WO2016161995A1 - Formes solides de dapagliflozine amorphe - Google Patents

Formes solides de dapagliflozine amorphe Download PDF

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Publication number
WO2016161995A1
WO2016161995A1 PCT/CZ2016/000037 CZ2016000037W WO2016161995A1 WO 2016161995 A1 WO2016161995 A1 WO 2016161995A1 CZ 2016000037 W CZ2016000037 W CZ 2016000037W WO 2016161995 A1 WO2016161995 A1 WO 2016161995A1
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WO
WIPO (PCT)
Prior art keywords
composition
dapagliflozin
accordance
amorphous
urea
Prior art date
Application number
PCT/CZ2016/000037
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English (en)
Inventor
Iva OBADALOVA
Ondrej Dammer
Lukas KREJCIK
Jakub Hert
Hana TOZICKOVA
Original Assignee
Zentiva, K.S.
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Publication of WO2016161995A1 publication Critical patent/WO2016161995A1/fr

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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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • 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
    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • the invention relates to new solid forms of amorphous dapagliflozin of formula I, their preparation methods and use in a dosage form. These solid forms can be advantageously used to increase the chemical and polymorphic stability of amorphous dapagliflozin.
  • Dapagliflozin is a highly selective inhibitor of SGLT2 (sodium glucose co-transporter 2), which is responsible for renal reuptake of glucose. Inhibition of SGLT2 by means of dapagliflozin leads to increased excretion of glucose by the kidneys and to subsequent reduction of glycaemia and improvement of diabetes compensation.
  • dapagliflozin is approved in Europe for administration to type 2 diabetic patients in monotherapy (in case of intolerance to metformin), or in combination with other antidiabetics, including insulin.
  • Administration of dapagliflozin leads not only to an improvement of diabetes compensation, but also to a slight reduction of the body weight and reduction of the blood pressure. What is advantageous is its quite unique mechanism of action, complementary to the effect of other types of antidiabetic treatment, as well as the fact that administration of dapagliflozin does not cause hypoglycaemia.
  • Dapagliflozin is first mentioned in the patent application WO2001027128, which does not mention any details of the character of the solid form of the product.
  • the patent application WO2002083066 describes preparation of cocrystals of dapagliflozin with (L)-proline and (L)- phenylalanine.
  • the amorphous form of dapagliflozin is described by the patent applications WO2003099836, WO2004063209 and WO2013064909.
  • the application WO2008002824 describes a crystalline monohydrate of an ( ⁇ -propylene glycol solvate of dapagliflozin and the patent application WO2013079501 describes crystalline hydrates of dapagliflozin (hydrate and dihydrate). Disclosure of Invention
  • the amorphous form of dapaghflozin is easy obtainable by various preparatory processes.
  • the glass transition temperature of amorphous dapaglifiozin is low. At higher temperatures and increased relative humidity the amorphous form of dapaglifiozin is not stable and its recrystallization and chemical degradation may occur.
  • solid solutions and dispersions with chemicals can be used that provide a higher glass transition value and thus higher chemical and polymorphic stability.
  • Chemical compounds that can be used in this manner comprise polymers, copolymers, saccharides, oligosaccharides, polysaccharides, fats, waxes and urea, and preferably polymers.
  • the prepared solid solution or solid dispersion then exhibits higher polymorphic and chemical stability at elevated temperatures and increased relative humidity.
  • the invention provides a composition in the form of a melt, containing dapaglifiozin and at least one pharmaceutical excipient.
  • the selection of the excipient for this rnixture is governed by the requirement for stability of the end product.
  • a suitable excipient is such that will make the glass transition temperature of the final mixture higher than 40°C, preferably higher than 70°C.
  • Preferred excipients are especially hydroxypropyl cellulose, hydroxypropyl methylcellulose, hypromellose acetate succinate, povidone PVP K30, SoluplusTM, PEG 6000, copovidone VA64, D (+) glucose, D (+) saccharose or urea.
  • a crystalline solid substance is characterized by a regular long-distance structure arrangement. On the other hand, amorphous solid substances do not exhibit this arrangement.
  • the molecular arrangement of an amorphous solid substance may be represented by "frozen liquid" with rheological properties of a solid substance.
  • a solid composition consisting at least of two components - the pharmaceutically active ingredient (API) and another at least one chemical compound (matrix), can have several forms.
  • the matrix for API stabilization is considered to consist of one component only. In fact, this matrix may consist of one, two, or more components (chemical compounds).
  • components of a matrix for solid compositions compounds of the type of polymers, copolymers, saccharides, oligosaccharides, polysaccharides, fats, waxes or urea can be preferably used.
  • solid dispersion represents a solid composition of a pharmaceutically active ingredient (API) that is dispersed in a matrix, said matrix manifesting a crystalline character.
  • API pharmaceutically active ingredient
  • a typical "amorphous solid dispersion” then represents a solid composition, where the pharmaceutically active ingredient and the matrix show an amorphous character in XRPD.
  • this "amorphous solid dispersion” exhibits at least two glass transitions (Tg), one for the dispersed component (pharmaceutically active ingredient) and the other one for the matrix, the number of Tg's depending on the number of the components of the matrix.
  • amorphous solid substances As mentioned above, compared to crystalline solid substances, amorphous solid substances have a different internal structure and a larger surface area, and therefore they exhibit a higher solubility. If the solubility and bioavailability of pharmaceutically active substances needs to be increased, it is preferable to prepare them in an amorphous form.
  • the glass transition temperature is advantageous for the glass transition temperature to be at least 20°C, preferably 30°C and most preferably at least 40°C above the temperature of the actual storage conditions.
  • the amorphous form of the API should be preferably stabilized by increasing of the glass transition temperature (Tg) to prevent re-crystallization and chemical degradation.
  • the glass transition temperature of amorphous dapaghflozin is 24°C and in its non-stabilized condition it is subject to chemical degradation during storage at an elevated temperature and humidity.
  • the amorphous form of dapagliflozin should be preferably stabilized by increasing of the glass transition temperature (Tg) to prevent chemical degradation and recrystallization.
  • Tg glass transition temperature
  • the prepared solid mixture then exhibits higher polymorphic and chemical stability at elevated temperatures and increased relative humidity.
  • a possibility of stabilizing amorphous dapagliflozin consists in creating solid compositions with polymers, copolymers, saccharides, oligosaccharides, polysaccharides, fats, waxes and urea, preferably especially with polymers.
  • These polymers may come from the group of polymers that are soluble or insoluble in water.
  • Typical water-soluble polymers for stabilization of dapagliflozin are polyvinyl pyrrolidone (povidone), copovidone, polyvinyl alcohol, hydroxypropyl methylcellulose (hypromellose), hydroxypropyl cellulose, polyethylene glycol, copolymers of polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol (SoluplusTM) and the like.
  • Typical water-insoluble polymers for stabilization of dapagliflozin are methylcellulose, ethylcellulose, polymethacrylates, hypromellose phthalate, hypromellose succinate, hypromellose acetate succinate (HPMCAS), cellulose acetate phthalate, carboxymethyl cellulose and the like.
  • An advantage of these polymers is the fact that their solubility is dependent on the pH value of the solution and their use makes it possible to influence releasing of the pharmaceutically active ingredient depending on pH of the alimentary tract.
  • One of the preparation methods of stabilized amorphous forms of dapagliflozin consists in the dissolution process.
  • the active substance is dissolved in a solvent or in any mixture of solvents.
  • the solvent may be water or any organic solvent.
  • a substance stabilizing the active pharmaceutical ingredient is added to this solution or suspension.
  • the solvent is quickly removed and amorphous solid matter is produced.
  • the solvent can be removed by means of a rotary vacuum evaporator, fluid granulation, spray drying, electrospinning, solvent freeze-drying etc.
  • Other options of preparation of stabilized amorphous substances are methods without the use of a solvent In these processes the active pharmaceutical ingredient (dapagliflozm) is mixed with a stabilizing substance (for example, a polymer).
  • This mixture is heated up and melted, producing a melt.
  • Common temperatures for the formation of a melt vary in the range of 20°C - 40°C above the Tg temperature, where the mixture is melted and has a suitable viscosity for its processing.
  • the melt is subsequently cooled down, which produces an amorphous solid substance.
  • Hot melt extrusion, hot melt granulation, high shear mixer, fluid bed granulation without the use of a solvent etc. may be mentioned as some examples of these processes.
  • This invention focuses on the preparation of a pharmaceutical composition containing dapagliflozin with polymers, copolymers, saccharides, oligosaccharides, polysaccharides, fats, waxes and urea, preferably especially with polymers.
  • polymers for the preparation of polymer stabilized amorphous solid forms of dapagliflozin the following polymers can be advantageously used: polyvinyl pyrrolidone (PVP), copovidone ( ollidon VA64), hydroxypropyl celluloses (Klucel), hydroxypropyl methylcelluloses (Methocel), derivatized hydroxypropyl methylcelluloses (e.g. HP C AS), polymethacrylate derivatives (Eudragit LI 00, Eudragit SI 00) and copolymers of polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol (SoluplusTM).
  • polymers in this invention are polyvinyl pyrrolidone (PVP K30) with the molecular weight of approximately 50,000 Da (g mol), Methocel E5 (HPMC) with the molecular weight of approximately 22,000 Da (g/mol), Eudragit S100 with the molecular weight of approximately 125,000 Da (g/mol), copovidone (Kollidon VA64), hydroxypropyl cellulose (HPC, Klucel), SoluplusTM and hypromellose acetate succinate (HPMC AS-LF).
  • PVP K30 polyvinyl pyrrolidone
  • HPMC Methocel E5
  • Eudragit S100 with the molecular weight of approximately 125,000 Da (g/mol)
  • copovidone Kerdon VA64
  • HPC hydroxypropyl cellulose
  • SoluplusTM and hypromellose acetate succinate HPMC AS-LF.
  • glucose, saccharose, galactose or urea can be advantageously used.
  • the differential scanning calorimetry (DSC) measurement makes it possible to distinguish a solid dispersion and a solid solution.
  • a solid solution an amorphous solid only exhibits one glass transition value (Tg) in the record.
  • Tg glass transition value
  • the prepared amorphous solids in the weight ratio of 1 : 2 (API : polymer) formed stable solid solutions whose stability increases with an increasing Tg value (Hancock and Zografi, 1997).
  • Load tests were used to check and compare stability of amorphous dapagliflozin and prepared solid solutions.
  • the glass transition temperature of amorphous dapagliflozin is 24°C.
  • solid solutions with different glass transition temperatures were selected, namely 76.9°C (Copovidone VA64) and 106.7°C (PVP K30).
  • Amorphous dapagliflozin is chemically unstable and under high temperature and humidity load the molecule gets degraded and the contents of impurities increases. Its chemical purity degraded from the original 96.7% (HPLC) to 95.4% (HPLC). In term of polymorphic purity, amorphous dapagliflozin is stable and is not subject to recrystallization (see Table 2).
  • Amorphous dapagliflozin stabilized in the form of a solid solution with Copovidone VA64 exhibits polymorphic stability under load conditions and no crystallization of the API occurs as in the case of non-stabilized amorphous dapagliflozin.
  • Composition in the form of a solid solution with copovidone VA64 has a positive influence on chemical stability of dapagliflozin (see Table 3).
  • Amorphous dapagliflozin stabilized in the form of a solid solution with PVP K30 exhibits polymorphic stability under load conditions and only being exposed to extreme humidity (10 days, 100% humidity), partial crystallization of the API occurs.
  • Chemical stability of amorphous dapagliflozin is also significantly improved by composition in the solid solution form and significant increase of the contents of impurities only occurs in case of extreme exposure to humidity (10 days, 100% humidity) (see Table 4).
  • Amorphous dapagiiflozin can also be stabilized by means of saccharides, oligosaccharides, polysaccharides, fats, waxes or urea.
  • D-glucose, D-saccharose or urea were tested.
  • D-glucose and urea generally occur in their crystalline form; therefore, in combination with dapagiiflozin D-glucose and urea do not form typical solid solutions, but solid dispersions wherein the amorphous API (dapagiiflozin) is dispersed in a crystalline matrix (D- glucose or urea).
  • the X-ray powder pattern then, besides the amorphous halo of the API (dapaglifiozin), shows a visible crystalline form of d-glucose (fig. 17).
  • Tg 24.2°C
  • Tm 122,3 °C
  • the X-ray powder pattern then, besides the amorphous halo (dapaglifiozin), shows a visible crystalline form of urea (fig. 19).
  • the prepared amorphous solid substances containing dapaglifiozin, stabilized by polymers, saccharides, oligosaccharides, polysaccharides or urea in accordance with this invention can be used for the preparation of pharmaceutical compositions, especially solid drug forms, e.g. tablets.
  • Such pharmaceutical mixtures can contain at least one excipient from the group of fillers (e.g. lactose), binders (e.g. microcrystalline cellulose), disintegrants (e.g. sodium salt of croscarmellose), lubricants (e.g. magnesium stearate), surfactants etc.
  • These tablets can be coated with common coating compounds, e.g. polyvinyl alcohol or polyethylene glycol.
  • Fig. 1 DSC record of the solid solution of dapaglifiozin - HPC
  • Fig.2 DSC record of the solid solution of dapaglifiozin - HPMC
  • Fig. 3 DSC record of the solid solution of dapaglifiozin - HPMC AS
  • Fig. 4 DSC record of the solid solution of dapaglifiozin - PVP K30
  • Fig. 5 DSC record of the amorphous solid dispersion of dapaglifiozin - PVP K30
  • Fig. 6 DSC record of the solid solution of dapaglifiozin - SoluplusTM
  • Fig. 7 DSC record of the solid solution of dapaglifiozin - Copovidone VA64
  • Fig. 8 DSC record of the amorphous solid dispersion of dapaglifiozin - D-(+)-glucose
  • Fig. 9 DSC record of the solid solution of dapaglifiozin - D-(+)-saccharose
  • Fig. 10 DSC record of the solid dispersion of dapaglifiozin - urea
  • Fig. 11 XRPD pattern of the solid solution of dapaglifiozin - HPC
  • Fig. 12 XRPD pattern of the solid solution of dapagliflozin - HPMC
  • Fig. 13 XRPD pattern of the solid solution of dapagliflozin - HPMC AS
  • Fig. 14 XRPD pattern of the solid solution of dapagliflozin - PVP K30
  • Fig. 15 XRPD pattern of the solid solution of dapagliflozin - SoluplusTM
  • Fig. 16 XRPD pattern of the solid solution of dapagliflozin - Copovidone VA64
  • Fig. 17 XRPD pattern of the solid dispersion of dapagliflozin - D-(+)-glucose
  • Fig. 18 XRPD pattern of the solid solution of dapagliflozin - D-(+)-saccharose
  • Fig. 19 XRPD pattern of the solid dispersion of dapagliflozin - urea Examples
  • Amorphous dapagliflozin was prepared according to the procedure published in the patent application WO2003099836.
  • the chemical purity of dapagliflozin prepared this way was 96.7% (HPLC).
  • the following ingredients were placed into a homogenizer: solid solution of dapagliflozin - povidone PVP 30, anhydrous lactose, microcrystalline cellulose, ollidon CL and water. The mixture was homogenized for 15 min at 20 rpm. Finally, magnesium stearate and S1O2 was added and the mixture was homogenized for another 3 min at 20 rpm.
  • the tabletting matter produced in the above mentioned way was compressed in a rotary tabletting machine and used for the production of cores with the approximate weight of 270 mg.
  • the obtained cores may possibly be coated (a mixture of hypromellose, PEG, talc, titanium dioxide, iron oxide).
  • the primary optical equipment programmable divergence slits with the irradiated area of the sample of 10 mm, 0.02 rad Soller slits and a 1 ⁇ 4° anti-diffusion slit were used.
  • For the setting of the secondary optical equipment an X'Celerator detector with maximum opening of the detection slot, 0.02 rad Soller slits and a 5.0 mm anti-diffusion slit were used.
  • the records of differential scanning calorimetry were measured using a Discovery DSC device made by TA Instruments.
  • the sample charge in a standard Al pot (40 ⁇ .) was between 4-5 and 5 mg and the heating rate was 5°C/min,
  • As the carrier gas 5.0 N 2 was used at the flow of 50 ml/min.

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Abstract

L'invention concerne une composition sous la forme d'une masse fondue, contenant de la dapagliflosine et au moins un excipient pharmaceutique. La sélection de l'excipient pour ce mélange est gouvernée par le besoin de stabilité du produit final. Un excipient est considéré convenable si ce dernier permet une température de transition vitreuse du mélange final supérieure à 40 °C et préférablement supérieure à 70 °C. Les excipients de choix sont en particulier l'hydroxypropyle cellulose, l'hydroxypropyl méthylcellulose, l'hypromellose acétate succinate, la povidone PVP K30, le Soluplus™, le PEG 6000, la copovidone VA64, le D (+) glucose, le D (+) saccharose ou l'urée.
PCT/CZ2016/000037 2015-04-08 2016-04-07 Formes solides de dapagliflozine amorphe WO2016161995A1 (fr)

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CZPV2015-240 2015-04-08
CZ2015240 2015-04-08

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11020412B2 (en) 2017-03-16 2021-06-01 Inventia Healthcare Limited Pharmaceutical composition comprising dapagliflozin
WO2021165316A1 (fr) 2020-02-21 2021-08-26 Zakłady Farmaceutyczne POLPHARMA S.A. Composition pharmaceutique comprenant de la dapagliflozine
EP4008317A1 (fr) * 2020-12-03 2022-06-08 Sanovel Ilac Sanayi Ve Ticaret A.S. Formulations pharmaceutiques solides de dapagliflozine amorphe
WO2022119543A1 (fr) * 2020-12-03 2022-06-09 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Procédé de préparation de comprimés comprenant de la dapagliflozine amorphe et du chlorhydrate de metformine
CN116421595A (zh) * 2023-02-21 2023-07-14 深圳市新阳唯康科技有限公司 一种达格列净药物组合物及制备方法和应用
EP4061378A4 (fr) * 2019-11-20 2023-12-06 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Composition pharmaceutique solide comprenant de la dapagliflozine amorphe isolée à partir d'un solvant polaire

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WO2015011113A1 (fr) * 2013-07-22 2015-01-29 Sandoz Ag Formulations contenant de la dapagliflozine amorphe
WO2015104658A2 (fr) * 2014-01-08 2015-07-16 Dr. Reddy’S Laboratories Limited Dispersion solide amorphe de dapagliflozine et procédé pour la préparation de dapagliflozine amorphe

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WO2013079501A1 (fr) 2011-11-28 2013-06-06 Sandoz Ag Hydrate de dapagliflozine cristallin
WO2015011113A1 (fr) * 2013-07-22 2015-01-29 Sandoz Ag Formulations contenant de la dapagliflozine amorphe
WO2015104658A2 (fr) * 2014-01-08 2015-07-16 Dr. Reddy’S Laboratories Limited Dispersion solide amorphe de dapagliflozine et procédé pour la préparation de dapagliflozine amorphe

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11020412B2 (en) 2017-03-16 2021-06-01 Inventia Healthcare Limited Pharmaceutical composition comprising dapagliflozin
US11660308B2 (en) 2017-03-16 2023-05-30 Inventia Healthcare Limited Pharmaceutical composition comprising dapagliflozin
EP4061378A4 (fr) * 2019-11-20 2023-12-06 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Composition pharmaceutique solide comprenant de la dapagliflozine amorphe isolée à partir d'un solvant polaire
WO2021165316A1 (fr) 2020-02-21 2021-08-26 Zakłady Farmaceutyczne POLPHARMA S.A. Composition pharmaceutique comprenant de la dapagliflozine
EP4008317A1 (fr) * 2020-12-03 2022-06-08 Sanovel Ilac Sanayi Ve Ticaret A.S. Formulations pharmaceutiques solides de dapagliflozine amorphe
WO2022119543A1 (fr) * 2020-12-03 2022-06-09 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Procédé de préparation de comprimés comprenant de la dapagliflozine amorphe et du chlorhydrate de metformine
WO2022119542A1 (fr) * 2020-12-03 2022-06-09 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi Formulations pharmaceutiques solides de dapagliflozine amorphe
CN116421595A (zh) * 2023-02-21 2023-07-14 深圳市新阳唯康科技有限公司 一种达格列净药物组合物及制备方法和应用
CN116421595B (zh) * 2023-02-21 2024-03-29 深圳市新阳唯康科技有限公司 一种达格列净药物组合物及制备方法和应用

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