WO2018124497A1 - Préparation compisite pharmaceutique contenant de la dapagliflozine l-proline et un agent antidiabétique - Google Patents

Préparation compisite pharmaceutique contenant de la dapagliflozine l-proline et un agent antidiabétique Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
dapagliflozin
proline
pharmaceutical
formulation
pharmaceutically acceptable
Prior art date
Application number
PCT/KR2017/013690
Other languages
English (en)
Korean (ko)
Inventor
권세호
탁진욱
김진철
김용일
박재현
우종수
Original Assignee
한미약품 주식회사
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 한미약품 주식회사 filed Critical 한미약품 주식회사
Publication of WO2018124497A1 publication Critical patent/WO2018124497A1/fr

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—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

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une préparation composite pharmaceutique contenant de la dapagliflozine L-proline et au moins un agent antidiabétique. De façon spécifique, la présente invention concerne une préparation composite pharmaceutique contenant de la dapagliflozine L-proline et, en plus, de la metformine et/ou un inhibiteur de DPP-IV, et concerne une préparation composite ayant d'excellentes propriétés d'uniformité de contenu et d'élution ainsi qu'une biodisponibilité élevée.
PCT/KR2017/013690 2016-12-30 2017-11-28 Préparation compisite pharmaceutique contenant de la dapagliflozine l-proline et un agent antidiabétique WO2018124497A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR20160184036 2016-12-30
KR10-2016-0184036 2016-12-30

Publications (1)

Publication Number Publication Date
WO2018124497A1 true WO2018124497A1 (fr) 2018-07-05

Family

ID=62710641

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2017/013690 WO2018124497A1 (fr) 2016-12-30 2017-11-28 Préparation compisite pharmaceutique contenant de la dapagliflozine l-proline et un agent antidiabétique

Country Status (2)

Country Link
KR (1) KR102240240B1 (fr)
WO (1) WO2018124497A1 (fr)

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021176096A1 (fr) 2020-03-05 2021-09-10 Krka, D.D., Novo Mesto Composition pharmaceutique comprenant un inhibiteur du sglt2
WO2021245253A1 (fr) 2020-06-05 2021-12-09 Krka, D.D., Novo Mesto Préparation de dapagliflozine amorphe très pure
CN114173766A (zh) * 2019-08-07 2022-03-11 诺和诺德股份有限公司 包含glp-1激动剂、sglt2抑制剂和n-(8-(2-羟基苯甲酰基)氨基)辛酸的盐的固体组合物
WO2023012817A1 (fr) * 2021-07-31 2023-02-09 Unison Pharmaceuticals Pvt. Ltd. Composition pharmaceutique comprenant une combinaison de dapagliflozine et de sitagliptine
TWI826841B (zh) * 2020-10-13 2023-12-21 南韓商Ｌｇ化學股份有限公司 包含格米列汀與達格列淨的口服組合製劑及其製備方法
EP4082532A4 (fr) * 2019-12-24 2024-03-13 Hanmi Pharm Ind Co Ltd Formulation complexe comprenant de la sitagliptine et de la dapagliflozine, et son procédé de préparation
EP4112047A4 (fr) * 2020-03-30 2024-03-27 Hanmi Pharmaceutical Co Ltd Comprimé oral complexe comprenant de la sitagliptine, de la dapagliflozine et de la metformine

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20220007446A (ko) * 2020-07-10 2022-01-18 한미약품 주식회사 시타글립틴 및 다파글리플로진을 포함하는 복합제제 및 그 제조방법

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008002824A1 (fr) * 2006-06-28 2008-01-03 Bristol-Myers Squibb Company Solvates cristallins et complexes de dérivés de (is)-1,5-anhydro-l-c-{3-[(phényl)méthyl]phényl}-d-glucitol avec des acides aminés en tant qu'inhibiteurs de sglt2 pour le traitement du diabète
US20130034606A1 (en) * 2009-11-13 2013-02-07 Astrazeneca Uk Limited Immediate release tablet formulations
WO2014030051A1 (fr) * 2012-08-23 2014-02-27 Aurobindo Pharma Limited Compositions pharmaceutiques stables comprenant de la saxagliptine
US20150238421A1 (en) * 2009-11-13 2015-08-27 Astrazeneca Ab Bilayer Tablet Formulations
WO2016147197A1 (fr) * 2015-03-17 2016-09-22 Harman Finochem Limited Nouveau procédé de préparation de (2s,3r,4r,5s,6r)-2-[4-chloro-3-(4-éthoxybenzyl)phényl]-6-(hydroxyméthyl)tétrahydro-2h-pyran-3,4,5-triol et sa forme amorphe
US20160347731A1 (en) * 2014-02-10 2016-12-01 Jiangsu Hansoh Pharmaceutical Group Co., Ltd. Dapagliflozin crystalline form and preparation method thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008002824A1 (fr) * 2006-06-28 2008-01-03 Bristol-Myers Squibb Company Solvates cristallins et complexes de dérivés de (is)-1,5-anhydro-l-c-{3-[(phényl)méthyl]phényl}-d-glucitol avec des acides aminés en tant qu'inhibiteurs de sglt2 pour le traitement du diabète
US20130034606A1 (en) * 2009-11-13 2013-02-07 Astrazeneca Uk Limited Immediate release tablet formulations
US20150238421A1 (en) * 2009-11-13 2015-08-27 Astrazeneca Ab Bilayer Tablet Formulations
WO2014030051A1 (fr) * 2012-08-23 2014-02-27 Aurobindo Pharma Limited Compositions pharmaceutiques stables comprenant de la saxagliptine
US20160347731A1 (en) * 2014-02-10 2016-12-01 Jiangsu Hansoh Pharmaceutical Group Co., Ltd. Dapagliflozin crystalline form and preparation method thereof
WO2016147197A1 (fr) * 2015-03-17 2016-09-22 Harman Finochem Limited Nouveau procédé de préparation de (2s,3r,4r,5s,6r)-2-[4-chloro-3-(4-éthoxybenzyl)phényl]-6-(hydroxyméthyl)tétrahydro-2h-pyran-3,4,5-triol et sa forme amorphe

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114173766A (zh) * 2019-08-07 2022-03-11 诺和诺德股份有限公司 包含glp-1激动剂、sglt2抑制剂和n-(8-(2-羟基苯甲酰基)氨基)辛酸的盐的固体组合物
EP4082532A4 (fr) * 2019-12-24 2024-03-13 Hanmi Pharm Ind Co Ltd Formulation complexe comprenant de la sitagliptine et de la dapagliflozine, et son procédé de préparation
WO2021176096A1 (fr) 2020-03-05 2021-09-10 Krka, D.D., Novo Mesto Composition pharmaceutique comprenant un inhibiteur du sglt2
EP4112047A4 (fr) * 2020-03-30 2024-03-27 Hanmi Pharmaceutical Co Ltd Comprimé oral complexe comprenant de la sitagliptine, de la dapagliflozine et de la metformine
WO2021245253A1 (fr) 2020-06-05 2021-12-09 Krka, D.D., Novo Mesto Préparation de dapagliflozine amorphe très pure
TWI826841B (zh) * 2020-10-13 2023-12-21 南韓商Ｌｇ化學股份有限公司 包含格米列汀與達格列淨的口服組合製劑及其製備方法
WO2023012817A1 (fr) * 2021-07-31 2023-02-09 Unison Pharmaceuticals Pvt. Ltd. Composition pharmaceutique comprenant une combinaison de dapagliflozine et de sitagliptine

Also Published As

Publication number Publication date
KR20180079176A (ko) 2018-07-10
KR102240240B1 (ko) 2021-04-14

Similar Documents

Publication Publication Date Title
WO2018124497A1 (fr) Préparation compisite pharmaceutique contenant de la dapagliflozine l-proline et un agent antidiabétique
US11426388B2 (en) Controlled release pharmaceutical formulations of nitazoxanide
WO2014142616A1 (fr) Préparation à libération prolongée de mosapride pour fournir des effets cliniques pharmacologiques avec une administration une fois par jour
WO2019117502A1 (fr) Préparation composite pour comprimé à noyau comprenant du mosapride et du rabéprazole
WO2019146937A1 (fr) Composition pharmaceutique stable comprenant de l'ésoméprazole et du bicarbonate de sodium
WO2016105084A2 (fr) Composition pharmaceutique pour le traitement du diabète
WO2019059557A2 (fr) Composition médicinale comprenant un inhibiteur de sglt-2 et un bloqueur du récepteur de l'angiotensine
WO2018097570A2 (fr) Formulation pharmaceutique comprenant de la l-proline de dapagliflozine
WO2021201461A1 (fr) Comprimé oral complexe comprenant de la sitagliptine, de la dapagliflozine et de la metformine
EP2648730A2 (fr) Formulation complexe contenant de l'hydrochlorure de lercanidipine et du valsartan et son procédé de préparation
WO2013032206A1 (fr) Composition orale à libération prolongée contenant du chlorhydrate d'itopride, et procédé de préparation associé
WO2024043358A1 (fr) Formulation composite orale comprenant de l'évogliptine et de la metformine, et son procédé de préparation
WO2022080815A1 (fr) Formulation orale composite comprenant de la gemigliptine et de la dapagliflozine et son procédé de préparation
WO2019098540A1 (fr) Formulation ayant une propriété hygroscopique et une vitesse de dissolution améliorées comportant du telmisartan ou son sel pharmaceutiquement acceptable
WO2021118004A1 (fr) Formulation complexe comprenant du donépézil et de la mémantine
CN114712488A (zh) Dorzagliatin和胰高血糖素样肽-1类似物的药物组合物
WO2022034944A1 (fr) Formulation composite pour le traitement du diabète sucré de type 2

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17886383

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17886383

Country of ref document: EP

Kind code of ref document: A1