CN109200026A - A kind of felodipine sustained-release tablets and preparation method thereof - Google Patents
A kind of felodipine sustained-release tablets and preparation method thereof Download PDFInfo
- Publication number
- CN109200026A CN109200026A CN201710532921.6A CN201710532921A CN109200026A CN 109200026 A CN109200026 A CN 109200026A CN 201710532921 A CN201710532921 A CN 201710532921A CN 109200026 A CN109200026 A CN 109200026A
- Authority
- CN
- China
- Prior art keywords
- felodipine
- adhesive
- release tablets
- sustained
- preparation
- Prior art date
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- RZTAMFZIAATZDJ-HNNXBMFYSA-N 5-o-ethyl 3-o-methyl (4s)-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC(Cl)=C1Cl RZTAMFZIAATZDJ-HNNXBMFYSA-N 0.000 title claims abstract description 46
- 229960003580 felodipine Drugs 0.000 title claims abstract description 46
- 239000007939 sustained release tablet Substances 0.000 title claims abstract description 41
- 238000002360 preparation method Methods 0.000 title claims description 27
- 239000000463 material Substances 0.000 claims abstract description 37
- 239000000853 adhesive Substances 0.000 claims abstract description 24
- 230000001070 adhesive effect Effects 0.000 claims abstract description 24
- 239000000945 filler Substances 0.000 claims abstract description 17
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 16
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 15
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 65
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 18
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 18
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 18
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 16
- ZTHYODDOHIVTJV-UHFFFAOYSA-N Propyl gallate Chemical compound CCCOC(=O)C1=CC(O)=C(O)C(O)=C1 ZTHYODDOHIVTJV-UHFFFAOYSA-N 0.000 claims description 14
- 235000006708 antioxidants Nutrition 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 14
- 102220487426 Actin-related protein 2/3 complex subunit 3_K15M_mutation Human genes 0.000 claims description 8
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 8
- 239000011230 binding agent Substances 0.000 claims description 8
- GXGAKHNRMVGRPK-UHFFFAOYSA-N dimagnesium;dioxido-bis[[oxido(oxo)silyl]oxy]silane Chemical compound [Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O GXGAKHNRMVGRPK-UHFFFAOYSA-N 0.000 claims description 8
- 238000004090 dissolution Methods 0.000 claims description 8
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 8
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 8
- 239000000391 magnesium silicate Substances 0.000 claims description 8
- 229940099273 magnesium trisilicate Drugs 0.000 claims description 8
- 229910000386 magnesium trisilicate Inorganic materials 0.000 claims description 8
- 235000019793 magnesium trisilicate Nutrition 0.000 claims description 8
- 238000002156 mixing Methods 0.000 claims description 8
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 7
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical group CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 7
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 7
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 7
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 7
- 239000000473 propyl gallate Substances 0.000 claims description 7
- 229940075579 propyl gallate Drugs 0.000 claims description 7
- 235000010388 propyl gallate Nutrition 0.000 claims description 7
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 7
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 4
- 239000000314 lubricant Substances 0.000 claims description 4
- RCEAADKTGXTDOA-UHFFFAOYSA-N OS(O)(=O)=O.CCCCCCCCCCCC[Na] Chemical compound OS(O)(=O)=O.CCCCCCCCCCCC[Na] RCEAADKTGXTDOA-UHFFFAOYSA-N 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- 229920002472 Starch Polymers 0.000 claims description 3
- 239000008107 starch Substances 0.000 claims description 3
- 235000019698 starch Nutrition 0.000 claims description 3
- 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
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims description 2
- 239000001856 Ethyl cellulose Substances 0.000 claims description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 229930003268 Vitamin C Natural products 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 229920001249 ethyl cellulose Polymers 0.000 claims description 2
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 2
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 235000019154 vitamin C Nutrition 0.000 claims description 2
- 239000011718 vitamin C Substances 0.000 claims description 2
- 235000020985 whole grains Nutrition 0.000 claims description 2
- 238000005461 lubrication Methods 0.000 claims 1
- 235000019441 ethanol Nutrition 0.000 description 22
- 229960004756 ethanol Drugs 0.000 description 19
- 239000002609 medium Substances 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000012535 impurity Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- 239000003826 tablet Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 6
- 229940079593 drug Drugs 0.000 description 5
- 206010020772 Hypertension Diseases 0.000 description 4
- 238000005469 granulation Methods 0.000 description 4
- 230000003179 granulation Effects 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 229920000136 polysorbate Polymers 0.000 description 4
- 238000000576 coating method Methods 0.000 description 3
- 238000012216 screening Methods 0.000 description 3
- 230000036772 blood pressure Effects 0.000 description 2
- 235000013339 cereals Nutrition 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000227 grinding Methods 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000012797 qualification Methods 0.000 description 2
- 210000001835 viscera Anatomy 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 208000001647 Renal Insufficiency Diseases 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 229940127292 dihydropyridine calcium channel blocker Drugs 0.000 description 1
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229940083649 felodipine 10 mg Drugs 0.000 description 1
- 229940083647 felodipine 2.5 mg Drugs 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- -1 hydroxypropyl Chemical group 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 201000006370 kidney failure Diseases 0.000 description 1
- 239000000832 lactitol Substances 0.000 description 1
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 description 1
- 235000010448 lactitol Nutrition 0.000 description 1
- 229960003451 lactitol Drugs 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000000877 morphologic effect Effects 0.000 description 1
- 230000036513 peripheral conductance Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 238000009492 tablet coating Methods 0.000 description 1
- 239000002700 tablet coating Substances 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
Classifications
-
- 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
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
-
- 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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of felodipine sustained-release tablets, the supplementary material of the sustained release tablets accounts for the percentage of piece heart gross weight are as follows: felodipine 1%~5%, framework material 30%-80%, filler 1~20%, solubilizer 1%~10%, excipients 10%~30%, adhesive are 1~10%, antioxidant 0.01%~0.1%.
Description
Technical field
The present invention relates to a kind of felodipine sustained-release tablets and preparation method thereof, belong to pharmaceutical field.
Background technique
Felodipine (felodipine) is third generation dihydropyridine type calcium antagonists, by inhibiting petty action smooth muscle thin
The interior stream and reduction peripheral vascular resistance of extracellular calcium are for treating hypertension.
Felodipine is dihydropyridine calcium channel antagonist, is listed first in Denmark within 1988, is a kind of efficient, peace
Entirely, the good hypertension therapeutic drug of tolerance to the elderly or merges coronary heart disease, heart failure, renal insufficiency, asthma, outer
The patient of all vascular diseases, gout or diabetes is relatively safer, and the treatments of high blood pressure are used in multiple countries.
Scientific research discovery, simple hypertension no doubt causes to damage to internal organs, but fluctuation of blood pressure is endangered caused by internal organs
Evil is especially serious.And felodipine conventional tablet need to repeatedly take medicine, and be bound to cause the large change of blood concentration, to make blood pressure
Generate fluctuation, impair cardiac, kidney et al. body vitals.
101843598 A of patent CN discloses a kind of preparation method of felodipine sustained-release tablets, which mainly uses
Part slow-release material and filler, main ingredient mixing, the granulation of wet process method.It mixes, tabletting, wraps with the slow-release material of surplus after drying
Clothing is made.In general particle and powder are differed greatly due to partial size, the high requirements on the equipment in production process, and are produced
The carrying, vibration of particle are likely to make its layering in journey, cause slow-release material content uneven, and release is uneven, are patient's
Using bringing risk.
102552200 A of patent CN discloses a kind of felodipine sustained-release tablets and preparation method thereof, the sustained release tablets mainly by
Felodipine, high viscosity hydroxypropyl methylcellulose, low viscosity hydroxypropyl methylcellulose, water-soluble filler also contain other auxiliary materials,
Preparation method is felodipine, after the mixing of high viscosity hydroxypropyl methylcellulose, low viscosity hydroxypropyl methylcellulose, water-soluble filler,
Adhesive granulation is added, lubricant is added after dry, is uniformly mixed, compress tablet coating to obtain the final product.It is assigned in the patent prescription without being added
Type agent, in the drug release determination later period, piece is easy to collapse, and grinding tablet with original, morphological differences is larger in the medium, releases between piece
It is big to put difference, it is too fast to there is a problem of that the later period discharges.
Patent CN104997750 A discloses a kind of felodipine sustained-release tablets and preparation method thereof the sustained release tablets and mainly passes through
Plain piece and coated slow release material realize dual release.It is main that control sample release is generally coated by slow-release material in solid pharmaceutical preparation
The preparation of pellet, this is because occurring that individual coating tablets are uneven or bonding die is possible to occur once in a while in the process in coating process
, this may cause tablet and is released in vivo, bring great risk to patient's use.
Summary of the invention
In view of the deficienciess of the prior art, technical problem to be solved by the invention is to provide a kind of felodipine sustained-releases
Piece and preparation method, release difference is small between the sustained release tablets piece, rate of release is uniform, and uniformity of dosage units is good, release completely, with original
It grinds and compares, the dissolution phenomenon in each medium is completely the same, and release and original, which are discussed and formulated, closes strong, and uniformity of dosage units is good, has
It is suitable with former triturate to close substance, impurity level, meets Conformance Assessment pharmaceutical requirements.
The purpose of the present invention is to provide a kind of felodipine sustained-release tablets and preparation method thereof.
A kind of felodipine sustained-release tablets, supplementary material account for the percentage of piece heart gross weight are as follows: felodipine 1%~5%, skeleton
Material 30%-80%, filler 1~20%, solubilizer 1%~10%, excipients 10%~30%, adhesive be 1~10%,
Antioxidant 0.01%~0.1%.
Preferably, supplementary material accounts for the percentage of piece heart gross weight are as follows: felodipine 1%~5%, framework material 40%-70%,
Filler 5~18%, solubilizer 1%~8%, excipients 13%~25%, adhesive be 1~8%, antioxidant 0.01%~
0.1%.
It is further preferred that supplementary material accounts for the percentage of piece heart gross weight are as follows: felodipine 1%~5%, framework material
50%-65%, filler 8~15%, solubilizer 1%~5%, excipients 15%~20%, adhesive are 1~5%, antioxidant
0.01%~0.1%.
Still more preferably, supplementary material accounts for the percentage of piece heart gross weight are as follows: felodipine 1%~5%, framework material
55%-62%, filler 9~12%, solubilizer 1%~5%, excipients 18%~20%, adhesive are 3~5%, antioxidant
0.01%~0.1%.
It wherein, further include lubricant 1%~5% in the auxiliary material.
The framework material is selected from one of hydroxypropyl methylcellulose E5, E50, K100, K4M, K15M, K15MCR or several
Kind；The filler is selected from one or more of lactose, microcrystalline cellulose, starch, mannitol；The solubilizer is selected from and spits
One or more of temperature -80, lauryl sodium sulfate, Crodaret；The excipients be selected from magnesium trisilicate,
One or more of diatomite, white bole；Described adhesive is selected from hydroxypropylcellulose and/or ethyl cellulose；Antioxidant choosing
From propylgallate and/or vitamin C；The lubricant is sodium stearyl fumarate.
The present invention further provides the preparation methods of the felodipine sustained-release tablets, and this method comprises the following steps:
Raw material felodipine and auxiliary material antioxidant, solubilizer are added ethanol solution dissolution, obtain material solution by step a；
Ethanol solution dissolution is added in adhesive, obtains binder solution；
Framework material, excipient are uniformly mixed by step b, obtain mixture I；Filler is uniformly mixed, and obtains mixture II；
The mixture I of step b, II mixing are added the material solution and binder solution of step a, pelletized by step c,
Whole grain, tabletting to get.
Further, the mass volume ratio (g/ml) of step a felodipine and ethanol solution is 1:(20-30)；It is preferred that non-Lip river
The mass volume ratio (g/ml) of Horizon and ethanol solution is 1:20.
Further, the mass volume ratio (g/ml) of step a adhesive and ethanol solution is 1:(10-20)；Preferably, step
The mass volume ratio (g/ml) of a adhesive and ethanol solution is 1:15.
Beneficial effects of the present invention:
This sustained release tablets controls its rate of release by the collocation of slow-release material, and passes through the preparatory of excipients and slow-release material
Mixing, keeps the rate of release of tablet extremely uniform, completely the same with dissolution phenomenon of the former triturate in each medium, in each medium
Middle release and original, which are discussed and formulated, closes strong, solves the problems, such as that release difference is larger between piece, rate of release is inhomogenous；Felodipine
It is light sensitive, it is oxidizable, it is indissoluble type drug and specification is smaller, by the way that ethyl alcohol is added in felodipine and solubilizer, antioxidant
Solution carries out wet granulation, solves the release of felodipine later period not exclusively, the small dimension medicament contg uniformity is poor, prepares
Impurity increases fast problem during journey and stability, and impurity level of the present invention is suitable with former triturate impurity moisture, is drug
Safety provide guarantee.
Specific embodiment
Embodiment 1
Preparation method:
Step a adds raw material felodipine and antioxidant propylgallate, solubilizer Crodaret
Enter 95% ethanol solution dissolution [felodipine: 95% ethyl alcohol=1:20 (g/ml)], obtains material solution；By adhesive hydroxypropyl fiber
95% ethanol solution dissolution [adhesive: 95% ethyl alcohol=1:15 (g/ml)] is added in element, obtains binder solution；
Step b, slow-release material hydroxypropyl methylcellulose K15M and hydroxypropyl methylcellulose E50 is uniform by equivalent gradually-increased premix
Progressively increase afterwards with excipient magnesium trisilicate by equivalent and be uniformly mixed, obtains mixture I；Lactis Anhydrous, microcrystalline cellulose progressively increase by equivalent
Method premix is uniform to obtain mixtures II；
Step c, mixture I and mixture II are set in three-dimensional mixer and are uniformly mixed；Wet granulation is transferred to after mixing
In machine, mixing is opened, the material solution of step a, high speed shear 1min is added；The adhesive of step a is added, when high speed shear
Between 2min；Cross 20 mesh sieves；
Step d, wet granular are placed in Fluidbedgranulatingdrier drying, and pellet moisture is controlled less than 3%；Dry particl sets the system of waving
20 mesh sieves are crossed in grain machine；Additional proportion amount sodium stearyl fumarate, hand mix are uniform；
Step e, tabletting (hardness 70-100N)；Coating (weight gain 2~4%).
Referred to the homemade sustained release tablets of the present embodiment and the degree of fitting (F2) of former triturate release and related substance to investigate
Mark, investigating result see the table below 1,2:
1 embodiment of table, 1 sustained-release tablet is compared with former triturate release result (specification 2.5mg)
Compared with 2 embodiment of table, 1 sustained-release tablet substance related with former triturate (specification 2.5mg)
By above-mentioned test result it is found that sustained-release tablet and original the triturate fitting degree in each medium prepared by embodiment 1
Height, rate of release is uniform, and impurity level is suitable with former triturate.
Note is 1.: the related substance-measuring method of this product and limit are slow with reference to felodipine in " British Pharmacopoeia " (2009 editions)
Related substance under piece item is released to formulate；
Note 2.: " equivalent gradually-increased " refer to will measure small drug with etc. quality other drugs mix, so times amount increase
It mixes to whole mixings.
Embodiment 2
| Supplementary material | Recipe quantity mg | 2000 g |
| Felodipine | 5.0mg | 10g |
| Hydroxypropylcellulose LF | 10mg | 20g |
| Hydroxypropyl methylcellulose E50 | 100mg | 200g |
| Hydroxypropyl methylcellulose K15M | 25mg | 50g |
| Lactis Anhydrous | 20mg | 40g |
| Crodaret | 5.0mg | 10g |
| Microcrystalline cellulose | 3mg | 6g |
| Propylgallate | 0.06mg | 0.12g |
| Magnesium trisilicate | 40mg | 80g |
| Sodium stearyl fumarate | 3.9mg | 8.4g |
Preparation method: with embodiment 1
Referred to the homemade sustained release tablets of the present embodiment and the degree of fitting (F2) of former triturate release and related substance to investigate
Mark, investigating result see the table below 3,4:
3 embodiment of table, 2 sustained release tablets are compared with former triturate release is to result (specification 5.0mg)
Compared with 4 embodiment of table, 2 sustained release tablets substance related with former triturate (specification 5.0mg)
By above-mentioned test result it is found that sustained release tablets and original prepared by embodiment 2 grind the fitting degree height in each medium, release
Speed is uniform, and impurity level is suitable with former triturate.
Embodiment 3
| Supplementary material | Recipe quantity mg | 2000 g |
| Felodipine | 10mg | 20g |
| Hydroxypropylcellulose LF | 10mg | 20g |
| Hydroxypropyl methylcellulose E50 | 100mg | 200g |
| Hydroxypropyl methylcellulose K15M | 25mg | 50g |
| Lactis Anhydrous | 20mg | 40g |
| Crodaret | 10mg | 20g |
| Microcrystalline cellulose | 3mg | 6g |
| Propylgallate | 0.06mg | 0.12g |
| Magnesium trisilicate | 40mg | 80g |
| Sodium stearyl fumarate | 4mg | 8.4g |
Preparation method: with embodiment 1
Referred to the homemade sustained release tablets of the present embodiment and the degree of fitting (F2) of former triturate release and related substance to investigate
Mark, investigating result see the table below 5,6:
5 embodiment of table, 3 sustained release tablets are compared with former triturate release is to result (specification 10mg)
Compared with 6 embodiment of table, 3 sustained release tablets substance related with former triturate (specification 10mg)
By above-mentioned test result it is found that sustained release tablets and original prepared by embodiment 3 grind the fitting degree height in each medium, release
Speed is uniform, and impurity level is suitable with former triturate.
Embodiment 4
| Supplementary material | Recipe quantity mg | 2000 g |
| Felodipine | 2.5mg | 5g |
| Hydroxypropylcellulose LF | 10mg | 20g |
| Hydroxypropyl methylcellulose E50 | 100mg | 200g |
| Hydroxypropyl methylcellulose K15M | 25mg | 50g |
| Lactis Anhydrous | 20mg | 40g |
| Lauryl sodium sulfate | 2.5mg | 5g |
| Starch | 3mg | 6g |
| Propylgallate | 0.06mg | 0.12g |
| Magnesium trisilicate | 40mg | 80g |
| Sodium stearyl fumarate | 4.2mg | 8.4g |
Preparation method: with embodiment 1.
Embodiment 5
| Supplementary material | Recipe quantity mg | 2000 g |
| Felodipine | 5.0mg | 10g |
| Hydroxypropylcellulose LF | 10mg | 20g |
| Hydroxypropyl methylcellulose E50 | 100mg | 200g |
| Hydroxypropyl methylcellulose K15M | 25mg | 50g |
| Lactis Anhydrous | 20mg | 40g |
| Crodaret | 5.0mg | 10g |
| Microcrystalline cellulose | 3mg | 6g |
| Propylgallate | 0.06mg | 0.12g |
| Diatomite | 40mg | 80g |
| Sodium stearyl fumarate | 3.9mg | 8.4g |
Preparation method: with embodiment 1.
Sustained release tablets and former triturate fitting degree in each medium prepared by above embodiments 4,5 are high, and rate of release is uniform,
Impurity level is suitable with former triturate.
6 auxiliary material order by merging screening experiment of embodiment
Supplementary material is taken by 1 prescription of embodiment, is prepared as follows sustained release tablets respectively:
Method one:
Substantially with embodiment 1, difference is the order by merging of slow-release material, excipient and filler in step b, specifically
Are as follows: hydroxypropyl methylcellulose K15M, hydroxypropyl methylcellulose E50 are uniformly mixed by equivalent gradually-increased, obtain mixture I；By anhydrous lactitol
Sugar, microcrystalline cellulose, magnesium trisilicate are uniformly mixed by equivalent gradually-increased, obtain mixtures II.
Method two:
The preparation method of embodiment 1.
To be investigated with fitting degree of the former triturate in 1% tween solution dissolution medium of pH1.2 hydrochloric acid as index, examine
Influence of the material order by merging of the sustained-release tablet of two methods preparation to releasing result is examined, the results are shown in Table 7.
Influence of the different preparation methods of table 7 to sustained-release tablet releasing result
| Order by merging | The similar factors F2 ground with original |
| Method one | 45.2 |
| Method two | 86.2 |
By the above results can, by the premixing of magnesium trisilicate and slow-release material, obtain fabulous effect, this method preparation
Sustained-release tablet and former triturate high, the product rate of release that discharges degree of fitting in 1% tween solution medium of pH1.2 hydrochloric acid
It is uniform.Efficiently solve it is fast before felodipine sustained-release tablets release after slow release behavior.And sample prepared by method one, it is being situated between
The degree of fitting ground in 1% tween solution of matter pH1.2 hydrochloric acid with original is underproof.
7 binder concn screening experiment of embodiment
Hydroxypropylcellulose is dissolved in water, easily causes material stickiness larger, influences technological feasibility, thus first select dehydrated alcohol or
95% alcohol granulation carries out late stage process parameter and gropes.
Take 5 parts of 20g hydroxypropylcellulose LF adhesive (batch: 2000 amount), be separately added into 200ml, 300ml, 400ml,
95% alcohol granulation of 500ml, 600ml investigate different binder concns to mobility of particle, granularity, compression ratio, grind and release with original
The influence for the degree of fitting put.The preparation method is the same as that of Example 1 for remaining.Investigation the results are shown in Table 8.
Influence of the different binder concns of table 8 to sustained-release tablet
Note: medium A is 1% tween solution of pH1.2 hydrochloric acid, and medium B is pH6.5 phosphate buffer 1 %SDS solution.
By testing result it is found that with ethanol consumption in adhesive increase, the mobility of particle, compressibility be deteriorated,
Grain granularity attenuates, and the degree of fitting for grinding release with original meets regulation (F2 is greater than 50), but fitting degree is reducing.Therefore adhesive
And the ratio of ethyl alcohol is preferably (1:15)
8 material concentration screening test of embodiment
4 parts of raw material felodipine 5.0g (batch: 2000 amounts) is taken, 50ml, 80ml, 100ml, 150ml are separately added into
95% ethyl alcohol investigates influence of the different ethanol consumptions to tablet content homogeneity.The preparation method is the same as that of Example 1 for remaining.Investigate knot
Fruit is shown in Table 9.
Influence of the different ethanol consumptions of table 9 to tablet content homogeneity
| Raw material | Amount of alcohol | Raw material and ethyl alcohol ratio | Content uniformity (A+2.2S) |
| 5.0g | 50ml | 1:10 | (19.29 unqualified) |
| 5.0g | 80ml | 1:13 | 15.8 (unqualified) |
| 5.0g | 100ml | 1:20 | 4.3 (qualifications) |
| 5.0g | 150ml | 1:30 | 5.4 (qualifications) |
The ratio of raw material and ethyl alcohol known to testing result, which is controlled, meets regulation in (1:20 and 1:30) uniformity of dosage units,
The preferred 1:20 of the ratio of raw material and ethyl alcohol in medical fluid.
Claims (10)
1. a kind of felodipine sustained-release tablets, which is characterized in that the supplementary material of the sustained release tablets accounts for the percentage of piece heart gross weight are as follows: non-Lip river
Horizon 1%~5%, framework material 30%-80%, filler 1~20%, solubilizer 1%~10%, excipients 10%~
30%, adhesive is 1~10%, antioxidant 0.01%~0.1%.
2. felodipine sustained-release tablets as described in claim 1, which is characterized in that the supplementary material accounts for the percentage of piece heart gross weight
Are as follows: felodipine 1%~5%, framework material 40%-70%, filler 5~18%, solubilizer 1%~8%, excipients 13%
~25%, adhesive is 1~8%, antioxidant 0.01%~0.1%.
3. felodipine sustained-release tablets as claimed in claim 2, which is characterized in that supplementary material accounts for the percentage of piece heart gross weight are as follows:
Felodipine 1%~5%, framework material 50%-65%, filler 8~15%, solubilizer 1%~5%, excipients 15%~
20%, adhesive is 1~5%, antioxidant 0.01%~0.1%.
4. felodipine sustained-release tablets as claimed in claim 3, which is characterized in that supplementary material accounts for the percentage of piece heart gross weight are as follows:
Felodipine 1%~5%, framework material 55%-62%, filler 9~12%, solubilizer 1%~5%, excipients 18%~
20%, adhesive is 3~5%, antioxidant 0.01%~0.1%.
5. felodipine sustained-release tablets according to any one of claims 1-4, which is characterized in that further include lubrication in the auxiliary material
Agent 1%~5%；The framework material be selected from one of hydroxypropyl methylcellulose E5, E50, K100, K4M, K15M, K15MCR or
It is several；The filler is selected from one or more of lactose, microcrystalline cellulose, starch, mannitol；The solubilizer is selected from and spits
One or more of temperature -80, lauryl sodium sulfate, Crodaret；The excipients be selected from magnesium trisilicate,
One or more of diatomite, white bole；Described adhesive is selected from hydroxypropylcellulose and/or ethyl cellulose；Antioxidant choosing
From propylgallate and/or vitamin C；The lubricant is sodium stearyl fumarate.
6. the preparation method of felodipine sustained-release tablets as described in claim any one of 1-4, which is characterized in that this method includes such as
Lower step:
Felodipine and antioxidant, solubilizer are added ethanol solution dissolution, obtain material solution by step a；Adhesive is added
Ethanol solution dissolution, obtains binder solution；
Framework material, excipient are uniformly mixed by step b, obtain mixture I；Filler is uniformly mixed, and obtains mixture II；
The mixture I of step b, II mixing are added the material solution and binder solution of step a, pelletized by step c, whole
Grain, tabletting.
7. preparation method as claimed in claim 6, which is characterized in that the quality volume of step a felodipine and ethanol solution
Than for 1:(20-30).
8. preparation method as claimed in claim 7, which is characterized in that the quality volume of step a felodipine and ethanol solution
Than for 1:20.
9. preparation method as claimed in claim 6, which is characterized in that the mass volume ratio of step a adhesive and ethanol solution
For 1:(10-20).
10. preparation method as claimed in claim 9, which is characterized in that the mass volume ratio of step a adhesive and ethanol solution
For 1:15.
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| CN201710532921.6A CN109200026B (en) | 2017-07-03 | 2017-07-03 | Felodipine sustained-release tablet and preparation method thereof |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1025150C (en) * | 1986-04-11 | 1994-06-29 | 哈斯莱股份公司 | Pharmaceutical preparations with extended release |
| US20030190356A1 (en) * | 2002-04-08 | 2003-10-09 | Yea-Sheng Yang | Process for preparing oral sustained-release formulation of felodipine |
| CN102188401A (en) * | 2011-05-10 | 2011-09-21 | 山东威高药业有限公司 | Felodipine sustained-release tablet and preparation method thereof |
| CN104997750A (en) * | 2015-07-30 | 2015-10-28 | 杭州康恩贝制药有限公司 | Felodipine sustained release tablet and preparation method thereof |
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2017
- 2017-07-03 CN CN201710532921.6A patent/CN109200026B/en active Active
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1025150C (en) * | 1986-04-11 | 1994-06-29 | 哈斯莱股份公司 | Pharmaceutical preparations with extended release |
| US20030190356A1 (en) * | 2002-04-08 | 2003-10-09 | Yea-Sheng Yang | Process for preparing oral sustained-release formulation of felodipine |
| CN102188401A (en) * | 2011-05-10 | 2011-09-21 | 山东威高药业有限公司 | Felodipine sustained-release tablet and preparation method thereof |
| CN104997750A (en) * | 2015-07-30 | 2015-10-28 | 杭州康恩贝制药有限公司 | Felodipine sustained release tablet and preparation method thereof |
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