L-프롤린, 미결정셀룰로오스, 락토오스, 크로스포비돈 및 스테아르산 마그네슘을 가하고 혼합하여 최종과립을 제조하였다.Dapagliflozin L-proline, microcrystalline cellulose, lactose, crospovidone and magnesium stearate were added to the prepared primary granules and mixed to prepare final granules.
상기 최종 과립을 로타리 타정기(GRC-18, 세종기계, 한국)를 이용하여 타정하여, 1정에 다파글리플로진 L-프롤린으로서 15.6 mg(다파글리플로진으로서 10 mg)을 포함하는 다파글리플로진 L-프롤린이 함유된 복합정제를 제조하였다.The final granules were compressed using a rotary tablet press (GRC-18, Sejong Machinery, Korea) to contain 15.6 mg (10 mg as dapagliflozin) as dapagliflozin L-proline in one tablet. A composite tablet containing pagliflozin L-proline was prepared.
구성 성분Composition 함량 (mg)Content (mg)
실시예4Example 4 실시예5Example 5 실시예6Example 6 실시예7Example 7
건식과립Dry granules 시타글립틴Cytagliptin 50 50 100 100 -- --
리나글립틴Linagliptin -- -- 5 5 10 10
미결절셀룰로오스 Microtubule cellulose 80 80 160 160 80 80 160 160
락토오스Lactose 25 25 50 50 25 25 50 50
HPC-LHPC-L 5 5 10 10 5 5 10 10
혼합mix 다파글리플로진 L-프롤린Dapagliflozin L-Proline 15.6 15.6 15.6 15.6 15.6 15.6 15.6 15.6
락토오스 Lactose 20 20 40 40 20 20 40 40
미결정셀룰로오스Microcrystalline cellulose 10 10 20 20 10 10 20 20
크로스포비돈Crospovidone 10 10 20 20 10 10 20 20
스테아르산 마그네슘 Magnesium stearate 3 3 6 6 3 3 6 6
총 중량Total weight 218.6 218.6 421.6 421.6 173.6 173.6 331.6 331.6
DPP-IV 억제제에 대한 다파글리플로진 중량(%)Dapagliflozin Weight (%) for DPP-IV Inhibitor 20 %20% 10 %10% 200 %200% 100 %100%
실시예 8 내지 11 : 다파글리플로진 L-프롤린의 약물코팅 복합 정제Examples 8-11: Drug Coated Tablets of Dapagliflozin L-Proline
하기 표 3의 조성으로 다파글리플로진 1:2 결정질복합체 (한미정밀, 한국)을 포함하는 정제를 제조하였다. To prepare a tablet comprising a dapagliflozin 1: 2 crystalline complex (Hanmi Precision, Korea) in the composition of Table 3.
구체적으로, 메트포르민 염산염을 HPMC2208, HPMC2910 및 로커스트빈검과 혼합한 후, 정제수를 넣어 연합한 후, 20 메쉬 체로 정립하여 1차 과립을 제조하였다.Specifically, metformin hydrochloride was mixed with HPMC2208, HPMC2910, and locust bean gum, combined with purified water, and then granulated in a 20 mesh sieve to prepare primary granules.
제조된 1차 과립에 이산화규소, 스테아르산 마그네슘을 가하고 혼합하여 최종과립을 제조하였다. 최종 과립을 로타리 타정기(GRC-18, 세종기계, 한국)를 이용하여 타정하였다.The final granules were prepared by adding and mixing silicon dioxide and magnesium stearate to the prepared primary granules. The final granules were compressed using a rotary tablet press (GRC-18, Sejong Machinery, Korea).
상기 타정된 정제에 다파글리플로진 L-프롤린을 포함하며 Kollicaot IR, PVP (K-30) 및 PEG 6000이 혼합된 코팅액을 코팅기(SFC-30F, 세종파마텍, 한국)를 이용하여 코팅하며, 다파글리플로진 L-프롤린이 15.6 mg(다파글리플로진으로서 10 mg)이 함유된 복합정제를 제조하였다.The tablets containing dapagliflozin L-proline and Kollicaot IR, PVP (K-30) and PEG 6000 is mixed with a coating solution (SFC-30F, Sejong Pharmatech, Korea), Combination tablets containing 15.6 mg of dapagliflozin L-proline (10 mg as dapagliflozin) were prepared.
구성 성분Composition 함량 (mg)Content (mg)
실시예8Example 8 실시예9Example 9 실시예10Example 10 실시예11Example 11
습식과립Wet granules 메트포르민 염산염Metformin hydrochloride 500 500 500 500 1000 1000 1000 1000
HPMC 2208HPMC 2208 135 135 135 135 270 270 270 270
HPMC 2910HPMC 2910 4 4 4 4 8 8 8 8
로커스트빈검 Locust Bean Sword 20 20 20 20 40 40 40 40
혼합mix 이산화규소Silicon dioxide 7 7 7 7 14 14 14 14
스테아르산마그네슘Magnesium stearate 15 15 15 15 30 30 30 30
코어 중량Core weight 681 681 681 681 1362 1362 1362 1362
약물코팅부Drug coating part 다파글리플로진 L-프롤린Dapagliflozin L-Proline 15.6 15.6 15.615.6 15.615.6 15.6 15.6
Kollicoat IR Kollicoat IR 8080 10 10 20 20 5 5
PVP (K-30)PVP (K-30) 4 4 2 2 4 4 2 2
PEG 6000PEG 6000 8 8 4 4 8 8 4 4
코팅중량Coating weight 107.6 107.6 31.6 31.6 47.6 47.6 26.6 26.6
총 중량Total weight 788.6 788.6 712.6 712.6 1409.6 1409.6 1388.6 1388.6
코어중량에 대한 코팅중량 (%)Coating weight to core weight (%) 15.8 %15.8% 4.6 %4.6% 3.5 %3.5% 2.0 %2.0%
실시예 12 및 13 : 다파글리플로진 L-프롤린과 메트포르민염산염, DPP-IV 억제제의 복합 정제Examples 12 and 13: Combination Purification of Dapagliflozin L-Proline with Metformin Hydrochloride and DPP-IV Inhibitor
하기 표 4의 조성으로 다파글리플로진 1:2 결정질복합체(한미정밀, 한국)을 포함하는 정제를 제조하였다. To prepare a tablet comprising a dapagliflozin 1: 2 crystalline complex (Hanmi Precision, Korea) in the composition of Table 4.
메트포르민 염산염을 시타글립틴, HPMC2208, HPMC2910 및 로커스트빈검과 혼합한 후, 정제수를 넣어 연합한 후, 20 메쉬 체로 정립하여 1차 과립을 제조하였다. Metformin hydrochloride was mixed with cytagliptin, HPMC2208, HPMC2910, and locust bean gum, combined with purified water, and then granulated in a 20 mesh sieve to prepare primary granules.
제조된 1차 과립에 이산화규소 및 스테아르산 마그네슘을 가하고 혼합하여 최종과립을 제조하였다. 최종 과립을 로타리 타정기(GRC-18, 세종기계, 한국)를 이용하여 타정하였다. The final granules were prepared by adding and mixing silicon dioxide and magnesium stearate to the prepared primary granules. The final granules were compressed using a rotary tablet press (GRC-18, Sejong Machinery, Korea).
상기 타정된 정제에 다파글리플로진 L-프롤린을 포함하며 Kollicoat IR, PVP (K-30) 및 PEG 6000이 혼합된 코팅액을 코팅기(SFC-30F, 세종파마텍, 한국)를 이용하여 코팅하며, 다파글리플로진 L-프롤린이 15.6 mg (다파글리플로진으로서 10 mg)이 함유된 복합정제를 제조하였다.Coating the tablet solution containing dapagliflozin L-proline in the tableted tablet and Kollicoat IR, PVP (K-30) and PEG 6000 are mixed using a coating machine (SFC-30F, Sejong Pharmatech, Korea), A composite tablet containing 15.6 mg of dapagliflozin L-proline (10 mg as dapagliflozin) was prepared.
구성 성분Composition 함량 (mg)Content (mg)
실시예12Example 12 실시예13Example 13
습식과립Wet granules 메트포르민 염산염Metformin hydrochloride 500 500 1000 1000
시타글립틴Cytagliptin 50 50 100 100
HPMC 2208HPMC 2208 135 135 270 270
HPMC 2910HPMC 2910 4 4 8 8
로커스트빈검 Locust Bean Sword 20 20 40 40
혼합mix 이산화규소Silicon dioxide 7 7 14 14
스테아르산마그네슘Magnesium stearate 15 15 30 30
코어 중량Core weight 731 731 1462 1462
약물코팅부Drug coating part 다파글리플로진 L-프롤린Dapagliflozin L-Proline 15.615.6 15.6 15.6
Kollicoat IRKollicoat IR 10 10 20 20
PVP (K-30)PVP (K-30) 2 2 4 4
PEG 6000PEG 6000 4 4 8 8
코팅중량Coating weight 31.6 31.6 47.6 47.6
총 중량Total weight 762.6 762.6 1509.6 1509.6
메트포르민염산염에 대한 다파글리플로진 중량(%)Dapagliflozin Weight (%) to Metformin Hydrochloride 2 %2 % 1 %One %
시타글립틴에 대한 다파글리플로진 중량(%)Dapagliflozin Weight (%) with respect to cytagliptin 20 %20% 10 %10%
코어중량에 대한 코팅중량(%) Coating weight (%) relative to core weight 4.3 %4.3% 3.3 %3.3%
실시예 14 및 15 : 다파글리플로진 L-프롤린과 메트포르민염산염, DPP-IV 억제제의 복합 정제Examples 14 and 15: Combined Purification of Dapagliflozin L-Proline with Metformin Hydrochloride and DPP-IV Inhibitor
하기 표 5의 조성으로 다파글리플로진 1:2 결정질복합체(한미정밀, 한국)을 포함하는 정제를 제조하였다. To prepare a tablet comprising a dapagliflozin 1: 2 crystalline complex (Hanmi Precision, Korea) in the composition of Table 5.
구체적으로, 메트포르민 염산염을 HPMC2208, HPMC2910 및 로커스트빈검과 혼합한 후, 정제수를 넣어 연합한 후, 20 메쉬 체로 정립하여 1차 과립을 제조하였다. Specifically, metformin hydrochloride was mixed with HPMC2208, HPMC2910, and locust bean gum, combined with purified water, and then granulated in a 20 mesh sieve to prepare primary granules.
제조된 1차 과립에 다파글리플로진 L-프롤린과 미결정셀룰로오스, 이산화규소, 크로스포비돈 및 스테아르산 마그네슘을 가하고 혼합하여 최종과립을 제조하였다. 최종 과립을 로타리 타정기(GRC-18, 세종기계, 한국)를 이용하여 타정하였다. Dapagliflozin L-proline and microcrystalline cellulose, silicon dioxide, crospovidone and magnesium stearate were added to the prepared primary granules and mixed to prepare final granules. The final granules were compressed using a rotary tablet press (GRC-18, Sejong Machinery, Korea).
상기 타정된 정제에 리나글립틴을 포함하며 Kollicoat IR, PVP (K-30) 및 PEG 6000이 혼합된 코팅액을 코팅기(SFC-30F, 세종파마텍, 한국)를 이용하여 코팅하며, 다파글리플로진 L-프롤린이 15.6 mg (다파글리플로진으로서 10 mg)이 함유된 복합정제를 제조하였다.The tableted tablet containing linagliptin and coated with Kollicoat IR, PVP (K-30) and PEG 6000 were coated using a coating machine (SFC-30F, Sejong Pharmatech, Korea), dapagliflozin A combination tablet containing 15.6 mg (10 mg as dapagliflozin) of L-proline was prepared.
구성 성분Composition 함량 (mg)Content (mg)
실시예14Example 14 실시예15Example 15
습식과립Wet granules 메트포르민 염산염Metformin hydrochloride 500 500 1000 1000
HPMC 2208HPMC 2208 135 135 270 270
HPMC 2910HPMC 2910 4 4 8 8
로커스트빈검 Locust Bean Sword 20 20 40 40
혼합mix 다파글리플로진 L-프롤린Dapagliflozin L-Proline 15.615.6 15.615.6
미결절셀룰로오스Microtubule cellulose 50 50 100 100
이산화규소Silicon dioxide 8 8 8 8
크로스포비돈Crospovidone 10 10 20 20
스테아르산 마그네슘Magnesium stearate 8 8 16 16
정제중량Tablet weight 750.6 750.6 1477.6 1477.6
약물코팅부Drug coating part 리나글립틴Linagliptin 10 10 10 10
Kollicoat IRKollicoat IR 10 10 20 20
PVP (K-30)PVP (K-30) 2 2 4 4
PEG 6000PEG 6000 4 4 8 8
코팅부 중량Coating weight 26 26 42 42
총 중량Total weight 776.6 776.6 1519.6 1519.6
<시험예 1> 다파글리플로진 L-프롤린의 함량균일성 평가Test Example 1 Evaluation of Content Uniformity of Dapagliflozin L-Proline
미국약전(USP) 제제균일성시험 <905> 항목에 따라, 실시예 1 내지 15의 정제들에 대한 제제균일성시험을 실시하여 아래와 같은 조건으로 액체 크로마토그래피를 실시하고, 판정치를 계산하여 하기 표 6 내지 9 및 도 1 내지 4에 나타내었다.According to the USP formulation uniformity test, the formulation uniformity test for the tablets of Examples 1 to 15 was carried out, liquid chromatography was performed under the following conditions, and the determination was calculated. Tables 6-9 and FIGS. 1-4 are shown.
<액체 크로마토그래피 조건> < Liquid chromatography conditions>
- 컬럼: 안지름 약 4.6 mm, 길이 25 cm인 스테인레스관에 입경 5 ㎛의 액체크로마토그래피용 옥타데실실릴화한 실리카겔이 충전된 컬럼 (Hypersil BDS C18, Thermo fisher scientific사)Column: A column filled with octadecylsilylated silica gel for liquid chromatography with a particle diameter of 5 μm in a stainless tube about 4.6 mm in diameter and 25 cm in length (Hypersil BDS C18, Thermo fisher scientific)
- 컬럼 온도: 30℃Column temperature: 30 ° C
- 시료 주입량: 20 μLSample injection volume: 20 μL
- 이동상: 0.1% 인산 (트리에틸아민으로 적정된 pH 6.8) /아세토니트릴 = 50/50 (v/v)Mobile phase: 0.1% phosphoric acid (pH 6.8 titrated with triethylamine) / acetonitrile = 50/50 (v / v)
- 유속: 1.0 mL/분Flow rate: 1.0 mL / min
- 검출기: 자외부 흡광 광도계 (측정파장 240 nm)Detector: ultraviolet absorbance photometer (wavelength 240 nm)
실시예1Example 1 실시예2Example 2 실시예3Example 3
평균(%)Average(%) 99.499.4 100.3100.3 98.998.9
편차Deviation 1.01.0 0.50.5 0.30.3
판정치Judgment 2.42.4 1.31.3 0.80.8
적합fitness 적합fitness 적합fitness
실시예4Example 4 실시예5Example 5 실시예6Example 6 실시예7Example 7
평균(%)Average(%) 99.499.4 98.998.9 100.1100.1 100.4100.4
편차Deviation 0.50.5 0.40.4 0.80.8 0.80.8
판정치Judgment 1.21.2 0.90.9 1.81.8 1.81.8
적합fitness 적합fitness 적합fitness 적합fitness
실시예8Example 8 실시예9Example 9 실시예10Example 10 실시예11Example 11
평균(%)Average(%) 100.3100.3 100.1100.1 99.899.8 99.599.5
편차Deviation 0.30.3 0.60.6 0.60.6 0.80.8
판정치Judgment 0.80.8 1.41.4 1.51.5 1.81.8
적합fitness 적합fitness 적합fitness 적합fitness
실시예12Example 12 실시예13Example 13 실시예14Example 14 실시예15Example 15
평균(%)Average(%) 101.3101.3 100.4100.4 100.4100.4 100.8100.8
편차Deviation 0.30.3 0.50.5 0.40.4 0.30.3
판정치Judgment 0.80.8 1.21.2 1.01.0 0.80.8
적합fitness 적합fitness 적합fitness 적합fitness
상기 표 6 내지 표 9에 나타낸 바와 같이, 실시예 1 내지 15의 정제는 함량균일성 시험 결과 모두 적합한 것을 확인하였다.As shown in Tables 6 to 9, the tablets of Examples 1 to 15 were found to be suitable for all content uniformity test results.
<시험예 2> 메트포르민 용출률Test Example 2 Metformin Dissolution Rate
미국약전(USP) 용출시험(Dissolution test) 항목의 제1법(Basket)에 따라 pH 6.8 인산염 용액 1000 mL을 이용하여 용출 온도 37℃, 회전수 100 rpm 으로 실시예 1 내지 3 및 실시예 8 내지 15의 정제들에 대한 용출시험을 실시하였다. According to the USP dissolution test item 1 (Basket) using a 1000 mL pH 6.8 phosphate solution using the elution temperature 37 ℃, rotation speed 100 rpm Examples 1 to 3 and Examples 8 to Dissolution test for 15 tablets was performed.
시험 시작 후 0, 0.5, 1, 2, 3, 4, 6시간 용출시험액 샘플을 채취하여 아래와 같은 조건으로 액체 크로마토그래피를 실시하고 메트포르민 용출률을 계산하여 하기 표 10 내지 12, 및 도 5 내지 7에 나타내었다.0, 0.5, 1, 2, 3, 4, 6 hours after the start of the test samples of the elution test solution was taken and subjected to liquid chromatography under the following conditions to calculate the metformin dissolution rate in Tables 10 to 12, and Figures 5 to 7 Indicated.
<액체 크로마토그래피 조건> < Liquid chromatography conditions>
- 컬럼: 안지름 약 4.6 mm, 길이 25 cm인 스테인레스관에 입경 5 ㎛의 액체크로마토그래피용 옥타데실실릴화한 실리카겔이 충전된 컬럼 (Hypersil BDS C18, Thermo fisher scientific사)Column: A column filled with octadecylsilylated silica gel for liquid chromatography with a particle diameter of 5 μm in a stainless tube about 4.6 mm in diameter and 25 cm in length (Hypersil BDS C18, Thermo fisher scientific)
- 컬럼 온도: 30℃Column temperature: 30 ° C
- 시료 주입량: 20 μLSample injection volume: 20 μL
- 이동상: 0.1% 인산 (트리에틸아민으로 적정된 pH 6.8) /아세토니트릴 = 50/50 (v/v)Mobile phase: 0.1% phosphoric acid (pH 6.8 titrated with triethylamine) / acetonitrile = 50/50 (v / v)
- 유속: 1.0 mL/분Flow rate: 1.0 mL / min
- 검출기: 자외부 흡광 광도계 (측정파장 240 nm)Detector: ultraviolet absorbance photometer (wavelength 240 nm)
시간time (hr)(hr) 메트포르민 용출률(%)Metformin Dissolution Rate (%)
실시예1Example 1 실시예2Example 2 실시예3Example 3
00 00 00 00
0.50.5 99 1010 1010
1One 1919 2020 1919
22 3737 3939 3636
33 4949 5151 4747
44 6161 6464 6060
66 7070 6969 6565
시간time (hr)(hr) 메트포르민 용출률(%)Metformin Dissolution Rate (%)
실시예8Example 8 실시예9Example 9 실시예10Example 10 실시예11Example 11
00 00 00 00 00
0.50.5 44 1010 1414 1616
1One 77 1818 2323 2727
22 1313 3535 4141 4444
33 1717 4848 5252 5656
44 2222 5858 6161 6565
66 3030 6767 7070 7878
시간time (hr)(hr) 메트포르민 용출률(%)Metformin Dissolution Rate (%)
실시예12Example 12 실시예13Example 13 실시예14Example 14 실시예15Example 15
00 00 00 00 00
0.50.5 88 99 66 88
1One 1717 2121 1818 2121
22 3737 3737 3939 4141
33 4949 5353 5050 5151
44 6161 6464 6262 6262
66 7070 6969 6767 6969
6시간에서 메트포르민의 용출 수준이 20% 이상, 80% 미만인 경우는 적합으로 판단하였으며, 상기 표 10 내지 12에서 나타낸 바와 같이 실시예 1 내지 3, 및 실시예 8 내지 15의 정제는 모두 우수한 용출 수준을 나타내는 것을 확인하였다.It was judged that the elution level of metformin of 20% or more and less than 80% at 6 hours was appropriate. It confirmed that it represents.

Claims (20)

  1. 다파글리플로진 L-프롤린 및 하나 이상의 항당뇨병제를 포함하는 약제학적 복합 제제.A pharmaceutical combination formulation comprising dapagliflozin L-proline and one or more antidiabetic agents.
  2. 제1항에 있어서, 상기 항당뇨병제는 메트포르민 또는 그의 약제학적으로 허용가능한 염인 약제학적 복합 제제.The pharmaceutical combination formulation of claim 1, wherein the antidiabetic agent is metformin or a pharmaceutically acceptable salt thereof.
  3. 제1항에 있어서, 상기 항당뇨병제는 DPP-IV 억제제 또는 그의 약제학적으로 허용가능한 염인 약제학적 복합 제제.The pharmaceutical combination formulation of claim 1, wherein the antidiabetic agent is a DPP-IV inhibitor or a pharmaceutically acceptable salt thereof.
  4. 제3항에 있어서, DPP-IV 억제제는 시타글립틴, 빌다글립틴, 삭사글립틴, 리나글립틴, 아나글립틴, 알로글립틴 및 제미글립틴으로 이루어진 군에서 하나 이상 선택되는 것을 특징으로 하는 약제학적 복합 제제.The method of claim 3, wherein the DPP-IV inhibitor is at least one selected from the group consisting of citagliptin, bilagliptin, saxagliptin, linagliptin, anagliptin, allogliptin and gemigliptin. Pharmaceutical combination formulation.
  5. 제1항에 있어서, 상기 다파글리플로진 L-프롤린은 다파글리플로진으로서 5 내지 20 mg을 포함하는, 약제학적 복합 제제.The pharmaceutical combination formulation of claim 1, wherein the dapagliflozin L-proline comprises 5 to 20 mg as dapagliflozin.
  6. 제2항에 있어서, 상기 다파글리플로진 L-프롤린은 다파글리플로진으로서 상기 메트포르민 및 그의 약제학상 허용가능한 염에 대하여 0.1 내지 10 중량 %로 포함되는 것을 특징으로 하는 약제학적 복합 제제.The pharmaceutical combination formulation of claim 2, wherein the dapagliflozin L-proline is included as dapagliflozin in an amount of 0.1 to 10% by weight relative to the metformin and its pharmaceutically acceptable salts.
  7. 제3항에 있어서, 상기 다파글리플로진 L-프롤린은 다파글리플로진으로서 상기 DPP-IV 억제제 및 그의 제약상 허용가능한 염에 대하여 5 내지 1,000 중량 %로 포함되는 것을 특징으로 하는 약제학적 복합 제제.4. The pharmaceutical composition according to claim 3, wherein the dapagliflozin L-proline is included as dapagliflozin in an amount of 5 to 1,000% by weight relative to the DPP-IV inhibitor and a pharmaceutically acceptable salt thereof. Complex formulations.
  8. 제1항에 있어서, 하나 이상의 항당뇨병제를 포함하는 제1 과립; 및 다파글리플로진 L-프롤린을 포함하는 약제학적 복합 제제.The method of claim 1, further comprising: a first granule comprising one or more antidiabetic agents; And dapagliflozin L-proline.
  9. 제8항에 있어서, 상기 항당뇨병제는 메트포르민, 시타글립틴, 빌다글립틴, 삭사글립틴, 리나글립틴, 아나글립틴, 알로글립틴, 제미글립틴 및 그의 약제학적으로 허용가능한 염으로 이루어진 군에서 하나 이상 선택되는 것을 특징으로 하는 약제학적 복합 제제.According to claim 8, wherein the anti-diabetic agent consists of metformin, citagliptin, bilagliptin, saxagliptin, linagliptin, anagliptin, allogliptin, gemigliptin and pharmaceutically acceptable salts thereof. A pharmaceutical combination formulation, characterized in that at least one selected from the group.
  10. 제8항에 있어서, 제1 과립은 하나 이상의 고분자중합체를 포함하는 것을 특징으로 하는 약제학적 복합 제제.The pharmaceutical composite formulation of claim 8, wherein the first granule comprises one or more polymers.
  11. 제10항에 있어서, 상기 고분자중합체는 하이드록시프로필메틸셀룰로오스(HPMC), 하이드록시프로필셀룰로오스(HPC), 저치환도 하이드록시프로필셀룰로오스(HPC-L), 정제 쉘락, 메타아크릴레이트중합체, 아크릴레이트공중합체, 천연검, 구아검, 트라가칸타, 아카시아검, 로커스트빈검 및 잔탄검으로 이루어진 군에서 하나 이상 선택되는 것을 특징으로 하는 약제학적 복합 제제.The method of claim 10, wherein the polymer is hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), low-substituted hydroxypropyl cellulose (HPC-L), tablet shellac, methacrylate polymer, acrylate A pharmaceutical complex preparation, characterized in that at least one selected from the group consisting of copolymers, natural gums, guar gum, tragacanta, acacia gum, locust bean gum and xanthan gum.
  12. 제1항에 있어서, The method of claim 1,
    하나 이상의 항당뇨병제를 포함하는 제1 과립, 및A first granule comprising one or more antidiabetic agents, and
    하나 이상의 활택제 또는 다파글리플로진 L-프롤린, 또는 활택제 및 다파글리플로진 L-프롤린을 포함하는 코어층; 및A core layer comprising one or more glidants or dapagliflozin L-proline, or a glidant and dapagliflozin L-proline; And
    상기 코어층을 코팅하는 코팅층을 포함하는 약제학적 복합 제제.A pharmaceutical composite formulation comprising a coating layer coating the core layer.
  13. 제12항에 있어서, 상기 항당뇨병제는 메트포르민, 시타글립틴, 빌다글립틴, 삭사글립틴, 리나글립틴, 아나글립틴, 알로글립틴, 제미글립틴 및 그의 약제학적으로 허용가능한 염으로 이루어진 군에서 하나 이상 선택되는 것을 특징으로 하는 약제학적 복합 제제.13. The antidiabetic agent according to claim 12, wherein the antidiabetic agent consists of metformin, citagliptin, bilagliptin, saxagliptin, linagliptin, anagliptin, allogliptin, gemigliptin and pharmaceutically acceptable salts thereof. A pharmaceutical combination formulation, characterized in that at least one selected from the group.
  14. 제12항에 있어서, 제1 과립은 하나 이상의 고분자중합체를 포함하는 것을 특징으로 하는 약제학적 복합 제제.13. The pharmaceutical composite formulation of claim 12, wherein the first granule comprises one or more polymers.
  15. 제14항에 있어서, 상기 고분자중합체는 하이드록시프로필메틸셀룰로오스(HPMC), 하이드록시프로필셀룰로오스(HPC), 저치환도 하이드록시프로필셀룰로오스(HPC-L), 정제 쉘락, 메타아크릴레이트중합체, 아크릴레이트공중합체, 천연검, 구아검, 트라가칸타, 아카시아검, 로커스트빈검 및 잔탄검으로 이루어진 군에서 하나 이상 선택되는 것을 특징으로 하는 약제학적 복합 제제.The method of claim 14, wherein the polymer is hydroxypropyl methyl cellulose (HPMC), hydroxypropyl cellulose (HPC), low-substituted hydroxypropyl cellulose (HPC-L), tablet shellac, methacrylate polymer, acrylate A pharmaceutical complex preparation, characterized in that at least one selected from the group consisting of copolymers, natural gums, guar gum, tragacanta, acacia gum, locust bean gum and xanthan gum.
  16. 제12항에 있어서, 상기 코팅층은 다파글리플로진 L-프롤린, 메트포르민, 시타글립틴, 빌다글립틴, 삭사글립틴, 리나글립틴, 아나글립틴, 알로글립틴, 제미글립틴 및 그의 약제학적으로 허용가능한 염으로 이루어진 군에서 선택된 하나 이상의 활성성분을 포함하는 것을 특징으로 하는 약제학적 복합 제제.The method of claim 12, wherein the coating layer is dapagliflozin L-proline, metformin, citagliptin, bilagliptin, saxagliptin, linagliptin, anagliptin, allogliptin, gemigliptin and medicament thereof A pharmaceutical combination formulation comprising at least one active ingredient selected from the group consisting of pharmaceutically acceptable salts.
  17. 제12항에 있어서, 상기 코팅층 중량은 상기 코어층 중량에 대하여 1 내지 20 중량%인 것을 특징으로 하는 약제학적 복합 제제.The pharmaceutical composite formulation of claim 12, wherein the coating layer weight is 1 to 20% by weight based on the weight of the core layer.
  18. 제1항에 있어서, 상기 제제가 경구투여 형태로 제형화되는 것을 특징으로 하는 약제학적 복합 제제.The pharmaceutical combination formulation of claim 1, wherein the formulation is formulated in oral dosage form.
  19. 제18항에 있어서, 상기 경구투여 형태는 정제 또는 캡슐제인 것을 특징으로 하는 약제학적 복합 제제.19. A combination pharmaceutical formulation according to claim 18, wherein said oral dosage form is a tablet or capsule.
  20. 제1항에 있어서, 당뇨병, 당뇨병 관련 질환 또는 당뇨병성 합병증의 예방 또는 치료를 위한 약제학적 복합 제제.The pharmaceutical combination formulation of claim 1 for the prevention or treatment of diabetes mellitus, diabetes related disease or diabetic complications.
PCT/KR2017/013690 2016-12-30 2017-11-28 Pharmaceutical composite preparation containing dapagliflozin l-proline and antidiabetic agent WO2018124497A1 (en)

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