Dapagliflozin and metformin sustained-release composition and preparation method thereof

Abstract

The invention discloses a dapagliflozin and metformin sustained-release composition and a preparation method thereof. The dapagliflozin and metformin sustained-release composition sequentially comprises a metformin sustained-release core, an isolating layer and a medicine carrying layer. According to the invention, dapagliflozin is coated outside the metformin core by adopting a coating medicine applying mode, and the content of dapagliflozin is easy to control through weight increment, so that the uniformity of the medicine content is improved; meanwhile, the isolating layer is arranged between the metformin sustained-release core and the medicine carrying layer, so that the influence of the metformin hydrochloride layer on the dissolution of the dapagliflozin can be effectively prevented, and the dissolution of the dapagliflozin is good. The dapagliflozin and metformin composition prepared by the invention provides an effective blood sugar control mode for patients, and effectively treats diabetes mellitus.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a dapagliflozin metformin sustained-release composition and a preparation method thereof. Background Art

[0002] The results of the diabetes epidemiological survey show that the prevalence of diabetes in adults is 12.8%, while the prevalence of prediabetes is as high as 35.2%. Diabetes can be divided into type I and type II according to the cause of the disease, and type II accounts for more than 80% of the total number of diabetic patients. Dapagliflozin metformin tablets, as a compound preparation, can be used as an adjunct to diet and exercise to improve blood sugar control in adult patients with type II diabetes.

[0003] Dapagliflozin metformin extended-release tablets were first developed by AstraZeneca Pharmaceuticals, and the main dosage form on the market is currently double-layer tablets. The original formulation of dapagliflozin layer uses a dry granulation preparation process, and the metformin hydrochloride layer uses a wet granulation preparation process. The two layers of materials are pressed into double-layer tablets and then film-coated. The process is cumbersome and complicated, and has high requirements for the fluidity and compressibility of the particles. Dry granulators and double-layer tablet presses are required for large-scale production, and industrial production is difficult.

[0004] Based on the complex process of double-layer tablets, a series of coated tablets have been developed in the prior art, striving to simplify the process, and the resulting tablets have stable process and dissolution. For example, CN116473934A provides a dapagliflozin metformin sustained-release tablet, which is coated on the outside of the metformin tablet core by coating the drug, and the content of dapagliflozin is easily controlled by weight gain. At the same time, an isolation layer is set between the metformin sustained-release tablet core and the dapagliflozin drug layer, and the dapagliflozin layer is coated on the surface of the isolation layer. CN116370430A provides a dapagliflozin metformin sustained-release tablet, which includes, from the inside to the outside, a metformin hydrochloride sustained-release micro-pellet core, an isolation layer, a dapagliflozin layer, and a film coating layer; dapagliflozin is combined with metformin, and the dapagliflozin metformin sustained-release tablet is prepared in combination with the controlled-release micro-pellet technology. CN117695233A provides a dapagliflozin metformin preparation and a preparation method thereof. The dapagliflozin metformin preparation comprises a metformin hydrochloride layer and a dapagliflozin layer, and the metformin hydrochloride layer contains povidone. Summary of the invention

[0005] In view of the deficiencies of the prior art, the present invention provides a dapagliflozin metformin sustained-release composition and a preparation method and application thereof. The dapagliflozin metformin sustained-release composition provided by the present invention contains lower genotoxic impurities than the original preparation, has good content uniformity, low cost, and good dissolution effect of the drug components; the stability of the dapagliflozin metformin sustained-release composition provided by the present invention is better than that of the coated tablets disclosed in the prior art.

[0006] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0007] On the one hand, the present invention provides a dapagliflozin metformin sustained-release composition, which comprises, in sequence: a metformin sustained-release core, an isolation layer and a drug-loading layer. Further, it comprises, in sequence: a metformin sustained-release core, an isolation layer coated on the metformin sustained-release core and a drug-loading layer coated on the isolation layer. Further, it also comprises an optional film coating layer. Further, the composition comprises, in sequence: a metformin sustained-release core, an isolation layer and a drug-loading layer, and the drug-loading layer contains an antioxidant. The isolation layer can effectively prevent or isolate the effect of metformin on the dissolution of dapagliflozin in the drug-loading layer, so that the drug-loading layer has a better solubility.

[0008] Further, the weight ratio between the metformin sustained-release core and the drug-loaded layer is 2:1 to 100:1, preferably, the weight ratio between the metformin sustained-release core and the drug-loaded layer is 2:1 to 20:1, 3:1 to 7:1, 3.2:1 to 6.4:1 or 3.4:1 to 5.5:1. Further, the weight ratio between the metformin sustained-release core and the isolation layer is 20:1 to 50:1, preferably, the weight ratio between the metformin sustained-release core and the isolation layer is 20:1 to 40:1, 20:1 to 35:1, or 25:1 to 35:1. Further, in a single-dose composition, the total weight of the drug-loaded layer is 25 to 550 mg, preferably 25, 50, 100, 150, 200, 250, 300, 350, 400, 450, 500 or 550 mg.

[0009] Furthermore, the metformin sustained-release core comprises metformin hydrochloride and sustained-release layer excipients. Preferably, the metformin sustained-release core is a tablet core or a pill core.

[0010] Furthermore, the metformin sustained-release core contains 40-95% metformin hydrochloride, preferably 40-82%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 124%, 125 %, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94% or 95%.

[0011] Furthermore, the auxiliary material of the sustained-release layer is selected from one or more of lubricants, adhesives, sustained-release materials, glidants, and colorants. Further, in the metformin sustained-release core, the percentage of each component of the sustained-release layer excipient is about 0-95%, preferably 0%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, %, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, or 98%. Furthermore, based on the total amount of the metformin sustained-release core, the sustained-release layer excipient is selected from one or more of 0.1-10% lubricant, 0.1-20% adhesive, 0.1-95% sustained-release material, 0.1-10% glidant, and 0-20% colorant. Furthermore, the total percentage of each component of the metformin sustained-release core is 100%.

[0012] Furthermore, the lubricant is selected from at least one of magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, and polyethylene glycol 6000.

[0013] Further, the binder is selected from at least one of hydroxypropyl methylcellulose (for example, hydroxypropyl methylcellulose K4M, hydroxypropyl methylcellulose K15M, hydroxypropyl methylcellulose K100M, hydroxypropyl methylcellulose K100LV, hydroxypropyl methylcellulose 2208, hydroxypropyl methylcellulose 2910), sodium carboxymethylcellulose, hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, anhydrous lactose, pregelatinized starch, calcium carbonate, dicalcium phosphate, calcium triphosphate, calcium sulfate, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, polyethylene oxide, acrylic resin, polyvinyl acetate-povidone mixture, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, gelatin, corn starch, povidone (k90, k30), sodium carboxymethylcellulose, maleic acid, methylene succinic acid, ethyl succinic acid, methylene adipic acid, guanidinoacetic acid, thioglycolic acid, acrylic acid, methacrylic acid, acrylamide and glyoxal.

[0014] Further, the sustained-release material is selected from ethylcellulose, stearic acid, hydrogenated castor oil, hydroxypropylmethylcellulose (e.g., 2208, 2910, K100M, E15, F100, K200), methyl hydroxyethyl cellulose, hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), ethyl hydroxyethyl cellulose (EHEC), glyceryl behenate, palm wax, and other film-forming polymers such as methacrylic acid copolymer-C-type carboxymethyl cellulose sodium, polydextrose, polyethylene glycol, acrylate polymers (e.g., polyethylene acrylate (PVA)), polyvinyl alcohol-polyethylene glycol graft copolymers, polyvinyl acetate-povidone mixtures, polyvinyl pyrrolidone (PVP) complexes such as povidone, polyvinyl alcohol, microcrystalline cellulose, carrageenan, pregelatinized starch, polyethylene glycol, and combinations thereof. Typically, the polymer has a molecular weight (weight average molecular weight and / or number average molecular weight) of at least one of 1,000 to 10,000,000, preferably 10,000 to 1,000,000, as measured by gel permeation chromatography.

[0015] Furthermore, the glidant is selected from at least one of silicon dioxide, magnesium stearate, talc or colloidal silicon dioxide.

[0016] Furthermore, the isolation layer includes at least one of a first film-forming agent, an anti-sticking agent or a first plasticizer.

[0017] Further, based on the total weight of the isolation layer, the first film-forming agent is 40-95%, the anti-adhesive agent is 10-55%, or the first plasticizer is 0-6%. Preferably, the first plasticizer accounts for 0%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10%. %, preferably, the proportion of the anti-adhesive agent is 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%; preferably, the first film-forming agent accounts for 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59% %, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94% or 95%. Further, the total percentage of each component of the isolation layer is 100%.

[0018] Furthermore, the isolation layer may be a commercially available coating powder, such as the "Opadry" series of gastric-soluble coating powders.

[0019] Furthermore, the film coating layer can be a commercially available coating powder, such as "Opadry" series gastric soluble coating powder, film coating premix (gastric soluble).

[0020] Furthermore, the isolation layer may also include a colorant, such as sunset yellow, lemon yellow, etc. The addition of the colorant facilitates the inspection of whether the isolation layer is coated uniformly.

[0021] Furthermore, the drug-carrying layer includes pharmaceutically active substances and drug-carrying layer excipients.

[0022] Further, the pharmaceutically active substance is dapagliflozin or dapagliflozin propylene glycol monohydrate. Further, the drug-carrying layer excipients include a second film-forming agent, a pore-forming agent and / or a second plasticizer. Further, the drug-carrying layer excipients further include an antioxidant.

[0023] Furthermore, based on the total weight of the drug-carrying layer, it includes 0.1-65% of a pharmaceutically active substance, 5-55% of a second film-forming agent, 40-95% of a pore-forming agent and / or 0-20% of a second plasticizer and / or 0-20% of an antioxidant. Preferably, the proportion of the pharmaceutically active substance is 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, %, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%; preferably, the proportion of the second film-forming agent is 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37% %, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%; preferably, the porogen accounts for 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, %, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94% or 95%; preferably, the second plasticizer and / or antioxidant account for 0%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20%, respectively.Furthermore, the total percentage of each component in the drug-carrying layer is 100%.

[0024] Furthermore, the drug-carrying layer excipients may be commercially available premixes, such as "Opadry" series gastric-soluble coating powders.

[0025] Furthermore, the first film-forming agent and the second film-forming agent are each independently selected from at least one of hydroxypropyl methylcellulose polymers (for example, hydroxypropyl methylcellulose (HPMC, such as 2208, 2910, K100M, E5, E15, E50, K4M, K15M), methyl hydroxyethyl cellulose (MHEC), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), ethyl hydroxyethyl cellulose (EHEC)), polyvinyl alcohol, polyvinyl acetate, methacrylic acid (ester) polymers, coating polymers of hydroxypropyl cellulose, cellulose acetate, ethyl cellulose, titanium dioxide and triacetin.

[0026] Further, the first plasticizer and the second plasticizer are each independently selected from at least one of glycerol, propylene glycol, polyethylene glycol (PEG200-6000), organic esters such as triacetin (glyceryl triacetate), triethyl citrate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, acetyl triethyl citrate, acetyl tributyl citrate, tributyl citrate, and oils / glycerides such as fractionated coconut oil, castor oil and distilled acetylated monoglycerides.

[0027] Furthermore, the anti-adhesive agent is selected from one or more of talc, stearic acid, magnesium stearate or glyceryl monostearate.

[0028] Furthermore, the pore-forming agent is selected from soluble materials such as sorbitol, povidone K30, hydroxypropyl cellulose, polyethylene glycol, sodium lauryl sulfate, mannitol, lactose or sucrose.

[0029] Further, the antioxidant is selected from polyphenol antioxidants, water-soluble antioxidants, oil-soluble antioxidants, and combinations thereof. The polyphenol antioxidants include flavonoid antioxidants, anthocyanin antioxidants, flavonol antioxidants, flavanol antioxidants, phenolic acid antioxidants, etc.; the water-soluble antioxidants preferably include rosmarinic acid, anthocyanidins, tea polyphenols, vitamin C, and combinations thereof. The flavonoid antioxidants include anthocyanidins; the phenolic acid antioxidants include rosmarinic acid.

[0030] Furthermore, the antioxidant is selected from one or more of tocopherol acetate (vitamin E acetate), butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium benzotriazolyl butylphenol sulfate, vitamin C (ascorbic acid), tea polyphenols, vitamin C ethyl ether, vitamin E, propyl gallate, sodium sulfite, sodium pyrosulfite, sodium bisulfite, thioglycerol, thioglycolic acid, rosmarinic acid, and anthocyanidins.

[0031] Further, the isolation layer includes hypromellose, talc, and polyethylene glycol 6000. Further, the isolation layer includes ethyl cellulose, stearic acid, and triethyl citrate. Further, the isolation layer includes hypromellose, talc, and triethyl citrate. Further, the isolation layer includes hypromellose, magnesium stearate, and dibutyl sebacate. Further, the isolation layer includes hypromellose, talc, polyethylene glycol 6000, and tartrazine. Further, the isolation layer includes hypromellose, talc, polyethylene glycol 6000, and sunset yellow. Further, the drug-carrying layer includes dapagliflozin propylene glycol monohydrate, hypromellose, lactose, and polyethylene glycol 6000. The proportion of talc in the isolation layer is beneficial to improving the phenomenon of sticking to the pan or one-sided adhesion during the coating process. The proportion of polyethylene glycol 6000 in the isolation layer has an impact on the drug application rate and the coating success rate.

[0032] Furthermore, the drug-carrying layer includes dapagliflozin propylene glycol monohydrate, hypromellose, sucrose and polyethylene glycol 6000.

[0033] Furthermore, the drug-carrying layer comprises dapagliflozin propylene glycol monohydrate, polyvinyl alcohol, lactose and polyethylene glycol 6000.

[0034] Furthermore, the drug-carrying layer includes dapagliflozin propylene glycol monohydrate, polyvinyl alcohol, lactose, vitamin C and polyethylene glycol 6000.

[0035] Furthermore, the drug-carrying layer comprises dapagliflozin propylene glycol monohydrate, polyvinyl alcohol, talc and polyethylene glycol 6000.

[0036] Furthermore, the drug-carrying layer comprises dapagliflozin propylene glycol monohydrate, polyvinyl alcohol, lactose, talc and polyethylene glycol 6000.

[0037] Furthermore, the drug-carrying layer comprises dapagliflozin propylene glycol monohydrate, polyvinyl alcohol, sucrose and polyethylene glycol 6000.

[0038] Furthermore, the drug-carrying layer includes dapagliflozin propylene glycol monohydrate, polyvinyl alcohol, sucrose, vitamin C and polyethylene glycol 6000.

[0039] Furthermore, the drug-carrying layer comprises dapagliflozin propylene glycol monohydrate, hypromellose, mannitol and polyethylene glycol 6000.

[0040] Furthermore, the drug-carrying layer includes dapagliflozin, polyvinyl alcohol, lactose and polyethylene glycol 6000.

[0041] Furthermore, the drug-carrying layer includes dapagliflozin, polyvinyl alcohol, lactose, vitamin C and polyethylene glycol 6000.

[0042] Furthermore, the drug-carrying layer comprises dapagliflozin, polyvinyl alcohol, talc and polyethylene glycol 6000.

[0043] Furthermore, the drug-carrying layer comprises dapagliflozin, polyvinyl alcohol, lactose, talc and polyethylene glycol 6000.

[0044] Furthermore, the drug-carrying layer includes dapagliflozin, polyvinyl alcohol, sucrose and polyethylene glycol 6000.

[0045] Furthermore, the drug-carrying layer includes dapagliflozin, polyvinyl alcohol, sucrose, vitamin C and polyethylene glycol 6000.

[0046] Furthermore, the drug-carrying layer comprises dapagliflozin, hypromellose, lactose and polyethylene glycol 6000.

[0047] Furthermore, the drug-carrying layer comprises dapagliflozin, hypromellose, sucrose and polyethylene glycol 6000.

[0048] Furthermore, the drug-carrying layer comprises dapagliflozin, hypromellose, mannitol and polyethylene glycol 6000.

[0049] Furthermore, the mass ratio of the first film-forming agent: anti-adhesive agent: first plasticizer is 0.5-2:0.1-0.5:0.05-0.2; preferably, the mass ratio is 1:0.3:0.1, 1:0.3:0.05, 0.5:0.1:0.05, 0.5:0.2:0.05, 0.5:0.3:0.05, 1:0.3:2, 2:0.3:0.05, 2:0.1:0.05, 2:0.5:0.05, 2:0.5:0.2, 2:0.1:0.2. Furthermore, the mass ratio of the pharmaceutically active substance: the second film-forming agent: the pore-forming agent: the second plasticizer is 2-10:1-10:2-80:1-5; preferably, 2.69:10:10:1, 2.69:10:20:1, 2.69:10:30:1, 2.69:10:40:1, 2.69:10:66:1, 5:10:10:1, 2.152:8:8:2, 3:10:66:1, 4:10:66:1, 5:10:66:1, 6:10:66:1, 7:10:66:1, 8:10 :66:1, 9:10:66:1, 10:10:66:1, 3:10:40:1, 3:10:45:1, 3:10:50:1, 3:10:60:1, 3:10:70:1, 3:10:66:2, 3:10:66:3, 3:10:66:4, 3:10:66:5, 3:1:66:1, 3:2:66:1, 3:3:66:1, 3:4:66:1, 3:5:66:1, 3:6:66:1, 3:7:66:1, 3:8:66:1, or 3:9:66:1.

[0050] Further, the weight gain of the isolation layer coating is 0.05-30% or 0.05-10% or 0.5-5%; preferably 0.05%, 0.1%, 0.2%, 0.4%, 0.5%, 1%, 2%, 3%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30%. After adding the isolation layer, the effect of the metformin hydrochloride layer on the dissolution of dapagliflozin can be effectively prevented. When the isolation layer gains 3-4%, the cumulative dissolution of dapagliflozin is better.

[0051] Further, the drug loading layer gains weight by 1-40% or 15-30% or 15-25%; preferably 1%, 1.45%, 2%, 2.5%, 3%, 3.3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39% or 40%.

[0052] On the other hand, the present invention provides a method for preparing a dapagliflozin metformin composition, comprising the following steps:

[0053] Step 1: uniformly mixing the components of the isolation layer with the first solvent to obtain an isolation layer coating solution; coating the metformin sustained-release core with the isolation layer to obtain a metformin sustained-release isolation coating composition;

[0054] Step 2: uniformly mix the components of the drug-carrying layer with the second solvent to obtain a drug-carrying layer coating solution; and perform drug-carrying layer coating to obtain a dapagliflozin metformin composition.

[0055] Furthermore, in step 1, the isolation layer coating solution can be prepared by uniformly mixing the first film-forming agent, the anti-adherent agent, the first plasticizer and the first solvent. Furthermore, a colorant can be included.

[0056] Furthermore, the preparation steps of the metformin sustained-release core include: mixing metformin hydrochloride, a binder and a first lubricant, wetting the mixture with a wetting agent, and performing wet granulation; mixing the obtained drug particles with a sustained-release material, a second lubricant and a glidant, and performing tableting.

[0057] Furthermore, the wet granulation comprises: weighing ingredients, premixing, wet granulation, drying, dry granulation, total mixing, and tableting.

[0058] Furthermore, the drying is fluidized drying, and the moisture content of the material is controlled to be 1-15%, preferably 2.5%-5.0%.

[0059] Furthermore, the wetting agent is purified water.

[0060] Furthermore, the amount of the wetting agent is 8-20% of the mass of metformin hydrochloride, preferably 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20%.

[0061] The present invention has no special requirements on the specific operating conditions of the wet granulation, and those familiar to those skilled in the art may be used.

[0062] Furthermore, the first solvent and the second solvent are each independently pure water or an ethanol aqueous solution with a volume ratio of 15 to 80%.

[0063] Furthermore, the volume ratio of the ethanol aqueous solution is 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 55%, 60%, 65%, 70%, 75% or 80%.

[0064] Furthermore, the solid content of the isolation layer coating solution is 5-15%, preferably 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% or 15%.

[0065] Further, the isolation layer coating has a weight gain of 0.05-30% or 0.05-10% or 0.5-5%; preferably 0.05%, 0.1%, 0.2%, 0.4%, 0.5%, 1%, 2%, 3%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30%.

[0066] Furthermore, the solid content of the drug-carrying layer coating solution is 5-30%; preferably 5%, 6%, 7%, 7.75%, 8%, 9%, 9.02%, 10%, 11%, 11.6%, 12%, 12.4%, 13%, 14%, 14.40%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30%.

[0067] Further, the drug loading layer gains weight by 1-40% or 15-30% or 15-25%; preferably 1%, 1.45%, 2%, 2.5%, 3%, 3.3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39% or 40%.

[0068] Furthermore, the weight gain of the isolation layer is the weight gain relative to the mass of the metformin sustained-release core; and the weight gain of the drug-loaded layer is the weight gain relative to the mass of the metformin sustained-release isolation coating composition.

[0069] Furthermore, in step 1, the isolation layer coating parameters include: tablet bed temperature 35°C to 38°C, air intake volume 100 to 140 m 3 / h, liquid supply pump speed 3-7rpm, spraying rate 5-20g / min, atomization pressure 0.05-0.5MPa, fan pressure 0.05-0.5MPa, coating time 0.5-10h, drying time 5-60min.

[0070] Furthermore, in step 2, the drug-loaded layer coating parameters include: tablet bed temperature 30°C to 45°C, air volume 100 to 140 m 3 / h, liquid supply pump speed 3-10rpm, spraying rate 5-20g / min, atomization pressure 0.05-0.5MPa, fan pressure 0.05-0.5MPa, coating time 0.5-10h, drying time 5-60min.

[0071] Furthermore, in step 2, shortening the distance between the coating gun and the tablet bed and adjusting the atomization and fan pressure can effectively reduce the loss of dapagliflozin API.

[0072] The present invention also provides the use of the dapagliflozin metformin sustained-release tablets or the dapagliflozin metformin sustained-release tablets prepared by the preparation method in the preparation of drugs for treating disorders or diseases; the disorders or diseases are selected from diabetes (including type I and type II diabetes), impaired glucose tolerance, insulin resistance, nephropathy, retinopathy, neuropathy and cataracts, hyperglycemia, hyperinsulinemia, hypercholesterolemia, dyslipidemia, increased blood levels of free fatty acids or glycerol, hyperlipidemia, hypertriglyceridemia, obesity, wound healing, tissue ischemia, atherosclerosis, angina pectoris, myocardial infarction and hypertension.

[0073] Compared with the prior art, the present invention has the following beneficial effects:

[0074] The present invention provides a dapagliflozin-metformin composition, which includes a metformin sustained-release core, an isolation layer, and a drug-carrying layer from the inside to the outside. The present invention adopts a coating method to coat dapagliflozin on the outside of the metformin sustained-release core, and the content of dapagliflozin or dapagliflozin propylene glycol monohydrate can be easily controlled by weight gain, and it is beneficial to improve the uniformity of the drug content; at the same time, the present invention sets an isolation layer between the metformin sustained-release core and the dapagliflozin drug layer, which can effectively prevent the influence of the metformin hydrochloride layer on the dissolution of dapagliflozin, so that dapagliflozin dissolves well.

[0075] The present invention also provides a method for preparing the dapagliflozin metformin sustained-release composition described in the above scheme. In the conventional method, metformin and dapagliflozin or dapagliflozin propylene glycol monohydrate are prepared into double-layer tablets, which requires the use of a double-layer tablet press. The process is complicated and the cost is high. In addition, material loss is prone to occur during the tableting process, which increases the preparation cost. The present invention adopts a coating method to coat the isolation layer and the drug-carrying layer on the surface of the metformin sustained-release core in sequence. The operation method is simple and no double-layer tablet press is required, which solves the problem of high production cost in the prior art. In addition, by optimizing the coating process of the dapagliflozin drug-carrying layer, the cost is reduced while the process is made simpler, and the production efficiency is greatly improved.

[0076] The present invention explores a series of drug-carrying layer components, isolation layer components and the content ratio of each component, and finally obtains a suitable isolation layer load and drug-carrying layer weight gain, and explores the preparation process to finally obtain the best dapagliflozin metformin sustained-release composition, so that the surface of the prepared composition tablet is smooth and can meet the requirements of drug preparation dissolution. In addition, due to the stability problem of the composition prepared in the preparation process, an antioxidant is added to the drug-carrying layer to effectively solve the problem of composition stability. BRIEF DESCRIPTION OF THE DRAWINGS

[0077] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0078] Figure 1 Dissolution curves of dapagliflozin in the dapagliflozin metformin compositions prepared in prescriptions 9 and 12.

[0079] Figure 2 The dissolution curve of dapagliflozin in the dapagliflozin metformin composition prepared by Prescriptions 12-14.

[0080] Figure 3 The dissolution curve of dapagliflozin in the dapagliflozin metformin composition prepared by Prescription 15-16.

[0081] Figure 4 Dissolution profiles of dapagliflozin in the test and reference formulations in the dissolution study.

[0082] Figure 5 Dissolution profiles of metformin hydrochloride in the test and reference preparations in the dissolution test. DETAILED DESCRIPTION

[0083] The technical solution of the present invention is illustrated below by way of example, and the scope of protection requested by the present invention includes but is not limited to the following embodiments.

[0084] In the following examples, HPMC refers to hydroxypropyl methylcellulose, PEG refers to polyethylene glycol, and API refers to dapagliflozin or dapagliflozin propylene glycol monohydrate.

[0085] Preparation Example 1

[0086] The preparation method of metformin sustained-release tablet core comprises the following steps:

[0087] Weighing ingredients: Accurately weigh metformin hydrochloride, adhesive, lubricant, sustained-release material and glidant according to the prescribed amount and set aside.

[0088] Premixing: Add the weighed metformin hydrochloride, binder and first lubricant into the wet granulator, set the stirring speed to 100 rpm and the cutting speed to 1000 rpm, turn on the stirring and cutting for premixing for 10 minutes.

[0089] Wet granulation: Weigh 13% of the total amount of metformin hydrochloride layer purified water for wet granulation soft material preparation. Set the stirring speed to 100rpm and the cutting speed to 1500rpm. Turn on the stirring and cutting, and pour the prescribed amount of purified water into the wet granulator to make soft material. Control the addition within 60 to 180 seconds. After the addition of liquid, continue granulation at the original speed for 1-2 minutes, and use a 8mm*8mm square screen for wet granulation.

[0090] Drying: The wet granulated material is fluidized dried using a boiling granulation dryer to control the moisture content of the material to 2.5% to 4.0%.

[0091] Dry granulation: Use a 1.2 mm sieve and a granulation speed of 300 rpm ± 100 rpm for dry granulation.

[0092] Total mixing: Add the dry granules, sustained-release material and glidant into the mixer in sequence, set the mixing speed to 10 rpm, mix for 10 min, add the second lubricant, set the mixing speed to 10 rpm, and continue mixing for 5 min.

[0093] Tableting: The metformin hydrochloride layer total mixed granules are subjected to single-layer tabletting, the hardness is controlled at 300-350N, and the tablet weight difference is controlled at ±5%, to prepare metformin hydrochloride sustained-release tablet cores.

[0094] Preparation Example 2

[0095] Step 1: Preparation of the isolation layer coating, the steps are as follows:

[0096] The components of the isolation layer were mixed with a 25% ethanol aqueous solution by volume to form an isolation layer coating solution with a solid content of 5.6%, and the metformin sustained-release tablet cores were coated in a coating pan to obtain metformin sustained-release isolation coated tablets. The coating parameters were: coating gun aperture 0.8 mm, coating pan volume 3 L, coating gun and tablet bed distance 10 cm, tablet bed temperature 35 ° C ~ 38 ° C, air intake 120 m 3 / h, liquid supply pump speed 3-7rpm, spraying rate 10g / min, atomization pressure 0.15MPa, fan pressure 0.15MPa, coating time 2h, drying time 30min.

[0097] Preparation Example 3

[0098] Step 2: Preparation method of drug-loaded layer coating, the steps are as follows:

[0099] The drug-carrying layer components were mixed with an ethanol aqueous solution with a volume ratio of 25% to form a drug-carrying layer coating solution with a solid content of 10%. The metformin sustained-release isolation coated tablets were coated in a coating pan to obtain dapagliflozin metformin sustained-release tablets. The coating parameters were: coating gun aperture 0.8 mm, coating pan volume 3 L, coating gun and tablet bed distance 7 cm, tablet bed temperature 33 ° C, air intake 120 m 3 / h, liquid supply pump speed 3-10rpm, spraying rate 11g / min, atomization pressure 0.05MPa, fan pressure 0.05MPa, coating time 2h, drying time 10min.

[0100] Example 1

[0101] Metformin sustained-release tablet core, including: metformin hydrochloride 1000 mg, magnesium stearate 7 mg, carboxymethylcellulose sodium 50 mg, hypromellose 235 mg, silicon dioxide 13 mg.

[0102] The preparation process is the same as that of Preparation Example 1, wherein the lubricant magnesium stearate is 5 mg in the step "premixing" and the lubricant magnesium stearate is 2 mg in the step "total mixing".

[0103] Example 2

[0104] The metformin sustained-release tablet core prepared in Example 1 was coated with an isolation layer; the prescription was as follows (in mg):

[0105] Serial number HPMC(E5) lactose PEG 6000 Weight gain of drug loading layer Drug coating solution Prescription 1 7.89 23.68 0.79 2.48％ 25% ethanol in water Prescription 2 8.75 26.26 0.88 2.75％ 25% ethanol in water Prescription 3 9.20 27.60 0.92 2.89％ 25% ethanol in water

[0106] The tablet bed temperature of Prescription 1 is 34.7-40.2°C, the coating gun aperture is 10 mm, and the atomization pressure and the fan pressure are both 0.15 MPa; the other operating parameters are the same as those in Preparation Example 2. The tablet bed temperature of Prescription 2 is 33°C, the coating gun is 10 cm away from the tablet bed, the atomization pressure and the fan pressure are both 0.15 MPa; the other operating parameters are the same as those in Preparation Example 3. The tablet bed temperature of Prescription 3 is 33°C, the coating gun is 7 cm away from the tablet bed, the atomization pressure and the fan pressure are both 0.15 MPa; the other operating parameters are the same as those in Preparation Example 2.

[0107] The coating solution yields of prescriptions 1-3 were 71.86%, 81.97%, and 82.42%, respectively; all were coated normally, and the surface of the sustained-release tablet core was smooth. The coating solution yield of prescription 3 was the highest, so the isolation layer coating operating parameters were determined: the tablet bed temperature was 33°C, and the coating gun was 7 cm away from the tablet bed.

[0108] Example 3

[0109] The metformin sustained-release tablet core prepared in Example 1 was coated with a drug-loaded layer. The API was dapagliflozin propylene glycol monohydrate, and the prescription was as follows (in mg):

[0110]

[0111] The preparation of drug-loaded coatings of prescriptions 4A-D to 5A-D is the same as that of Preparation Example 3.

[0112] The coating solution yields of prescriptions 4A-D to 5A-D were 93.23% and 99.81%, respectively; it can be seen that using 25% ethanol aqueous solution as the coating solution solvent has a better effect.

[0113] Example 4

[0114] The preparation process is the same as that of Preparation Example 3, and the metformin sustained-release tablet core prepared in Example 1 is coated with a drug-loaded layer; the API is dapagliflozin propylene glycol monohydrate, and the second solvent is 25% ethanol aqueous solution. The prescription is as follows (in mg):

[0115]

[0116] The preparation of the drug-carrying layer coating of prescriptions 6-11 was the same as that of preparation example 3. The coating surface of prescriptions 6 and 7 was uneven, and there were surface protrusions like drug precipitation. After the coating of prescriptions 8-11, the tablets had orange peel, but no surface protrusions like precipitation were observed. It can be seen that the drug-carrying layer coating of prescriptions 8-11 was more uniform.

[0117] Example 5

[0118] The preparation process is the same as that of Example 2-3, and the metformin sustained-release tablet core prepared in Example 1 is coated with an isolation layer and a drug-carrying layer; the API is dapagliflozin propylene glycol monohydrate, and the second solvent is 25% ethanol aqueous solution. The prescription is as follows (in mg):

[0119]

[0120]

[0121] Prescription 12-16, the isolation layer preparation method is the same as Preparation Example 2, and the drug-carrying layer coating preparation is the same as Preparation Example 3.

[0122] Dissolution test was performed on the coated tablets prepared from prescription 9 and prescription 13-15. The dissolution medium was pH 6.8 phosphate buffer. The dissolution conditions were: 1000 mL of dissolution medium, 12 tablets of the test sample were placed in a sinker, the rotation speed was 75 rpm, and the operation was carried out according to the law. Samples were taken for testing after 5 min, 10 min, 15 min, 30 min, 45 min, and 60 min. The dissolution results were as follows: Figures 2-3 shown.

[0123] The dissolution curves of dapagliflozin in formulations 9 and 12 show that the addition of the isolation layer can effectively prevent the effect of the metformin hydrochloride layer on the dissolution of dapagliflozin, making dapagliflozin have a better dissolution rate. The dissolution curves are shown in Figure 1 As shown. From the dissolution curves of formulations 12-14 ( Figure 2 ) It can be seen that when the weight of the isolation layer increases by 3-4%, the cumulative dissolution of dapagliflozin is better.

[0124] In the coating process of prescription 15, tablet sticking occurred. The sticking phenomenon during the coating process was improved by reducing the sucrose concentration or adding talcum powder. In prescription 16, the drug application rate and coating success rate were improved by reducing the proportion of PEG 6000 in the isolation layer.

[0125] Example 6

[0126] The difference from Example 4 is that the API is dapagliflozin, and the other components remain unchanged. The prescription numbers are 17-22.

[0127] Example 7

[0128] The difference from Example 5 is that the API is dapagliflozin, and the other components remain unchanged. The prescription numbers are 23-26.

[0129] Example 8

[0130] Based on the prescription and preparation method of prescription 16 in Example 5, each component was slightly adjusted, and the changes were as shown in the following table (unit: mg):

[0131]

[0132] Based on prescription 27, the components of the drug-carrying layer were slightly adjusted, and the changes were as shown in the following table (unit: mg):

[0133]

[0134]

[0135] Based on prescription 27, the components of the drug-carrying layer were slightly adjusted, and the changes were as shown in the following table (unit: mg):

[0136]

[0137] Example 9

[0138] The difference from the prescriptions 27-32 of Example 8 is that the API is dapagliflozin, and the dosage of the API is calculated based on dapagliflozin propylene glycol hydrate. The prescription numbers are 40-45.

[0139] Dissolution test

[0140] Dapagliflozin metformin sustained-release tablets prepared from prescription 15D were used as the test preparation and the reference preparation ( Specification: 10mg / 1000mg) for dissolution test; the dissolution medium is: pH 6.8 phosphate buffer; the dissolution conditions are: the dissolution medium is 1000mL, 12 test pieces are used, the paddle method is used, 75rpm, and the operation is carried out according to the law. Sampling tests are carried out after 5min, 10min, 15min, 30min, 45min, 60min, 90min, 120min, 180min, 240min, 300min, and 360min. The dissolution results are as follows Figures 4-5 shown.

[0141] It can be seen from the dissolution curve of dapagliflozin that at 30 minutes, the cumulative dissolution rates of the test preparation and the reference preparation were 95.72% and 93.57%, respectively, which are very close.

[0142] From the dissolution curve of metformin hydrochloride, it can be seen that the dissolution curves of the test preparation and the reference preparation are consistent.

[0143] Stability test

[0144] The example products and reference preparations were taken to examine the stability at room temperature, accelerated 40°C / 75%RH, 60°C / 75%RH and other conditions. The detection of peroxides and impurities is as follows:

[0145]

[0146] Note: “ / ” indicates not detected

[0147] From 0 days to 10 days, the product of the embodiment of the present application is stable, and the peroxide detection result is only 0.009 ppm; the peroxide detection result of the reference preparation is significantly higher than that of the product of the embodiment of the present application. It can be seen that the dapagliflozin metformin sustained-release composition prepared in the embodiment of the present application has good stability and the advantages of low peroxide impurities.

[0148] The example products and reference preparations were used to investigate the impurities of dapagliflozin and metformin as shown in the following table:

[0149]

[0150]

[0151]

[0152]

[0153] It can be seen that the dapagliflozin metformin sustained-release composition prepared in the examples of the present application has good stability.

Claims

1. A dapagliflozin metformin sustained-release composition, characterized in that: Including: A metformin sustained-release core, a separation layer coated on the metformin sustained-release core, and a drug-carrying layer coated on the separation layer; The isolation layer includes a first film former, an anti-adhesive agent and / or a first plasticizer; The drug-carrying layer comprises a pharmaceutically active substance and a drug-carrying layer excipient; the drug-carrying layer excipient comprises a second film-forming agent, a pore-forming agent and / or a second plasticizer; preferably, the drug-carrying layer excipient further optionally comprises an antioxidant; the pharmaceutically active substance is selected from dapagliflozin or dapagliflozin propylene glycol monohydrate.

2. The composition according to claim 1, characterized in that The weight ratio between the metformin sustained-release core and the drug-loaded layer is 2:1 to 100:

1. Preferably, in a single-dose composition, the total weight of the drug-carrying layer is 25 to 550 mg; Preferably, the weight ratio between the metformin sustained-release core and the isolation layer is 20:1 to 50:1; Preferably, relative to the total amount of the metformin sustained-release core, the weight of the isolation layer increases by 0.05-30% or 0.05-10% or 0.5-5%; the weight of the drug-carrying layer increases by 1-40% or 15-30% or 15-25% or 15-30%; Preferably, based on the total weight of the isolation layer, it includes 40-95% of the first film-forming agent, 10-55% of the anti-adhesive agent or 0-6% of the first plasticizer, and the total percentage of the components of the isolation layer is 100%; based on the total weight of the drug-carrying layer, it includes 0.1-65% of the active pharmaceutical ingredient, 5-55% of the second film-forming agent, 40-95% of the pore-forming agent and / or 0-20% of the second plasticizer and / or 0-20% of the antioxidant, and the total percentage of the components of the drug-carrying layer is 100%; further preferably, based on the total amount of the metformin sustained-release core, the auxiliary materials of the sustained-release layer are selected from one or more of 0.1-10% lubricants, 0.1-20% adhesives, 0.1-95% sustained-release materials, 0.1-10% glidants, and 0-20% colorants, and the total percentage of the components of the metformin sustained-release core is 100%.

3. The composition according to claim 1, characterized in that The first film-forming agent and the second film-forming agent are each independently selected from at least one of hydroxypropyl methylcellulose polymers, polyvinyl alcohol, polyvinyl acetate, methacrylic acid (ester) polymers, hydroxypropyl cellulose coating polymers, cellulose acetate, and ethyl cellulose; The first plasticizer and the second plasticizer are each independently selected from at least one of glycerol, propylene glycol, polyethylene glycol, triacetin, triethyl citrate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, acetyl triethyl citrate, acetyl tributyl citrate, tributyl citrate, and oil / glyceride; The anti-adhesive agent is selected from one or more of talc, stearic acid, magnesium stearate or glyceryl monostearate; The pore-forming agent is selected from at least one of sorbitol, povidone K30, hydroxypropyl cellulose, polyethylene glycol, sodium lauryl sulfate, mannitol, lactose or sucrose; The antioxidant is selected from one or more of tocopherol acetate, butylated hydroxyanisole, butylated hydroxytoluene, sodium benzotriazolyl butylphenol sulfate, vitamin C, tea polyphenols, vitamin C ethyl ether, vitamin E, propyl gallate, sodium sulfite, sodium pyrosulfite, sodium bisulfite, thioglycerol, thioglycolic acid, rosmarinic acid, and anthocyanidins.

4. The composition according to claim 3, characterized in that The isolation layer includes hypromellose, talc, and polyethylene glycol 6000; or, the isolation layer includes ethyl cellulose, stearic acid, and triethyl citrate; or, the isolation layer includes hypromellose, talc, and triethyl citrate; or, the isolation layer includes hypromellose, magnesium stearate, and dibutyl sebacate; or, the isolation layer includes hypromellose, talc, polyethylene glycol 6000, and tartrazine; or, the isolation layer includes hypromellose, talc, polyethylene glycol 6000, and sunset yellow; The drug-carrying layer includes dapagliflozin propylene glycol monohydrate, hydroxypropyl methylcellulose, sucrose and polyethylene glycol 6000; the drug-carrying layer includes dapagliflozin propylene glycol monohydrate, polyvinyl alcohol, lactose and polyethylene glycol 6000; the drug-carrying layer includes dapagliflozin propylene glycol monohydrate, polyvinyl alcohol, lactose, vitamin C and polyethylene glycol 6000; the drug-carrying layer includes dapagliflozin propylene glycol monohydrate, polyvinyl alcohol, talc and polyethylene glycol 6000; the drug-carrying layer includes dapagliflozin propylene glycol monohydrate, polyvinyl alcohol, lactose, talc and polyethylene glycol 6000; the drug-carrying layer includes dapagliflozin propylene glycol monohydrate, polyvinyl alcohol, sucrose and polyethylene glycol 6000; the drug-carrying layer includes dapagliflozin propylene glycol monohydrate, polyvinyl alcohol, sucrose, vitamin C and polyethylene glycol 6000; the drug-carrying layer includes dapagliflozin propylene glycol monohydrate, hypromellose, mannitol and polyethylene glycol 6000; the drug-carrying layer includes dapagliflozin, polyvinyl alcohol, lactose and polyethylene glycol 6000; the drug-carrying layer includes dapagliflozin, polyvinyl alcohol, lactose, vitamin C and polyethylene glycol 6000; the drug-carrying layer includes dapagliflozin, polyvinyl alcohol, talc and polyethylene glycol 6000; the drug-carrying layer includes dapagliflozin, polyvinyl alcohol, lactose, talc and polyethylene glycol 6000; the drug-carrying layer includes dapagliflozin, polyvinyl alcohol, lactose, talc and polyethylene glycol 6000; The drug-carrying layer comprises dapagliflozin, polyvinyl alcohol, sucrose, vitamin C and polyethylene glycol 6000; the drug-carrying layer comprises dapagliflozin, hydropropyl methylcellulose, lactose and polyethylene glycol 6000; the drug-carrying layer comprises dapagliflozin, hydropropyl methylcellulose, sucrose and polyethylene glycol 6000; the drug-carrying layer comprises dapagliflozin, hydropropyl methylcellulose, sucrose and polyethylene glycol 6000; the drug-carrying layer comprises dapagliflozin, hydropropyl methylcellulose, mannitol and polyethylene glycol 6000.

5. The composition according to claim 1, characterized in that The composition comprises, in order: A metformin extended-release core comprising metformin hydrochloride, magnesium stearate, sodium carboxymethylcellulose, hypromellose, and silicon dioxide; a separation layer including hypromellose, talc and polyethylene glycol 6000; A drug-carrying layer comprising dapagliflozin or dapagliflozin propylene glycol hydrate, hypromellose, sucrose and PEC6000; or comprising dapagliflozin or dapagliflozin propylene glycol hydrate, polyvinyl alcohol, lactose, an antioxidant and PEC6000; Preferably, relative to the total amount of the metformin sustained-release core, the isolation layer increases in weight by 0.5-5%; and the drug-carrying layer increases in weight by 15-30%.

6. The composition according to claim 5, characterized in that Based on the total weight of the isolation layer, the isolation layer comprises 65-80% of hypromellose, 15-25% of talc or 1-5% of polyethylene glycol 6000, and the total percentage of each component of the isolation layer is 100%; Based on the total weight of the drug-carrying layer, it comprises 1-10% of dapagliflozin or dapagliflozin propylene glycol hydrate, 15-30% of hydroxypropyl methylcellulose, 60-70% of sucrose and / or 5-10% of polyethylene glycol 6000 and / or 1-2% of an antioxidant, or comprises 1-10% of dapagliflozin or dapagliflozin propylene glycol hydrate, 15-30% of polyvinyl alcohol, 60-70% of lactose and / or 5-10% of polyethylene glycol 6000 and / or 1-2% of an antioxidant, and the total percentage of each component of the drug-carrying layer is 100%; Further preferably, based on the total amount of the metformin sustained-release core, the sustained-release layer excipients include 0.1-10% magnesium stearate, 0.1-5% sodium carboxymethylcellulose, 10-25% hydroxypropyl methylcellulose, and 0.5-1.5% silicon oxide, and the total percentage of each component of the metformin sustained-release core is 100%.

7. The method for preparing the dapagliflozin metformin composition according to any one of claims 1 to 6, characterized in that: The following steps are involved: Step 1: uniformly mixing the components of the isolation layer with the first solvent to obtain an isolation layer coating solution; Coating the metformin sustained-release core with an isolation layer to obtain a metformin sustained-release isolation coating composition; Step 2: uniformly mix the components of the drug-carrying layer with the second solvent to obtain a drug-carrying layer coating solution; and perform drug-carrying layer coating to obtain a dapagliflozin metformin composition.

8. The preparation method according to claim 7, characterized in that: The metformin sustained-release core is prepared by wet granulation followed by tableting; further, in step 1, the isolation layer coating parameters include: tablet bed temperature 35°C to 38°C, air intake volume 100 to 140 m 3 / h, liquid supply pump speed 3-7rpm, spraying rate 5-20g / min, atomization pressure 0.05-0.5MPa, fan pressure 0.05-0.5MPa, coating time 0.5-10h, drying time 5-60min; further, in step 2, the drug-carrying layer coating parameters include: tablet bed temperature 30℃~45℃, air intake volume 100-140m 3 / h, liquid supply pump speed 3-10rpm, spraying rate 5-20g / min, atomization pressure 0.05-0.5MPa, fan pressure 0.05-0.5MPa, coating time 0.5-10h, drying time 5-60min.

9. The preparation method according to claim 7, characterized in that: The first solvent and the second solvent are each independently pure water or an ethanol aqueous solution with a volume ratio of 15 to 80%; the solid content of the isolation layer coating solution is 5 to 15%; the isolation layer coating weight gain is 0.5 to 5%; the solid content of the drug-carrying layer coating solution is 5 to 25%; the drug-carrying layer weight gain is 1 to 30%.

10. Use of the dapagliflozin metformin composition according to any one of claims 1 to 6 or the dapagliflozin metformin composition prepared by the preparation method according to any one of claims 7 to 9 in the preparation of a drug for treating a disorder or disease; the disorder or disease is selected from diabetes (including type I and type II diabetes), impaired glucose tolerance, insulin resistance, nephropathy, retinopathy, neuropathy and cataracts, hyperglycemia, hyperinsulinemia, hypercholesterolemia, dyslipidemia, increased blood levels of free fatty acids or glycerol, hyperlipidemia, hypertriglyceridemia, obesity, wound healing, tissue ischemia, atherosclerosis, angina pectoris, myocardial infarction and hypertension.

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