CN107496370A - A kind of Sildenafil citrate tablets agent composition and preparation method thereof - Google Patents
A kind of Sildenafil citrate tablets agent composition and preparation method thereof Download PDFInfo
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- CN107496370A CN107496370A CN201710631623.2A CN201710631623A CN107496370A CN 107496370 A CN107496370 A CN 107496370A CN 201710631623 A CN201710631623 A CN 201710631623A CN 107496370 A CN107496370 A CN 107496370A
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- sildenafil citrate
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- DEIYFTQMQPDXOT-UHFFFAOYSA-N sildenafil citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 DEIYFTQMQPDXOT-UHFFFAOYSA-N 0.000 title claims abstract description 31
- 229960002639 sildenafil citrate Drugs 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 239000000203 mixture Substances 0.000 title claims description 26
- 239000000463 material Substances 0.000 claims abstract description 42
- 239000011248 coating agent Substances 0.000 claims abstract description 36
- 238000000576 coating method Methods 0.000 claims abstract description 36
- 238000000034 method Methods 0.000 claims abstract description 33
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 24
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 20
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 18
- 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 abstract description 16
- 229920002472 Starch Polymers 0.000 claims abstract description 16
- 239000011734 sodium Substances 0.000 claims abstract description 16
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 16
- 235000019698 starch Nutrition 0.000 claims abstract description 16
- 239000008107 starch Substances 0.000 claims abstract description 16
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 10
- 229920000881 Modified starch Polymers 0.000 claims abstract description 9
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 9
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 7
- 238000007908 dry granulation Methods 0.000 claims abstract description 7
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 7
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 7
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 7
- 238000002156 mixing Methods 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- 239000008213 purified water Substances 0.000 claims description 10
- 239000002245 particle Substances 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 8
- 239000007888 film coating Substances 0.000 claims description 7
- 238000009501 film coating Methods 0.000 claims description 7
- UHZZMRAGKVHANO-UHFFFAOYSA-M chlormequat chloride Chemical compound [Cl-].C[N+](C)(C)CCCl UHZZMRAGKVHANO-UHFFFAOYSA-M 0.000 claims description 6
- 238000005469 granulation Methods 0.000 claims description 4
- 230000003179 granulation Effects 0.000 claims description 4
- 238000000227 grinding Methods 0.000 claims description 4
- 239000002994 raw material Substances 0.000 claims description 4
- 239000007916 tablet composition Substances 0.000 claims 7
- 229940032147 starch Drugs 0.000 claims 4
- 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 1
- 239000001768 carboxy methyl cellulose Substances 0.000 claims 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims 1
- 229940080313 sodium starch Drugs 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 23
- 239000008279 sol Substances 0.000 abstract description 10
- 238000005265 energy consumption Methods 0.000 abstract description 3
- 239000003826 tablet Substances 0.000 description 27
- 230000000052 comparative effect Effects 0.000 description 17
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- 238000005516 engineering process Methods 0.000 description 10
- 230000008569 process Effects 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- ZOOGRGPOEVQQDX-KHLHZJAASA-N cyclic guanosine monophosphate Chemical compound C([C@H]1O2)O[P@](O)(=O)O[C@@H]1[C@H](O)[C@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-KHLHZJAASA-N 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 6
- 239000012738 dissolution medium Substances 0.000 description 6
- 235000020985 whole grains Nutrition 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000007853 buffer solution Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 230000036259 sexual stimuli Effects 0.000 description 4
- HRQDCDQDOPSGBR-UHFFFAOYSA-M sodium;octane-1-sulfonate Chemical compound [Na+].CCCCCCCCS([O-])(=O)=O HRQDCDQDOPSGBR-UHFFFAOYSA-M 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000001913 cellulose Substances 0.000 description 3
- 229920002678 cellulose Polymers 0.000 description 3
- 235000010980 cellulose Nutrition 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 238000007907 direct compression Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000002604 ultrasonography Methods 0.000 description 3
- 238000005550 wet granulation Methods 0.000 description 3
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 235000019257 ammonium acetate Nutrition 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 235000013339 cereals Nutrition 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000009702 powder compression Methods 0.000 description 2
- 239000013558 reference substance Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 208000010228 Erectile Dysfunction Diseases 0.000 description 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 244000068988 Glycine max Species 0.000 description 1
- 108010078321 Guanylate Cyclase Proteins 0.000 description 1
- 102000014469 Guanylate cyclase Human genes 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 1
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 1
- 235000008331 Pinus X rigitaeda Nutrition 0.000 description 1
- 235000011613 Pinus brutia Nutrition 0.000 description 1
- 241000018646 Pinus brutia Species 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- BNRNXUUZRGQAQC-UHFFFAOYSA-N Sildenafil Natural products CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 229940046011 buccal tablet Drugs 0.000 description 1
- 239000006189 buccal tablet Substances 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 210000005226 corpus cavernosum Anatomy 0.000 description 1
- 238000000280 densification Methods 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 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 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 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 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 201000001881 impotence Diseases 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 238000005374 membrane filtration Methods 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 238000005453 pelletization Methods 0.000 description 1
- 210000003899 penis Anatomy 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000008288 physiological mechanism Effects 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000004648 relaxation of smooth muscle Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000011122 softwood Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 229940094720 viagra Drugs 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- 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
- 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
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Landscapes
- Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a kind of Sildenafil citrate tablets agent and preparation method thereof, the Sildenafil citrate tablets agent includes label and coating；The material of the label is sildenafil citrate, microcrystalline cellulose, pregelatinized starch, Ac-Di-Sol, magnesium stearate, silica, carboxyrnethyl starch sodium；The label is made of compressing dry granulation.This technique has very big superiority compared with the prior art, and operation is simpler, and the equipment used is few, with short production cycle, less energy consumption, can reduce production cost, can meet to commercially produce.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition and preparation method thereof, and in particular to a kind of Sildenafil citrate tablets agent group
Compound and preparation method thereof.
Background technology
Silaenafil is a kind of medicine of oral medication erectile dysfunction.In natural environment, i.e., adjoint sexual stimulus, it
Pass through the erection function for increasing the CBF of penis to recover impaired.The physiological mechanism of telotism is related to the moon during sexual stimulus
The release of stem cavernous body intracellular nitric oxide (NO).NO activates guanylate cyclase, causes cyclic guanosine monophosphate (cGMP) level to increase,
So that smooth muscle relaxation in cavernous body, blood flows into.Silaenafil is 5 type phosphodiesterases of cGMP specificity in cavernous body
(PDE5) effective and selective depressant, in cavernous body, PDE5 causes cGMP to decompose.Silaenafil is to erecing with outer
The effect of enclosing.Silaenafil does not have direct relexation in vitro human corpus cavernosum, but effectively enhances pines of the NO to the tissue
Relaxation acts on.When NO/cGMP paths are activated, such as generation sexual stimulus, cavernous body cGMP can be increased by suppressing PDE5 by silaenafil
Level.Therefore silaenafil needs sexual stimulus to produce expected pharmacological action.
Tablet means the disc-shaped that medicine suppresses after uniformly being mixed with proper auxiliary materials or the solid pharmaceutical preparation of special-shaped sheet,
Due to its dosage is accurate, content uniformly, because small volume, densification, influenceed by outside air, light, water grading factors it is smaller,
If necessary can by be coated protect, so chemical stability is good, carry, transport, take it is more convenient；The mechanization of production,
Automaticity is higher, and yield is big, cost and price are relatively low；Different types of various tablets can be made, such as scattered (quick-acting)
Piece, controlled release (long-acting) piece, enteric coated tablets, chewable tablets and buccal tablet etc., to meet the needs of different clinical treatments, turn into current
One of formulation being most widely used, method for preparing tablet thereof includes granulating tabletting process and direct compression method is divided into direct powder compression
Method and half dry type granulation method.
Main during China's tablet manufacturing at present to select granulating tabletting process, direct compression method is due to traditional former, auxiliary material
Many-sided limited reason such as matter and production equipment does not obtain a wide range of popularization and application, but as China's medicine in recent years is related
Industry development is rapid, and from supplementary material performance improvement and pharmaceutical equipment, there occurs rapid development, such as high speed tablet press are automatic
The constantly improve of filling technique is forced, promotes the development of direct powder compression, it is direct according to document announcement developed country powder
The kind of pressed disc method is up to more than 60%, is one of tablet prefered method, and direct pressed powder eliminates granulating process, step
Suddenly so that technique is simpler, and production equipment species is less, and production power consumption reduces, and the production cycle shortens, is produced into so as to reduce
This, due to avoiding heating and influence of the moisture to supplementary material, direct tablet compressing technique can improve the quality of medicine, particularly end-on
Heat, chance water unstable medicine have special benefits, do not have pelletization in direct compression method technique, so after disintegration of tablet, particle
Relatively carefully, the advantages that dissolution surface area is big, and dissolution rate is very fast.
The content of the invention
The invention discloses a kind of Sildenafil citrate tablets agent and preparation method thereof, the Sildenafil citrate tablets agent bag
Include label and coating；
The material of the label is as follows：
The parts by weight of sildenafil citrate 35.12~105.36,
The parts by weight of microcrystalline cellulose 62~186,
The parts by weight of pregelatinized starch 35~105,
The parts by weight of Ac-Di-Sol 6~18,
The parts by weight of magnesium stearate 1~3,
Silica 2-6 parts by weight,
The parts by weight of carboxyrnethyl starch sodium 5.5~16.5
The label is made of compressing dry granulation.
It is described coating raw material be：
It is coated pre-mixing agent 4.5-13.5 parts by weight
95% ethanol 4.5-13.5 parts by weight
Purified water 18.0-54.0 parts by weight
The coating pre-mixing agent refers to available commercially available prod, such as polyvinyl alcohol, titanium dioxide, talcum powder, phosphatide (soybean
Phosphatide), hydroxypropyl methylcellulose composition product grade be 295W680000 coating pre-mixing agent, can be coated by Shanghai Ka Lekang
Technology Co., Ltd. provides.
The preparation method of Sildenafil citrate tablets agent of the present invention, comprises the following steps：
1. label preparation technology
It is standby that label material is crossed into 60 eye mesh screens, sildenafil citrate, microcrystalline cellulose is weighed, wherein takes 1/3-2/3
Amount Ac-Di-Sol and carboxyrnethyl starch sodium, pregelatinized starch are put in three-dimensional mixer and mixed；In dry granulating machine
On to said mixture material carry out precompressed；Precompressed material is put into attrition grinding and granulation on Fastgranulatemachine；By unsanctioned
Grain is crushed and by 24 eye mesh screen again, and remaining Ac-Di-Sol, carboxyrnethyl starch sodium, hard is added in above-mentioned material
Fatty acid magnesium, silica, mixing；Tabletting.
2. it is coated preparation technology
Take label to be coated, take film coating pre-mix dose：95% ethanol：Purified water=1:1:4 materials are put in agitator, stirring
Time, 40min was standby.Coating parameter：55 DEG C of EAT, 40 DEG C of piece bed tempertaure；Coating pan revolution：Start 2 hours 1r/min,
Middle 2r/min, terminate 2r/min；Coating solution usage amount：With solids basis weightening 2%；Produce Tablets composition.
Brief description of the drawings
Fig. 1：Sildenafil citrate tablets stripping curve comparison diagram
Tablets composition can realize following technique effect：
1st, the composition of Sildenafil citrate tablets agent of the invention is formed reasonable, and lmpurities are few, in stripping curve, have
Had a clear superiority in terms of closing the index such as material and tablet uniformity.
2nd, the compressing dry granulation that the present invention uses refers to be well mixed medicine with partial supplementary material after rear precompressed through phase
Corresponding device pulverizes and sieves rear with remaining auxiliary materials and mixing direct tablet compressing method, and silaenafil raw material is unstable, illumination, height
Apt to deteriorate under temperature, super-humid conditions, medicine easily turns yellow after especially meeting water, compared with existing wet granulation production technology, adopts
With the process do not pelletized in dry granulation tabletting production technology with the aqueous solution, also without the process of heat drying, so production
The controllable stabilization of drug quality out.
3rd, this technique has very big superiority compared with the prior art, and operation is simpler, and the equipment used is few, production week
Phase is short, less energy consumption, can reduce production cost, can meet to commercially produce.
Embodiment 1：
Preparation technology：It is standby that label material is crossed into 60 eye mesh screens, weighs sildenafil citrate, microcrystalline cellulose, pre- glue
Change starch, take 2/3 recipe quantity Ac-Di-Sol and carboxyrnethyl starch sodium to put and mix 20min in three-dimensional mixer；
Precompressed is carried out to said mixture material on dry granulating machine；Precompressed material is put on Fastgranulatemachine attrition grinding and by 20 mesh
Screen cloth is pelletized；Unsanctioned particle is crushed again and by 24 eye mesh screens, remaining cross-linked carboxymethyl is added in above-mentioned material
Sodium cellulosate, carboxyrnethyl starch sodium, magnesium stearate, silica, mixing；Tabletting；Take label to be coated, take film coating pre-mix dose：
95% ethanol：Purified water=1:1:4 materials are put in agitator, and mixing time 40min is standby.Coating parameter：55 DEG C of EAT,
40 DEG C of piece bed tempertaure；Coating pan revolution：Start 2 hours 1r/min, middle 2r/min, terminate 2r/min；Coating solution usage amount：With
Solids basis weightening 2%；Produce Tablets composition.
Embodiment 2：
Preparation technology：Taking label component materials, 60 eye mesh screens excessively are standby respectively, take recipe quantity sildenafil citrate, crystallite
Cellulose, pregelatinized starch, 1/3 recipe quantity Ac-Di-Sol and carboxyrnethyl starch sodium is taken to put 3 D multi-directional mixer
Middle mixing 20min, the precompressed in above-mentioned material addition dry granulating machine, put Fastgranulatemachine whole grain by material and cross 20 eye mesh screens,
24 eye mesh screens will not crushed again by particle, mix, add remaining Ac-Di-Sol and carboxyrnethyl starch sodium,
Silica, magnesium stearate are well mixed, tabletting；Take label to be coated, take film coating pre-mix dose：95% ethanol：Purified water=
1:1:4 materials are put in agitator, and mixing time 40min is standby.Coating parameter：55 DEG C of EAT, 40 DEG C of piece bed tempertaure；Coating
Pot revolution：Start 2 hours 1r/min, middle 2r/min, terminate 2r/min；Coating solution usage amount：With solids basis weightening 2%；
Produce Tablets composition.
Embodiment 3：
Preparation technology：Taking label component materials, 60 eye mesh screens excessively are standby respectively, take recipe quantity sildenafil citrate, crystallite
Cellulose, pregelatinized starch, the Ac-Di-Sol of recipe quantity 2/3 and the carboxyrnethyl starch sodium of 1/3 recipe quantity is taken to put three
Tie up and 20min is mixed in multidirectional mixer, add precompressed in dry granulating machine in above-mentioned material, material is put into Fastgranulatemachine whole grain
Cross 20 eye mesh screens, will not crushed 24 eye mesh screens again by particle, mix, add remaining Ac-Di-Sol and
Carboxyrnethyl starch sodium, silica, magnesium stearate are well mixed, tabletting；Take label to be coated, take film coating pre-mix dose：95% second
Alcohol：Purified water=1:1:4 materials are put in agitator, and mixing time 40min is standby.Coating parameter：55 DEG C of EAT, piece bed temperature
40 DEG C of degree；Coating pan revolution：Start 2 hours 1r/min, middle 2r/min, terminate 2r/min；Coating solution usage amount：With solid content
Meter weightening 2%；Produce Tablets composition.
Embodiment 4：
Preparation technology：Taking label component materials, 60 eye mesh screens excessively are standby respectively, take recipe quantity sildenafil citrate, crystallite
Cellulose, pregelatinized starch, Ac-Di-Sol are put in 3 D multi-directional mixer and mix 20min, add in above-mentioned material
Enter precompressed in dry granulating machine, material is put into Fastgranulatemachine whole grain and crosses 20 eye mesh screens, will not crushed 24 again by particle
Eye mesh screen, mixing, addition carboxyrnethyl starch sodium, silica, magnesium stearate are well mixed, tabletting；Take label to be coated, take film bag
Clothing pre-mixing agent：95% ethanol：Purified water=1:1:4 materials are put in agitator, and mixing time 40min is standby.Coating parameter：Air intake
55 DEG C of temperature, 40 DEG C of piece bed tempertaure；Coating pan revolution：Start 2 hours 1r/min, middle 2r/min, terminate 2r/min；Coating solution
Usage amount：With solids basis weightening 2%；Produce Tablets composition.
On above-described embodiment and comparative example, by production time, quality versus, (relevant material, content, dissolution are bent respectively
Line) result of study see the table below：
Experimental example 1, embodiment and comparative example production hour contrast
Table：Embodiment collects with the contrast of comparative example production hour
| Process | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Comparative example |
| Sieving | 40 minutes | 40 minutes | 40 minutes | 40 minutes | 40 minutes |
| Mixing | 30 minutes | 30 minutes | 30 minutes | 30 minutes | 30 minutes |
| Precompressed | 30 minutes | 30 minutes | 30 minutes | 30 minutes | - |
| Granulation | - | - | - | - | 30 minutes |
| Dry | - | - | - | - | 150 minutes |
| Whole grain | 30 minutes | 30 minutes | 30 minutes | 30 minutes | 30 minutes |
| It is total mixed | 30 minutes | 30 minutes | 30 minutes | 30 minutes | 30 minutes |
| Tabletting | 60 minutes | 60 minutes | 60 minutes | 60 minutes | 60 minutes |
| Coating | 60 minutes | 60 minutes | 60 minutes | 60 minutes | 60 minutes |
| Production hour | 280 minutes | 280 minutes | 280 minutes | 280 minutes | 430 minutes |
It will be compared the production time, the production hour of embodiment 1 to embodiment 4 is 280 minutes, comparative example
Man-hour is 430 minutes, hence it is evident that embodiment production hour is less than using conventional normal wet granulation comparative example man-hour, due to dry method system
Grain has removed drying process less with existing frequently-used wet granulation contrast, so while the production time is reduced, can also save drop
Consumption reduces production cost.
Experimental example 2, embodiment and comparative example quality versus study
Relevant substance method：
Chemicals and reagent：Ammonium acetate：Analyze pure rank；Sodium 1-octanesulfonate：Analyze pure rank；Acetonitrile：Efficient liquid phase
Chromatogram rank；Water：Milli-Q ranks
The preparation of buffer solution：About 15.43g ammonium acetates are weighed, are put in the beaker containing 1000mL water, ultrasonic dissolution.
The preparation of mobile phase A：700mL buffer solutions and 300mL acetonitriles are mixed, adds 100mg sodium 1-octanesulfonates, ultrasound
Dissolving.Filtered, and deaerated by 0.45 μm of membrane filter.
The preparation of Mobile phase B：300mL buffer solutions and 700mL acetonitriles are mixed, adds 100mg sodium 1-octanesulfonates, ultrasound
Dissolving.Filtered, and deaerated by 0.45 μm of membrane filter.
The preparation of dilution：500mL buffer solutions and 500mL acetonitriles are mixed, adds 100mg sodium 1-octanesulfonates, ultrasound is molten
Solution.Filtered, and deaerated by 0.45 μm of membrane filter.
Chromatographic condition：
Table：Embodiment material relevant with comparative example, content balance collect
By 60 DEG C of comparative example and embodiment high temperature accelerate 10 days relevant material Comparative results find comparative example single contaminants with
Total miscellaneous increase is obvious, illustrates that dry granulation process is advantageous to improve the stability of drug quality, after comparative example accelerates with embodiment
Content is substantially without significant change.
Experimental example 3, embodiment and comparative example and original grind the contrast of sample stripping curve
Medicine " viagra " is ground to Sildenafil citrate tablets embodiment 1 to embodiment 4, comparative example and original to exist
Stripping curve comparative study in medium in 0.01mol/L hydrochloric acid.
Stripping curve method：
Dissolution medium：0.01mol/L hydrochloric acid volumes：900ml；Device：Basket method；Rotating speed：100rpm；
Temperature：37℃±0.5℃；Sample time：5th, sample within 10,15,20,30,45 minutes；Sample volume：
Per sub-sampling 10ml, while supplement corresponding dissolution medium 10ml；Detection method：UV, wavelength 292nm
It is prepared by solution：
Reference substance solution：Separately take sildenafil citrate reference substance appropriate, it is accurately weighed, add dissolution medium to dissolve and quantify
Dilution is made in every 1ml containing about the μ g of silaenafil 27 solution.
It is prepared by test sample：
In each stripping rotor, 900ml dissolution mediums are separately added into.Reserving the time of abundance makes dissolution medium balance to 37
DEG C ± 0.5 DEG C, adjustment rotating speed to 100rpm, 1 tablet is put into each basket, reduction is installed in dissolution medium, starter.
Respectively at 5,10,15,20,30,45 minutes, dissolution is taken out from dissolution medium surface to the centre position turned at the top of basket
Medium decoction 10ml and fluid infusion 10ml, using membrane filtration, discard appropriate primary filtrate, subsequent filtrate is standby.
Stripping curve (Fig. 1) is compared, the f of embodiment 3 and embodiment 42Similar factors are all higher than 85,
Show and the former sample that grinds has good similitude, the similar factors of comparative example have substantially for 56 and embodiment contrast
Gap.
Comparative example in above-mentioned experimental example is prepared by the following method：
Preparation technology：The HPMC of formula ratio is dissolved in the aqueous solution that water is made 4%, by the sildenafil citrate of formula ratio
(140.5mg/ pieces are equivalent to silaenafil 100mg) is placed in wet mixing pelletizer, opens stirring and shearing, adds formula ratio
The HPMC aqueous solution, softwood processed, wet granular processed in 16 mesh oscillating granulators is put, wet granular is put in fluidized bed dryer and dried, done
Dry temperature is 45 ± 5 DEG C, is dried to moisture below 2.5%, by above-mentioned particle by 16 eye mesh screen whole grains, by above-mentioned particle with matching somebody with somebody
Excipient, disintegrant and the lubricant just measured are added in high efficient mixer and are well mixed, and intermediate detection, tabletting, will premix
Agent is configured to 15% homogeneous aqueous solution, coating, and coating pre-mixing agent is configured into coating solution uniformly sprays in tablet surface, makes
It is unilateral to form uniform film-coating
In summary, because embodiment does not use water or other solvents as bonding in granulating process using dry granulation
Agent is pelletized, also the process without heat drying, so embodiment quality in relevant material, content and stripping curve investigation project
It is more stably and controllable, while ingredient in tablets is formed rationally compared with conventional wet lay granulating process in embodiment, with short production cycle, energy
Consumption is few, and Recipe more meets and commercially produced in embodiment.
Claims (7)
- A kind of 1. Sildenafil citrate tablets agent composition, it is characterised in that the label of the tablet compositionMaterial is：The parts by weight of sildenafil citrate 35.12~105.36,The parts by weight of microcrystalline cellulose 62~186,The parts by weight of pregelatinized starch 35~105,The parts by weight of Ac-Di-Sol 6~18,The parts by weight of magnesium stearate 1~3,Silica 2-6 parts by weight,The parts by weight of carboxyrnethyl starch sodium 5.5~16.5.
- 2. a kind of Sildenafil citrate tablets agent composition as claimed in claim 1, it is characterised in that the tablet composition Label material is：
- A kind of 3. Sildenafil citrate tablets agent composition as claimed in claim 1 or 2, it is characterised in that the tablet composition Label be made of compressing dry granulation.
- A kind of 4. Sildenafil citrate tablets agent composition as described in claim 1,2 or 3, it is characterised in that the tablet composition Thing also includes coating, and the coating raw material is：It is coated pre-mixing agent 4.5-13.5 parts by weight95% ethanol 4.5-13.5 parts by weightPurified water 18.0-54.0 parts by weight.
- 5. a kind of Sildenafil citrate tablets agent composition as claimed in claim 4, it is characterised in that the tablet composition is also Including coating, the coating raw material is：It is coated the parts by weight of pre-mixing agent 4.50The parts by weight of 95% ethanol 4.50The parts by weight of purified water 18.00.
- A kind of 6. preparation method of Sildenafil citrate tablets agent composition as claimed in claim 3, it is characterised in that the party Method is：It is standby that label material is crossed into 60 eye mesh screens, sildenafil citrate, microcrystalline cellulose is weighed, wherein takes 1/3-2/3 amounts to hand over Connection sodium carboxymethylcellulose and carboxyrnethyl starch sodium, pregelatinized starch are put in three-dimensional mixer and mixed；It is right on dry granulating machine Said mixture material carries out precompressed；Precompressed material is put into attrition grinding and granulation on Fastgranulatemachine；By unsanctioned particle weight It is new to crush, remaining Ac-Di-Sol, carboxyrnethyl starch sodium, magnesium stearate, silica are added in above-mentioned material, is mixed Close；Tabletting.Label is coated, takes film coating pre-mix dose, 95% ethanol, purified water is put in agitator, and mixing time 40min is standby； Coating parameter：55 DEG C of EAT, 40 DEG C of piece bed tempertaure；Coating pan revolution：Start 2 hours 1r/min, middle 2r/min, terminate 2r/min；Coating solution usage amount：With solids basis weightening 2%；Produce tablet composition.
- A kind of 7. preparation method of Sildenafil citrate tablets agent composition as claimed in claim 6, it is characterised in that the party Method is：It is standby that label material is crossed into 60 eye mesh screens, sildenafil citrate, microcrystalline cellulose is weighed, pregelatinized starch, takes at 2/3 Side's amount Ac-Di-Sol and carboxyrnethyl starch sodium are put and 20min are mixed in three-dimensional mixer；It is right on dry granulating machine Said mixture material carries out precompressed；Precompressed material is put into attrition grinding on Fastgranulatemachine and pelletized by 20 eye mesh screens；Will not The particle passed through crushes and by 24 eye mesh screens, remaining Ac-Di-Sol, carboxylic first is added in above-mentioned material again Sodium starch, magnesium stearate, silica, mixing；Tabletting, coating；Art for coating is：Label is coated, takes film coating pre-mix dose, 95% ethanol, purified water is put in agitator, mixing time 40min is standby；Coating parameter：55 DEG C of EAT, 40 DEG C of piece bed tempertaure；Coating pan revolution：Start 2 hours 1r/min, it is middle 2r/min, terminate 2r/min；Coating solution usage amount：With solids basis weightening 2%.；Produce tablet composition.
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| CN113456604A (en) * | 2021-07-08 | 2021-10-01 | 天地恒一制药股份有限公司 | Sildenafil citrate orally disintegrating tablet and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1586483A (en) * | 2004-07-12 | 2005-03-02 | 北京科信必成医药科技发展有限公司 | Oral disintegration tablet of silaenafil and its pharmaceutically receptible salt and its preparing method |
| CN104546779A (en) * | 2013-10-14 | 2015-04-29 | 深圳海王药业有限公司 | Sildenafil citrate tablet with high medicine loading and preparation method thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1586483A (en) * | 2004-07-12 | 2005-03-02 | 北京科信必成医药科技发展有限公司 | Oral disintegration tablet of silaenafil and its pharmaceutically receptible salt and its preparing method |
| CN104546779A (en) * | 2013-10-14 | 2015-04-29 | 深圳海王药业有限公司 | Sildenafil citrate tablet with high medicine loading and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113456604A (en) * | 2021-07-08 | 2021-10-01 | 天地恒一制药股份有限公司 | Sildenafil citrate orally disintegrating tablet and preparation method thereof |
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