CN105769803A - Medicinal composition for treating 2-diabetes mellitus and preparation method of medicinal composition - Google Patents
Medicinal composition for treating 2-diabetes mellitus and preparation method of medicinal composition Download PDFInfo
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- CN105769803A CN105769803A CN201410773880.6A CN201410773880A CN105769803A CN 105769803 A CN105769803 A CN 105769803A CN 201410773880 A CN201410773880 A CN 201410773880A CN 105769803 A CN105769803 A CN 105769803A
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- diabetes mellitus
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- 239000000203 mixture Substances 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- 206010012601 diabetes mellitus Diseases 0.000 title abstract description 6
- 229960001713 canagliflozin Drugs 0.000 claims abstract description 38
- VHOFTEAWFCUTOS-TUGBYPPCSA-N canagliflozin hydrate Chemical compound O.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1 VHOFTEAWFCUTOS-TUGBYPPCSA-N 0.000 claims abstract description 37
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 10
- 238000004090 dissolution Methods 0.000 claims abstract description 8
- 239000000314 lubricant Substances 0.000 claims abstract description 8
- 239000008187 granular material Substances 0.000 claims description 38
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 24
- 239000008194 pharmaceutical composition Substances 0.000 claims description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 16
- 238000000576 coating method Methods 0.000 claims description 14
- 239000007779 soft material Substances 0.000 claims description 13
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 11
- 229920002472 Starch Polymers 0.000 claims description 11
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 11
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 11
- 238000004132 cross linking Methods 0.000 claims description 11
- 239000011734 sodium Substances 0.000 claims description 11
- 229910052708 sodium Inorganic materials 0.000 claims description 11
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 11
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 11
- 239000008107 starch Substances 0.000 claims description 11
- 235000019698 starch Nutrition 0.000 claims description 11
- 239000011248 coating agent Substances 0.000 claims description 10
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 8
- 235000019359 magnesium stearate Nutrition 0.000 claims description 8
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 claims description 8
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 8
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 8
- 239000000741 silica gel Substances 0.000 claims description 8
- 229910002027 silica gel Inorganic materials 0.000 claims description 8
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- -1 inorganic acid salts Chemical class 0.000 claims description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 229920001223 polyethylene glycol Polymers 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 239000012453 solvate Substances 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 2
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 230000002378 acidificating effect Effects 0.000 claims description 2
- 235000001014 amino acid Nutrition 0.000 claims description 2
- 235000003704 aspartic acid Nutrition 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 claims description 2
- 229940092714 benzenesulfonic acid Drugs 0.000 claims description 2
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 2
- 159000000007 calcium salts Chemical class 0.000 claims description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 2
- 239000007888 film coating Substances 0.000 claims description 2
- 238000009501 film coating Methods 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 235000011087 fumaric acid Nutrition 0.000 claims description 2
- 235000013922 glutamic acid Nutrition 0.000 claims description 2
- 239000004220 glutamic acid Substances 0.000 claims description 2
- 238000005469 granulation Methods 0.000 claims description 2
- 230000003179 granulation Effects 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- 229940071870 hydroiodic acid Drugs 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- 229910003002 lithium salt Inorganic materials 0.000 claims description 2
- 159000000002 lithium salts Chemical class 0.000 claims description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 2
- 159000000003 magnesium salts Chemical class 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 150000004682 monohydrates Chemical class 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 239000008188 pellet Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 229920001983 poloxamer Polymers 0.000 claims description 2
- 229960000502 poloxamer Drugs 0.000 claims description 2
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 2
- 159000000000 sodium salts Chemical class 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 210000002784 stomach Anatomy 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 claims description 2
- 230000007547 defect Effects 0.000 abstract description 2
- 238000005265 energy consumption Methods 0.000 abstract description 2
- 239000004480 active ingredient Substances 0.000 abstract 3
- 239000004615 ingredient Substances 0.000 abstract 1
- 239000007962 solid dispersion Substances 0.000 abstract 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 238000003556 assay Methods 0.000 description 12
- 238000001035 drying Methods 0.000 description 11
- 235000010603 pastilles Nutrition 0.000 description 8
- 239000008213 purified water Substances 0.000 description 8
- TZBAVQKIEKDGFH-UHFFFAOYSA-N n-[2-(diethylamino)ethyl]-1-benzothiophene-2-carboxamide;hydrochloride Chemical compound [Cl-].C1=CC=C2SC(C(=O)NCC[NH+](CC)CC)=CC2=C1 TZBAVQKIEKDGFH-UHFFFAOYSA-N 0.000 description 7
- 239000012467 final product Substances 0.000 description 6
- 238000010438 heat treatment Methods 0.000 description 6
- 238000007689 inspection Methods 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 238000005070 sampling Methods 0.000 description 6
- 238000007873 sieving Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 239000003814 drug Substances 0.000 description 5
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 5
- 238000010792 warming Methods 0.000 description 5
- 239000012530 fluid Substances 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 108091006269 SLC5A2 Proteins 0.000 description 2
- 102000058081 Sodium-Glucose Transporter 2 Human genes 0.000 description 2
- 102000003673 Symporters Human genes 0.000 description 2
- 108090000088 Symporters Proteins 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 229940121377 sodium-glucose co-transporter inhibitor Drugs 0.000 description 2
- 210000005239 tubule Anatomy 0.000 description 2
- HOOVGTBWZNSMBL-KYVQUIMTSA-N CC(C=CC=C1)=C1C1=CC=C[S+]1[C@@H]([C@@H]([C@H]1O)O)O[C@H](CO)[C@H]1O Chemical class CC(C=CC=C1)=C1C1=CC=C[S+]1[C@@H]([C@@H]([C@H]1O)O)O[C@H](CO)[C@H]1O HOOVGTBWZNSMBL-KYVQUIMTSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 108091006277 SLC5A1 Proteins 0.000 description 1
- 102000000070 Sodium-Glucose Transport Proteins Human genes 0.000 description 1
- 108010080361 Sodium-Glucose Transport Proteins Proteins 0.000 description 1
- 102000058090 Sodium-Glucose Transporter 1 Human genes 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 230000006377 glucose transport Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
The invention provides a medicinal composition for treating 2-diabetes mellitus and a preparation method of the medicinal composition. The medicinal composition for treating 2-diabetes mellitus is prepared from an active ingredient, namely, canagliflozin, and medicinal auxiliary ingredients including a water-soluble solid dispersion carrier, a disintegrating agent and a lubricating agent. The medicinal composition for treating 2-diabetes mellitus has no special requirements for the grain diameter of the active ingredient, the superfine grinding is not needed, so that the energy consumption is low, the dissolution rate achieves 90% or above, the bioavailability is high, the defects that the active ingredient is poor in solubility and low in bioavailability are overcome, the quality is stable and reliable, and thus the medicinal composition has extremely good market development prospects.
Description
Technical field
The invention belongs to technical field of medicine, relate to a kind of for pharmaceutical composition treating type 2 diabetes mellitus and preparation method thereof, invention also provides the pharmaceutical composition for treating type 2 diabetes mellitus of a kind of quality safety, good stability.
Background technology
Add up according to IDF, there is diabetics 1.51 hundred million in the whole world in 2000, and there is diabetics 2.85 hundred million in the whole world at present, by the words of current speed increment, estimating that the year two thousand thirty whole world will have nearly 500,000,000 people to suffer from diabetes, wherein type 2 diabetes mellitus patient accounts for more than 90%.Life and the quality of life of patient are threatened greatly by the chronic vascular complications of diabetes, bring heavy financial burden to family and patient individual.
Canagliflozin (Canagliflozin) is initial to be researched and developed by limit, the field Rhizoma Sparganii pharmacy (MitsubishiTanabePharma) under Mitsubishi, after transfer Johnson Co..Canagliflozin is the white 2(SGLT2 of first sodium glucose co-transporter 2 of FDA approval) inhibitor, for treating the type 2 diabetes mellitus of adult patients.Sodium glucose co-transporter 2 white (SGLT) has two kinds of hypotypes and SGLT1 and SGLT2, is distributed in mucous membrane of small intestine and renal tubules respectively, it is possible to glucose transport is entered blood.Canagliflozin can suppress SLCT2, makes the glucose in renal tubules can not heavily be absorbed into blood smoothly and discharge with urine, thus reducing blood sugar concentration.
A kind of crystal type canagliflozin semihydrate and preparation method thereof, medical composition and purposes disclosed in CN101573368A.The preparation method that CN101801371B discloses the compound that can be used as SGLT inhibitor.CN102985075A discloses tablet clean containing Ka Nagelie and preparation method thereof.CN102883726A discloses and comprises 1-(β-D-glucopyranosyl)-2-thienyl-methyl benzene derivative is as the pharmaceutical preparation of SGLT inhibitor.CN103641822A discloses the canagliflozin compound of a kind of crystal form and pharmaceutical composition thereof and preparation method.
Owing to canagliflozin is a medicine being insoluble in water, the absorption of medicine depends primarily on the dissolution of medicine, existing canagliflozin preparation exist quality instability, dissolution not high, to defects such as particle diameter require.
Summary of the invention
It is desirable to provide a kind of dissolution is high, stay-in-grade for pharmaceutical composition treating type 2 diabetes mellitus and preparation method thereof.
Pharmaceutical composition for treating type 2 diabetes mellitus prepared by the present invention is made up of pharmaceutic adjuvants such as active component and water-soluble solid dispersible carrier, disintegrating agent, lubricants.
Above-mentioned active component is canagliflozin (Canagliflozin) or its pharmaceutically acceptable salt, solvate.
Above-mentioned active component is the pharmaceutically acceptable salt of canagliflozin (Canagliflozin) is the inorganic acid salts such as its sodium salt, potassium salt, calcium salt, magnesium salt, lithium salts and hydrochloric acid, hydrobromic acid, hydroiodic acid, the acylates such as succinic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, benzenesulfonic acid, the acidic amino acid salt such as aspartic acid, glutamic acid；Described solvate is semihydrate, monohydrate, alcohol adduct, ethanolates.
The above-mentioned pharmaceutical composition for treating type 2 diabetes mellitus consists of the following composition by weight percentage: active component 30%～70%, water-soluble solid dispersible carrier 20% ~ 60%, disintegrating agent 3% ~ 10%, lubricant 0.2%～2.0%.
Above-mentioned water-soluble solid dispersible carrier is one or more the mixture in Polyethylene Glycol, polyvidone, poloxamer, citric acid, mannitol, it is preferable that Polyethylene Glycol；Disintegrating agent is one or more the mixture in dried starch, carboxymethyl starch sodium, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, it is preferable that polyvinylpolypyrrolidone；Lubricant is one or more the mixture in magnesium stearate, stearic acid, zinc stearate, micropowder silica gel, Pulvis Talci, it is preferable that magnesium stearate.
Prepare the above-mentioned pharmaceutical composition for treating type 2 diabetes mellitus to comprise the steps of
1. supplementary material process: active component is mixed homogeneously with water-soluble solid dispersible carrier, disintegrating agent with 60 orders with upper screen cloth sieving for standby；
2. to above-mentioned active component and the dehydrated alcohol of addition mixture weight 5 ~ 15 times amount in water-soluble solid dispersible carrier mixture, putting the heating in water bath of 60 ~ 90 DEG C, stirring is to entirely molten；
3. after entirely molten, reclaim dehydrated alcohol, when dehydrated alcohol is recycled to the 20% ~ 50% of active component and water-soluble solid dispersible carrier mixture weight, add appropriate disintegrating agent, mix homogeneously, make soft material；
4. the wet grain of system: take above-mentioned soft material granulation；
5. dry: by wet grain drying；
6. granulate: by dry granule granulate；
7. always mix: granulate granule adds the lubricant of recipe quantity and appropriate disintegrating agent, mixing, and sampling carries out intermediate inspection；
Intermediate carries out tabletting or capsule charge after the assay was approved according to different sizes such as 50mg, 100mg, 200mg, 300mg and 600mg.
Treat that Bao Pin packs after the assay was approved and get final product.
The above-mentioned pharmaceutical composition preparation process for treating type 2 diabetes mellitus is granulated and mesh size used by granulate is 16 order ~ 40 orders, it is preferable that 18 order ~ 24 orders；It is 30 DEG C ~ 45 DEG C that dry materials temperature controls, it is preferable that 38 DEG C ~ 45 DEG C；Pellet moisture controls 1% ~ 3%, it is preferable that less than 2%；Always do time is 15 ~ 40 minutes, it is preferable that 30 minutes.
The above-mentioned pharmaceutical composition tabletting for treating type 2 diabetes mellitus can be prepared the stomach dissolution type film coating liquid such as Opadry, Opadry II if desired after completing end and carry out coating, and film-coat layer gain in weight is 2% ~ 4%.
Present invention have the advantage that
1, supplementary material of the present invention is through strict proportioning, and adjuvant selects kind few, and drug dissolution is high, good stability, and safety is high；
2, to the particle diameter of canagliflozin without particular/special requirement, it is not necessary to micronizing, energy consumption is low；
3, production technology is simple, is suitable for industrialized production；
4, without surfactant, unnecessary risk will not be brought to patient.
Detailed description of the invention
Following enforcement can illustrate in greater detail the present invention, but does not limit the present invention in any form.
Embodiment 1
Canagliflozin sheet Core formulation (specification: 100mg):
Canagliflozin 100.0g(gives money as a gift pure)
Macrogol 4000 80.0g
Polyvinylpolypyrrolidone 16.0g
Magnesium stearate 2.0g
Make 1000 altogether
Coating fluid prescription:
Opadry II85F184226.0g
Purified water 44.0g
Preparation method:
1, the preparation of pastille label
1. supplementary material processes: canagliflozin mixed homogeneously with Macrogol 4000, and polyvinylpolypyrrolidone is by 60 eye mesh screen sieving for standby；
2. adding the dehydrated alcohol of 1.2kg in above-mentioned canagliflozin and Macrogol 4000 mixture, put the heating in water bath of 70 DEG C, stirring is to entirely molten；
3., after entirely molten, it be warming up to 90 DEG C and reclaim dehydrated alcohol, when dehydrated alcohol is recycled to 60 ~ 80ml, add 12.0g polyvinylpolypyrrolidone, mix homogeneously, make soft material；
4. the wet grain of system: take above-mentioned soft material and granulate with 18 eye mesh screens；
5. drying: by above-mentioned wet grain drying, controlling temperature of charge is 40 ~ 42 DEG C；
6. granulate: by dry granule with 18 eye mesh screen granulate；
7. always mix: granulate granule adds magnesium stearate and the 4.0g polyvinylpolypyrrolidone of recipe quantity, mixing, and sampling carries out intermediate inspection；
Intermediate carries out tabletting after the assay was approved.
2, the preparation of coated tablet:
Being dissolved in purified water using recipe quantity Opadry II85F18422 and prepare the solution into about 12% as film-coat liquid, by pastille label coating, controlling temperature of charge in coating process is 38 DEG C ~ 42 DEG C, and after this operation completes, label increases weight about 3%.
3, treat that Bao Pin packs after the assay was approved and get final product.
Embodiment 2
Canagliflozin sheet Core formulation (specification: 100mg):
Canagliflozin semihydrate 1020.0g(gives money as a gift pure)
Polyethylene glycol 6000 100.0g
Cross-linking sodium carboxymethyl cellulose 20.0g
Micropowder silica gel 2.0g
Make 1000 altogether
Coating fluid prescription:
Opadry II85F421297.0g
Purified water 40.0g
Preparation method:
1, the preparation of pastille label
1. supplementary material processes: mixed homogeneously with polyethylene glycol 6000 by canagliflozin semihydrate, and cross-linking sodium carboxymethyl cellulose is by 80 eye mesh screen sieving for standby；
2. adding the dehydrated alcohol of 1.5kg in above-mentioned canagliflozin semihydrate and polyethylene glycol 6000 mixture, put the heating in water bath of 65 DEG C, stirring is to entirely molten；
3., after entirely molten, it be warming up to 88 DEG C and reclaim dehydrated alcohol, when dehydrated alcohol is recycled to 75 ~ 90ml, add 15.0g cross-linking sodium carboxymethyl cellulose, mix homogeneously, make soft material；
4. the wet grain of system: take above-mentioned soft material and granulate with 24 eye mesh screens；
5. drying: by above-mentioned wet grain drying, controlling temperature of charge is 42 ~ 45 DEG C；
6. granulate: by dry granule with 24 eye mesh screen granulate；
7. always mix: granulate granule adds micropowder silica gel and the 5.0g cross-linking sodium carboxymethyl cellulose of recipe quantity, mixing, and sampling carries out intermediate inspection；
Intermediate carries out tabletting after the assay was approved.
2, the preparation of coated tablet:
Being dissolved in purified water using recipe quantity Opadry II85F42129 and prepare the solution into about 15% as film-coat liquid, by pastille label coating, controlling temperature of charge in coating process is 40 DEG C ~ 42 DEG C, and after this operation completes, label increases weight about 3%.
3, treat that Bao Pin packs after the assay was approved and get final product.
Embodiment 3
Canagliflozin sheet Core formulation (specification: 300mg):
Canagliflozin 300.0g(gives money as a gift pure)
Polyvidone 150.0g
Cross-linking sodium carboxymethyl cellulose 30.0g
Magnesium stearate 3.0g
Make 1000 altogether
Coating fluid prescription:
Opadry II85F1842220.0g
Purified water 145.0g
Preparation method:
1, the preparation of pastille label
1. supplementary material processes: canagliflozin mixed homogeneously with polyvidone, and cross-linking sodium carboxymethyl cellulose is by 60 eye mesh screen sieving for standby；
2. adding the dehydrated alcohol of 3.0kg in above-mentioned canagliflozin and povidone mixture, put the heating in water bath of 75 DEG C, stirring is to entirely molten；
3., after entirely molten, it be warming up to 85 DEG C and reclaim dehydrated alcohol, when dehydrated alcohol is recycled to 180 ~ 200ml, add 20.0g cross-linking sodium carboxymethyl cellulose, mix homogeneously, make soft material；
4. the wet grain of system: take above-mentioned soft material and granulate with 18 eye mesh screens；
5. drying: by above-mentioned wet grain drying, controlling temperature of charge is 38 ~ 40 DEG C；
6. granulate: by dry granule with 18 eye mesh screen granulate；
7. always mix: granulate granule adds magnesium stearate and the 10.0g cross-linking sodium carboxymethyl cellulose of recipe quantity, mixing, and sampling carries out intermediate inspection；
Intermediate carries out tabletting after the assay was approved.
2, the preparation of coated tablet:
Being dissolved in purified water using recipe quantity Opadry II85F18422 and prepare the solution into about 12% as film-coat liquid, by pastille label coating, controlling temperature of charge in coating process is 40 DEG C ~ 42 DEG C, and after this operation completes, label increases weight about 4%.
3, treat that Bao Pin packs after the assay was approved and get final product.
Embodiment 4
Canagliflozin sheet Core formulation (specification: 300mg):
Canagliflozin semihydrate 306.0g(gives money as a gift pure)
Macrogol 4000 160.0g
Carboxymethyl starch sodium 30.0g
Micropowder silica gel 5.0g
Make 1000 altogether
Coating fluid prescription:
Opadry II85F4212920.0g
Purified water 115.0g
Preparation method:
1, the preparation of pastille label
1. supplementary material processes: mixed homogeneously with Macrogol 4000 by canagliflozin semihydrate, and carboxymethyl starch sodium is by 80 eye mesh screen sieving for standby；
2. adding the dehydrated alcohol of 3.2kg in above-mentioned canagliflozin semihydrate and Macrogol 4000 mixture, put the heating in water bath of 80 DEG C, stirring is to entirely molten；
3., after entirely molten, it be warming up to 88 DEG C and reclaim dehydrated alcohol, when dehydrated alcohol is recycled to 160 ~ 200ml, add 15.0g carboxymethyl starch sodium, mix homogeneously, make soft material；
4. the wet grain of system: take above-mentioned soft material and granulate with 20 eye mesh screens；
5. drying: by above-mentioned wet grain drying, controlling temperature of charge is 38 ~ 40 DEG C；
6. granulate: by dry granule with 20 eye mesh screen granulate；
7. always mix: granulate granule adds micropowder silica gel and the 15.0g carboxymethyl starch sodium of recipe quantity, mixing, and sampling carries out intermediate inspection；
Intermediate carries out tabletting after the assay was approved.
2, the preparation of coated tablet:
Being dissolved in purified water using recipe quantity Opadry II85F42129 and prepare the solution into about 15% as film-coat liquid, by pastille label coating, controlling temperature of charge in coating process is about 40 DEG C, and after this operation completes, label increases weight about 4%.
3, treat that Bao Pin packs after the assay was approved and get final product.
Embodiment 5
Canagliflozin capsule prescription (specification: 100mg):
Canagliflozin 100.0g(gives money as a gift pure)
Polyethylene glycol 6000 85.0g
Cross-linking sodium carboxymethyl cellulose 12.0g
Micropowder silica gel 2.0g
Make 1000 altogether
Preparation method:
1. supplementary material processes: canagliflozin mixed homogeneously with Macrogol 4000, and carboxymethyl starch sodium is by 80 eye mesh screen sieving for standby；
2. adding the dehydrated alcohol of 1.2kg in above-mentioned canagliflozin and polyethylene glycol 6000 mixture, put the heating in water bath of 75 DEG C, stirring is to entirely molten；
3., after entirely molten, it be warming up to 90 DEG C and reclaim dehydrated alcohol, when dehydrated alcohol is recycled to 65 ~ 80ml, add 8.0g carboxymethyl starch sodium, mix homogeneously, make soft material；
4. the wet grain of system: take above-mentioned soft material and granulate with 18 eye mesh screens；
5. drying: by above-mentioned wet grain drying, controlling temperature of charge is 40 ~ 42 DEG C；
6. granulate: by dry granule with 18 eye mesh screen granulate；
7. always mix: granulate granule adds micropowder silica gel and the 4.0g carboxymethyl starch sodium of recipe quantity, mixing, and sampling carries out intermediate inspection；
Intermediate carries out capsule charge after the assay was approved.
Treat that Bao Pin packs after the assay was approved and get final product.
Test example 1
The sample of embodiment 1,2,3,5 is placed in relative humidity (RH) be 75%, temperature be that 40 DEG C of incubators are placed 6 months continuously, respectively at the 0th, 1,2,3, June time pick test.Result all samples all meets regulation, it was shown that products obtained therefrom of the present invention has good stability, reliable in quality, wherein content, have related substance (always assorted), dissolution results in Table 1.
Table 1 accelerated test investigates result
Claims (8)
1. one kind is used for pharmaceutical composition treating type 2 diabetes mellitus and preparation method thereof, it is characterized in that, the pharmaceutical composition for treating type 2 diabetes mellitus prepared by the method is made up of pharmaceutic adjuvants such as active component and water-soluble solid dispersible carrier, disintegrating agent, lubricants.
2. one kind is used for pharmaceutical composition treating type 2 diabetes mellitus and preparation method thereof, it is characterized in that, the described pharmaceutical composition for treating type 2 diabetes mellitus of preparation is prepared by processes such as supplementary material process, soft material processed, granulation, dry, granulate, total mixed, tabletting or capsule charges.
3. according to claim 1 a kind of for pharmaceutical composition treating type 2 diabetes mellitus and preparation method thereof, it is characterised in that described active component is canagliflozin (Canagliflozin) or its pharmaceutically acceptable salt, solvate.
4. according to claim 1 a kind of for pharmaceutical composition treating type 2 diabetes mellitus and preparation method thereof, it is characterized in that, described active component is the pharmaceutically acceptable salt of canagliflozin (Canagliflozin) is the inorganic acid salts such as its sodium salt, potassium salt, calcium salt, magnesium salt, lithium salts and hydrochloric acid, hydrobromic acid, hydroiodic acid, the acylates such as succinic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, benzenesulfonic acid, the acidic amino acid salt such as aspartic acid, glutamic acid；Described solvate is the hydrate such as semihydrate, monohydrate, alcohol adduct, ethanolates.
5. according to claim 1 a kind of for pharmaceutical composition treating type 2 diabetes mellitus and preparation method thereof, it is characterized in that, the described pharmaceutical composition for treating type 2 diabetes mellitus consists of the following composition by weight percentage: active component 30%～70%, water-soluble solid dispersible carrier 20% ~ 60%, disintegrating agent 3% ~ 10%, lubricant 0.2%～2.0%.
6. according to claim 1 a kind of for pharmaceutical composition treating type 2 diabetes mellitus and preparation method thereof, it is characterized in that, described water-soluble solid dispersible carrier is one or more the mixture in Polyethylene Glycol, polyvidone, poloxamer, citric acid, mannitol, it is preferable that Polyethylene Glycol；Disintegrating agent is one or more the mixture in dried starch, carboxymethyl starch sodium, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, it is preferable that polyvinylpolypyrrolidone；Lubricant is one or more the mixture in magnesium stearate, stearic acid, zinc stearate, micropowder silica gel, Pulvis Talci, it is preferable that magnesium stearate.
7. according to claim 2 a kind of for pharmaceutical composition treating type 2 diabetes mellitus and preparation method thereof, it is characterized in that, the described pharmaceutical composition preparation process for treating type 2 diabetes mellitus is granulated and mesh size used by granulate is 16 order ~ 40 orders, it is preferable that 18 order ~ 24 orders；It is 30 DEG C ~ 50 DEG C that dry materials temperature controls, it is preferable that 38 DEG C ~ 45 DEG C；Pellet moisture controls 1% ~ 3%, it is preferable that less than 2%；Always do time is 15 ~ 40 minutes, it is preferable that 25 ~ 35 minutes.
8. according to claim 2 a kind of for pharmaceutical composition treating type 2 diabetes mellitus and preparation method thereof, it is characterized in that, the described pharmaceutical composition tabletting for treating type 2 diabetes mellitus can be prepared the stomach dissolution type film coating liquid such as Opadry, Opadry II if desired after completing end and carry out coating, and film-coat layer gain in weight is 2% ~ 4%.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111773194A (en) * | 2019-04-04 | 2020-10-16 | 常州恒邦药业有限公司 | Canagliflozin tablet and preparation method thereof |
| CN111920804A (en) * | 2020-09-10 | 2020-11-13 | 浙江诺得药业有限公司 | Canagliflozin solid dispersion, preparation method and application thereof |
| WO2022065895A1 (en) * | 2020-09-24 | 2022-03-31 | 동아에스티 주식회사 | Novel salt of empagliflozin derivative, which is sglt-2 inhibitor, and hydrate of salt |
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| CN102985075A (en) * | 2010-05-11 | 2013-03-20 | 田边三菱制药株式会社 | Tablets containing canagliflozin |
| CN103239719A (en) * | 2012-08-24 | 2013-08-14 | 药源药物化学（上海）有限公司 | Metformin compound pharmaceutical composition and preparation method thereof |
| WO2014195966A2 (en) * | 2013-05-30 | 2014-12-11 | Cadila Healthcare Limited | Amorphous form of canagliflozin and process for preparing thereof |
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| CN102985075A (en) * | 2010-05-11 | 2013-03-20 | 田边三菱制药株式会社 | Tablets containing canagliflozin |
| CN103239719A (en) * | 2012-08-24 | 2013-08-14 | 药源药物化学（上海）有限公司 | Metformin compound pharmaceutical composition and preparation method thereof |
| WO2014195966A2 (en) * | 2013-05-30 | 2014-12-11 | Cadila Healthcare Limited | Amorphous form of canagliflozin and process for preparing thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111773194A (en) * | 2019-04-04 | 2020-10-16 | 常州恒邦药业有限公司 | Canagliflozin tablet and preparation method thereof |
| CN111773194B (en) * | 2019-04-04 | 2023-06-30 | 常州恒邦药业有限公司 | Canagliflozin tablet and preparation method thereof |
| CN111920804A (en) * | 2020-09-10 | 2020-11-13 | 浙江诺得药业有限公司 | Canagliflozin solid dispersion, preparation method and application thereof |
| WO2022065895A1 (en) * | 2020-09-24 | 2022-03-31 | 동아에스티 주식회사 | Novel salt of empagliflozin derivative, which is sglt-2 inhibitor, and hydrate of salt |
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Application publication date: 20160720 |