WO2018097570A2 - Formulation pharmaceutique comprenant de la l-proline de dapagliflozine - Google Patents

Formulation pharmaceutique comprenant de la l-proline de dapagliflozine Download PDF

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Publication number
WO2018097570A2
WO2018097570A2 PCT/KR2017/013243 KR2017013243W WO2018097570A2 WO 2018097570 A2 WO2018097570 A2 WO 2018097570A2 KR 2017013243 W KR2017013243 W KR 2017013243W WO 2018097570 A2 WO2018097570 A2 WO 2018097570A2
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dapagliflozin
proline
pharmaceutical formulation
pharmaceutical
present
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Korean (ko)
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WO2018097570A3 (fr
Inventor
권세호
김재호
김진철
김용일
박재현
우종수
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Hanmi Pharmaceutical Co Ltd
Hanmi Pharmaceutical Industries Co Ltd
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Hanmi Pharmaceutical Co Ltd
Hanmi Pharmaceutical Industries Co Ltd
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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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • 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

Definitions

  • the present invention relates to a pharmaceutical formulation comprising dapagliflozin L-proline as an active ingredient exhibiting improved dissolution properties.
  • Diabetes is a disease that causes high blood sugar for a long time due to problems with insulin secretion, problems with insulin function, or a combination of both.
  • Insulin is a hormone secreted by the pancreatic beta cells, which help send glucose into cells to convert nutrients such as glucose in the blood into energy.
  • glucose does not enter the muscles or cells, accumulate in the blood, resulting in high blood sugar, and sugar in the urine.
  • Long-term hyperglycemia causes many complications in the microvascular system. These complications can result in amputation of the lower extremities and loss of vision.
  • Diabetes is one of the leading causes of adult death worldwide, and the number of diabetics is increasing rapidly with the increase in the obese population.
  • SGLT-2 selective inhibition of SGLT-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.
  • 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.
  • dapagliflozin L-proline is excellent in efficacy, but there is a problem in pharmaceutical compatibility, such as elution. Therefore, in order to increase the bioavailability of dapagliflozin, it is necessary to improve the content uniformity and dissolution characteristics of the pharmaceutical preparation including dapagliflozin L-proline, but still exhibit satisfactory characteristics. There is no development of pharmaceutical formulations.
  • the present inventors studied a method for improving the dissolution characteristics and the content uniformity of a pharmaceutical preparation including dapagliflozin L-proline, and as a result, the present invention was completed.
  • the present invention to solve the above problems
  • the d (0.9) particle size of the dapagliflozin L-proline provides a pharmaceutical formulation, characterized in that less than 60 ⁇ m.
  • the d (0.9) particle size of the dapagliflozin L-proline may be 1 ⁇ m or more and less than 30 ⁇ m.
  • the dapagliflozin L-proline may be included in less than 20% by weight of the total weight of the composition.
  • the dapagliflozin L-proline may be included in 0.1 to 10% by weight of the total weight of the composition.
  • the preparation may be formulated in an oral dosage form
  • the oral dosage form may be a tablet.
  • the dissolution rate of dapagliflozin L-proline within 15 minutes when the dissolution test in the pH 4.5 test solution according to the second method of the U.S. Pharmacopeia dissolution test item more preferably, Within 10 minutes, the dissolution rate of dapagliflozin L-proline can be at least 80%.
  • the pharmaceutical preparation may further include one or more drugs selected from the group consisting of diabetes treatment, diabetes complication treatment, hyperlipidemia treatment and hypertension treatment.
  • the medicament may be at least one diabetes treatment or diabetic complication.
  • the medicament may be at least one selected from the group consisting of metformin, citagliptin, bilagliptin, saxagliptin, linagliptin, anagliptin, allogliptin and gemigliptin.
  • the pharmaceutical preparation may be for the prevention or treatment of diabetes mellitus, diabetes related diseases and diabetic complications.
  • compositions containing dapagliflozin L-proline according to the present invention is excellent in the dissolution properties of the active ingredient, and exhibits high content uniformity. Therefore, the pharmaceutical preparations of the present invention can be used as a prophylactic or therapeutic agent for diabetes mellitus, diabetes-related diseases and diabetic complications having excellent quality and bioabsorption rate.
  • Figure 2 is a dissolution rate graph of the tablets of Examples 3, 4, Comparative Example 1, and 3.
  • the present invention includes dapagliflozin L-proline,
  • the d (0.9) particle size of the dapagliflozin L-proline provides a pharmaceutical formulation, characterized in that less than 60 ⁇ m.
  • Dapagliflozin L-proline that can be used in the present invention is a crystalline complex of formula (2).
  • the dapagliflozin L-proline of the invention may be a 1: 2 crystalline complex.
  • the particle size of the drug is expressed based on the particle size distribution.
  • the d (0.9) particle size indicates the particle size distribution of the drug obtained by measuring the particle diameter of the drug by a cumulative curve. It means the particle diameter of 90%.
  • the particle size of dapagliflozin L-proline can be performed using a commercially available apparatus based on the laser diffraction and scattering method based on Mie theory.
  • a commercially available apparatus such as HELOS (Helium-neon Laser for Optical Spectrometry, Sympatec company) laser diffraction apparatus.
  • HELOS Helium-neon Laser for Optical Spectrometry, Sympatec company
  • the measuring method can be any of a dry method and a wet method, the following example showed the result measured using the dry method.
  • the d (0.9) particle size of the dapagliflozin L-proline is less than 60 ⁇ m, preferably less than 30 ⁇ m, and more preferably 1 to 20 ⁇ m.
  • the particle size of dapagliflozin L-proline in the present invention preferably satisfies the above range.
  • the method for controlling the particle size of the dapagliflozin L-proline is not particularly limited, and a method known in the art may be appropriately selected.
  • the chlorthalidone is a conventional mill capable of micronizing particles such as a jet mill, a hammer mill, a ball mill, a fluid energy mill, and the like. Can be crushed.
  • a size classification method such as a sieve method or air current classification performed using a sieve may be used to subdivide the particle size of the drug.
  • the particle size of dapagliflozin L-proline was adjusted using a jet mill.
  • the dose of dapagliflozin L-proline may vary depending on the age, sex, weight, severity, and route of administration of the patient, but in general, dapagliflozin based on an adult (weight: 60 kg) As an amount of 5 to 10 mg per day.
  • the pharmaceutical formulation of the present invention comprises dapagliflozin L-proline up to 20% by weight of the total weight of the composition, more preferably from 0.1 to 10% by weight.
  • the pharmaceutical preparation of the present invention contains dapagliflozin L-proline as an active ingredient, and is added to the conventional pharmaceutically acceptable carrier, additives, excipients, etc.
  • it may be formulated into oral or parenteral preparations such as tablets, capsules, beads, beadlets, granules, pills, troches, solutions, suspensions and the like.
  • Solid preparations for oral administration may be prepared by mixing at least one additive, such as excipients, disintegrants, binders, glidants and the like with dapagliflozin L-proline.
  • additives such as excipients, disintegrants, binders, glidants and the like with dapagliflozin L-proline.
  • lactose lactose monohydrate
  • microcrystalline cellulose mannitol
  • sodium citrate calcium phosphate
  • glycine starch or a combination thereof
  • disintegrant examples include crospovidone, pregelatinized starch, corn starch, methylcellulose, hydroxypropylmethylcellulose, sodium starch glyconate, croscarmellose sodium, low-substituted hydroxypropylcellulose, starch, pregelatinized Starch, alginic acid or its sodium salt or combinations thereof can be used.
  • binder for example, polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), copovidone, macrogol, hard silicic anhydride, synthetic aluminum silicate, calcium silicate, magnesium metasilicate Aluminate, calcium hydrogen phosphate, sucrose, gelatin, acacia gum or combinations thereof can be used.
  • lubricant for example, silicon dioxide, palmitic acid, talc (talc), magnesium stearate, zinc stearate, calcium stearate or a combination thereof may be used.
  • suspending agents As a liquid preparation for oral administration, suspending agents, liquid solutions, emulsions, syrups and the like are used. In addition to water and liquid paraffin, which are commonly used simple diluents, various additives such as wetting agents, sweeteners, fragrances, and preservatives may also be used.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories, and the like.
  • non-aqueous solvent or suspension solvent examples include vegetable oils such as propylene glycol, polyethylene glycol and olive oil; Injectable esters such as ethyl oleate and the like can be used, and suppositories, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin and the like can be used for the suppository.
  • the pharmaceutical formulation of the present invention may further include a pH adjusting agent, suspending agent, preservative, flavoring agent, colorant, sweetening agent, adsorbent, solubilizer and the like as necessary.
  • a pH adjusting agent suspending agent, preservative, flavoring agent, colorant, sweetening agent, adsorbent, solubilizer 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.
  • the pharmaceutical formulation of the present invention may be in oral dosage form, and the oral dosage form is not particularly limited in the present invention, but may be, for example, in the form of capsules, tablets, beads, beadlets, granules or pills. .
  • the oral dosage form may be a tablet.
  • the tablet is dapagliflo within 15 minutes of the dissolution test in a pH 4.5 test solution according to the second method of the U.S. Pharmacopoeia Dissolution Test.
  • the dissolution rate of gin L-proline may be 80% or more, and more preferably, the dissolution rate may be 80% or more within 10 minutes.
  • the second method of the US Pharmacopeia dissolution test item means a paddle method (Paddle)
  • pH acetate test solution may be used as a sodium acetate (Sodium Acetate) solution.
  • the pharmaceutical formulation of the present invention can be adjusted to the d (0.9) particle size of dapagliflozin L-proline is less than 60 ⁇ m, it can exhibit such excellent dissolution properties, according to the pharmaceutical formulation of the present invention is an excellent biological It can show the water absorption.
  • the pharmaceutical formulation of the present invention described above may be prepared by a manufacturing method comprising mixing dapagliflozin L-proline and a pharmaceutically acceptable additive.
  • the tablet is prepared by mixing Dapagliflozin L-proline and a pharmaceutically acceptable additive to form granules and tableting the granules into tablets. It can be manufactured by the method.
  • 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.
  • the tablet may be prepared by mixing dapagliflozin L-proline and excipients to prepare primary dry granules; Preparing a final granule by mixing the primary dry granules with a disintegrant and a lubricant; And it may be prepared by a manufacturing method comprising the step of tableting the final granules as a tablet.
  • a manufacturing method comprising the step of tableting the final granules as a tablet.
  • the excipient may preferably be a mixture of mannitol, microcrystalline cellulose and lactose, the content of the excipient may be included in 80 to 90% by weight of the total weight of the tablet.
  • crospovidone may be used as the disintegrant
  • a mixture of silicon dioxide and magnesium stearate may be used as a lubricant.
  • the disintegrant and lubricant may be included in 0.1 to 5% by weight of the total weight of the tablet.
  • the pharmaceutical formulation comprising the dapagliflozin L-proline of the present invention may be selected from sustained or immediate release.
  • the sustained release means that the release of the active ingredient occurs slowly, including the base used for the purpose of sustained release in addition to the active ingredient, the immediate release means that the active ingredient is released immediately.
  • the pharmaceutical formulations of the present invention described above can be used for the prevention or treatment of diseases or conditions mediated by hyperglycemia such as diabetes, diabetes related diseases and diabetic complications by inhibiting SGLT activity.
  • Such diabetes includes insulin dependent diabetes mellitus (type I diabetes) and insulin independent diabetes mellitus (type II diabetes), and also includes other forms of diabetes due to certain causes.
  • diabetes-related diseases include obesity, hyperinsulinemia, abnormal glucose metabolism, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism abnormality, hypertension, congestive heart failure, edema, hyperuricemia, gout and the like. However, it is not limited to these.
  • the diabetic complications include both acute and chronic complications.
  • Examples of the acute complications include hyperglycemia (ketoassissis and the like) and diabetic infections (skin infection, soft tissue infection, biliary tract infection, respiratory infection, urinary tract infection and the like).
  • hyperglycemia ketoassissis and the like
  • diabetic infections skin infection, soft tissue infection, biliary tract infection, respiratory infection, urinary tract infection and the like.
  • the chronic complications include diabetic microangiopathy (nephropathy, renal failure, retinopathy, etc.), diabetic arteriosclerosis (atherosclerosis, myocardial infarction, cerebral infarction, lower limb artery occlusion), diabetic neuropathy (sensory neuropathy, motor nerve) Disorders, autonomic neuropathy), and diabetic foot ulcers.
  • diabetic microangiopathy nephropathy, renal failure, retinopathy, etc.
  • diabetic arteriosclerosis arteriosclerosis
  • myocardial infarction myocardial infarction, cerebral infarction, lower limb artery occlusion
  • diabetic neuropathy sensor neuropathy, motor nerve
  • autonomic neuropathy autonomic neuropathy
  • Major diabetic complications include, but are not limited to, diabetic retinopathy, diabetic renal failure, diabetic neuropathy.
  • dapagliflozin L-proline of the present invention may be used in combination with one or more therapeutic agents selected from anti-diabetic agents, diabetic complications, hyperlipidemia agents, hypertensive agents, etc., in addition to inhibitors of SGLT activity.
  • an insulin sensitivity enhancer for example, an insulin sensitivity enhancer, an ⁇ -glucosidase inhibitor, a biguanide compound, an insulin secretagogue, an insulin preparation, a glucagon receptor antagonist, an insulin receptor kinase promoter , Tripeptidyl peptidase II inhibitors, dipeptidyl peptidase IV inhibitors, protein tyrosine phosphatase 1B inhibitors, glycogenphosphorylase inhibitors, glucose-6-phosphatase inhibitors, tetracycline inhibitors, fructose bisphosphatase inhibitors, pyruvic acid dehydro Genease inhibitors, glucokinase activators, D-chiroinositol, glycogen-like peptide-1 agonists, amilines, amiline flexibles, amiline agonists, glucocorticoid receptor antagonists, 11 ⁇ -hydroxysteroid dehydrogenase inhibitors,
  • the following drugs can be exemplified as the diabetes treatment agent and the diabetic complication treatment agent, but are not limited thereto.
  • Examples of the biguanide compound include metformin hydrochloride and phenformin.
  • sulfonylureas include, for example, glybide (glybenclamide), glyphidede, glyclazide, chloropropamide, and the like, and non-sulfonylurea compounds include nateglinide, repaglinide, Mitiglinide etc. are mentioned.
  • the insulin preparations include recombinant human insulin and animal derived insulin. It is classified into three types according to the time of action, specifically, the immediate effect type (human insulin, human neutral insulin), the intermediate type (insulin-human isopeninsulin aqueous suspension, human neutral insulin-human isopeninsulin aqueous suspension, human insulin zinc) Aqueous suspension, insulin zinc aqueous suspension), sustained form (human crystalline insulin zinc suspension).
  • ⁇ -glucosidase inhibitor examples include acarbose, bogribose, migritol and the like.
  • insulin sensitivity enhancer examples include triglitazone, pioglitazone, rosiglitazone, MK-767 (KRP-297), tesaglitazar, LM4156, LY510929, TY-51501, GW-501516, and the like.
  • dipeptidyl peptidase IV inhibitors examples include citagliptin, chanagliptin, saxagliptin, linagliptin, anagliptin, allogliptin, gemigliptin, and the like.
  • aldose reductase inhibitor examples include ascorbic acid, ascorbyl, tolestart, epalestat, fidarestat, solvinyl, ponalestat, risarastat, and genarestat.
  • Topiramate etc. are mentioned as said (alpha)-aminobutyric-acid acceptor antagonist.
  • sodium channel antagonists examples include mexyl hydrochloride and the like.
  • Dexlipotam etc. are mentioned as said transcription factor NF- (alpha) B inhibitor.
  • lipid peroxidase inhibitors examples include mesylic acid tyrilazad.
  • GPI-5693 etc. are mentioned as said N-acetylation- (alpha) -binding-acid-dipeptidase inhibitor.
  • carnitine derivatives examples include carnitine, levasecarnin hydrochloric acid, and the like.
  • an antihyperlipidemic agent and an antihypertensive agent which can be used together it is a hydroxymethyl glutaryl coenzyme A reductase inhibitor, a fibrate type compound, the (alpha) 3- adrenergic receptor agonist, an AMPK activator, an acylcoenzyme A: Cholesterol acyl transferase inhibitors, probe calls, thyroid hormone receptor agonists, cholesterol absorption inhibitors, lipase inhibitors, microsomtriglyceride transfer protein inhibitors, lipoxygenase inhibitors, carnitine palmitoyltransferase inhibitors, squalene synthetase inhibitors, low specific gravity lipo Protein receptor promoters, nicotinic acid derivatives, bile acid adsorbents, sodium conjugated bile acid transporter inhibitors, cholesterol ester transport protein inhibitors, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, endothelin
  • the following drugs can be exemplified as the hyperlipidemia treatment agent and the hypertension treatment agent, but are not limited thereto.
  • Provastatin, lovastatin, pravastatin, cerivastatin, pitavastatin, etc. are mentioned as said hydroxymethyl glutaryl coenzyme A reductase inhibitor.
  • fibrate-based compound examples include fenofibrate, bezafibrate, becrobrate, and vinifibrate.
  • squalene synthetase inhibitor examples include TAK-475 and ⁇ -phosphonosulfonate derivatives (see US Patent No. 5712396).
  • acylcoenzyme A cholesterol acyl group transfer enzyme inhibitor
  • examples of the acylcoenzyme A cholesterol acyl group transfer enzyme inhibitor include CI-1011, NTE-122, FCE-27677, RP-73163, MCC-147, and DPU-129.
  • MD-700 As said low specific gravity lipoprotein receptor promoter, MD-700, LY-295427, etc. are mentioned.
  • microsomtriglyceride transfer protein inhibitors examples include compounds disclosed in US Pat. No. 5,39,135, US Pat. No. 5,572,279, US Pat.
  • appetite suppressant examples include adrenergic-noradrenergic agonists (margindol, ephedrine, etc.), serotonin agonists (selective serotonin reinhibitor inhibitors, e.g. fluvoxamine, etc.), adrenergic-serotonin agonists (sibutramine, etc.), melano Cortin 4 receptor (MC4R) agonists, ⁇ -melanosite stimulating hormone ( ⁇ -MSH), leptin, cocaine and amphetamine-regulated transcripts (CART), and the like.
  • adrenergic-noradrenergic agonists margindol, ephedrine, etc.
  • serotonin agonists selective serotonin reinhibitor inhibitors, e.g. fluvoxamine, etc.
  • adrenergic-serotonin agonists e.g. fluvoxamine, etc.
  • thyroid hormone receptor agonists examples include lyothyronine sodium, repotyroxine sodium, and the like.
  • Ezetimibe etc. are mentioned as said cholesterol absorption inhibitor.
  • carnitine palmitoyl transferase inhibitor examples include etmokysyl and the like.
  • nicotinic acid derivatives examples include nicotinic acid, nicotinic acid amide, nicomol, and nicorandil.
  • angiotensin-converting enzyme inhibitor examples include capryl, maleic acid enalapril, alacepril, silazapril, and the like.
  • anziontensin II receptor antagonist examples include candesaltanexetyl, potassium losaltan, mesyl acid eprosaltan and the like.
  • the dapagliflozin L-proline of the present invention in the treatment of diabetes and the like, an insulin sensitivity enhancer, an ⁇ -glucosidase inhibitor, a biguanide compound, an insulin secretagogue, an insulin preparation, and a dipeptidyl peptidida Combination with at least one drug selected from the group consisting of the IV inhibitors is preferred.
  • the dapagliflozin L-proline of the present invention is selected from the group consisting of metformin, citagliptin, chanagliptin, saxagliptin, linagliptin, anagliptin, allogliptin and gemigliptin It may be used in combination with at least one agent.
  • the combination with at least 1 type of agent chosen from the group which consists of a real transfer enzyme inhibitor, a low specific gravity lipoprotein receptor promoter, a microsomtriglyceride transfer protein inhibitor, and an appetite suppressant is preferable.
  • the present invention provides a method of preventing or treating diabetes mellitus, diabetes related diseases and diabetic complications of a mammal comprising administering to the mammal the above-described pharmaceutical agent in an effective amount.
  • a tablet comprising a dapagliflozin L-proline 1: 2 crystalline complex (Hanmi Precision, Korea) with different particle sizes in the composition of Table 1.
  • the particle size unit of dapagliflozin L-proline is ⁇ m.
  • Crospovidone, silicon dioxide 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. Tablets containing pagliflozin L-proline were prepared.
  • Example 1 Example 2
  • Example 3 Example 4
  • Raw materials including 1st dry granule Dapagliflozin L-Proline 0.1 ⁇ d (0.1) ⁇ 1 15.6 - - - 1 ⁇ d (0.5) ⁇ 10 5 ⁇ d (0.9) ⁇ 10 0.1 ⁇ d (0.1) ⁇ 1 - 15.6 - - 1 ⁇ d (0.5) ⁇ 10 10 ⁇ d (0.9) ⁇ 30 0.1 ⁇ d (0.1) ⁇ 1 - - 15.6 - 1 ⁇ d (0.5) ⁇ 10 30 ⁇ d (0.9) ⁇ 60 0.1 ⁇ d (0.1) ⁇ 1 - - - 15.6 10 ⁇ d (0.5) ⁇ 30 30 ⁇ d (0.9) ⁇ 60 Mannitol 100.0 100.0 100.0 100.0 100.0 100.0
  • Raw granules included Crospovidone 10.0 10.0 10.0 10.0 Silicon dioxide 3.4 3.4 3.4 3.4 Magne
  • Dapagliflozin tablets were prepared in the same manner as in Table 2 and Example 1 using dapagliflozin L-proline having a d (0.9) particle size of 60 ⁇ m or more.
  • the particle size unit of dapagliflozin L-proline is ⁇ m.
  • Dissolution time (minutes) 0 5 10 15 20 30 Dissolution rate (%)
  • Example 1 0 63 91 97 100 100
  • Example 2 0 56 86 94 98 100
  • Example 3 0 49 79 89 95 99
  • Example 4 0 48
  • 80 91 94 97 Comparative Example 1 0 35 58 78 88 94 Comparative Example 2 0 29 54 70 79 88 Comparative Example 3 0 32 59 76 85 91
  • Examples 1 and 2 having a d (0.9) particle size of dapagliflozin L-proline of less than 30 ⁇ m showed a dissolution rate of 85% or more in 10 minutes, showing very excellent dissolution properties.
  • the pharmaceutical formulation of the present invention having a controlled particle size can improve the dissolution properties and increase the in vivo absorption rate of dapagliflozin, and exhibits high content uniformity. It can be used as a preventive or therapeutic agent for complications.

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Abstract

La présente invention concerne une formulation pharmaceutique comprenant de la L-proline de dapagliflozine. La formulation pharmaceutique comprenant de la L-proline de dapagliflozine selon la présente invention présente d'excellentes propriétés de dissolution d'agents actifs et une uniformité de contenu élevée. Par conséquent, la formulation pharmaceutique comprenant de la L-proline de dapagliflozine selon la présente invention peut être utilisée en tant qu'agent préventif ou thérapeutique, qui a une excellente qualité et une excellente biodisponibilité, pour le diabète, les maladies associées au diabète et les complications diabétiques.
PCT/KR2017/013243 2016-11-24 2017-11-21 Formulation pharmaceutique comprenant de la l-proline de dapagliflozine Ceased WO2018097570A2 (fr)

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KR1020160157550A KR20180058510A (ko) 2016-11-24 2016-11-24 다파글리플로진 l-프롤린을 포함하는 약제학적 제제

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Cited By (4)

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CN110922372A (zh) * 2019-11-04 2020-03-27 天津大学 达格列净的氨基酸共晶物及其制备方法
CN117120037A (zh) * 2021-04-14 2023-11-24 株式会社Lg化学 包含具有受控粒度的鞘氨醇-1-磷酸酯受体激动剂的药物组合物
WO2024037221A1 (fr) * 2022-08-17 2024-02-22 扬子江药业集团上海海尼药业有限公司 Procédé de mesure de la dimension des particules d'agent pharmaceutique actif de dapagliflozine
EP4162929A4 (fr) * 2020-07-10 2024-07-24 Hanmi Pharm. Co., Ltd. Formulation composite comprenant de la sitagliptine et de la dapagliflozine, et son procédé de préparation

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CN110922372A (zh) * 2019-11-04 2020-03-27 天津大学 达格列净的氨基酸共晶物及其制备方法
EP4162929A4 (fr) * 2020-07-10 2024-07-24 Hanmi Pharm. Co., Ltd. Formulation composite comprenant de la sitagliptine et de la dapagliflozine, et son procédé de préparation
CN117120037A (zh) * 2021-04-14 2023-11-24 株式会社Lg化学 包含具有受控粒度的鞘氨醇-1-磷酸酯受体激动剂的药物组合物
WO2024037221A1 (fr) * 2022-08-17 2024-02-22 扬子江药业集团上海海尼药业有限公司 Procédé de mesure de la dimension des particules d'agent pharmaceutique actif de dapagliflozine

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