CN1634050A - Novel nimodipine composition - Google Patents
Novel nimodipine composition Download PDFInfo
- Publication number
- CN1634050A CN1634050A CN 200310110369 CN200310110369A CN1634050A CN 1634050 A CN1634050 A CN 1634050A CN 200310110369 CN200310110369 CN 200310110369 CN 200310110369 A CN200310110369 A CN 200310110369A CN 1634050 A CN1634050 A CN 1634050A
- Authority
- CN
- China
- Prior art keywords
- nimodipine
- tween
- peg400
- injection
- white color
- 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
- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 title claims abstract description 89
- 229960000715 nimodipine Drugs 0.000 title claims abstract description 89
- 239000000203 mixture Substances 0.000 title claims abstract description 28
- 239000007924 injection Substances 0.000 claims abstract description 57
- 238000002347 injection Methods 0.000 claims abstract description 57
- 238000004108 freeze drying Methods 0.000 claims abstract description 25
- 238000003756 stirring Methods 0.000 claims description 50
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 35
- 229920000053 polysorbate 80 Polymers 0.000 claims description 35
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 claims description 34
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 claims description 34
- 239000000243 solution Substances 0.000 claims description 25
- 238000010438 heat treatment Methods 0.000 claims description 22
- 238000002360 preparation method Methods 0.000 claims description 13
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 12
- 238000009413 insulation Methods 0.000 claims description 10
- 238000012856 packing Methods 0.000 claims description 8
- 229940079593 drug Drugs 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 16
- 239000008215 water for injection Substances 0.000 abstract description 10
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 abstract 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 abstract 1
- 229940090044 injection Drugs 0.000 description 55
- 238000012360 testing method Methods 0.000 description 42
- 239000007788 liquid Substances 0.000 description 23
- 241000700199 Cavia porcellus Species 0.000 description 14
- 239000000047 product Substances 0.000 description 13
- 241000283973 Oryctolagus cuniculus Species 0.000 description 12
- 210000003743 erythrocyte Anatomy 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- 206010018910 Haemolysis Diseases 0.000 description 9
- 239000003153 chemical reaction reagent Substances 0.000 description 9
- 230000008859 change Effects 0.000 description 8
- 230000008588 hemolysis Effects 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 210000003462 vein Anatomy 0.000 description 8
- 230000037396 body weight Effects 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 206010070834 Sensitisation Diseases 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 230000008313 sensitization Effects 0.000 description 6
- 239000008354 sodium chloride injection Substances 0.000 description 6
- 238000010998 test method Methods 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 5
- 239000000470 constituent Substances 0.000 description 5
- 230000007774 longterm Effects 0.000 description 5
- 239000013558 reference substance Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 230000034994 death Effects 0.000 description 4
- 238000005286 illumination Methods 0.000 description 4
- 239000013642 negative control Substances 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- 239000006228 supernatant Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 206010011224 Cough Diseases 0.000 description 3
- 208000000059 Dyspnea Diseases 0.000 description 3
- 206010013975 Dyspnoeas Diseases 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 230000002490 cerebral effect Effects 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 238000007689 inspection Methods 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 230000035945 sensitivity Effects 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 206010002198 Anaphylactic reaction Diseases 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 108010058846 Ovalbumin Proteins 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 208000001431 Psychomotor Agitation Diseases 0.000 description 2
- 206010038743 Restlessness Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 230000000172 allergic effect Effects 0.000 description 2
- 230000036783 anaphylactic response Effects 0.000 description 2
- 208000003455 anaphylaxis Diseases 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 229940093181 glucose injection Drugs 0.000 description 2
- 230000002949 hemolytic effect Effects 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229940092253 ovalbumin Drugs 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 208000031229 Cardiomyopathies Diseases 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 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 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 208000021908 Myocardial disease Diseases 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000032851 Subarachnoid Hemorrhage Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000004520 agglutination Effects 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008499 blood brain barrier function Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 210000001218 blood-brain barrier Anatomy 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 229920005549 butyl rubber Polymers 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 210000003027 ear inner Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000003118 histopathologic effect Effects 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 208000001286 intracranial vasospasm Diseases 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 230000007654 ischemic lesion Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 206010033675 panniculitis Diseases 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical class [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 210000004304 subcutaneous tissue Anatomy 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000011003 system suitability test Methods 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention relates to a novel nimodipine composition, in particular the freeze-drying pharmaceutical composition for injection, wherein the composition Nimodipine, polyethylene glycol 400, Twain-80, Hydroxypropyl-beta-cyclodextrin, and water for injection.
Description
Technical field:
The present invention relates to a kind of new compositions of antihypertensive drug nimodipine, particularly injection freeze-dried drug injection composition.
Background technology:
Nimodipine is the bihydropyridine type calcium-channel antagonists, is fat-soluble, easily by blood brain barrier, can reach higher concentration in brain.The expansion of cerebral vascular of nimodipine improves effect such as brain blood supply and has obtained certainly and be applied to clinical over nearly 20 years, is mainly used to prevent and treat the acute ischemic cerebrovascular disease disease, and migraine, angina pectoris, myocardial infarction and disease of inner ear are also had good drug effect.
It mainly blocks the calcium channel of central nervous system's inner cell film to nimodipine through the zoopery confirmation, regulate the level of intracellular Ca2+ effectively, make it to keep normal physiological function, particularly outstanding to cerebrovascular effect, can effectively prevent and treat the cerebral tissue ischemic lesions that causes because of the caused cerebral vasospasm of subarachnoid hemorrhage.It can reduce erythrocyte fragility and blood viscosity, anticoagulant, and antithrombotic forms, and selectivity expansion of cerebral vascular under optimal dose influences peripheral blood vessel hardly.
The nimodipine dosage form of listing at present has tablet, little pin, venous transfusion agent.Lyophilized injectable powder is not still gone public at present, and lyophilized injectable powder promptly helps transportation and stores, again than the good stability of injection.Chinese patent: CN02155645 discloses a kind of freeze dried injection prescription that contains nimodipine, contains phospholipid, cyclodextrin and derivant thereof or surfactant in this prescription.This prescription is because its contained material is unfavorable for stability, safety and preparation.
In order to improve stability of drug, safety reduces medical expense convenient the preparation and medication, meets clinical needs, and the inventor has developed a kind of new injection nimodipine prescription.
Summary of the invention:
The invention provides a kind of prescription of new injection nimodipine injection, comprise nimodipine, PEG400, tween 80, HP-, the quantity relative ratio relationship between each component is as follows:
Nimodipine 0.1-20mg
PEG400 0.1-200mg
Tween 80 0.1-200mg
HP-0.1-500mg
Water for injection an amount of (preferred 0.5-10ml)
Nimodipine 0.5-10mg preferably
PEG400 0.1-200mg
Tween 80 0.1-200mg
HP-0.1-500mg
More preferably
Nimodipine 1-8mg
PEG400 0.1-200mg
Tween 80 0.1-200mg
HP-0.1-500mg
Most preferably
Nimodipine 4mg
PEG400 0.1-200mg
Tween 80 0.1-200mg
HP-0.1-500mg
With
Nimodipine 2mg
PEG400 0.1-200mg
Tween 80 0.1-200mg
HP-0.1-500mg
With
Nimodipine 8mg
PEG400 0.1-200mg
Tween 80 0.1-200mg
HP-0.1-500mg
More than prescription is the quantity relative ratio relationship of a preparation unit dose, i.e. the quantity relative ratio relationship of each component of one bottle of freeze drying injection, or the quantity relative ratio relationship of each component of the freeze drying injection of a use amount.When suitability for industrialized production, the amount that this prescription is formed can increase, and as being that unit carries out large-scale production with gram, kilogram, ton, but the constant rate between each component is distributed into unit packaging after the large-scale production, as is distributed into bottle, is above-mentioned quantity relative ratio relationship.
The present invention also comprises the preparation method of the injection nimodipine freeze drying injection of above prescription, and this method may further comprise the steps:
1. nimodipine is joined in the mixture of PEG400 and tween 80, make dissolving;
2. HP-is added in the entry, make dissolving, step solution is 1. added;
3. add proper amount of active carbon;
4. filter packing, lyophilization.
Preferably
1. nimodipine is joined in the mixture of PEG400 and tween 80, heating and stirring make dissolving;
2. HP-is added in the entry, heating and stirring make dissolving, while stirring above-mentioned solution are added, and continue to stir, to room temperature;
3. add proper amount of active carbon, 60 ℃ of insulation 20min also stir.
4. filter, fine straining is measured content, and is canned, lyophilization, promptly.
Prescription of the present invention is formed, because amount mean allocation with adjuvants such as Polyethylene Glycol, tween 80, HP-, bring into play the advantage of each component more fully, formed a series of benefit, the experimental data that the medicine that the preferred prescription of following the application of the invention is made is done illustrates beneficial effect of the present invention.
Injection nimodipine hypersensitive test
1. test objective
Observe the injection nimodipine Cavia porcellus is had or not sensitization, provide test basis for clinical safety uses.
2. test material
2.1 for the reagent thing
The injection nimodipine, specification: 4mg, lot number: 030404, provide by Shangdong Ruiyang Pharmaceutical Co., Ltd.
Ovalbumin, lot number: 980926, the Shanghai biochemical research is produced.
2.2 the animal Cavia porcellus, body weight 250～350g purchases in Shin Wong, Shanghai laboratory animal plant, licence card number: SCXK (Shanghai) 2002-0011.
2.3 instrument BS4000S animal electronic balance, Sartorius company product.
3. test method
Preparation for reagent liquid: get injection nimodipine an amount of (6-8mg), after an amount of 5% glucose injection or the dark dissolving of physiologic dose brine, inject 100ml5% glucose injection or normal saline.
Get 18 of body weight 250～350g healthy guinea pigs, the male and female dual-purpose, be divided into 3 groups at random by body weight, every group 6, i.e. medicine group (supply reagent liquid as sensitization liquid and attack liquid), negative control group (give sodium chloride injection as sensitization liquid and attack liquid), positive controls (giving 0.4% ovalbumin solution makes sensitization liquid and attack liquid).The corresponding sensitization liquid of lumbar injection 0.5ml/ only injects 3 times continuously next day of 3 groups of Cavia porcelluss difference.Behind first time lumbar injection 14 days, every Cavia porcellus was got 3, respectively from the corresponding attack liquid of vena femoralis injection 1ml/ only; Behind first time lumbar injection 21 days, every group of Cavia porcellus got 3 of residues, respectively from the corresponding attack liquid of vena femoralis injection 1ml/ only.The reaction that produces in the 15min behind the observation intravenous injection confession reagent liquid.If any two or more person in hard hair, dyspnea, sneeze, retch or the phenomenon such as cough 3, or one of hello sound, tic, collapse or phenomena of mortality person is arranged, should be judged to the positive.
4. result
Behind the lumbar injection 14 days for the first time, behind vena femoralis injection in the 15min, reactions such as perpendicular hair, dyspnea, sneeze, retch, cough all do not appear in medicine group and negative control group totally 6 Cavia porcelluss, do not have phenomenons such as hello sound, tic, collapse or death yet, and the result is all negative; In 3 Cavia porcelluss of positive controls injection back 1min is restlessness, begins to occur above-mentioned allergic symptom in various degree, and 3 Cavia porcelluss are all dead, and the death time, 3 Cavia porcellus anaphylaxiss were all positive about injection back 5min.
Behind the lumbar injection 21 days for the first time, behind vena femoralis injection in the 15min, reactions such as perpendicular hair, dyspnea, sneeze, retch, cough all do not appear in medicine group and negative control group totally 6 Cavia porcelluss, do not have phenomenons such as hello sound, tic, collapse or death yet, and the result is all negative; In 3 Cavia porcelluss of positive controls injection back 1min is restlessness, begins to occur above-mentioned allergic symptom in various degree, and 3 Cavia porcelluss are all dead, and the death time, 3 Cavia porcellus anaphylaxiss were all positive about injection back 5min.
5. conclusion
The injection nimodipine is not had sensitization to trying Cavia porcellus.
Injection nimodipine hemolytic test
1. test objective
Observe the injection nimodipine man rabbit erythrocyte is had or not haemolysis and cohesion.
2. test material
2.1 for the reagent thing
The injection nimodipine, the injection nimodipine, specification: 4mg, lot number: 030404, provide by Shangdong Ruiyang Pharmaceutical Co., Ltd.
2.2 animal
White rabbit, body weight 2.6kg, male, New Zealand's strain is purchased in warren that herding is planted, academy of agricultural sciences, Shandong Province, quality certification numbering: Shandong kinoplaszm word D20021135.
2.3 instrument
The LDZ5-2 low speed autobalancing centrifuge, Beijing Medical Centrifugal Machine Factory's product;
SHH.21.600 type electronic thermostatic water tank, the comprehensive electrical apparatus factory in Huanghua City.
3. test method
3.1 get for the examination rabbit, an amount of from the rabbit heart puncture blood collecting, put into the triangular flask jolting that fills sterile glass beads, remove and defibrinate, make into defibrinated blood, add the chlorination sodium injection, shake up, centrifugal, remove supernatant, sedimentary erythrocyte reuse sodium chloride injection such as method washing 3 times does not show red to supernatant, and the gained erythrocyte is made into 2% suspension with sodium chloride injection, is for experiment.
3.2 get 7 in test tube, press table 1 proportioning, add 2% red blood cell suspension and sodium chloride injection successively, behind the mixing, place 30min in 37 ℃ of water-baths, 1～No. 5 pipe adds injection nimodipine 0.5ml respectively then, 0.4ml, 0.3ml, 0.2ml, 0.1ml No. 6 pipes are as negative control, No. 7 pipe adds sterilized water 2.5ml, as positive control, each is managed final volume and is 5ml, gently behind the mixing, put in 37 ℃ of water-baths, observe the haemolysis situation respectively at different time.Every 15min observes once during beginning, and every 1h observes once behind the 1h, observes 4h altogether.Be transparent redness as solution, promptly represent haemolysis, as brownish red or rufous flocculent deposit are arranged in the solution, expression has erythroagglutination.If any the red blood cell condensation phenomenon, to answer tube shaken or examine under a microscope, judgement is true cohesion or pseudo agglutination.
4. result of the test
Observe at the appointed time, 1～No. 6 pipe supernatant liquid water white transparency, erythrocyte is sunken to the pipe end gradually, illustrate haemolysis does not take place, No. 7 the pipe supernatant liquid takes on a red color transparent, illustrate haemolysis takes place, above-mentioned each Guan Junwu brownish red or rufous flocculent deposit illustrate no red blood cell condensation phenomenon (the results are shown in Table 1).
Table 1 injection nimodipine hemolytic test
Pipe numbers 1234567
2% red blood cell suspension (ml) 2.5 2.5 2.5 2.5 2.5 2.5 2.5
Sodium chloride injection (ml) 2.0 2.1 2.2 2.3 2.4 2.5 0
For reagent liquid (ml) 0.5 0.4 0.3 0.2 0.1 00
Sterilized water (ml) 000000 2.5
0.25h????????????????-????-????-????-????-????-????+
0.5h?????????????????-????-????-????-????-????-????+
Molten
0.75h????????????????-????-????-????-????-????-????+
Blood
1.0h?????????????????-????-????-????-????-????-????+
Feelings
2.0h?????????????????-????-????-????-????-????-????+
Condition
3.0h?????????????????-????-????-????-????-????-????+
4.0h?????????????????-????-????-????-????-????-????+
Annotate :-haemolysis not; + haemolysis
5. conclusion
Injection nimodipine 4～8mg does not produce haemolysis and cohesion to erythrocyte in 4h.Generally with 0.3ml injection (the 3rd pipe), but the person that do not produce the haemolysis in 2h thinks injection, therefore, but this product injection.
The test of injection nimodipine blood vessel irritation
1. test objective
Observe the irritant reaction of intravenous drip injection nimodipine to the rabbit blood vessel.
2. test material
2.1 be subjected to the reagent thing
The injection nimodipine, the injection nimodipine, specification: 4mg, lot number: 030404, provide by Shangdong Ruiyang Pharmaceutical Co., Ltd.
2.2 animal
White rabbit, body weight 2.0-2.5kg, the male and female dual-purpose, New Zealand's strain is purchased in warren that herding is planted, academy of agricultural sciences, Shandong Province, quality certification numbering: Shandong kinoplaszm word D20021135.
2.3 instrument
Disposable infusion set, specification B-5
20=1 ± 0.1ml, lot number: 20020905, Yanzhou City Easthome medical apparatus and instruments company limited product.
RTZ-10A type pedometer, Wuxi City weighing apparatus factory product.
3. test method
Get 6 in the healthy family of body weight 2.0～2.5g, the male and female dual-purpose, by being divided into two groups at random, every group is only, i.e. medicine group and matched group.Rabbit is placed in the holder, medicine group rabbit left side auricular vein instillation injection nimodipine 5ml/kg, calculate by every kg body weight dosage, be equivalent to be grown up 3 times of each maximum consumption 100ml of 60kg, matched group rabbit left side auricular vein instillation sodium chloride injection 5ml/kg.Drip velocity is 20 (1ml)/min, every morning instils once, for three days on end, observe the auricular vein reaction of a rabbit left side, 24h is with sacrifice of animal after the last administration, take off left ear, draw materials along the auricular vein trend, the position of drawing materials is the entad end distance inserting needle position 1～4cm at inserting needle position, divides 1～2.5cm and 2.5～4cm two-stage nitration to draw materials, and the specimen of getting should include auricular vein, with tissue with 10% formalin fixed, carry out histopathologic examination's (light microscopy checking is also taken pictures for routine paraffin wax section, dyeing).
4. result
Observe after reaching administration during each the instillation, local excitation reactions such as the auricular vein appearance of a medicine group rabbit left side is red, swollen, heat are not seen in perusal, histopathological examination matched group and medication group skin, subcutaneous tissue form are normal, the auricular vein vascular endothelial cell is arranged normal, do not see that level increases the change of arrangement disorder, the change of no mural thrombus and inflammatory cell infiltration in the tube chamber.Tube wall does not have and thickens, and the tube wall surrounding tissue is not seen pathological changes such as degeneration necrosis and inflammation.
5. conclusion
Intravenous drip injection nimodipine is to rabbit auricular vein nonirritant.
Stability study testing data and documents and materials
Supply test agent: the injection nimodipine
Packing:
The 10C glass tube vial seals with butyl rubber plug external pressure plastic-aluminum composite cover
Lot number: 030304,030305,030306,030307,030308,030309
Be the preliminary stability of investigating the injection nimodipine, we have carried out the long term test of accelerated test and six months by a definite date to above batch products.Character, inspection item, content and the related substance of sample have been investigated in the process of the test.
Investigated before the test for character, inspection item, content and the related substance of test agent and with the test back and contrasted.The results are shown in Table 14-1,14-2,14-3, liquid chromatogram is attached.
1. assay method
1.1. instrument and reagent
1.1.1. Tianjin, island LC-10AT pump; The SPD-10A UV-detector.
Chromatographic condition
Chromatographic column: Agilent C
185um 250 * 4.6mm
Mobile phase: methanol: water: ether=75: 25: 9
Detect wavelength: 238nm
Sensitivity: 0.0100AUFS flow velocity: 1.0ml/min column temperature: room temperature
Sample size: 20 μ l
1.1.2 electro-heating standing-temperature cultivator: DH3600A type Tianjin Tai Site Instr Ltd.
1.1.3 lighting box: illumination: 4500lx self-control
1.1.4 clarity detector: YB-2 type Precision Instrument Factory, Tianjin Univ.
1.1.5 accurate pH meter: pHS-25 type Shanghai thunder magnetic instrument plant
1.1.6 reagent: acetonitrile (chromatographically pure), phosphoric acid (analytical pure)
1.1.7 reference substance: nimodipine reference substance
The unit of providing: Nat'l Pharmaceutical ﹠ Biological Products Control Institute
1.2. measure
1.2.1 injection nimodipine content and determination of related substances
1.2.1.1 injection nimodipine assay
Measure according to high performance liquid chromatography (two appendix V of Chinese Pharmacopoeia version in 2000 D).
Chromatographic condition and system suitability test: with the octadecylsilane chemically bonded silica is filler; Mobile phase: methanol: water: ether=75: 25: 9; Detect wavelength: 238nm; Flow velocity: 1.0ml/min; Sensitivity: 0.01AUFS.
With this understanding, theoretical cam curve is not less than 1500 by nimodipine.
Reference substance solution: it is an amount of to get the nimodipine reference substance, is mixed with the solution of 20ug/ml with mobile phase.
Need testing solution: get nimodipine preproduction (about nimodipine 10mg), put the 100ml measuring bottle, shake up, precision is measured 2ml, puts the 10ml measuring bottle, shakes up.
Algoscopy: get each 20ul injecting chromatograph of reference substance solution and need testing solution, the record chromatogram uses external standard method with calculated by peak area content, promptly.
1.2.1.2 determination of related substances
Get this product an amount of (about nimodipine 20mg), the accurate title, decide, and puts the 100ml measuring bottle, and thin up shakes up to scale, as need testing solution; The accurate need testing solution 1ml that draws puts the 100ml measuring bottle, adds mobile phase and is diluted to scale, in contrast liquid.According to chromatographic condition under the assay item, get contrast liquid 20 μ l and inject chromatograph of liquid, regulate instrumental sensitivity, make the main constituent peak heights reach 20% of monitor full scale.Get need testing solution 20 μ l, inject chromatograph of liquid, the record chromatogram is to 2.5 times of main constituent peak retention time.Except that the main constituent peak, the ratio of retention time and main constituent peak retention time is impurity peaks more than or equal to 0.55 peak, and the summation of the peak area of each impurity peaks must not be greater than 1.5% of impurity peaks and main constituent peak area summation.
1.2.2 the clarity of solution, pH
Regulation inspection according to Ministry of Public Health standard " clarity test detailed rules and regulations and criterion " and injection nimodipine quality standard.
2. influence factor's test
2.1. the test method sample places in 60 ℃ the electro-heating standing-temperature cultivator and 4500lx lighting box, respectively 5 days and sampling in 10 days, and the relevant every index of examination.
2.2. result of the test
Influence factor's result of the test sees Table 14-1, and liquid chromatogram is attached.
The result shows: this product was through high temperature (60 ℃) 10 days, and every index there is no significant change.Illumination (illumination is 4500lx) 10 days, related substance slightly increases, but limit requirement up to specification, other indexs are not seen significant change yet.Illustrate that this product is more stable to temperature, slightly responsive to light.
3. accelerated test
3.1. test method
Sample is packed the exsiccator that places saturated nacl aqueous solution together with its listing, and the control relative humidity is 75%, and exsiccator places in 40 ℃ of electrothermostats, respectively at sampling at the 1st, 2,3,6 the end of month, and the relevant every index of examination.
3.2. result of the test
Accelerated test the results are shown in Table 14-2, and liquid chromatogram is attached.
The result shows: this product is under terms of packing, accelerated test was placed after six months under 40 ℃, 75% relative humidity, and the sign percentage composition of injection nimodipine changes not obvious, the limit requirement that related substance is up to specification, character, pH also do not have significant change, are stable.
4. long term test
4.1. test method
Sample places the exsiccator of saturated sodium nitrite solution together with its packing, and the control relative humidity is 60 ± 5%, and exsiccator places in 25 ℃ of electrothermostats, respectively at sampling at the 3rd, 6 the end of month, and the relevant every index of examination.
4.2. result of the test
The long-term test results of injection nimodipine sees Table 14-3, and liquid chromatogram is attached.
The result shows: this product was placed six months at 25 ℃ under terms of packing, and it is stable that every index of examining or check does not have significant change.
5. conclusion
Accelerated test result shows, this product under terms of packing, under 40 ℃ and 75% relative humidity acceleration environment, place six months after, the injection nimodipine indicates percentage composition and changes not obvious, the limit requirement that related substance is up to specification, character does not have significant change, is stable; Six batch sample long term tests were observed after six months, and every index of being examined or check has no significant change, and is stable.Comprehensive The above results, the injection nimodipine is under the listing terms of packing, and quality is stable.
Table 14-1.030304 criticizes the preproduction influence factor and tests the investigation result
| Project | Time (my god) | Character | PH value | Clarity | Content (%) | Related substance (%) |
| Initially | ????0 | The loose block of off-white color | 6.01 | Up to specification | 98.96 | ????0.50 |
| Illumination | ????5 | The loose block of off-white color | 6.04 | Up to specification | 98.53 | ????0.78 |
| ????10 | The loose block of off-white color | 6.02 | Up to specification | 98.29 | ????0.82 | |
| ????60℃ | ????5 | The loose block of off-white color | 6.00 | Up to specification | 98.67 | ????0.62 |
| ????10 | The loose block of off-white color | 6.03 | Up to specification | 98.34 | ????0.67 |
Six batches of preproduction accelerated tests of table 14-2. are investigated the result
| Lot number | Time (moon) | Character | PH value | Clarity | Content (%) | Related substance (%) |
| ??030304 | ??0 | The loose block of off-white color | 6.01 | Up to specification | 98.96 | 0.50 |
| ????1 | The loose block of off-white color | 6.06 | Up to specification | 98.12 | ????0.38 | |
| ????2 | The loose block of off-white color | 6.11 | Up to specification | 99.01 | ????0.62 | |
| ????3 | The loose block of off-white color | 6.07 | Up to specification | 98.17 | ????0.70 | |
| ????6 | The loose block of off-white color | 6.02 | Up to specification | 99.60 | ????0.74 | |
| ??030305 | ????0 | The loose block of off-white color | 5.95 | Up to specification | 99.71 | ????0.24 |
| ????1 | The loose block of off-white color | 5.92 | Up to specification | 99.33 | ????0.38 | |
| ????2 | The loose block of off-white color | 5.97 | Up to specification | 100.19 | ????0.62 | |
| ????3 | The loose block of off-white color | 6.00 | Up to specification | 99.72 | ????0.76 | |
| ????6 | The loose block of off-white color | 6.03 | Up to specification | 99.11 | ????0.73 | |
| ??030306 | ????0 | The loose block of off-white color | 6.11 | Up to specification | 100.00 | ????0.31 |
| ????1 | The loose block of off-white color | 6.15 | Up to specification | 100.39 | ????0.39 | |
| ????2 | The loose block of off-white color | 6.08 | Up to specification | 99.06 | ????0.61 | |
| ????3 | The loose block of off-white color | 6.02 | Up to specification | 100.44 | ????0.60 | |
| ????6 | The loose block of off-white color | 6.09 | Up to specification | 100.86 | ????0.72 | |
| ??030307 | ????0 | The loose block of off-white color | 5.91 | Up to specification | 99.42 | ????0.29 |
| ????1 | The loose block of off-white color | 6.01 | Up to specification | 100.13 | ????0.37 | |
| ????2 | The loose block of off-white color | 6.04 | Up to specification | 98.08 | ????0.64 | |
| ????3 | The loose block of off-white color | 5.99 | Up to specification | 98.69 | ????0.65 | |
| ????6 | The loose block of off-white color | 5.91 | Up to specification | 98.77 | ????0.77 | |
| ??030308 | ????0 | The loose block of off-white color | 6.25 | Up to specification | 99.64 | ????0.36 |
| ????1 | The loose block of off-white color | 6.23 | Up to specification | 100.18 | ????0.34 | |
| ????2 | The loose block of off-white color | 6.23 | Up to specification | 100.70 | ????0.63 | |
| ????3 | The loose block of off-white color | 6.26 | Up to specification | 100.65 | ????0.56 | |
| ????6 | The loose block of off-white color | 6.25 | Up to specification | 100.90 | ????0.78 | |
| ??030309 | ????0 | The loose block of off-white color | 6.17 | Up to specification | 100.62 | ????0.44 |
| ????1 | The loose block of off-white color | 6.19 | Up to specification | 100.03 | ????0.41 | |
| ????2 | The loose block of off-white color | 6.17 | Up to specification | 101.18 | ????0.74 |
| ????3 | The loose block of off-white color | 6.20 | Up to specification | 101.86 | ????0.65 | |
| ????6 | The loose block of off-white color | 6.20 | Up to specification | 101.17 | ????0.78 |
Six batches of preproduction long term tests of table 14-3. are investigated the result
| Lot number | Time (moon) | Character | PH value | Clarity | Content (%) | Related substance (%) |
| ?030304 | ????0 | The loose block of off-white color | 6.01 | Up to specification | ????98.96 | ????0.50 |
| ????3 | The loose block of off-white color | 6.05 | Up to specification | ????99.47 | ????0.82 | |
| ????6 | The loose block of off-white color | 6.01 | Up to specification | ????99.67 | ????0.55 | |
| ?030305 | ????0 | The loose block of off-white color | 5.95 | Up to specification | ????99.71 | ????0.24 |
| ????3 | The loose block of off-white color | 5.95 | Up to specification | ????99.84 | ????0.56 | |
| ????6 | The loose block of off-white color | 5.97 | Up to specification | ????99.45 | ????0.67 | |
| ?030306 | ????0 | The loose block of off-white color | 6.11 | Up to specification | ????100.00 | ????0.31 |
| ????3 | The loose block of off-white color | 6.15 | Up to specification | ????100.53 | ????0.62 | |
| ????6 | The loose block of off-white color | 6.15 | Up to specification | ????100.05 | ????0.58 | |
| ?030307 | ????0 | The loose block of off-white color | 5.91 | Up to specification | ????99.42 | ????0.29 |
| ????3 | The loose block of off-white color | 5.99 | Up to specification | ????99.02 | ????0.61 | |
| ????6 | The loose block of off-white color | 5.95 | Up to specification | ????98.92 | ????0.61 | |
| ?030308 | ????0 | The loose block of off-white color | 6.25 | Up to specification | ????99.64 | ????0.36 |
| ????3 | The loose block of off-white color | 6.25 | Up to specification | ????100.79 | ????0.57 | |
| ????6 | The loose block of off-white color | 6.26 | Up to specification | ????100.89 | ????0.64 | |
| ?030309 | ????0 | The loose block of off-white color | 6.17 | Up to specification | ????100.62 | ????0.44 |
| ????3 | The loose block of off-white color | 6.19 | Up to specification | ????101.49 | ????0.56 | |
| ????6 | The loose block of off-white color | 6.18 | Up to specification | ????101.46 | ????0.63 |
The specific embodiment:
Further specify the present invention by the following examples.
Embodiment 1
Nimodipine freeze-drying powder pin
Nimodipine 20g
PEG400 200g
Tween 80 200g
HP-500g
Water for injection is an amount of
1. the nimodipine with recipe quantity joins in the mixture of PEG400 and tween 80, and heating and stirring make dissolving;
2. HP-is added in the entry, heating and stirring make dissolving, while stirring above-mentioned solution are added, and continue to stir, to room temperature;
3. add proper amount of active carbon, 60 ℃ of insulation 20min also stir.
4. filter, fine straining is measured content, 1000 bottles of canned one-tenth, and lyophilization, promptly.
Embodiment 2
Nimodipine freeze-drying powder pin
Nimodipine 10g
PEG400 100g
Tween 80 100g
HP-250g
Water for injection is an amount of
1. the nimodipine with recipe quantity joins in the mixture of PEG400 and tween 80, and heating and stirring make dissolving;
2. HP-is added in the entry, heating and stirring make dissolving, while stirring above-mentioned solution are added, and continue to stir, to room temperature;
3. add proper amount of active carbon, 60 ℃ of insulation 20min also stir.
4. filter, fine straining is measured content, 1000 bottles of canned one-tenth, and lyophilization, promptly.
Embodiment 3
Nimodipine freeze-drying powder pin
Nimodipine 5g
PEG400 200g
Tween 80 200g
HP-500g
Water for injection is an amount of
1. the nimodipine with recipe quantity joins in the mixture of PEG400 and tween 80, and heating and stirring make dissolving;
2. HP-is added in the entry, heating and stirring make dissolving, while stirring above-mentioned solution are added, and continue to stir, to room temperature;
3. add proper amount of active carbon, 60 ℃ of insulation 20min also stir.
4. filter, fine straining is measured content, 1000 bottles of canned one-tenth, and lyophilization, promptly.
Embodiment 4
Nimodipine freeze-drying powder pin
Nimodipine 2.5g
PEG400 100g
Tween 80 100g
HP-250g
Water for injection is an amount of
1. the nimodipine with recipe quantity joins in the mixture of PEG400 and tween 80, and heating and stirring make dissolving;
2. HP-is added in the entry, heating and stirring make dissolving, while stirring above-mentioned solution are added, and continue to stir, to room temperature;
3. add proper amount of active carbon, 60 ℃ of insulation 20min also stir.
4. filter, fine straining is measured content, 1000 bottles of canned one-tenth, and lyophilization, promptly.
Embodiment 5
Nimodipine freeze-drying powder pin
Nimodipine 4g
PEG400 50g
Tween 80 50g
HP-100g
Water for injection is an amount of
1. the nimodipine with recipe quantity joins in the mixture of PEG400 and tween 80, and heating and stirring make dissolving;
2. HP-is added in the entry, heating and stirring make dissolving, while stirring above-mentioned solution are added, and continue to stir, to room temperature;
3. add proper amount of active carbon, 60 ℃ of insulation 20min also stir.
4. filter, fine straining is measured content, 1000 bottles of canned one-tenth, and lyophilization, promptly.
Embodiment 6
Nimodipine freeze-drying powder pin
Nimodipine 8g
PEG400 200g
Tween 80 200g
HP-500g
Water for injection is an amount of
1. the nimodipine with recipe quantity joins in the mixture of PEG400 and tween 80, and heating and stirring make dissolving;
2. HP-is added in the entry, heating and stirring make dissolving, while stirring above-mentioned solution are added, and continue to stir, to room temperature;
3. add proper amount of active carbon, 60 ℃ of insulation 20min also stir.
4. filter, fine straining is measured content, 1000 bottles of canned one-tenth, and lyophilization, promptly.
Embodiment 7
Nimodipine freeze-drying powder pin
Nimodipine 2g
PEG400 200g
Tween 80 200g
HP-500g
Water for injection is an amount of
1. the nimodipine with recipe quantity joins in the mixture of PEG400 and tween 80, and heating and stirring make dissolving;
2. HP-is added in the entry, heating and stirring make dissolving, while stirring above-mentioned solution are added, and continue to stir, to room temperature;
3. add proper amount of active carbon, 60 ℃ of insulation 20min also stir.
4. filter, fine straining is measured content, 1000 bottles of canned one-tenth, and lyophilization, promptly.
Embodiment 8
Nimodipine freeze-drying powder pin
Nimodipine 4g
PEG400 200g
Tween 80 200g
HP-500g
Water for injection is an amount of
1. the nimodipine with recipe quantity joins in the mixture of PEG400 and tween 80, and heating and stirring make dissolving;
2. HP-is added in the entry, heating and stirring make dissolving, while stirring above-mentioned solution are added, and continue to stir, to room temperature;
3. add proper amount of active carbon, 60 ℃ of insulation 20min also stir.
4. filter, fine straining is measured content, 1000 bottles of canned one-tenth, and lyophilization, promptly.
Claims (8)
1. a Nimodipine freeze-drying drug injection compositions comprises nimodipine, PEG400, and tween 80, HP-is characterized in that, the quantity relative ratio relationship of each component of preparation unit dose is as follows:
Nimodipine 0.1-20mg
PEG400 0.1-200mg
Tween 80 0.1-200mg
HP-0.1-500mg
2. the compositions of claim 1, the quantity relative ratio relationship of one of them each component of preparation unit dose is as follows:
Nimodipine 0.5-10mg
PEG400 0.1-200mg
Tween 80 0.1-200mg
HP-0.1-500mg
3. the compositions of claim 1, the quantity relative ratio relationship of one of them each component of preparation unit dose is as follows:
Nimodipine 1-8mg
PEG400 0.1-200mg
Tween 80 0.1-200mg
HP-0.1-500mg
4. the compositions of claim 1, the quantity relative ratio relationship of one of them each component of preparation unit dose is as follows:
Nimodipine 4mg
PEG400 0.1-200mg
Tween 80 0.1-200mg
HP-0.1-500mg
5. the compositions of claim 1, the quantity relative ratio relationship of one of them each component of preparation unit dose is as follows:
Nimodipine 2mg
PEG400 0.1-200mg
Tween 80 0.1-200mg
HP-0.1-500mg
6. the compositions of claim 1, the quantity relative ratio relationship of one of them each component of preparation unit dose is as follows:
Nimodipine 8mg
PEG400 0.1-200mg
Tween 80 0.1-200mg
HP-0.1-500mg
7. the preparation of compositions method of claim 1 is characterized in that, may further comprise the steps:
1. nimodipine is joined in the mixture of PEG400 and tween 80, make dissolving;
2. HP-is added in the entry, make dissolving, step solution is 1. added;
3. add proper amount of active carbon;
4. filter packing, lyophilization.
8. the preparation of compositions method of claim 5 is characterized in that, may further comprise the steps:
1. nimodipine is joined in the mixture of PEG400 and tween 80, heating and stirring make dissolving;
2. HP-is added in the entry, heating and stirring make dissolving, while stirring above-mentioned solution are added, and continue to stir, to room temperature;
3. add proper amount of active carbon, 60 ℃ of insulation 20min also stir;
4. filter, fine straining is measured content, and is canned, lyophilization.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200310110369XA CN100393315C (en) | 2003-12-31 | 2003-12-31 | Novel nimodipine composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB200310110369XA CN100393315C (en) | 2003-12-31 | 2003-12-31 | Novel nimodipine composition |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1634050A true CN1634050A (en) | 2005-07-06 |
| CN100393315C CN100393315C (en) | 2008-06-11 |
Family
ID=34843217
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB200310110369XA Expired - Lifetime CN100393315C (en) | 2003-12-31 | 2003-12-31 | Novel nimodipine composition |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100393315C (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105497909A (en) * | 2014-09-25 | 2016-04-20 | 蚌埠丰原涂山制药有限公司 | Composition containing clevidipine butyrate and hydroxypropyl-beta-cyclodextrin |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1165305C (en) * | 2002-12-13 | 2004-09-08 | 北京东方天翔医药技术开发有限公司 | Lyophilized composition of nimodipine |
-
2003
- 2003-12-31 CN CNB200310110369XA patent/CN100393315C/en not_active Expired - Lifetime
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105497909A (en) * | 2014-09-25 | 2016-04-20 | 蚌埠丰原涂山制药有限公司 | Composition containing clevidipine butyrate and hydroxypropyl-beta-cyclodextrin |
Also Published As
| Publication number | Publication date |
|---|---|
| CN100393315C (en) | 2008-06-11 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1109049C (en) | Novel cyclodextrin-derivatives and method for the preparation thereof | |
| CN1185253C (en) | Neoglycoproteins | |
| CN1800221A (en) | Hydroxypropyl- sulfobutyl-beta- cyclodextrin and its preparation method, analytical method and pharmaceutical uses | |
| CN1174557A (en) | Keratan sulfate oligosaccharide fraction and drug containing the same | |
| CN87107220A (en) | The mensuration of cell growth rate | |
| CN1685236A (en) | N-11 truncated amyloid-beta monoclonal antibodies, compositions, methods and uses | |
| CN1018640B (en) | Process for the preparation of compounds for the induction of in vivo and in vitro production of cytokines | |
| CN1505519A (en) | Amphotericin B aqueous composition | |
| CN1742748A (en) | Methy cobalamine dispersion tablet and preparing method | |
| CN1344158A (en) | Gardos channel antagonists | |
| CN100344647C (en) | Marking method and selective adsorption method for phosphorylating peptide, coordination compound used for the same method and producing method for the same coordination compound | |
| CN1172952C (en) | Mannosan peptide and its prepn and use | |
| CN1918143A (en) | Linker compound, ligand complex and process for producing them | |
| CN1489461A (en) | Triglyceride depressant composition | |
| CN1634050A (en) | Novel nimodipine composition | |
| CN100341492C (en) | Ginseng-astragalus blood-sugar lowering soft capsule, and its preparing and detecting method | |
| CN1895263A (en) | Use of taurine in preparation of injection containing puerarin | |
| CN1752107A (en) | Preparation method of anti apoA1, apoB antibody and reagent box used for detecting apoAI, apoB | |
| CN1615296A (en) | Carboxamidine derivatives and their use in the treatment of vascular diseases | |
| CN1422616A (en) | Use of hydroxy saflor yellow pigment A in preparing medicine for treating and preventing cardiovascular and cerebrovascular disease | |
| CN1241577C (en) | Medicine use of cyclodextrin derivs. and medicine composition thereof | |
| CN1792367A (en) | Method for controlling quality of injection for treating tumor | |
| CN1194678C (en) | Tiopronin freeze-dried powder injection | |
| CN101058567A (en) | Novel pharmacology acceptable salt for cinepazide | |
| CN1251677C (en) | Anti-cancer assistant medicine contg. 20(S)-protopanaxadiol as effective component, and its application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C56 | Change in the name or address of the patentee |
Owner name: RUIYANG PHARMACY CO., LTD. Free format text: FORMER NAME OR ADDRESS: SHANGDONG RUIYANG PHARMACEUTICAL CO., LTD. |
|
| CP03 | Change of name, title or address |
Address after: No. 6 Erlang mountain road, Yiyuan County, Shandong, Zibo Patentee after: REYOUNG PHARMACEUTICAL Co.,Ltd. Address before: No. 6 Erlang mountain road, Yiyuan County, Shandong, Zibo Patentee before: SHANDONG REYOUNG PHARMACEUTICA |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Novel nimodipine composition Effective date of registration: 20161027 Granted publication date: 20080611 Pledgee: Agricultural Bank of China Limited by Share Ltd. Yiyuan county subbranch Pledgor: REYOUNG PHARMACEUTICAL Co.,Ltd. Registration number: 2016990000912 |
|
| PLDC | Enforcement, change and cancellation of contracts on pledge of patent right or utility model | ||
| CP01 | Change in the name or title of a patent holder |
Address after: 256100 No. 6 Erlang Road, Yiyuan County, Shandong, Zibo Patentee after: Ruiyang Pharmaceutical Co.,Ltd. Address before: 256100 No. 6 Erlang Road, Yiyuan County, Shandong, Zibo Patentee before: REYOUNG PHARMACEUTICAL Co.,Ltd. |
|
| CP01 | Change in the name or title of a patent holder | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20201228 Granted publication date: 20080611 Pledgee: Agricultural Bank of China Limited by Share Ltd. Yiyuan county subbranch Pledgor: REYOUNG PHARMACEUTICAL Co.,Ltd. Registration number: 2016990000912 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| CX01 | Expiry of patent term |
Granted publication date: 20080611 |
|
| CX01 | Expiry of patent term |