CN106924208A - A kind of compound Dapagliflozin Metformin Extended-release Tablets and preparation method thereof - Google Patents

A kind of compound Dapagliflozin Metformin Extended-release Tablets and preparation method thereof Download PDF

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CN106924208A
CN106924208A CN201511005094.2A CN201511005094A CN106924208A CN 106924208 A CN106924208 A CN 106924208A CN 201511005094 A CN201511005094 A CN 201511005094A CN 106924208 A CN106924208 A CN 106924208A
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dapagliflozin
release
hpmc
metformin
adhesive
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刘慧�
颜携国
陶安进
袁建成
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Hybio Pharmaceutical Co Ltd
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Hybio Pharmaceutical Co Ltd
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Priority to CN201511005094.2A priority Critical patent/CN106924208A/en
Priority to PCT/CN2016/111032 priority patent/WO2017114227A1/en
Publication of CN106924208A publication Critical patent/CN106924208A/en
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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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • 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
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Life Sciences & Earth Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

The present invention relates to a kind of compound Dapagliflozin Metformin Extended-release Tablets, comprising：Label containing Metformin hydrochloride, Dapagliflozin release layer and film-coating layer.Correspondingly, the present invention also provides the preparation method of compound Dapagliflozin Metformin Extended-release Tablets of the invention, including 1) prepares the label for including melbine；2) pack Dapagliflozin release layer and 3) pack film-coating layer.

Description

A kind of compound Dapagliflozin Metformin Extended-release Tablets and preparation method thereof
Technical field
The application is related to field of pharmaceutical preparations.Specifically, it is slow the present invention relates to a kind of compound Dapagliflozin melbine Release piece and preparation method thereof.
Background technology
At present, the common drug for the treatment of type ii diabetes has biguanides, sulfonylurea, the sweet enzyme inhibitor of a- glucose, thiophene The conventional medicaments such as oxazolidinedione class and (SGLT-2) the inhibitor class of sodium-glucose symport body -2, dipeptidyl peptidase-IV (DDP-IV) the new antidiabetic drug such as inhibitor.Sodium-glucose symport body -2 (SGLT-2) is mainly to express in renal proximal Protein in tubule, Main Function is that the glucose filtered in renal tubule is to urine carries out reabsorption.
Metformin hydrochloride molecular formula is C4H11N5HCl, molecular weight is 165.62, shown in structure such as formula (I).Hydrochloric acid two First biguanides is highly dissoluble, the hypotonicity medicine of BCS Group IIIs, mainly acts on and organized outside pancreas islet, suppresses intestinal absorption grape Sugar, increases utilization of the peripheral tissues to glucose, reduces hepatic gluconeogenesis, and the purpose of blood sugar is reduced so as to reach.Due to hydrochloric acid Melbine blood sugar reducing function substantially, does not cause hypoglycemia, can obviously reduce postprandial hyperglycemia, is adapted to type ii diabetes patient, is Treat the first-line drug of type ii diabetes；It also improves insulin resistance etc. simultaneously, therefore is used widely in clinic.
Dapagliflozin molecular formula is C21H25ClO6·C3H8O2·H2O, molecular weight is 502.98, shown in structure such as formula (II). Dapagliflozin is highly dissoluble, the hypotonicity medicine of BCS Group IIIs.Dapagliflozin is SGLT-2 inhibitor, by suppressing SGLT-2 filters the reabsorption of glucose to reduce, and reduces kidney (grape) sugar threshold value, increases the excretion of glucose in urine.
However, shortcoming of the Metformin hydrochloride as oral hypoglycemic is：Half-life short (2~6h), biological utilisation Spend that low (40%~60%), dosage big (1000~2550mg/d), daily medicining times are more, gastrointestinal side effect generation Rate is high.Therefore need to develop the sustained release preparation of melbine, with improve its half-life period and bioavilability in patient's body, Administration number of times is reduced, reduced blood sugar concentration fluctuation, reduced adverse reaction rate.Additionally, for physical property, melbine Compressibility it is poor, how to obtain the tablet with acceptable mechanical strength, be the major issue of formulation development.
It is in the same direction that two kinds of OHA Dapagliflozins of the present invention and Metformin hydrochloride are belonging respectively to sodium-glucose (SGLT-2) the inhibitor class of transporter -2 and biguanides, the two hypoglycemic mechanism are different, and drug combination has synergy, additionally it is possible to Adverse reaction is reduced, therefore compound preparation can be developed.
The compound Dapagliflozin Metformin Extended-release Tablets for listing at present, trade name Xigduo XR, for treating adult II Patients with type Ⅰ DM.Said preparation is bilayer tablet, including：Ground floor comprising melbine alleviating prolongation delivery formulations；Comprising Dapagliflozin The second layer；With optional coating membrane.However, preparing, requirement of the method for bilayer tablet to auxiliary material is high, compacting difficulty is big, needs Special equipment, is unfavorable for industrialization.
Therefore, the present invention provides a kind of preparation process is simple, is easy to the Dapagliflozin melbine sustained release of large-scale production Piece.
The content of the invention
The present inventor has invented a kind of new compound Dapagliflozin Metformin Extended-release Tablets by research.
Therefore, the present invention provides a kind of new compound Dapagliflozin Metformin Extended-release Tablets, comprising：
The label of (a) containing Metformin hydrochloride；
(b) Dapagliflozin release layer；With
(c) film-coating layer.
Correspondingly, the present invention also provides the method for preparing above-mentioned preparation, comprises the following steps：
1) Metformin hydrochloride is pulverized and sieved, is well mixed after adding adhesive, pelletized in a wet process with wetting agent, done It is dry, whole grain is ground, slow-release material, lubricant, glidant and/or filler are added, compressing tablet after being well mixed is obtained hydrochloride Biguanides is sustained label；
2) Dapagliflozin stirring or homogeneous after adhesive water dissolves, will be added, obtains Dapagliflozin-adhesive water-soluble Liquid/suspension packs Dapagliflozin release layer as upper drug solns；
C) stomach dissolution type film-coating material is configured to coating solution with solvent, packs film-coating layer.
Compared with commercial preparation, the advantage of compound Dapagliflozin melbine sustained release preparation of the invention is preparation technology Simply, it is easy to large-scale production.
Brief description of the drawings
Fig. 1 shows the release curve of melbine in the compound Dapagliflozin Metformin Extended-release Tablets of embodiment 1-3.
Fig. 2 shows the release curve of Dapagliflozin in the compound Dapagliflozin Metformin Extended-release Tablets of embodiment 1-3.
Specific embodiment
The present invention provides a kind of compound Dapagliflozin Metformin Extended-release Tablets.
Compound Dapagliflozin Metformin Extended-release Tablets of the invention, comprising：
The label of (a) containing Metformin hydrochloride；
(b) Dapagliflozin release layer；With
(c) film-coating layer.
In a preferred embodiment, the metformin hydrochloride tablet core is included：It is Metformin hydrochloride, adhesive, slow Material, lubricant are released, filler and glidant is optionally also included.
In a preferred embodiment, the metformin hydrochloride tablet core is included：Metformin hydrochloride 20-90%, it is excellent Select 30-85%, most preferably 40-80%；Adhesive 0.01-10%, preferably 0.5-7%, most preferably 1-5%；Slow-release material 5- 60%, preferably 10-50%, most preferably 15-45%；Lubricant 0.01-2%, preferably 0.05-1.5%, most preferably 0.1-1%.Appoint Selection of land, the metformin hydrochloride tablet core also includes filler 0-20%, most preferably preferably 0-15%, 0-10%；And glidant 0-3%, preferably 0-1.5%, most preferably 0-1.2%；More than it is mass percent.
In a preferred embodiment, described adhesive is selected from HPMC, hydroxypropyl cellulose, poly- dimension One or more in ketone, sodium carboxymethylcellulose；The slow-release material is selected from HPMC 2208 or hydroxypropyl The mixture of cellulose 2208 and HPMC 2910, wherein, the HPMC 2208 is K4M, K15M Or K100M, most preferably HPMC K100M；The HPMC 2910 be E3LV, E5LV, E6LV, E15LV, E50LV, E4M, E10M, most preferably HPMC E15LV；The lubricant is selected from magnesium stearate, stearic acid One or more in calcium, sodium stearyl fumarate, stearic acid, talcum powder, preferably magnesium stearate；The filler is selected from crystallite One or more in cellulose, lactose, mannitol, preferably microcrystalline cellulose；The glidant is selected from silica or colloidal state Silica.
In a preferred embodiment, the Dapagliflozin release layer is included：Dapagliflozin and adhesive；Wherein, institute Adhesive is stated selected from one or more in HPMC, hydroxypropyl cellulose, PVP.
In a preferred embodiment, the Dapagliflozin release layer includes Dapagliflozin 2-40%, preferably 4-35%, Most preferably 5-30%；With adhesive 60-98%, most preferably preferably 65-96%, 70-95%；More than it is mass percent.
In a preferred embodiment, compound Dapagliflozin Metformin Extended-release Tablets of the invention include film-coating layer, The film-coating layer is stomach dissolution type coating material, selected from mainly by HPMC, polyvinyl alcohol or hydroxypropyl cellulose In one or more composition stomach dissolution type coating powders, wherein also include other auxiliary materials, such as but not limited to antiplastering aid, shading Agent, plasticizer.It is preferred that premixed type " Opadry " series stomach dissolution type coating powder or " easily releasing beautiful " series stomach dissolution type coating powder, preferably " Opadry " series stomach dissolution type coating powder, most preferably Opadry II.
Correspondingly, the present invention also provides a kind of method for preparing the compound Dapagliflozin Metformin Extended-release Tablets.
Specifically, the method for preparing the compound Dapagliflozin Metformin Extended-release Tablets of the invention includes 1) preparing and includes The label of melbine；2) pack Dapagliflozin release layer and 3) pack film-coating layer.
In a preferred embodiment, the method for preparing sustained release tablets of the invention is comprised the following steps：
1) Metformin hydrochloride is pulverized and sieved, is well mixed after adding adhesive, pelletized in a wet process with wetting agent, done It is dry, whole grain is ground, slow-release material, lubricant, glidant and/or filler are added, compressing tablet after being well mixed is obtained hydrochloride Biguanides is sustained label；
2) Dapagliflozin stirring or homogeneous after adhesive water dissolves, will be added, obtains Dapagliflozin-adhesive water-soluble Liquid/suspension packs Dapagliflozin release layer as upper drug solns；
3) stomach dissolution type film-coating material is configured to coating solution with solvent, packs film-coating layer.
In a preferred embodiment, described wet granulation is included but is not limited to using fluidized bed granulation or high shear Wet-mixing is pelletized.
In a preferred embodiment, the wetting agent is selected from water or ethanol-water mixed solvent.
In a preferred embodiment, the coating weight gain of the Dapagliflozin release layer is 0.01-10%, preferably 0.05-7%, most preferably 0.1-5%.
In a preferred embodiment, in step 3) in use water as solvent preparation coating solution.
In a preferred embodiment, the solid content of the coating solution is 5-20%.
In a preferred embodiment, the coating weight gain of film-coating layer is 0.01-10%, preferably 0.05-7%, Most preferably 0.1-5%.
Following examples are used to further illustrate the present invention, but following examples are not necessarily to be construed as to limit of the invention System.
Embodiment
Embodiment 1：The preparation of compound Dapagliflozin Metformin Extended-release Tablets
(1) preparation of Metformin hydrochloride 1000mg labels
Table 1：Metformin hydrochloride tablet core is constituted
Piece core component Mg/ pieces Percentage composition (%)
Metformin hydrochloride 1000 68.63
Sodium carboxymethylcellulose 50 3.43
HPMC K100M 385 26.42
Silica 15 1.03
Magnesium stearate 7 0.48
Piece weight 1457 100
Metformin hydrochloride is pulverized and sieved, sodium carboxymethylcellulose is added, with water as wetting agent bulk drug of pretreatment adds with interior system Grain, is dried, and grinds whole grain, adds HPMC K100M and colloidal silica, and magnesium stearate is added after being well mixed Compressing tablet, is obtained diabecron sustained-release tablet core.
(2) preparation of Dapagliflozin release layer
Table 2：Dapagliflozin release layer is constituted
Quick-release layer component Mg/ pieces Percentage composition (%)
Dapagliflozin 6.15 13.33
Hydroxypropyl cellulose 40 86.67
Weightening total amount 46.15 100
Dapagliflozin and hydroxypropyl cellulose are weighed respectively in the ratio of table 2, after hydroxypropyl cellulose is dissolved in into water, are added Dapagliflozin, homogeneous dispersion is obtained upper drug solns, and control medicine-feeding weightening packs the release layer containing Dapagliflozin；
(3) film-coating layer pack
Opadry II is configured to the coating solution that solid content is 18% by solvent of water, film-coating layer, coating weight gain is packed 2.0%, compound Dapagliflozin Metformin Extended-release Tablets are obtained.
Embodiment 2：The preparation of compound Dapagliflozin Metformin Extended-release Tablets
(1) preparation of Metformin hydrochloride 1000mg labels
Table 3：Metformin hydrochloride tablet core is constituted
Piece core component Mg/ pieces Percentage composition (%)
Metformin hydrochloride 1000 76.22
Sodium carboxymethylcellulose 50 3.81
HPMC K100M 240 18.29
Silica 15 1.14
Magnesium stearate 7 0.53
Piece weight 1312 100
Metformin hydrochloride is pulverized and sieved, sodium carboxymethylcellulose is added, with 70% ethanol-water solution as wetting agent Fluidized bed granulation, dries, and grinds whole grain, adds HPMC K100M, colloidal silica mixing, adds stearic acid Magnesium compressing tablet, is obtained diabecron sustained-release tablet core.
(2) preparation of Dapagliflozin release layer
Table 4：Dapagliflozin release layer is constituted
Quick-release layer component Mg/ pieces Percentage composition (%)
Dapagliflozin 12.3 23.52
Hydroxypropyl cellulose 40 76.48
Weightening total amount 52.3 100
Dapagliflozin and hydroxypropyl cellulose are weighed in the ratio of table 4, hydroxypropyl cellulose is dissolved in water, add Da Gelie Only, homogeneous dispersion, is obtained upper drug solns, and control medicine-feeding weightening packs the release layer containing Dapagliflozin；
(3) film-coating layer pack
Opadry I is configured to the coating solution that solid content is 6% by solvent of water, film-coating layer, coating weight gain is packed 4.0%, compound Dapagliflozin Metformin Extended-release Tablets are obtained.
Embodiment 3：The preparation of compound Dapagliflozin Metformin Extended-release Tablets
(a) Metformin hydrochloride 500mg labels
Table 5：Metformin hydrochloride tablet core is constituted
Piece core component Mg/ pieces Percentage composition (%)
Metformin hydrochloride 500 48.24
PVP 50 4.82
HPMC K100M 385 37.14
HPMC E15LV 10 0.96
Microcrystalline cellulose 88 8.49
Magnesium stearate 3.5 0.34
Piece weight 1036.5 100
Metformin hydrochloride is pulverized and sieved, PVP is added, is pelletized as wetting agent bulk drug of pretreatment adds with interior with water, dried, Grinding whole grain, adds HPMC K100M, HPMC E15LV and microcrystalline cellulose, and mixing is added hard Fatty acid magnesium compressing tablet, is obtained diabecron sustained-release tablet core.
The preparation of (b) Dapagliflozin release layer
Table 6：Dapagliflozin release layer is constituted
Dapagliflozin and hydroxypropyl cellulose are weighed in the ratio of table 6, hydroxypropyl cellulose is dissolved in water, add Da Gelie Only, homogeneous dispersion, is obtained upper drug solns, and control medicine-feeding weightening packs the release layer containing Dapagliflozin；
(c) film-coating layer pack
Opadry II is configured to the coating solution that solid content is 14% by solvent of water, film-coating layer, coating weight gain is packed 1.5%, compound Dapagliflozin Metformin Extended-release Tablets are obtained.
Embodiment 4：The measurement of uniformity of dosage units and friability
Checked according to 2010 editions annex XE Content uniformity tests of Chinese Pharmacopoeia and XG tablet friabilities inspection technique respectively The friability of Dapagliflozin uniformity of dosage units and tablet in the compound Dapagliflozin Metformin Extended-release Tablets of embodiment 1-3.As a result As shown in table 7.
Table 7：The uniformity of dosage units and friability of embodiment 1-3
Embodiment 5：The measure of vitro release
Compound Dapagliflozin Metformin Extended-release Tablets with embodiment 1-3 as sample, according to 2010 editions annex of Chinese Pharmacopoeia The method of XC dissolution methods second (paddle method), are detected, respectively at predetermined time point with 50rpm, 37 DEG C, the dissolution mediums of pH 1.2 Sampling, using the burst size of Dapagliflozin and melbine in high effective liquid chromatography for measuring dissolution medium, draws release profiles (Fig. 1 and Fig. 2).
Obviously, the above of the invention, according to the ordinary technical knowledge and customary means of this area, is not departing from Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification of other diversified forms can also be carried out, is replaced or is changed.People from this area Member is it is understood that each feature of technical solution of the present invention described herein can as needed carry out appropriate combination.

Claims (10)

1. a kind of Dapagliflozin Metformin Extended-release Tablets, it includes
The label of (a) containing Metformin hydrochloride, comprising Metformin hydrochloride, adhesive, slow-release material, lubricant, optionally Also include filler and glidant；
(b) Dapagliflozin release layer, comprising Dapagliflozin and adhesive；With
(c) film-coating layer.
2. Dapagliflozin Metformin Extended-release Tablets according to claim 1, wherein, the piece containing Metformin hydrochloride Core is included：
Metformin hydrochloride 20-90%, preferably 30-85%, most preferably 40-80%；
Adhesive 0.01-10%, preferably 0.5-7%, most preferably 1-5%；
Slow-release material 5-60%, preferably 10-50%, most preferably 15-45%；
Lubricant 0.01-2%, preferably 0.05-1.5%, most preferably 0.1-1%；
Optional filler 0-20%, most preferably preferably 0-15%, 0-10%；
With optional glidant 0-3%, most preferably preferably 0-1.5%, 0-1.2%；
More than it is mass percent.
3. Dapagliflozin Metformin Extended-release Tablets according to claim 2, wherein
Described adhesive is selected from HPMC, hydroxypropyl cellulose, PVP, sodium carboxymethylcellulose or its mixing Thing, preferably carboxymethyl cellulose sodium；
The slow-release material is selected from HPMC 2208 or HPMC 2208 and HPMC 2910 mixture, wherein, the HPMC 2208 is HPMC K4M, K15M or K100M, optimal Select HPMC K100M；The HPMC 2910 be E3LV, E5LV, E6LV, E15LV, E50LV, E4M, E10M, most preferably HPMC E15LV；
The lubricant is selected from magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, talcum powder or its mixture, excellent Select magnesium stearate；
The filler is selected from microcrystalline cellulose, lactose, mannitol or its mixture, preferably microcrystalline cellulose；
The glidant is selected from silica or colloidal silica.
4. Dapagliflozin Metformin Extended-release Tablets according to claim 1, wherein, it is described state lattice and arrange net release layer include：
Dapagliflozin 2-40%, preferably 4-35%, most preferably 5-30%；
With adhesive 60-98%, most preferably preferably 65-96%, 70-95%；
More than it is mass percent.
5. Dapagliflozin Metformin Extended-release Tablets according to claim 4, wherein, it is fine that described adhesive is selected from hydroxypropyl Dimension element, hydroxypropyl cellulose, PVP or its mixture.
6. Dapagliflozin Metformin Extended-release Tablets according to claim any one of 1-5, wherein, the film-coating layer is by stomach Molten type film-coating material is constituted, and the stomach dissolution type film-coating material is selected from by HPMC, polyvinyl alcohol or hydroxypropyl The stomach dissolution type coating powder of one or more compositions in cellulose, preferably " Opadry " or " easily releasing beautiful " series stomach dissolution type is coated Powder, more preferably " Opadry " series stomach dissolution type coating powder, most preferably Opadry II.
7. the method for preparing the Dapagliflozin Metformin Extended-release Tablets described in claim any one of 1-6, comprises the following steps：
(1) Metformin hydrochloride is pulverized and sieved, is well mixed after adding adhesive, pelletized in a wet process with wetting agent, dried, ground Mill whole grain, adds slow-release material, lubricant, glidant and/or filler, and compressing tablet after being well mixed is obtained Metformin hydrochloride Sustained release label；
(2) Dapagliflozin stirring or homogeneous will be added after adhesive water dissolves, will obtain Dapagliflozin-binder aqueous solution/mixed Suspension packs Dapagliflozin release layer as upper drug solns；
(3) stomach dissolution type film-coating is prepared with solvent, packs film-coating layer.
8. method according to claim 7, wherein the wetting agent is selected from the mixed solution of water or alcohol-water.
9. the method according to any one of claim 7 or 8, wherein Dapagliflozin release layer weightening is 0.01-10%, It is preferred that 0.05-7%, most preferably 0.1-5%.
10. the method according to claim any one of 7-9, wherein based calcium weightening is 0.01-10%, preferably 0.05-7%, most preferably 0.1-5%.
CN201511005094.2A 2015-12-30 2015-12-30 A kind of compound Dapagliflozin Metformin Extended-release Tablets and preparation method thereof Pending CN106924208A (en)

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PCT/CN2016/111032 WO2017114227A1 (en) 2015-12-30 2016-12-20 Dapagliflozin and metformin complex extended release tablet and preparation method thereof

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