CN109718214A - A kind of preparation method of calcium dobesilate - Google Patents
A kind of preparation method of calcium dobesilate Download PDFInfo
- Publication number
- CN109718214A CN109718214A CN201711021880.0A CN201711021880A CN109718214A CN 109718214 A CN109718214 A CN 109718214A CN 201711021880 A CN201711021880 A CN 201711021880A CN 109718214 A CN109718214 A CN 109718214A
- Authority
- CN
- China
- Prior art keywords
- calcium dobesilate
- preparation
- anhydrous sodium
- sodium sulfite
- filler
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- QGNBTYAQAPLTMX-UHFFFAOYSA-L calcium dobesilate Chemical compound [Ca+2].OC1=CC=C(O)C(S([O-])(=O)=O)=C1.OC1=CC=C(O)C(S([O-])(=O)=O)=C1 QGNBTYAQAPLTMX-UHFFFAOYSA-L 0.000 title claims abstract description 71
- 229960005438 calcium dobesilate Drugs 0.000 title claims abstract description 70
- 238000002360 preparation method Methods 0.000 title claims abstract description 18
- 229940101006 anhydrous sodium sulfite Drugs 0.000 claims abstract description 36
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims abstract description 36
- 239000002245 particle Substances 0.000 claims abstract description 33
- 239000000945 filler Substances 0.000 claims abstract description 21
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 45
- 229930195725 Mannitol Natural products 0.000 claims description 45
- 239000000594 mannitol Substances 0.000 claims description 45
- 235000010355 mannitol Nutrition 0.000 claims description 45
- 239000000243 solution Substances 0.000 claims description 27
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 24
- 238000012856 packing Methods 0.000 claims description 20
- 239000004033 plastic Substances 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 239000000463 material Substances 0.000 claims description 14
- HWPKGOGLCKPRLZ-UHFFFAOYSA-M monosodium citrate Chemical compound [Na+].OC(=O)CC(O)(C([O-])=O)CC(O)=O HWPKGOGLCKPRLZ-UHFFFAOYSA-M 0.000 claims description 13
- 239000002524 monosodium citrate Substances 0.000 claims description 13
- 235000018342 monosodium citrate Nutrition 0.000 claims description 13
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 12
- 229910052782 aluminium Inorganic materials 0.000 claims description 12
- 239000004411 aluminium Substances 0.000 claims description 12
- 235000019359 magnesium stearate Nutrition 0.000 claims description 12
- 238000004806 packaging method and process Methods 0.000 claims description 9
- 238000005469 granulation Methods 0.000 claims description 7
- 230000003179 granulation Effects 0.000 claims description 7
- 235000020985 whole grains Nutrition 0.000 claims description 7
- 239000007864 aqueous solution Substances 0.000 claims description 6
- 238000003756 stirring Methods 0.000 claims description 6
- 239000000314 lubricant Substances 0.000 claims description 5
- 238000002203 pretreatment Methods 0.000 claims description 5
- 150000008064 anhydrides Chemical class 0.000 claims description 4
- 230000006641 stabilisation Effects 0.000 claims description 4
- 238000011105 stabilization Methods 0.000 claims description 4
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 3
- 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 3
- 239000008101 lactose Substances 0.000 claims description 3
- 239000011149 active material Substances 0.000 claims description 2
- -1 addition step (2) Chemical compound 0.000 claims description 2
- 238000011068 loading method Methods 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims 3
- 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 1
- 239000001913 cellulose Substances 0.000 claims 1
- 229920002678 cellulose Polymers 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 6
- 230000001133 acceleration Effects 0.000 abstract description 4
- 238000005550 wet granulation Methods 0.000 abstract description 4
- 229940079593 drug Drugs 0.000 abstract description 3
- 238000011160 research Methods 0.000 abstract description 3
- 238000002845 discoloration Methods 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 239000000546 pharmaceutical excipient Substances 0.000 abstract 1
- 230000000052 comparative effect Effects 0.000 description 11
- 239000000203 mixture Substances 0.000 description 11
- 229910000831 Steel Inorganic materials 0.000 description 8
- 239000010959 steel Substances 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- 239000008213 purified water Substances 0.000 description 5
- 239000013558 reference substance Substances 0.000 description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N methyl cyanide Natural products CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- YNPNZTXNASCQKK-UHFFFAOYSA-N phenanthrene Chemical compound C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000011575 calcium Substances 0.000 description 3
- 229910052791 calcium Inorganic materials 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 239000007791 liquid phase Substances 0.000 description 3
- 229960001855 mannitol Drugs 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000011574 phosphorus Substances 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 206010012689 Diabetic retinopathy Diseases 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 238000010812 external standard method Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 230000004089 microcirculation Effects 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 239000011812 mixed powder Substances 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- 238000002604 ultrasonography Methods 0.000 description 2
- WHOZNOZYMBRCBL-OUKQBFOZSA-N (2E)-2-Tetradecenal Chemical compound CCCCCCCCCCC\C=C\C=O WHOZNOZYMBRCBL-OUKQBFOZSA-N 0.000 description 1
- 208000007342 Diabetic Nephropathies Diseases 0.000 description 1
- 108010003272 Hyaluronate lyase Proteins 0.000 description 1
- 102000001974 Hyaluronidases Human genes 0.000 description 1
- 206010023126 Jaundice Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- UKTDQTGMXUHPIF-UHFFFAOYSA-N [Na].S(O)(O)=O Chemical compound [Na].S(O)(O)=O UKTDQTGMXUHPIF-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 210000003484 anatomy Anatomy 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000004856 capillary permeability Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 201000002816 chronic venous insufficiency Diseases 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 208000033679 diabetic kidney disease Diseases 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 235000021050 feed intake Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 229960002773 hyaluronidase Drugs 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- DKXULEFCEORBJK-UHFFFAOYSA-N magnesium;octadecanoic acid Chemical compound [Mg].CCCCCCCCCCCCCCCCCC(O)=O DKXULEFCEORBJK-UHFFFAOYSA-N 0.000 description 1
- 239000002075 main ingredient Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 229940044654 phenolsulfonic acid Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 239000011122 softwood Substances 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000002550 vasoactive agent Substances 0.000 description 1
- 201000002282 venous insufficiency Diseases 0.000 description 1
- 238000004383 yellowing Methods 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
The present invention relates to pharmaceutical preparation research fields, and in particular to the preparation method containing drug calcium dobesilate.The tablet is made of Calcium Dobesilate, anhydrous sodium sulfite and pharmaceutic adjuvant necessary to other, it is primarily characterized in that anhydrous sodium sulfite needs to be configured to solution and the independent wet granulation of filler, gained particle and other supplementary material mixed pressuring plates, the preparation method can significantly improve the stability of tablet, it is effectively improved tablet discoloration problem during Acceleration study, tablet stability is improved, the validity period of calcium dobesilate is extended.
Description
Technical field
The present invention relates to pharmaceutical preparation research fields, and in particular to a kind of drug calcium dobesilate for adjusting microcirculation
Preparation method.
Background technique
Calcium Dobesilate is that capillary protects medicine, and by inhibiting vaso-active substance, (histamine, serotonin delay and swash
Peptide, hyaluronidase, prostaglandin) caused by high penetration act on, to reduce capillary permeability and blood can be inhibited small
Plate aggreation reduces blood viscosity etc..It is equal to a variety of diseases caused by microcirculation obstacle (capillary circulation obstacle)
It is effective in cure.Phenolsulfonic acid calcium preparation is clinically used for the prevention and treatment of diabetic retinopathy in 1970s investment, and 1997
It is loaded into European Pharmacopoeia, load in 1998 is loaded into British Pharmacopoeia, and the country introduces the medicine to the market in June, 2001.With drug Mechanism
Deepen continuously, find the medicine for kidney trouble, chronic venous insufficiency, thrombotic diseases and certain heart diseases etc.,
Extensive use especially in terms of diabetic nephropathy indicates that it has good application prospect.
Inventor has found that stability is poor in Calcium Dobesilate tablet research process, during storage easily
The phenomenon that changing colour.
I arrange to the Calcium Dobesilate tablet composition listed at present and summarize, while using accelerated test
(40 DEG C, RH75%) have carried out deep anatomy to its intrinsic stability, the results showed that the calcium dobesilate of OM company production is most
Stablize, details are as follows:
Common name: calcium dobesilate
English name: Calcium Dobesilate Tablets
Trade name: Doxium
Accredited quotient: OM PHARMAS.A. (OM drugmaker)
Manufacturer: Sanofi Winthrop Industrie (pharmacy of Sino phenanthrene)
The composition that its specification is recorded are as follows: Calcium Dobesilate, mannitol, anhydrous sodium sulfite, sodium dihydrogen citrate, stearic acid
Magnesium；Packaged form is aluminium-plastic bubble plate packing.
Inventor shows by Experimental comparison: anhydrous sodium sulfite is of crucial importance the stability of tablet,
Calcium Dobesilate tablet stability is poor in the case where without containing anhydrous sodium sulfite, easily occurs within 1 month under acceleration conditions related
Substance increases obvious and tablet yellowing phenomenon etc., affects Calcium Dobesilate tablet appearance and interior quality.But OM company is raw
Although the calcium dobesilate of production contains anhydrous sodium sulfite, accelerating still have the case where significant discoloration within 3 months.
Inventor is in the trial discovery Jing Guo test of many times, on the basis of the calcium dobesilate composition of OM company production,
As long as calcium dobesilate can be significantly improved by changing simultaneously packaged form by the adding manner for changing anhydrous sodium sulfite
Stability.
Summary of the invention
Calcium dobesilate stability problem in storing process, provides during present invention aims to solve the prior art
A kind of preparation method of calcium dobesilate is prepared the filler in calcium dobesilate using wet granulation technology, gained
Again with other supplementary material mixed pressuring plates, Calcium Dobesilate tablet stability increases substantially particle.
Object above of the invention is realized by following technological means:
At present calcium dobesilate or capsule its there are mainly two types of specifications: 250mg and 500mg, screen below with
For 500mg specification, 250mg specification is proportionally reduced on the basis of 500mg prescription.
The composition composition is as follows:
Calcium Dobesilate: 500mg (in terms of Calcium Dobesilate anhydride)
Filler: 40mg-200mg
Lubricant: 5mg-20mg
Anhydrous sodium sulfite: 0.2mg-3mg
Sodium dihydrogen citrate: 0.2mg-3mg
Wherein filler can be mannitol, lactose, microcrystalline cellulose etc., and lubricant can be magnesium stearate.Specifically
Calcium dobesilate is by active material Calcium Dobesilate, the filler of auxiliary tabletting and lubricant and guarantees prescription stability
Anhydrous sodium sulfite and auxiliary material with stabilization, the filler need pre-treatment, and the pre-treatment of filler is filler
With the independent wet granulation of anhydrous sodium sulfite solution, gained particle again with other supplementary material mixed pressuring plates.
The anhydrous sodium sulfite solution is the anhydrous sodium sulfite aqueous solution containing 1.0%-20.0%, anhydrous sulfurous acid
Sodium solution dosage is 5.5%-9.5% with respect to filler ratio.
The calcium dobesilate every contains Calcium Dobesilate 500mg or 250mg (according to anhydride meter).It is described to fill out
Filling agent is mannitol, lactose or microcrystalline cellulose, and the filler loading compares with respect to Calcium Dobesilate (according to anhydride meter)
Example is 8%-40%.
The auxiliary material with stabilization is sodium dihydrogen citrate.
The packaged form of the calcium dobesilate uses the form of the additional aluminium bag of aluminium-plastic bubble plate packing.
The calcium dobesilate specific the preparation method comprises the following steps:
(1) it weighs recipe quantity anhydrous sodium sulfite to be added to the water, dissolve；
(2) mannitol of recipe quantity is weighed, anhydrous sodium sulfite solution obtained by step (1) is added, stirring granulation, drying is extremely
Moisture less than 1% after whole grain, obtain mannitol particles, put into the next step；
(3) Calcium Dobesilate is weighed according to prescription, mannitol particles, sodium dihydrogen citrate, stearic acid obtained by step (2) are added
Magnesium is uniformly mixed, and obtains hybrid particles object；
(4) by hybrid particles object tabletting obtained by step (3)；
(5) packaged form used to step (4) gained tablet is additional for aluminium-plastic bubble plate packing or aluminium-plastic bubble plate packing
The additional aluminium bag packaging of aluminium bag packaging, preferably aluminium-plastic bubble plate packing.
Calcium Dobesilate tablet of the present invention is for preventing and treating diabetic retinopathy.
The present invention using filler and the independent wet granulation of anhydrous sodium sulfite solution, gained particle again with other supplementary materials
Mixed pressuring plate.Compared with prior art, stability significantly improves gained calcium dobesilate.
Specific embodiment
The following are a specific embodiment of the invention, the embodiment described be in order to further describe the present invention, rather than
The limitation present invention.
Comparative example 1
Technical process:
(1) Calcium Dobesilate raw material, mannitol, magnesium stearate is weighed according to recipe quantity to be uniformly mixed.
(2) using mixed powder tabletting above.
(3) gained tablet uses aluminium-plastic bubble plate packing.
Comparative example 2
Technical process:
(1) Calcium Dobesilate raw material, mannitol, anhydrous sodium sulfite, sodium dihydrogen citrate, stearic acid are weighed according to recipe quantity
Magnesium is uniformly mixed.
(2) the above mixed pressuring plate is used.
(3) gained tablet uses aluminium-plastic bubble plate packing.
Comparative example 3
Technical process:
(1) Calcium Dobesilate, mannitol, anhydrous sodium sulfite, sodium dihydrogen citrate, magnesium stearate is weighed according to recipe quantity to mix
It closes uniform.
(2) suitable water is added, prepares softwood, is pelletized using 24 mesh screens.
(3) 50 DEG C are dried to moisture less than 1%, 24 mesh screen whole grain.
(4) magnesium stearate total mix is added.
(5) tabletting.
(6) gained tablet uses aluminium-plastic bubble plate packing.
Comparative example 4
Prescription:
After auxiliary material mannitol is pelletized due to this product, then weigh prescription dosage investment the next step, it is contemplated that mannitol
Particle preparation loss, mannitol particles prepare according to 1500 amounts, weigh 1000 amounts and feed intake.
Mannitol particles prescription:
| Composition | Prescription dosage |
| Mannitol | 264g |
| Purified water | 18.3g |
| In batches | 1500 |
Calcium Dobesilate composition prescription:
Technical process:
(1) mannitol of recipe quantity is weighed, recipe quantity purified water is added, stirring granulation 5min is sieved using 24 mesh steel and is pelletized,
It is dry to moisture less than 1% after, mannitol particles are arrived using 24 mesh steel sieve whole grain, put into the next step.
(2) Calcium Dobesilate, mannitol, anhydrous sodium sulfite, sodium dihydrogen citrate, magnesium stearate are weighed according to prescription
(3) the above auxiliary material is uniformly mixed.
(4) tabletting
(5) gained tablet uses aluminium-plastic bubble plate packing.
Comparative example 5
Marketed tablet:
Common name: calcium dobesilate
English name: Calcium Dobesilate Tablets
Trade name: Doxium
Accredited quotient: OM PHARMA S.A. (OM drugmaker)
Manufacturer: Sanofi Winthrop Industrie (pharmacy of Sino phenanthrene)
Lot number: AY002
Embodiment 1
Mannitol is subjected to pre-treatment in embodiment, is pelletized using the aqueous solution of anhydrous sodium sulfite, obtained
Grain investment the next step, it is contemplated that mannitol particles preparation loss, mannitol particles are prepared according to 1500 amounts, weigh 1000
Piece amount feeds intake.
Mannitol particles prescription:
| Composition | Prescription dosage |
| Mannitol | 264g |
| Purified water | 18.3g |
| Anhydrous sodium sulfite | 1.2g |
| In batches | 1500 |
The anhydrous sodium sulfite and water of recipe quantity are weighed, preparing becomes the anhydrous sodium sulfite aqueous solution that concentration is 6.2%,
It is added in mannitol, stirring granulation 5min is sieved using 24 mesh steel and pelletized, after drying to moisture is less than 1%, sieved using 24 mesh steel
Whole grain puts into the next step to get mannitol particles are arrived.
Calcium Dobesilate tablet recipe:
Technical process:
(1) Calcium Dobesilate, mannitol particles, sodium dihydrogen citrate, magnesium stearate are weighed according to prescription
(2) the above auxiliary material is uniformly mixed.
(3) tabletting
(4) gained tablet uses aluminium-plastic bubble plate packing.
Embodiment 2
Mannitol particles prescription:
| Composition | Prescription dosage |
| Mannitol | 264g |
| Purified water | 18.3g |
| Anhydrous sodium sulfite | 1.8g |
| In batches | 1500 |
The anhydrous sodium sulfite and water of recipe quantity are weighed, preparing becomes the anhydrous sodium sulfite aqueous solution that concentration is 9.0%,
It is added in mannitol, stirring granulation 5min is sieved using 24 mesh steel and pelletized, after drying to moisture is less than 1%, sieved using 24 mesh steel
Whole grain puts into the next step to get mannitol particles are arrived.
Calcium Dobesilate tablet recipe:
Technical process:
(1) Calcium Dobesilate, mannitol particles, sodium dihydrogen citrate, magnesium stearate are weighed according to prescription
(2) the above auxiliary material is uniformly mixed.
(3) tabletting
(4) gained tablet uses aluminium-plastic bubble plate packing.
Embodiment 3
Mannitol particles prescription:
| Composition | Prescription dosage |
| Mannitol | 264g |
| Purified water | 18.3g |
| Anhydrous sodium sulfite | 0.6g |
| In batches | 1500 |
The anhydrous sodium sulfite and water of recipe quantity are weighed, preparing becomes the anhydrous sodium sulfite aqueous solution that concentration is 3.1%,
It is added in mannitol, stirring granulation 5min is sieved using 24 mesh steel and pelletized, after drying to moisture is less than 1%, sieved using 24 mesh steel
Whole grain puts into the next step to get mannitol particles are arrived.
Calcium Dobesilate tablet recipe:
Technical process:
(1) Calcium Dobesilate, mannitol particles, sodium dihydrogen citrate, magnesium stearate are weighed according to prescription
(2) the above auxiliary material is uniformly mixed.
(3) tabletting
(4) gained tablet uses aluminium-plastic bubble plate packing.
Embodiment 4
1 gained tablet of embodiment is using the additional aluminium bag packaging of aluminium-plastic bubble plate packing.
Embodiment 5
Using mannitol particles prepared by embodiment 1.
Calcium Dobesilate tablet recipe:
Technical process:
(1) Calcium Dobesilate, mannitol particles, sodium dihydrogen citrate, magnesium stearate are weighed according to prescription.
(2) the above auxiliary material is uniformly mixed.
(3) tabletting
(4) gained tablet is using the additional aluminium bag packaging of aluminium-plastic bubble plate packing.
Embodiment 6
Using mannitol particles prepared by embodiment 1.
Calcium Dobesilate tablet recipe:
Technical process:
(1) Calcium Dobesilate, mannitol particles, sodium dihydrogen citrate, magnesium stearate are weighed according to prescription
(2) the above auxiliary material is uniformly mixed.
(3) tabletting
(4) gained tablet is using the additional aluminium bag packaging of aluminium-plastic bubble plate packing.
Mobility, the compressibility that the present invention mainly investigates the mixed powder in tableting processes to formulation and technology feasibility (can reach
To highest hardness), friability (being measured according to official method).
The stability of prescription is investigated simultaneously: above each prescription is placed on using the additional aluminium bag packaging of aluminium-plastic bubble plate packing
Under acceleration environment: 40 DEG C, RH75%.Character is observed 1,2,3,4,5, June, measures related substance, content etc..In relation to substance and
Content assaying method is as follows:
Related substance, is protected from light operation, and precision weighs this product fine powder in right amount (being approximately equivalent to Calcium Dobesilate 0.1g), sets
In 100ml measuring bottle, add the solution of mobile phase (with phosphorus acid for adjusting pH to 4.0) appropriate, ultrasound keeps Calcium Dobesilate molten in about 2 minutes
Solution, is diluted to scale with the solution of the solution of mobile phase (with phosphorus acid for adjusting pH to 4.0), shakes up, and filters, and filtrate is taken to be used as examination
Product solution.Precision measurement test solution is appropriate, adds water quantitatively to dilute and is made in every 1ml containing about the solution of 1 μ g, molten as compareing
Liquid.Separately take quinhydrones reference substance appropriate, accurately weighed, being dissolved in water and quantifying dilution is made in every 1ml containing about the solution of 1 μ g, makees
For reference substance solution.It tests according to high performance liquid chromatography (four general rules 0512 of Chinese Pharmacopoeia version in 2015), is pacified using wearing
U3000 type efficient liquid phase, is filler with octadecylsilane chemically bonded silica；With 0.2% triethylamine solution, adjusted with phosphoric acid
PH is mobile phase to 6.5- acetonitrile (98:2)；Column temperature is 30 DEG C；Detection wavelength is 220nm；Flow velocity is 1ml/min.Precision measures
10 μ l of system suitability solution under content determination item injects liquid chromatograph, and number of theoretical plate is based on Calcium Dobesilate peak
It calculates and is not less than 1000, Calcium Dobesilate peak and the separating degree at quinhydrones peak should meet regulation.10 μ l of contrast solution is taken to inject liquid phase color
Spectrometer adjusts detection sensitivity, and making the peak height of principal component chromatographic peak is about the 10%~25% of full scale；It is accurate again to measure for examination
Product solution, contrast solution and each 10 μ l of reference substance solution, are injected separately into liquid chromatograph, and record chromatogram to principal component peak retains
4 times of time.In the chromatogram of test solution if any with the consistent chromatographic peak of quinhydrones retention time, by external standard method with peak area
It calculates, 0.1% (internal control: 0.08%) must not be crossed；Other single impurity peak areas are not greater than contrast solution main peak area
(0.1%) (internal control: 0.08%), total impurities must not cross 0.5% (internal control: 0.3%).
Assay is measured according to high performance liquid chromatography (four general rules 0512 of Chinese Pharmacopoeia version in 2015).
Chromatographic condition and system suitability are using peace U3000 type efficient liquid phase is worn, with octadecylsilane bonded silica
Glue is filler；It is mobile phase with phosphorus acid for adjusting pH to 6.5- acetonitrile (98:2) with 0.2% triethylamine solution；Column temperature is 30
℃；Detection wavelength is 300nm；Flow velocity is 1ml/min.It weighs Calcium Dobesilate and quinhydrones reference substance is each appropriate, be dissolved in water simultaneously
Every 1ml is made respectively containing about the mixed solution of 100 μ g and 1 μ g, as system suitability solution in quantitative dilution.Precision measures 10 μ l,
Liquid chromatograph is injected, number of theoretical plate is calculated by Calcium Dobesilate peak is not less than 1000, point at Calcium Dobesilate peak and quinhydrones peak
Regulation should be met from degree.
Measuring method takes this product 10, and accurately weighed, finely ground, precision weighs appropriate (being approximately equivalent to Calcium Dobesilate 0.1g),
It sets in 100ml measuring bottle, adds appropriate amount of water, ultrasound shaking makes main ingredient after completely dissolution in 3 minutes, lets cool to room temperature, be diluted with water to quarter
Degree, shakes up, and filters, and precision measures subsequent filtrate 5ml, sets in 50ml measuring bottle, is diluted with water to scale, shakes up, molten as test sample
Liquid, precision measure 10 μ l and inject liquid chromatograph, record chromatogram；Separately take Calcium Dobesilate reference substance appropriate, it is accurately weighed, add
Water, which dissolves and quantifies dilution, to be made solution of every 1ml containing about 0.1mg and is measured in the same method, by external standard method with calculated by peak area, containing oxybenzene
Sulfoacid calcium (C12H10CaO10S2) should be 95.0%~105.0% (internal control: 96.0%~104.0%) of labelled amount.Oxybenzene sulphur
The content limit that sour calcium tablet is surveyed is 95.0%-105.0%, related substance limit are as follows: quinhydrones must not cross 0.1%, other are single miscellaneous
Matter must not cross 0.1%, and total impurities must not cross 0.3%, and character is without substantially changeing during storage.
It the results are shown in Table 1 and table 2, the results showed that the prescription stability that anhydrous sulfurous acid is not added is poor, accelerates 6 months characters
It is serious to change (see comparative example 1), it is directly added into the prescription of anhydrous sodium sulfite, stability increases, but still serious
Change colour (see comparative example 2), the prescription stability relative contrast example 1 and 2 that all supplementary materials are all pelletized is increased, but it is crisp
Broken degree poor (see comparative example 3), mannitol is individually pelletized with water, and stability and comparative example 1 and 2 are suitable (see comparative example 4), city
It is suitable to comparative example 3 to sell tablet stability, using this patent optimizing prescriptions technique, sees embodiment 1,2,3,4, compressibility is preferable, surely
Qualitative also preferable, best in particular by the additional aluminium bag packaging rear stability of aluminium-plastic bubble plate packing, content and related substance accord with
Standardization.
Embodiment 5 uses 250mg specification, and compressibility and stability are preferable, and 6 mannitol particles materials of embodiment are reduced,
Mobility is declined, and stability is slightly poor with respect to embodiment 5.
Each prescription mobility of table 1, compressibility, friability comparison
2 Acceleration study result of table
* annotate: character variation classification: 0 without significant changes；1 slight jaundice；2 colors are more deep；3 turn to be yellow and with ash
Spot；4 serious gray corrosions；5 serious characters change.
Claims (8)
1. a kind of preparation method of calcium dobesilate, the calcium dobesilate is pressed by active material Calcium Dobesilate, auxiliary
The filler and lubricant of piece and the anhydrous sodium sulfite of guarantee prescription stability and the auxiliary material with stabilization, feature
It is, the filler needs pre-treatment, and the pre-treatment of the filler is that filler and anhydrous sodium sulfite solution are individually wet
Method granulation, gained particle again with other supplementary material mixed pressuring plates.
2. preparation method according to claim 1, which is characterized in that the anhydrous sodium sulfite solution is to contain 1.0%-
20.0% anhydrous sodium sulfite aqueous solution, the anhydrous sodium sulfite solution usage are 5.5%- with respect to filler ratio
9.5%.
3. preparation method according to claim 1, the calcium dobesilate every containing Calcium Dobesilate 500mg or
250mg (according to anhydride meter).
4. preparation method according to claim 1, which is characterized in that the filler is mannitol, lactose or crystallite
Cellulose, the filler loading are 8%-40% with respect to Calcium Dobesilate (according to anhydride meter) ratio.
5. preparation method according to claim 1, which is characterized in that the lubricant is magnesium stearate.
6. preparation method according to claim 1, which is characterized in that the auxiliary material with stabilization is citric acid one
Sodium.
7. preparation method according to claim 1, which is characterized in that the packaged form of the calcium dobesilate uses aluminium
Mould the form of the additional aluminium bag of blister package.
8. according to claim 1 to the preparation method of calcium dobesilate described in 7 any one, it is characterised in that:
(1) it weighs recipe quantity anhydrous sodium sulfite to be added to the water, dissolve；
(2) mannitol of recipe quantity is weighed, anhydrous sodium sulfite solution obtained by step (1) is added, stirring granulation is dry to moisture
Whole grain after less than 1% obtains mannitol particles, puts into the next step；
(3) mannitol particles obtained by Calcium Dobesilate, addition step (2), sodium dihydrogen citrate, magnesium stearate is weighed according to prescription to mix
It closes uniformly, obtains hybrid particles object；
(4) by hybrid particles object tabletting obtained by step (3)；
(5) packaged form used to step (4) gained tablet is aluminium-plastic bubble plate packing or the additional aluminium bag of aluminium-plastic bubble plate packing
The additional aluminium bag packaging of packaging, preferably aluminium-plastic bubble plate packing.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101062011A (en) * | 2006-04-30 | 2007-10-31 | 沈阳市兴齐制药有限责任公司 | Calcium dobesilate injection |
| CN105213343A (en) * | 2015-11-09 | 2016-01-06 | 石家庄市华新药业有限责任公司 | A kind of calcium dobesilate tablet and preparation method thereof |
| CN106727345A (en) * | 2015-11-20 | 2017-05-31 | 江苏正大丰海制药有限公司 | A kind of pharmaceutical composition of montelukast sodium |
-
2017
- 2017-10-27 CN CN201711021880.0A patent/CN109718214B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101062011A (en) * | 2006-04-30 | 2007-10-31 | 沈阳市兴齐制药有限责任公司 | Calcium dobesilate injection |
| CN105213343A (en) * | 2015-11-09 | 2016-01-06 | 石家庄市华新药业有限责任公司 | A kind of calcium dobesilate tablet and preparation method thereof |
| CN106727345A (en) * | 2015-11-20 | 2017-05-31 | 江苏正大丰海制药有限公司 | A kind of pharmaceutical composition of montelukast sodium |
Non-Patent Citations (2)
| Title |
|---|
| 孟胜男: "《药剂学》", 30 September 2011, 上海科学技术出版社 * |
| 无: "doxium 250mg cp", 《无》 * |
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Effective date of registration: 20231227 Address after: No. 63, Kexin Road, Jiangbei New District, Nanjing, Jiangsu 211505 Patentee after: CHANG'AO PHARMACEUTICAL TECHNOLOGY (HOLDINGS) LTD. Address before: 210038 No. 1 Heng Fei Road, Nanjing economic and Technological Development Zone, Jiangsu, China Patentee before: NANJING CHANGAO PHARMACEUTICAL SCIENCE & TECHNOLOGY Co.,Ltd. |