CN116327769A - Pharmaceutical composition containing sitagliptin phosphate and metformin hydrochloride and preparation method thereof - Google Patents
Pharmaceutical composition containing sitagliptin phosphate and metformin hydrochloride and preparation method thereof Download PDFInfo
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- CN116327769A CN116327769A CN202111540863.4A CN202111540863A CN116327769A CN 116327769 A CN116327769 A CN 116327769A CN 202111540863 A CN202111540863 A CN 202111540863A CN 116327769 A CN116327769 A CN 116327769A
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- Prior art keywords
- sitagliptin
- metformin hydrochloride
- metformin
- phosphate monohydrate
- sitagliptin phosphate
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- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin hydrochloride Natural products CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 title claims abstract description 47
- 229960004329 metformin hydrochloride Drugs 0.000 title claims abstract description 27
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 title claims abstract description 26
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 10
- 238000002360 preparation method Methods 0.000 title abstract description 32
- 229960004115 sitagliptin phosphate Drugs 0.000 title description 7
- RTZRUVMEWWPNRR-UHFFFAOYSA-N tert-butyl n-(3-iodo-1h-pyrrolo[2,3-b]pyridin-5-yl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CN=C2NC=C(I)C2=C1 RTZRUVMEWWPNRR-UHFFFAOYSA-N 0.000 title description 7
- 229960004034 sitagliptin Drugs 0.000 claims abstract description 40
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 claims abstract description 40
- 239000002245 particle Substances 0.000 claims abstract description 14
- 239000000203 mixture Substances 0.000 claims abstract description 13
- 239000004480 active ingredient Substances 0.000 claims abstract description 8
- 238000000034 method Methods 0.000 claims abstract description 8
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- 230000001070 adhesive effect Effects 0.000 claims abstract description 4
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- 239000000314 lubricant Substances 0.000 claims abstract description 4
- 229960003105 metformin Drugs 0.000 claims description 23
- 238000002156 mixing Methods 0.000 claims description 15
- 238000001035 drying Methods 0.000 claims description 9
- 239000011248 coating agent Substances 0.000 claims description 7
- 238000000576 coating method Methods 0.000 claims description 7
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 6
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 6
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 6
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 6
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 6
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- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 6
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 5
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 3
- 238000009835 boiling Methods 0.000 claims description 3
- 229940083575 sodium dodecyl sulfate Drugs 0.000 claims description 3
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- 238000005303 weighing Methods 0.000 claims description 3
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- 235000019333 sodium laurylsulphate Nutrition 0.000 claims 2
- 229940103776 metformin hydrochloride 500 mg Drugs 0.000 claims 1
- 229940098805 metformin hydrochloride 850 mg Drugs 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 18
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
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- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 2
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 2
- 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 2
- 102100040918 Pro-glucagon Human genes 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
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- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 description 2
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- YPULIQLVSSZRST-KLQYNRQASA-N (3R)-3-amino-1-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one hydrate hydrochloride Chemical compound O.Cl.N[C@@H](CC(=O)N1CCn2c(C1)nnc2C(F)(F)F)Cc1cc(F)c(F)cc1F YPULIQLVSSZRST-KLQYNRQASA-N 0.000 description 1
- PNXSHNOORJKXDW-SBSPUUFOSA-N (3r)-3-amino-1-[3-(trifluoromethyl)-6,8-dihydro-5h-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one;hydrochloride Chemical compound Cl.C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F PNXSHNOORJKXDW-SBSPUUFOSA-N 0.000 description 1
- GQPYTJVDPQTBQC-KLQYNRQASA-N (3r)-3-amino-1-[3-(trifluoromethyl)-6,8-dihydro-5h-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one;phosphoric acid;hydrate Chemical compound O.OP(O)(O)=O.C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F GQPYTJVDPQTBQC-KLQYNRQASA-N 0.000 description 1
- 208000002249 Diabetes Complications Diseases 0.000 description 1
- 206010012655 Diabetic complications Diseases 0.000 description 1
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 1
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 1
- ZFMITUMMTDLWHR-UHFFFAOYSA-N Minoxidil Chemical compound NC1=[N+]([O-])C(N)=CC(N2CCCCC2)=N1 ZFMITUMMTDLWHR-UHFFFAOYSA-N 0.000 description 1
- 206010033307 Overweight Diseases 0.000 description 1
- 229920001328 Polyvinylidene chloride Polymers 0.000 description 1
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- 230000009471 action Effects 0.000 description 1
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- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
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- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
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- 230000001258 dyslipidemic effect Effects 0.000 description 1
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- 229960003632 minoxidil Drugs 0.000 description 1
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- WHQSYGRFZMUQGQ-UHFFFAOYSA-N n,n-dimethylformamide;hydrate Chemical compound O.CN(C)C=O WHQSYGRFZMUQGQ-UHFFFAOYSA-N 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 239000003538 oral antidiabetic agent Substances 0.000 description 1
- 229940127209 oral hypoglycaemic agent Drugs 0.000 description 1
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- 229920003023 plastic Polymers 0.000 description 1
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- 239000005033 polyvinylidene chloride Substances 0.000 description 1
- GCYXWQUSHADNBF-AAEALURTSA-N preproglucagon 78-108 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 GCYXWQUSHADNBF-AAEALURTSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
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Abstract
The invention relates to a pharmaceutical composition containing sitagliptin phosphate monohydrate and metformin hydrochloride and a preparation method thereof. The composition adopts filler, lubricant, adhesive and surfactant as auxiliary materials, adopts metformin hydrochloride bulk drug with the particle diameter D90 of 30-80 mu m and sitagliptin phosphate monohydrate as active ingredients, and the composition surfactants with different specifications account for 0.2-0.4 percent. The invention is prepared by adopting a conventional wet granulation method. Compared with the original preparation, the sitagliptin phosphate monohydrate and metformin hydrochloride composition disclosed by the invention has better stability, fast dissolution and similar dissolution curves in 4 dissolution mediums.
Description
Technical Field
The invention relates to the technical field of medicines, and relates to a pharmaceutical composition containing sitagliptin phosphate monohydrate and metformin and a preparation method thereof.
Background
Sitagliptin metformin tablet (trade name: merozod), developed by the company moesadong, was approved by the national food and drug administration for marketing in china in 2013. The first DPP-4 inhibitor (sitagliptin) and metformin hydrochloride compound preparation on the global market is the approved indications: the product is used for treating type 2 diabetes patients with poor blood sugar control or undergoing combined therapy of two patients via metformin single drug treatment in combination with diet and exercise therapy.
Sitagliptin phosphate monohydrate structural formula:
the sitagliptin phosphate monohydrate is white or white-like solid, has no hygroscopicity, is easy to dissolve in water and N, N-dimethylformamide, is slightly soluble in methanol, and is extremely slightly soluble in ethanol, acetone and acetonitrile.
Metformin hydrochloride is a white crystalline powder, odorless. Is soluble in water, soluble in methanol, and slightly soluble in ethanol.
Metformin hydrochloride has been demonstrated as an oral hypoglycemic agent which reduces the overall burden of microvascular and macrovascular diabetic complications and prolongs the life span of diabetic patients, and its treatment is also closely related to weight loss in overweight patients and to a reduction in fat content in dyslipidemic patients. Sitagliptin phosphate is the first marketed dipeptidyl peptidase-4 (DPP-4) inhibitor that increases the level of endogenous glucagon-like peptide-1 by inhibiting dipeptidyl peptidase-4 thereby reducing the inactivation of endogenous glucagon-like peptide-1 (GLP-1) in vivo. Glucagon-like peptide-1 enhances insulin secretion in a glucose concentration dependent manner, achieving pharmacological effects of lowering blood glucose. The sitagliptin metformin tablet (minoxidil) is a compound preparation of sitagliptin phosphate monohydrate and metformin hydrochloride, and combines two complementary mechanisms of action of hypoglycemic drugs.
In the early-stage research, the inventor finds that in the experimental investigation of influence factors, the impurity is obviously increased, particularly the degradation under high-temperature and high-humidity conditions is most obvious, the unknown impurity in the influence factors is separated and identified by the inventor through a liquid chromatography-mass spectrometry technology, and the main degradation path and degradation impurity of the sitagliptin metformin tablet are summarized as follows:
as shown above, the degradation impurity FP-F is a degradation impurity which is not reported in the prior art at present, I can separate and identify the degradation impurity by a liquid chromatography-mass spectrometry technology, and an impurity reference substance is prepared for positioning research. The inventor finds that the impurity can be generated in the processes of influencing factors, accelerating and placing for long time stability of a raw preparation (Jienoda) in earlier research, and the influence factors inspect that the impurity in a sample exceeds the limit of an import quality standard (single impurity is less than or equal to 0.2 percent), and potential quality risks exist in long-time placing, so that the preparation impurity is controlled by a preparation prescription or a preparation process, and the dissolution release degree is guaranteed.
Disclosure of Invention
In the process of researching the prescription and the preparation technology of the sitagliptin metformin tablet, the inventor finds that the particle size of the raw material medicine is about 20 mu m in the process of researching the internal environment of the original research preparation (Jienoda) by an electron microscope, and the original research (Jienoda) adopts a fluidized bed to carry out wet granulation technology to produce the sitagliptin metformin tablet according to registration information disclosed by FDA (FDA) functional network of the original research preparation and composition patent information disclosed by an original research company, so that the purpose of uniformly mixing the active ingredients and the auxiliary materials is achieved. According to prescription information disclosed by the original preparation, the biggest prescription of the sitagliptin metformin hydrochloride tablet (50 mg/500mg, 50mg/850mg, 50mg/1000 mg) is the active ingredient metformin hydrochloride. The inventor analyzes the formation process of unknown impurities FP-F generated by the influence factors of the original grinding of the agiline, supposes that the preparation is mainly produced by degrading the sitagliptin phosphate monohydrate and the metformin hydrochloride in a local acidic environment, aggravates the generation speed under the condition of high temperature and high humidity, supposes that whether the degradation impurities of the preparation can be controlled by reducing the contact area of two main components of the metformin hydrochloride and the sitagliptin phosphate in the sitagliptin metformin hydrochloride tablet and the water content of the preparation, and ensures that the dissolution of the preparation is similar to that of the original preparation.
The invention aims to provide a pharmaceutical composition of sitagliptin phosphate monohydrate and metformin hydrochloride, which has stable and controllable quality and can dissolve out similar to the prior development agent, and a preparation method thereof.
The sitagliptin phosphate, the sitagliptin hydrochloride and the sitagliptin monohydrate are sitagliptin phosphate monohydrate, and the metformin is metformin hydrochloride.
The invention discloses a pharmaceutical composition of sitagliptin and metformin and a preparation method thereof, wherein the pharmaceutical composition comprises sitagliptin hydrochloride monohydrate, metformin hydrochloride, a filler, a lubricant, an adhesive and a surfactant, wherein the particle size D90 of the metformin hydrochloride is 30-80 mu m.
The particle size of the metformin hydrochloride bulk drug is preferably 50-80 mu m;
wherein the filler is microcrystalline cellulose;
wherein the lubricant is sodium stearyl fumarate;
wherein the adhesive is polyvinylpyrrolidone;
wherein the surfactant is sodium dodecyl sulfate;
in particular, the surfactant is used in an amount of 0.2 to 0.4%.
The invention also discloses a method for preparing the sitagliptin-metformin pharmaceutical composition, which comprises the following steps:
(1) Mixing sitagliptin, metformin, microcrystalline cellulose and sodium dodecyl sulfate according to a conventional method, and performing wet granulation by adopting a polyvinylpyrrolidone aqueous solution;
(2) Drying, finishing, and adding sodium stearyl fumarate for total mixing;
(3) Tabletting and coating.
The specific preparation method is as follows:
(1) Mixing: weighing the crushed and sieved sitagliptin, metformin, microcrystalline cellulose and sodium dodecyl sulfate according to the prescription amount, and uniformly mixing;
(2) Preparation: adding 5% polyvinylpyrrolidone aqueous solution with the prescription amount into the mixture in the step one, preparing a soft material, and granulating in a wet mixing granulator;
(3) And (3) drying: drying with a boiling dryer, and controlling the water content of the particles to be 1-3%;
(4) Finishing and mixing: the dried particles are sieved by a 18-mesh sieve, added with sodium stearyl fumarate and uniformly mixed;
(5) Tabletting: after the content of the intermediate is measured, tabletting to obtain sitagliptin metformin tablets;
(6) And (5) coating.
The invention has the following technical effects: (1) The sitagliptin-metformin pharmaceutical composition disclosed by the invention has the advantages of quick in-vitro dissolution, and similar dissolution curves as those of dissolution mediums in 4 of a raw preparation (f 2 > 50); (2) The sitagliptin-metformin composition disclosed by the invention has good stability, is obviously superior to an original ground preparation, has small change of related substances of sitagliptin phosphate in influence factors and acceleration tests, does not exceed the quality standard limit, and particularly has the advantages that the content of unknown impurities FP-F which are not reported in the prior art is obviously lower than that of the original ground preparation, and the dissolution rate in stability is not reduced; (3) The sitagliptin metformin composition disclosed by the invention adopts a conventional wet granulation process, does not use a fluidized bed, has a simple process and good repeatability, and is suitable for industrial mass production.
Drawings
Fig. 1: dissolution profile trend of the as-ground formulation (sitagliptin) in four different dissolution media;
fig. 2: dissolution profile trend of the as-ground formulation (metformin hydrochloride) in four different dissolution media;
fig. 3: example 5 (sitagliptin) dissolution profile trend graph in four different dissolution media;
fig. 4: example 5 (metformin hydrochloride) dissolution profile trend in four different dissolution media.
Detailed Description
The following examples are merely illustrative of the present invention and are not to be construed as limiting the scope of the invention. Some insubstantial adaptations and modifications of the invention as far as possible within the scope of the invention are within the reach of a person skilled in the art.
Example 1
Prescription ratio:
the preparation method comprises the following steps:
1) Mixing: weighing 1000 pieces of sitagliptin with prescription amount according to the prescription, and uniformly mixing the sitagliptin, the metformin, the microcrystalline cellulose and the sodium dodecyl sulfate;
2) Granulating: adding 5% polyvinylpyrrolidone water solution with the prescription amount of 1000 tablets into the mixture to prepare a soft material, and granulating in a wet granulator;
3) And (3) drying: drying by a boiling dryer, and controlling the drying time and the drying temperature to make the moisture of the particles about 1%;
4) Finishing and mixing: the dried particles are sieved by a 18-mesh sieve, added with sodium stearyl fumarate and uniformly mixed;
5) Tabletting: after the content of the intermediate is measured, tabletting to obtain sitagliptin metformin tablets;
6) Coating: coating is carried out according to the weight of 3% of the coating weight of the unit preparation.
Examples 2 to 5
The following examples differ from example 1 in the particle size of metformin, the amount of surfactant used and the moisture control of the particles, and the other preparation methods are the same as example 1.
Test example 6
The above examples used reference formulation package form, PVDC aluminum plastic, placed at high temperature 60 deg.C, placed for 30d, and high performance liquid phase detection of relevant substances of raw formulation and sitagliptin of examples 1-5, metformin relevant substances, sitagliptin and metformin contents, and dissolution in standard medium, the results are summarized in the following table:
test example 7
The raw preparation and the preparation of the invention example 5 adopt the standard dissolution condition of an inlet, the dissolution medium is 900ml of 0.025M sodium chloride solution, the rotation speed is 75 revolutions per minute, the temperature is 37+/-0.5 ℃, and the dissolution rates of the metformin hydrochloride and the sitagliptin phosphate are detected by sampling for 5, 10, 15, 20 and 30 minutes, and the cumulative dissolution rate and f are calculated 2 The dissolution curve (see figure) was plotted and the data summarized below:
Claims (5)
1. a pharmaceutical combination of sitagliptin phosphate monohydrate and metformin hydrochloride comprising
Active ingredients: sitagliptin phosphate monohydrate
Active ingredients: metformin hydrochloride
Filler: microcrystalline cellulose
And (2) an adhesive: polyvinylpyrrolidone
And (2) a surfactant: sodium lauryl sulfate
And (3) a lubricant: stearyl magnesium fumarate
Coating powder
Wherein the mass ratio of the surfactant is 0.2-0.4%
The particle diameter D90 of the active ingredient metformin hydrochloride is 30-80 mu m.
2. Pharmaceutical combination according to claim 1, characterized in that the metformin hydrochloride active ingredient has a particle size D90 of preferably 50-80 μm.
3. Pharmaceutical combination according to claim 1, characterized in that the active ingredient content is sitagliptin phosphate monohydrate 50mg (calculated as sitagliptin)/metformin hydrochloride 500mg or sitagliptin phosphate monohydrate 50mg (calculated as sitagliptin)/metformin hydrochloride 850mg or sitagliptin phosphate monohydrate.
4. A process for preparing a pharmaceutical combination of sitagliptin phosphate monohydrate and metformin hydrochloride according to claim 1, comprising the steps of:
1) Mixing: weighing the crushed and sieved sitagliptin, metformin, microcrystalline cellulose and sodium dodecyl sulfate according to the prescription amount, and uniformly mixing;
2) Granulating: adding 5% polyvinylpyrrolidone aqueous solution with the prescription amount into the mixture in the step one, preparing a soft material, and granulating in a wet mixing granulator;
3) And (3) drying: drying by using a boiling dryer, and controlling the moisture of the particles;
4) Finishing and mixing: the dried particles are sieved by an 18-mesh sieve, and the prescribed amount of sodium stearyl fumarate is added for uniform mixing;
5) Tabletting: after the content of the total mixed intermediate is measured, tabletting is carried out to obtain sitagliptin metformin tablets;
6) And (5) coating.
5. The method of preparing a pharmaceutical composition according to claim 4, wherein the water content is controlled to 1-3% in step (4).
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| CN101365432A (en) * | 2005-12-16 | 2009-02-11 | 默克公司 | Pharmaceutical compositions of combinations of dipeptidyl peptidase-4 inhibitors with metformin |
| CN102266325A (en) * | 2011-07-28 | 2011-12-07 | 海南锦瑞制药股份有限公司 | Melbine crystal and medicinal composition of melbine and saxagliptin and preparation method thereof |
| CN104324033A (en) * | 2014-11-20 | 2015-02-04 | 哈尔滨圣吉药业股份有限公司 | Sitagliptin and dimethyldiguanide sustained release tablets and preparation method thereof |
| CN105769796A (en) * | 2016-05-04 | 2016-07-20 | 杭州百诚医药科技股份有限公司 | Medicinal preparation containing vildagliptin and metformin hydrochloride and preparation method of medicinal preparation |
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2021
- 2021-12-16 CN CN202111540863.4A patent/CN116327769A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101365432A (en) * | 2005-12-16 | 2009-02-11 | 默克公司 | Pharmaceutical compositions of combinations of dipeptidyl peptidase-4 inhibitors with metformin |
| US20090105265A1 (en) * | 2005-12-16 | 2009-04-23 | Merck & Co., Inc. | Pharmaceutical Compositions of Combinations of Dipeptidyl Peptidase-4 Inhibitors With Metformin |
| CN102266325A (en) * | 2011-07-28 | 2011-12-07 | 海南锦瑞制药股份有限公司 | Melbine crystal and medicinal composition of melbine and saxagliptin and preparation method thereof |
| CN104324033A (en) * | 2014-11-20 | 2015-02-04 | 哈尔滨圣吉药业股份有限公司 | Sitagliptin and dimethyldiguanide sustained release tablets and preparation method thereof |
| CN105769796A (en) * | 2016-05-04 | 2016-07-20 | 杭州百诚医药科技股份有限公司 | Medicinal preparation containing vildagliptin and metformin hydrochloride and preparation method of medicinal preparation |
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