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WO2020009352A1 - Préparation pharmaceutique contenant de la dapagliflozine/l-proline amorphe et son procédé de préparation - Google Patents

Préparation pharmaceutique contenant de la dapagliflozine/l-proline amorphe et son procédé de préparation Download PDF

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Publication number
WO2020009352A1
WO2020009352A1 PCT/KR2019/007360 KR2019007360W WO2020009352A1 WO 2020009352 A1 WO2020009352 A1 WO 2020009352A1 KR 2019007360 W KR2019007360 W KR 2019007360W WO 2020009352 A1 WO2020009352 A1 WO 2020009352A1
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Prior art keywords
coating layer
dapagliflozin
proline
present
metformin
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Ceased
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PCT/KR2019/007360
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English (en)
Korean (ko)
Inventor
김형서
조정현
김용일
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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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Publication of WO2020009352A1 publication Critical patent/WO2020009352A1/fr
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Ceased legal-status Critical Current

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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
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to a combination comprising metformin and dapagliflozin as an active ingredient. More specifically, the present invention relates to a composite agent containing metformin and dapagliflozin as an active ingredient and having an excellent dissolution pattern and improved bioavailability.
  • 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
  • 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 represented by the following formula (1) and is disclosed in US Pat. No. 6,515,117.
  • Diabetes is a chronic disease, and its condition is complicated, so the symptoms of the disease often progress with various complications, and the nature of the disease requires long-term administration of the drug. 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, it is often difficult to select a drug in the clinical field.
  • the dissolution rate is lowered due to the problem of stability due to the interaction of two or more drugs, or the dissolution rate of each component is lower than that of the single agent. Problems may arise.
  • Patent Document 1 US Patent No. 6,515,117
  • the present invention provides a core comprising metformin or a pharmaceutically acceptable salt thereof; And it provides a composite comprising a coating layer comprising amorphous dapagliflozin L-proline.
  • the present invention is a core comprising a metformin or a pharmaceutically acceptable salt thereof; And it provides a method for producing a composite comprising a coating layer comprising amorphous dapagliflozin L-proline.
  • the present invention is a.
  • a core comprising metformin or a pharmaceutically acceptable salt thereof
  • a composite comprising a coating layer comprising amorphous dapagliflozin L-proline.
  • the coating layer is
  • a second coating layer formed on the first coating layer is formed on the first coating layer
  • the second coating layer may include amorphous dapagliflozin L-proline.
  • the core may include metformin hydrochloride.
  • the combination may be for the prevention or treatment of diabetes mellitus, diabetes-related diseases or diabetes complications.
  • the present invention is a.
  • a core comprising metformin or a pharmaceutically acceptable salt thereof
  • a method of providing a composite comprising a coating layer comprising amorphous dapagliflozin L-proline.
  • the second coating layer may be formed using a coating solution prepared by dissolving a co-crystal of dapagliflozin L-proline in at least one solvent selected from the group consisting of C1 to C4 alcohols and acetone of straight or branched chains. .
  • the solvent may further include water.
  • the coating layer may be formed by using a coating solution prepared by dissolving a co-crystal of dapagliflozin L-proline in at least one solvent selected from the group consisting of C1 to C4 alcohol and acetone of straight or branched chain.
  • the present invention is a combination comprising metformin and dapagliflozin L-proline, despite the fact that two components having different mechanisms of action are included in one unit dosage form, the initial dissolution of dapagliflozin is remarkably excellent. Bioavailability can be improved. As a result, the effects of dapagloflozin and metformin can be maximized while minimizing side effects and significantly improving patient convenience.
  • 1 is a view showing the appearance of the coating liquid used in the preparation of the tablets of the Examples and the tablets of the Comparative Examples.
  • FIG. 2 is a view showing a powder XRD pattern for the coating layer formed by the coating liquid used in the preparation of the tablets of the examples.
  • Figure 3 is a view showing a powder XRD pattern for the coating layer formed by the coating liquid used in the manufacture of the tablets of the comparative examples.
  • Figure 5 shows the dissolution of dapagliflozin in the tablets of Examples and Comparative Examples.
  • the terms such as the first and the second are only used to distinguish the various layers, the films, the steps, and the like, respectively, but are not intended to indicate the order or the importance.
  • the terminology does not limit the features of layers, films, steps, and the like. Therefore, the terms such as the first and the second may not be used the same in the detailed description of the invention, the examples, the claims, and the like. .
  • ⁇ pharmaceutically acceptable '' means a pharmacologically acceptable autologous pharmaceutical agent having ordinary skill in the art without causing any allergic reactions such as gastrointestinal disorders, dizziness or similar reactions when administered to humans. It may mean that the conventional use in the manufacture.
  • the term 'complex' refers to a molecule in which dapagliflozin, metformin or a pharmaceutically acceptable salt thereof is combined with another molecule having no pharmacological activity by intermolecular force, and thus another molecule having no pharmacological activity. It may be included in an amount, and may specifically include a co-crystal, a solvate or a hydrate thereof as well as an amorphous form of the complex.
  • the complex of dapagliflozin can be an amorphous form of dapagliflozin complex, cocrystal of dapagliflozin, dapagliflozin solvate, dapagliflozin hydrate or mixtures thereof
  • it may be a co-crystal or amorphous dapagliflozin L-proline of dapagliflozin L-proline.
  • 'co-crystal' refers to the stoichiometric amount of a co-tablet as the intermolecular force of dapagliflozin, metformin, or a pharmaceutically acceptable salt thereof and the like in a solid state, rather than a liquid, at room temperature. It may include. Specifically, the co-crystal may include from about 0.25 mole to about 10 molar ratio of coformer based on 1 mole of active ingredient, and more specifically about 0.5 mole, about 1 mole, about 1.5 mole, about 2 mole, about 2.5 moles, about 3 moles, about 5 moles, and the like.
  • the 'solvate' is that dapagliflozin, metformin, or a pharmaceutically acceptable salt thereof, and the like, are bound by intermolecular force with a solvent other than water, and may include a stoichiometric amount of the solvent.
  • the solvate may include a solvent molecule in a ratio of about 0.25 mol to about 10 mol based on 1 mol of the active ingredient, more specifically about 0.5 mol, about 1 mol, about 1.5 mol, and about 2 mol , About 2.5 moles, about 3 moles, about 5 moles, and the like.
  • the term “hydrate” refers to having a stoichiometric amount of water in which dapagliflozin, metformin, or a pharmaceutically acceptable salt thereof, and water are bound by non-covalent intermolecular force.
  • the hydrate may include about 0.25 moles to about 10 moles of water based on 1 mole of the active ingredient, and more specifically about 0.5 moles, about 1 moles, about 1.5 moles, about 2 moles, about 2.5 moles, about 3 moles, about 5 moles, and the like.
  • 'comprising dapagliflozin as an active ingredient means' dapagliflozin itself (crystalline or amorphous), or a complex of dapagliflozin (amorphous, co-crystal, hydrate or solvate, Or mixtures thereof).
  • a layer comprising dapagliflozin as an active ingredient may comprise dapagliflozin itself or a complex of dapagliflozin (amorphous, co-crystal, hydrate or solvate, or mixtures thereof). It may refer to the containing layer.
  • 'including metformin as an active ingredient' may mean 'comprising metformin free base or a pharmaceutically acceptable salt thereof'.
  • 'layer comprising metformin as an active ingredient' may refer to a layer including a free base of metformin or a pharmaceutically acceptable salt thereof.
  • the present invention is a.
  • a core comprising metformin or a pharmaceutically acceptable salt thereof
  • a composite comprising a coating layer comprising amorphous dapagliflozin L-proline.
  • the composite agent of the present invention shows excellent dissolution rate for dapagliflozin.
  • the complex of the present invention is remarkably excellent in the initial dissolution of dapagliflozin, and can improve the bioavailability.
  • the effects of dapagloflozin and metformin can be maximized while minimizing side effects and significantly improving patient convenience.
  • the composite agent of the present invention may exhibit excellent stability.
  • the preparation according to the present invention is remarkably excellent in content uniformity if it shows a sufficient content during formulation.
  • dapagliflozin L-proline contained in the coating layer may be a compound represented by the following formula (2).
  • x is 1 or 2
  • y is 0 to 1.
  • x may be 2
  • y may be 0.
  • Metformin is a biguanide antihyperglycemic agent used to treat insulin-independent diabetes mellitus (type II). 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 release of insulin, reduces the amount of insulin in the blood, and also protects blood vessels. In addition, since it reduces fat in the body and does not cause hypoglycemia, it is a drug suitable for use in patients who do not have ideal blood sugar control as obesity, hyperlipidemia or food control.
  • the pharmaceutically acceptable salt of metformin may be an acid addition salt of metpromin.
  • the pharmaceutically acceptable salt of metformin may be hydrochloride, succinate, fumarate, methanesulfonate, benzenesulfonate or toluenesulfonate, but is not limited thereto. More specifically, it may be metformin hydrochloride.
  • the co-formulation of the present invention may include unitary amorphous dapagliflozin L-proline and metformin hydrochloride.
  • the composite agent of the present invention may include metformin hydrochloride in the core and the coating layer may include amorphous dapagliflozin L-proline.
  • a coating layer containing amorphous dapagliflozin L-proline may be directly formed on a core including metformin as an active ingredient.
  • the core may include granules containing metformin as an active ingredient, the granules may be formed by wet granulation.
  • the granules included in the core may further include a polymer.
  • the polymer is hydroxypropyl methyl 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, or mixtures thereof.
  • the polymer may be HPMC 2208, HPMC 2910, HPC-L, locust bean gum or mixtures thereof, and more specifically HPMC 2208, HPMC 2910, locust bean gum or mixtures thereof.
  • the coating layer is
  • It includes a second coating layer formed on the first coating layer
  • the second coating layer may include amorphous dapagliflozin L-proline, and the first coating layer may not include a pharmacologically active ingredient.
  • the composite agent of the present invention may include the following configurations.
  • a core comprising metformin or a pharmaceutically acceptable salt thereof
  • a second coating layer formed on the first coating layer and containing amorphous dapagliflozin L-proline.
  • the first coating layer may not include a component exhibiting pharmacological activity.
  • the first coating layer may include a coating base of hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinylpyrrolidone-polyethylene glycol graft polymer or mixtures thereof, and more specifically, It may include a coating base of oxypropyl methyl cellulose, polyethylene glycol or a mixture thereof.
  • the first coating layer does not include a pharmacologically active ingredient, and may function to separate metformin and Dapagliflozin L-proline contained in the second coating layer as an active ingredient in the core, and stabilize the composite. You can improve even more.
  • the second coating layer may further include a coating base of hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinylpyrrolidone-polyethylene glycol graft polymer or mixtures thereof.
  • it may further include a coating base of polyvinylpyrrolidone, polyvinylpyrrolidone-polyethylene glycol graft polymer or a mixture thereof.
  • the present invention provides amorphous dapagliflozin L-proline.
  • the present invention provides a solid dispersion comprising amorphous dapagliflozin L-proline and a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier may be hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinylpyrrolidone-polyethylene glycol graft polymer or mixtures thereof, specifically polyvinylpyrrolidone , Polyvinylpyrrolidone-polyethylene glycol graft polymer or mixtures thereof.
  • the solid dispersion comprising the amorphous dapagliflozin L-proline or dapagliflozin L-proline of the present invention may exhibit excellent initial dissolution of dapagliflozin when included in the formulation, and shows excellent bioavailability. Can be represented. Therefore, the solid dispersion containing dapagliflozin L-proline or dapagliflozin L-proline of the present invention can maximize the efficacy of dapagliflozin while minimizing side effects and significantly improving the convenience of patient medication. have.
  • the combination may exhibit a prophylactic or therapeutic effect of diabetes mellitus, diabetes related diseases or diabetic complications.
  • the combination may include about 100 mg to 3000 mg of metformin or a pharmaceutically acceptable salt thereof as metformin, and about 2 mg of dapagliflozin L-proline as dapagliflozin. To 30 mg. Specifically, the combination may include about 500 mg to 2000 mg of metformin or a pharmaceutically acceptable salt thereof as metformin, and about 5 mg to 20 mg of dapagliflozin L-proline as dapagliflozin. . For example, the combination may include about 500 mg to 2000 mg of metformin or a pharmaceutically acceptable salt thereof as metformin and about 5 mg to 20 mg of dapagliflozin per unit formulation.
  • the pharmaceutical combination of the invention may be prepared by adding conventional pharmaceutically acceptable carriers, excipients, binders, disintegrants, and the like, such as conventional formulations such as tablets, capsules, Oral or parenteral preparations, such as beads, powders, beadlets, granules, pills, troches, solutions, suspensions, and the like, specifically, oral preparations, and more specifically, May be formulated into tablets, capsules, powders, and the like, and even more specifically, into tablets.
  • conventional pharmaceutically acceptable carriers such as tablets, capsules, Oral or parenteral preparations, such as beads, powders, beadlets, granules, pills, troches, solutions, suspensions, and the like, specifically, oral preparations, and more specifically, May be formulated into tablets, capsules, powders, and the like, and even more specifically, into tablets.
  • 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.
  • Binders include polyvinylpyrrolidone derivatives such as povidone and copovidone, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, cellulose derivatives such as sodium carboxymethylcellulose, starch, gelatin, and the like. no.
  • 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 coating layer may further include a stabilizer
  • the second coating layer including the amorphous dapagliflozin L-proline may further include a stabilizer
  • the stabilizer may be butyl hydroxytoluene, propyl gallate, sodium hydrogen carbonate, magnesium carbonate, calcium carbonate, meglumine, sodium citrate or mixtures thereof, but is not limited thereto.
  • the combination may be administered once to several times a unit dosage form, specifically, once a day to three times a day, more specifically once a day or one day It may be administered twice, more specifically once a day, but is not limited thereto and may be appropriately adjusted according to the condition of the patient.
  • the present invention provides a core comprising metformin or a pharmaceutically acceptable salt thereof; A first coating layer formed on the core; And a second coating layer formed on the first coating layer and including an amorphous dapagliflozin L-proline.
  • the second coating layer is formed using a coating solution prepared by dissolving dapagliflozin L-proline in at least one solvent selected from the group consisting of straight or branched C1 to C4 alcohol and acetone. .
  • a composite agent exhibiting excellent dissolution properties, bioavailability and stability can be easily produced by a simple process.
  • the method also shows good yields and is suitable for mass production.
  • the straight or branched C1 to C4 alcohol may be methanol, ethanol or linear or branched propanol or a mixture thereof, specifically ethanol, isopropanol or a mixture thereof. have.
  • the coating liquid for the second coating layer may not include water.
  • the coating liquid for the second coating layer may further include water.
  • the coating solution may be prepared by adding dapagliflozin L-proline to a mixed solvent including at least one organic solvent and water selected from the group consisting of C1 to C4 alcohols and acetone of straight or branched chains.
  • the mixed solvent may be a mixed solvent including water and at least one organic solvent selected from ethanol, isopropanol and acetone.
  • the solvent used in the preparation of the coating liquid for the second coating layer is a mixed solvent containing an organic solvent and water
  • the mixed solvent is 1 to 6: 1 to 10 of the organic solvent and water. It may be included as a volume ratio of, more specifically, may be included in a volume ratio of 2 to 5: 1 to 8, and more specifically may be included in a volume ratio of 4: 1 to 6.
  • the coating solution for the second coating layer is a crystalline complex of Dapagliflozin L-proline (L-proline co-crystal of dapagliflozin) represented by the formula (2) It can be added to form.
  • x is 1 or 2
  • y is 0 to 1.
  • x may be 2
  • y may be 0.
  • the coating liquid for the second coating layer may be in a solution state in which all the added materials are dissolved. Therefore, the coating layer formed using the coating liquid contains an amorphous form of dapagliflozin L-proline regardless of whether the added form of dapagliflozin L-proline is crystalline.
  • the coating liquid for the second coating layer may further comprise hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinylpyrrolidone-polyethylene glycol graft polymer or mixtures thereof. And, more specifically, it may further include hydroxypropyl methyl cellulose, polyethylene glycol or a mixture thereof.
  • the first coating layer may not include a pharmacologically active material.
  • the first coating layer is a coating liquid prepared by adding a coating base to a mixed solvent of organic solvents such as C1 to C4 alcohol, acetone or a mixture of linear or branched chains such as methanol, ethanol, isopropanol, n-propanol, and water Can be formed.
  • the coating base may include hydroxypropyl methyl cellulose, polyvinylpyrrolidone, polyethylene glycol, polyvinylpyrrolidone-polyethylene glycol graft polymer or mixtures thereof, and specifically, hydroxypropyl methyl cellulose, polyethylene glycol Or mixtures thereof.
  • the step of manufacturing the core is a step of manufacturing the core
  • the granules may be prepared by a wet granulation method.
  • the present invention provides a core comprising metformin or a pharmaceutically acceptable salt thereof; And it relates to a method for producing a composite comprising a coating layer comprising amorphous dapagliflozin L-proline.
  • the coating layer is formed by using a coating solution prepared by dissolving dapagliflozin L-proline in at least one solvent selected from the group consisting of linear or branched C1 to C4 alcohols and acetone.
  • a composite agent exhibiting excellent dissolution properties, bioavailability and stability can be easily produced by a simple process.
  • the method also shows good yields and is suitable for mass production.
  • compositions included in the coating layer of the present invention, the coating liquid used for manufacturing the coating layer, components contained in the coating liquid, etc. may be the same as the case of the second coating layer described above.
  • the present invention provides a core comprising metformin or a pharmaceutically acceptable salt thereof; A first coating layer formed on the core; And it provides a pharmaceutical composition for treating or preventing diabetes, diabetes-related diseases or diabetic complications comprising a second coating layer formed on the first coating layer and comprising amorphous dapagliflozin L-proline.
  • the present invention provides a core comprising metformin or a pharmaceutically acceptable salt thereof; A first coating layer formed on the core; And a second coating layer formed on the first coating layer and comprising a second coating layer comprising amorphous dapagliflozin L-proline in a therapeutically effective amount to treat diabetes, diabetes related diseases or diabetic complications.
  • a method of preventing or treating Provide a method of preventing or treating.
  • the present invention provides a core comprising metformin or a pharmaceutically acceptable salt thereof; A first coating layer formed on the core; And a second coating layer formed on the first coating layer and including a second coating layer including amorphous dapagliflozin L-proline, for preventing or treating diabetes, diabetes related diseases, or diabetic complications.
  • Metformin hydrochloride is mixed with hypromellose 2208 (HPMC2208), hypromellose 2910 (HPMC2910) and locust bean gum, and then combined with purified water using a high shear coalescing machine to form a 20 mesh sieve. Primary granules were prepared.
  • the final granules were prepared by adding and mixing silicon dioxide and magnesium stearate to the primary granules.
  • the final granules were prepared using a rotary tablet press (GRC-18, Sejong Machinery, Korea) to prepare a core tablet containing metformin hydrochloride.
  • a coating solution prepared by dissolving hypromellose 2910 (HPMC 2910) and polyethylene glycol (PEG 6000) in a mixed solvent of ethanol and water was prepared with a coating machine (SFC-30F, Sejong Pharmatech, Korea).
  • the coating solution mixed in the composition of Table 2 to the tablet prepared in Preparation Example 1 was coated using a coating machine (SFC-30F, Sejong Pharmatech, Korea), dapagliflozin L-proline 15.6mg (dapagle The combined tablets of Examples 1 to 7 containing 10 mg) as riflozin were prepared.
  • the coating solution was prepared by dissolving the rolledone (K-30) in a mixed solvent of an organic solvent (one selected from ethanol, acetone and isopropyl alcohol) and water to prepare a composite by coating using a coating machine.
  • a composite tablet of Comparative Examples 1 to 4 was prepared by forming a coating layer in the same manner as in Example except that the coating solution was prepared in the composition and content of Table 3.
  • the coating liquid used in the preparation of the tablets of the Example of Table 2 and the coating liquid used in the preparation of the tablets of the comparative example of Table 3 were prepared and their properties were confirmed, and the results are shown in FIG. 1.
  • the coating solution having the composition shown in Table 2 was found to form a transparent solution by dissolving all the added materials in a solvent.
  • the coating solution having the composition shown in Table 3 was in an opaque state because the added material did not dissolve, and it was found that the added dapagliflozin L-proline did not melt to form a gel.
  • the coating liquid having the composition of Table 2 of Examples 1 to 7 and Table 3 of Comparative Examples 1 to 4 was sprayed onto a petri dish surface and dried to form a coating film on the petri dish. After the membrane was separated from the Petri dish, the crystalline form was confirmed according to the following conditions using an X-ray Powder Diffractometer (Bruker, D8 Advance) on the separated coating membrane. Dapagliflozin L-proline used in the preparation of the coating solution was also confirmed the crystal form using the X-ray Powder Diffractometer.
  • the powder XRD pattern showed a halo pattern. It can be seen from this that the coating layer formed from the coating liquid according to Table 2 of Examples 1 to 7 does not contain a crystalline form, and thus the coating layer formed from the coating liquid according to Table 2 contains an amorphous form of dapagliflozin L-proline. there was.
  • the coating layer formed from the coating liquid according to Table 3 of Comparative Examples 1 to 4 contained dapagliflozin L-proline cocrystal.
  • the composite according to Examples 1 to 7 the content of dapagliflozin reached within 95% to 105%, there was little variation in content between formulations.
  • the composites of Comparative Examples 1 to 4 were found to have a content of dapagliflozin of 85% or less, and the content variation between the formulations was significantly higher than that of the tablets of the examples.
  • the composite according to the present invention showed a content result suitable for development into a formulation, but the tablet according to the comparative example was found to be inappropriate to develop into a formulation.
  • the composites of Examples 1 to 7 showed a very rapid dissolution rate of dissolution rate of 60% or more until 5 minutes. The elution up to 15 minutes also exceeded 90%.
  • the composite agents of Comparative Examples 1 to 4 showed a lower dissolution rate than the composite agents of Examples 1 to 7 with a dissolution rate of 45% or less up to 5 minutes.

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Abstract

La présente invention concerne une préparation combinée contenant de la metformine et de la dapagliflozine/L-proline. La présente invention peut améliorer remarquablement la commodité d'administration de médicament puisque le taux de dissolution et la biodisponibilité de la dapagliflozine sont excellents et sa stabilité est élevée.
PCT/KR2019/007360 2018-07-06 2019-06-18 Préparation pharmaceutique contenant de la dapagliflozine/l-proline amorphe et son procédé de préparation Ceased WO2020009352A1 (fr)

Applications Claiming Priority (2)

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WO2022119540A3 (fr) * 2020-12-03 2022-08-04 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Procédé pour formulations de dapagliflozine et de chlorhydrate de metformine
WO2023136797A3 (fr) * 2022-01-13 2023-08-17 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Composition de comprimé bicouche comprenant de la metformine et de la dapagliflozine amorphe
WO2025106043A1 (fr) * 2023-11-14 2025-05-22 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Composition de comprimé bicouche comprenant de la dapagliflozine et de la metformine

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