CN1698622A - "Gandejian" injection without hemolysis and its composition - Google Patents
"Gandejian" injection without hemolysis and its composition Download PDFInfo
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- CN1698622A CN1698622A CN 200510046281 CN200510046281A CN1698622A CN 1698622 A CN1698622 A CN 1698622A CN 200510046281 CN200510046281 CN 200510046281 CN 200510046281 A CN200510046281 A CN 200510046281A CN 1698622 A CN1698622 A CN 1698622A
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- injection
- essentiale
- glucose
- gandejian
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- 238000002347 injection Methods 0.000 title claims abstract description 89
- 239000007924 injection Substances 0.000 title claims abstract description 89
- 206010018910 Haemolysis Diseases 0.000 title claims abstract description 46
- 230000008588 hemolysis Effects 0.000 title claims abstract description 46
- 239000000203 mixture Substances 0.000 title claims abstract description 19
- 229940090044 injection Drugs 0.000 claims abstract description 85
- 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 claims abstract description 45
- 229940093181 glucose injection Drugs 0.000 claims abstract description 31
- 150000005846 sugar alcohols Polymers 0.000 claims abstract description 7
- 238000001802 infusion Methods 0.000 claims abstract 3
- 150000003904 phospholipids Chemical class 0.000 claims description 22
- 239000008103 glucose Substances 0.000 claims description 9
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 8
- 229930195725 Mannitol Natural products 0.000 claims description 8
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 8
- 239000000594 mannitol Substances 0.000 claims description 8
- 235000010355 mannitol Nutrition 0.000 claims description 8
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 8
- 239000000811 xylitol Substances 0.000 claims description 8
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 8
- 235000010447 xylitol Nutrition 0.000 claims description 8
- 229960002675 xylitol Drugs 0.000 claims description 8
- 239000000843 powder Substances 0.000 claims description 7
- 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 4
- 239000008101 lactose Substances 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 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 235000001727 glucose Nutrition 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 235000010356 sorbitol Nutrition 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 229920005862 polyol Polymers 0.000 claims 4
- 150000003077 polyols Chemical class 0.000 claims 4
- 239000008176 lyophilized powder Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 5
- 239000012530 fluid Substances 0.000 abstract 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 45
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 42
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 36
- 238000012360 testing method Methods 0.000 description 28
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 239000008215 water for injection Substances 0.000 description 27
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 25
- 239000000243 solution Substances 0.000 description 25
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 21
- 239000008347 soybean phospholipid Substances 0.000 description 21
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical class C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 19
- 238000003756 stirring Methods 0.000 description 19
- 229960003964 deoxycholic acid Drugs 0.000 description 18
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 230000002949 hemolytic effect Effects 0.000 description 15
- 235000019445 benzyl alcohol Nutrition 0.000 description 14
- 238000002360 preparation method Methods 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 230000004520 agglutination Effects 0.000 description 10
- 239000012528 membrane Substances 0.000 description 10
- 229910052757 nitrogen Inorganic materials 0.000 description 10
- 239000011550 stock solution Substances 0.000 description 10
- 238000002156 mixing Methods 0.000 description 9
- 238000012856 packing Methods 0.000 description 9
- 238000005303 weighing Methods 0.000 description 9
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 8
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 7
- 239000004380 Cholic acid Substances 0.000 description 7
- 229960002471 cholic acid Drugs 0.000 description 7
- 235000019416 cholic acid Nutrition 0.000 description 7
- 210000003743 erythrocyte Anatomy 0.000 description 7
- 239000000463 material Substances 0.000 description 6
- 238000004321 preservation Methods 0.000 description 6
- 101100118976 Mus musculus Clint1 gene Proteins 0.000 description 5
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 description 4
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 description 4
- 229930003471 Vitamin B2 Natural products 0.000 description 4
- 239000003708 ampul Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 230000003203 everyday effect Effects 0.000 description 4
- 238000010253 intravenous injection Methods 0.000 description 4
- 229960002477 riboflavin Drugs 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 235000002639 sodium chloride Nutrition 0.000 description 4
- 239000011716 vitamin B2 Substances 0.000 description 4
- 235000019164 vitamin B2 Nutrition 0.000 description 4
- 239000011579 vitamin B4 Substances 0.000 description 4
- 239000006285 cell suspension Substances 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 208000006454 hepatitis Diseases 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 240000007711 Peperomia pellucida Species 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 125000001095 phosphatidyl group Chemical group 0.000 description 2
- 230000008929 regeneration Effects 0.000 description 2
- 238000011069 regeneration method Methods 0.000 description 2
- 235000008979 vitamin B4 Nutrition 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- 235000017166 Bambusa arundinacea Nutrition 0.000 description 1
- 235000017491 Bambusa tulda Nutrition 0.000 description 1
- 206010008635 Cholestasis Diseases 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 206010010075 Coma hepatic Diseases 0.000 description 1
- 229920002527 Glycogen Polymers 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 244000082204 Phyllostachys viridis Species 0.000 description 1
- 235000015334 Phyllostachys viridis Nutrition 0.000 description 1
- 208000005374 Poisoning Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000011425 bamboo Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 231100000359 cholestasis Toxicity 0.000 description 1
- 230000007870 cholestasis Effects 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 229940096919 glycogen Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 201000001059 hepatic coma Diseases 0.000 description 1
- 208000007386 hepatic encephalopathy Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 229960002591 hydroxyproline Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
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- 238000010998 test method Methods 0.000 description 1
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- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to an essentiale injection without hemolysis effect and its composition, which comprises essentiale and polyhydric alcohols. It may also comprises the currently available essentiale injection and 50% glucose injection or 25% glucose injection, during the use, the essentiale injection and the glucose injection are mixed by the ratio of 1:1-1:3. The injection includes small injection, fluid infusion and freeze dried injection.
Description
Technical field:
The present invention relates to the pharmaceutical technology field, exactly is a kind of " essentiale " injection and compositions thereof that does not produce haemolysis.
Technical background:
" essentiale " has another name called " Essentiale/Essentiale Forte ", " Essentiale N/Essentiale Forte N ", and formal product essential phospholipid injection (Essentiale Phospholipids Injection) by name is " An Wante medicine Aventis Pharma " product.Contain essential phospholipid (Phospholipide ausSojabohnen enthaltend 93% (3-sn Phosphatidyl)-cholin (Extraktionsmittel:Ethanol 96%V/V)) 250mg among existing " essentiale " prescription 5ml, benzyl alcohol (as protective agent) 45mg.The project of carrying out assay in the quality standard also is these two.The prescription of external another commodity Lipostabil N i.v. injection by name indicates identical with " essentiale ": Amp.5ml:5ml Amp.enth.:250mg Phospholipideaus Sojabohnen enth.93% (3-sn Phosphatidyl) cholin, Extraktionsm.:Ethanol96%V/V, Benzylalkohol (zur Konservierung) 45mg promptly contains 250mg soybean phospholipid (containing the 93%3-sn-phosphatidylcholine) and benzyl alcohol 45mg among the 5ml.
The pharmacodynamics of " essentiale " comprising: essential phospholipid can be protected sinusoidal endothelial cell regulating liver-QI cell biological film to avoid damage, repair membrane damage, promote film regeneration; Reduce hepatocellular fatty infiltration; Reduce inflammatory reaction; Promote liver cell regeneration by increasing RNA and proteinic synthesizing with glycogen content; By suppressing collagenation, reducing collagen/DNA ratio and the formation of liver hydroxyproline generation reduction connective tissue.Indication: acute or chronic hepatitis, liver cirrhosis, hepatic coma, liver poisoning disease, the liver fat degeneration, the cholestasis that cause by a variety of causes.Dosage and administration: usually dosage is 1-2 ampoule every day, serious case then every day injectable 2-4 ampoule, solution can be done once slowly to inject simultaneously within two ampoules.
Summary of the invention:
Because essential phospholipid can not dissolve in water, only can disperse, increase dissolving so need to add deoxycholic acid class surfactants such as (or cholic acid), the preparation solution type injection agent.And deoxycholic acid (or cholic acid) salts substances has hemolytic.We consult external Essentiale
N, i.v. document also contains (Essentiale such as deoxycholic acid except essential phospholipid (250mg Phospholipide aus Sojabohnen enthaltend 93% (3-snPhosphatidyl)-cholin (Extraktionsmittel:Ethanol 96%V/V)), benzyl alcohol in its prescription
N, i.v.Injektionsl sung:1 Ampulle zu 5ml enth lt:; Benzylalkohol 45mg, Desolychols ure), the using method of existing commercially available injection is: " adult and teenager general every day of slow quiet notes 1-2 ampoule, seriously case is injected the 2-4 ampoule every day.Hepatitis gravis patient, the increase dosage of can following the doctor's advice.", " if will dilute, suggestion with patient's self the blood ratio by dilution in 1: 1 " all suggestion employing patient's self blood carries out administration in the ratio of diluting at 1: 1.Consider in " essentiale " prescription to have added deoxycholic acid (or cholic acid), and deoxycholic acid (or cholic acid) can produce haemolysis down at high pH (under the pH of existing commercially available prod), we carry out the test of this respect.By our research, original prescription has been carried out bigger improvement.Obtained effect preferably.
Hemolytic test
The experimental condition room temperature: 22 ℃, relative humidity: 55%.
Test method and result
The rabbit ear edge vein exploitating blood, with bamboo let stir defibrinate after, with normal saline washing back centrifugal (2000rpm), remove supernatant, again with the normal saline cyclic washing for several times (all centrifugal supernatant of abandoning) until the supernatant redfree, it is standby to be made into 2% red blood cell suspension with normal saline by volume then.Get 7 in test tube, press shown in the table 1, each pipe adds the medicinal liquid of different volumes and the red blood cell suspension of equal volume respectively, wherein the 6th manages not dosing, be 5% glucose injection (or 10% glucose injection) blank, the 7th pipe adding distil water is done complete haemolysis contrast (positive control pipe).After each pipe shakes up gently, put in 37 ℃ of water-baths temperature and incubated 4 hours, observe whether each pipe has haemolysis and erythrocyte aggregation phenomenon in 0.25 hour to 4.0 hours, (list of references: Qi Chen edits press the judgement of table 2 standard.The herbal pharmacology research methodology, the People's Health Publisher.1993：168～169)。
The results are shown in Table 3.
The external hemolytic test application of sample of table 1. table
| Application of sample volume (ml) | Test tube number | ||||||
| ??1 | ??2 | ??3 | ??4 | ??5 | ??6 | ??7 | |
| 2% red blood cell suspension | ??2.5 | ??2.5 | ??2.5 | ??2.5 | ??2.5 | ??2.5 | ??2.5 |
| 5% glucose injection | ??2.0 | ??2.1 | ??2.2 | ??2.3 | ??2.4 | ??2.5 | ??0 |
| Distilled water | ??0 | ??0 | ??0 | ??0 | ??0 | ??0 | ??2.5 |
| Need testing solution | ??0.5 | ??0.4 | ??0.3 | ??0.2 | ??0.1 | ??0 | ??0 |
Table 2. haemolysis result judges
| Degree | Sign | Phenomenon |
| No haemolysis | - | Erythrocyte all sinks, upper strata liquid water white transparency. |
| Part haemolysis | ± | Clear and bright redness of solution or brownish red,, there is a small amount of erythrocyte at the pipe end. |
| Full haemolysis coagulation | + | The clear and bright redness of solution, the pipe end, is acellular residual.The erythrocyte aggregation in bulk does not disperse after shaking up. |
The external hemolytic test result of table 3.
| Time (hour) | Test tube number | ||||||
| ??1 | ??2 | ??3 | ??4 | ??5 | ??6 | ??7 | |
| ??0.25 | ??+ | ??+ | ??+ | ??+ | ??- | ??- | ??+ |
| ??0.5 | ??+ | ??+ | ??+ | ??+ | - | - | ??+ |
| ??0.75 | ??+ | ??+ | ??+ | ??+ | - | - | ??+ |
| ??1.0 | ??+ | ??+ | ??+ | ??+ | - | - | ??+ |
| ??2.0 | ??+ | ??+ | ??+ | ??+ | - | - | ??+ |
| ??3.0 | ??+ | ??+ | ??+ | ??+ | - | - | ??+ |
| ??4.0 | ??+ | ??+ | ??+ | ??+ | - | - | ??+ |
As shown in Table 3,5% each pipe of glucose injection group did not all have haemolysis in 0.25～4.0 hour, do not have agglutination yet; 1,2,3, No. 4 the pipe and the distilled water group in each time point complete hemolysis, produce red clear solution; No. 5 pipe did not all have haemolysis in 0.25～4.0 hour, did not have agglutination yet, and promptly under the condition of low concentration, " essentiale " do not produce haemolysis.
Given this, we study preventing " essentiale " haemolysis, have carried out following test respectively.
1, gained solution after " essentiale " injection stock solution and 5% glucose injection diluted by 1: 10.
2, gained solution after " essentiale " injection stock solution and 5% glucose injection diluted by 1: 20.
3, gained solution after " essentiale " injection stock solution and 10% glucose injection diluted by 1: 10.
4, gained solution after " essentiale " injection stock solution and 10% glucose injection diluted by 1: 20.
The results are shown in Table 4～table 7.
Table 4. " essentiale " injection stock solution: 5% glucose injection=1: 10 external hemolytic test result
| Time (hour) | Test tube number | ||||||
| ??1 | ??2 | ??3 | ??4 | ??5 | ??6 | ??7 | |
| ??0.25 | ??+ | ??- | ??- | ??- | ??- | ??- | ??+ |
| ??0.5 | ??+ | ??- | ??- | ??- | ??- | ??- | ??+ |
| ??0.75 | ??+ | ??- | ??- | ??- | ??- | ??- | ??+ |
| ??1.0 | ??+ | ??- | ??- | ??- | ??- | ??- | ??+ |
| ??2.0 | ??+ | ??- | ??- | ??- | ??- | ??- | ??+ |
| ??3.0 | ??+ | ??- | ??- | ??- | ??- | ??- | ??+ |
| ??4.0 | ??+ | ??- | ??- | ??- | ??- | ??- | ??+ |
As shown in Table 4,5% each pipe of glucose injection group did not all have haemolysis in 0.25～4.0 hour, do not have agglutination yet; No. 1 the pipe and the distilled water group in each time point complete hemolysis, produce red clear solution; 2,3,4, No. 5 pipes did not all have haemolysis in 0.25～4.0 hour, did not have agglutination yet.
Table 5. " essentiale " injection stock solution: 5% glucose injection=1: 20 external hemolytic test result
| Time (hour) | Test tube number | ||||||
| ??1 | ??2 | ??3 | ??4 | ??5 | ??6 | ??7 | |
| ??0.25 | ??+ | ??- | ??- | ??- | ??- | ??- | ??+ |
| ??0.5 | ??+ | ??- | ??- | ??- | ??- | ??- | ??+ |
| ??0.75 | ??+ | ??- | ??- | ??- | ??- | ??- | ??+ |
| ??1.0 | ??+ | ??- | ??- | ??- | ??- | ??- | ??+ |
| ??2.0 | ??+ | ??- | ??- | ??- | ??- | ??- | ??+ |
| ??3.0 | ??+ | ??- | ??- | ??- | ??- | ??- | ??+ |
| ??4.0 | ??+ | ??- | ??- | ??- | ??- | ??- | ??+ |
As shown in Table 5,5% each pipe of glucose injection group did not all have haemolysis in 0.25～4.0 hour, do not have agglutination yet; No. 1 the pipe and the distilled water group in each time point complete hemolysis, produce red clear solution; 2,3,4, No. 5 pipes did not all have haemolysis in 0.25～4.0 hour, did not have agglutination yet.
Table 6. " essentiale " injection stock solution: 10% glucose injection=1: 10 external hemolytic test result
| Time (hour) | Test tube number | ||||||
| ??1 | ??2 | ??3 | ??4 | ??5 | ??6 | ??7 | |
| ??0.25 | ??+ | ??- | ??- | ??- | ??- | ??- | ??+ |
| ??0.5 | ??+ | ??- | ??- | ??- | ??- | ??- | ??+ |
| ??0.75 | ??+ | ??- | ??- | ??- | ??- | ??- | ??+ |
| ??1.0 | ??+ | ??- | ??- | ??- | ??- | ??- | ??+ |
| ??2.0 | ??+ | ??- | ??- | ??- | ??- | ??- | ??+ |
| ??3.0 | ??+ | ??- | ??- | ??- | ??- | ??- | ??+ |
| ??4.0 | ??+ | ??- | ??- | ??- | ??- | ??- | ??+ |
As shown in Table 6,10% each pipe of glucose injection group did not all have haemolysis in 0.25～4.0 hour, do not have agglutination yet; No. 1 the pipe and the distilled water group in each time point complete hemolysis, produce red clear solution; 2,3,4, No. 5 pipes did not all have haemolysis in 0.25～4.0 hour, did not have agglutination yet.
Table 7. " essentiale " injection stock solution: 10% glucose injection=1: 20 external hemolytic test result
| Time (hour) | Test tube number | ||||||
| ??1 | ??2 | ??3 | ??4 | ??5 | ??6 | ??7 | |
| ??0.25 | ??- | ??- | ??- | ??- | ??- | ??- | ??+ |
| ??0.5 | ??- | ??- | ??- | ??- | ??- | ??- | ??+ |
| ??0.75 | ??- | ??- | ??- | ??- | ??- | ??- | ??+ |
| ??1.0 | - | - | - | - | - | - | ??+ |
| ??2.0 | - | - | - | - | - | - | ??+ |
| ??3.0 | - | - | - | - | - | - | ??+ |
| ??4.0 | - | - | - | - | - | - | ??+ |
As shown in Table 7,10% each pipe of glucose injection group did not all have haemolysis in 0.25～4.0 hour, do not have agglutination yet; The distilled water group produces red clear solution in each time point complete hemolysis; Stock solution: 10% glucose injection=1: 20 group of each pipe did not all have haemolysis, does not have agglutination yet in 0.25～4.0 hour.Hence one can see that, and " essentiale " injection stock solution and 10% glucose injection be by 1: 20 dilution proportion, and promptly 1 5ml dilutes the solution of gained in the 100ml10% glucose injection into, external no haemolysis.
In addition, we are also according to external medicine Lipostabil N i.v. prescription: Amp.5ml:5mlAmp.enth.:250mg Phospholipide aus Sojabohnen enth.93% (3-snPhosphatidyl) cholin, Extraktionsm.:Ethanol 96%V/V, Benzylalkohol (zurKonservierung) 45mg, be to contain 250mg soybean phospholipid (containing the 93%3-sn-phosphatidylcholine) and benzyl alcohol 45mg among the 5ml, carry out hemolytic test, the result is consistent with " essentiale " experimental phenomena, promptly under not dilution situation, manage equal haemolysis 1～No. 5, and with the external hemolytic that can suppress medicine after the 5% or 10% glucose dilution.
By the result of above-mentioned test, we have designed prescription of the present invention.Being a kind of " essentiale " injection and compositions thereof that does not produce haemolysis, is to be made up of " essentiale ", polyalcohols material.Said injection comprises " small-volume injection ", " transfusion " and " lyophilized injectable powder ".Said polyalcohols material is a kind of, two or more the material in glucose, mannitol, sorbitol, xylitol, the lactose.In said " small-volume injection ", the ratio of essential phospholipid and polyalcohols material is 1: 1～～1 in " essentiale ": 20, and optimal proportion is 1: 5～～1: 10, can be prepared into 5～～injection of 25ml.In said " transfusion ", the ratio of the essential phospholipid of " essentiale " and polyalcohols material is 1: 100～～1: 1000, and optimal proportion is 1: 100～～1: 200, can be prepared into 25～～injection of 1000ml.In said " lyophilized injectable powder ", the ratio of the essential phospholipid of " essentiale " and polyalcohols material is 1: 1～～1: 20, and optimal proportion is 1: 5～～1: 10, can be prepared into 5～～injection of 25ml.Said " essentiale " injection composition that does not produce haemolysis is made up of " essentiale " injection and 50% glucose injection (or 25% glucose injection) two parts, and the time spent was by 1: 1～1: 3 (" essentiale " injection: glucose injection) both are mixed.
Among the present invention, have the part prescription not adopt the benzyl alcohol (particularly " lyophilized injectable powder ") of ill effect, for original " essentiale " preparation, safety is higher.
The specific embodiment:
Detailed component of the present invention is provided by the following example, but protection scope of the present invention not only is confined to this.Annotate: used soybean phospholipid is for meeting the phospholipid that " essentiale " requires.
Embodiment 1, " essentiale " " small-volume injection "
Composition weight (gram)
Injection soybean phospholipid 2.5
Deoxycholic acid is an amount of
Ethanol is an amount of
Mannitol 2.5
Water for injection adds to 50ml
Preparation technology:
Take by weighing the injection soybean phospholipid (containing the 93%3-sn-phosphatidylcholine) of recipe quantity, use an amount of dissolve with ethanol, add water for injection 30ml and disperse phospholipid solution, after adding an amount of injection deoxycholic acid and regulating pH value 7.5 stirring and dissolving with sodium hydroxide, add 2.5g injection mannitol, stirring and dissolving is added water for injection to 50ml, mixing, the following microporous filter membrane (that the most frequently used is degerming 0.22um) of mistake 0.3um, packing, inflated with nitrogen, every 5ml, get product, 2～8 ℃ of preservations.
Embodiment 2, " essentiale " " small-volume injection "
Composition weight (gram)
Injection soybean phospholipid 2.5
Deoxycholic acid is an amount of
Benzyl alcohol 0.45
Ethanol is an amount of
Glucose 25
Water for injection adds to 100ml
Preparation technology:
Take by weighing the injection soybean phospholipid (containing the 93%3-sn-phosphatidylcholine) and the benzyl alcohol of recipe quantity, use an amount of dissolve with ethanol, add water for injection 60ml and disperse phospholipid solution, add an amount of injection deoxycholic acid and regulate pH value 8, after the stirring and dissolving, add the 25g glucose for injection with sodium hydroxide, stirring and dissolving, add water for injection to 100ml, mixing, 0.22um microporous filter membrane degerming excessively, packing, inflated with nitrogen, every 10ml gets product, 2～8 ℃ of preservations.
Embodiment 3, " essentiale " " small-volume injection "
Composition weight (gram)
Injection soybean phospholipid 2.5
Cholic acid is an amount of
Benzyl alcohol 0.45
Ethanol is an amount of
Vitamin B2 is an amount of
Sodium chloride is an amount of
Xylitol 50
Water for injection adds to 250ml
Preparation technology:
Take by weighing the injection soybean phospholipid (containing the 93%3-sn-phosphatidylcholine) and the benzyl alcohol of recipe quantity, use an amount of dissolve with ethanol, add water for injection 100ml and disperse phospholipid solution, add an amount of injection cholic acid and regulate pH value 8.5, after the stirring and dissolving, add 50g injection xylitol, vitamin B2, sodium chloride with sodium hydroxide, stirring and dissolving, add water for injection to 250ml, mixing, 0.22um microporous filter membrane degerming excessively, packing, inflated with nitrogen, every 25ml gets product, 2～8 ℃ of preservations.
Embodiment 4, " essentiale " " transfusion " (children's uses)
Composition weight (gram)
Injection soybean phospholipid 2.5
Deoxycholic acid is an amount of
Ethanol is an amount of
Glucose 25
Water for injection adds to 250ml
Preparation technology:
Take by weighing the injection soybean phospholipid (containing the 93%3-sn-phosphatidylcholine) of recipe quantity, use an amount of dissolve with ethanol, add water for injection 100ml and disperse phospholipid solution, add an amount of injection deoxycholic acid and regulate pH value 7.5, after the stirring and dissolving, add the 25g glucose with sodium hydroxide, stirring and dissolving, add water for injection to 250ml, mixing, 0.22um microporous filter membrane degerming excessively, packing, inflated with nitrogen, every 25ml (children's uses) gets product, 2～8 ℃ of preservations.Annotate: owing to be to aim at children's's configuration, so do not add the benzyl alcohol that children's is had ill effect in prescription, all operations all needs strict control aseptic condition to produce this product.
Embodiment 5, " essentiale " " transfusion "
Composition weight (gram)
Injection soybean phospholipid 0.25
Deoxycholic acid is an amount of
Ethanol is an amount of
Benzyl alcohol 0.45
Mannitol 12.5
Water for injection adds to 250ml
Preparation technology:
Take by weighing injection soybean phospholipid (containing the 93%3-sn-phosphatidylcholine), the benzyl alcohol of recipe quantity, use an amount of dissolve with ethanol, add water for injection 100ml and disperse phospholipid solution, add an amount of injection deoxycholic acid and regulate pH value 7.8, after the stirring and dissolving, add 12.5g mannitol with sodium hydroxide, stirring and dissolving, add water for injection to 250ml, mixing, 0.22um microporous filter membrane degerming excessively, packing, inflated with nitrogen, every 250ml gets product, 2～8 ℃ of preservations.
Embodiment 6, " essentiale " " transfusion "
Composition weight (gram)
Injection soybean phospholipid 2.5
Deoxycholic acid is an amount of
Ethanol is an amount of
Benzyl alcohol 0.45
Xylitol 50
Water for injection adds to 500ml
Preparation technology:
Take by weighing injection soybean phospholipid (containing the 93%3-sn-phosphatidylcholine), the benzyl alcohol of recipe quantity, use an amount of dissolve with ethanol, add water for injection 100ml and disperse phospholipid solution, add an amount of injection deoxycholic acid and regulate pH value 8.0, after the stirring and dissolving, add the 50g xylitol with sodium hydroxide, stirring and dissolving, add water for injection to 500ml, mixing, 0.22um microporous filter membrane degerming excessively, packing, every 250ml, inflated with nitrogen gets product, 2～8 ℃ of preservations.
Embodiment 7, " essentiale " " lyophilized injectable powder "
Composition weight (gram)
Injection soybean phospholipid 2.5
Deoxycholic acid is an amount of
Ethanol is an amount of
Mannitol 2.5
Xylitol 2.5
Water for injection adds to 50ml
Preparation technology:
Take by weighing the injection soybean phospholipid (containing the 93%3-sn-phosphatidylcholine) of recipe quantity, use an amount of dissolve with ethanol, add water for injection 30ml and disperse phospholipid solution, after adding an amount of injection deoxycholic acid and regulating pH value 8 stirring and dissolving with sodium hydroxide, add 2.5g injection mannitol, 2.5g xylitol, stirring and dissolving is added water for injection to 50ml, mixing, 0.22um microporous filter membrane degerming excessively, packing, every 5ml, lyophilization, applying argon gas gets product.
Embodiment 8, " essentiale " " lyophilized injectable powder "
Composition weight (gram)
Injection soybean phospholipid 2.5
Deoxycholic acid is an amount of
Ethanol is an amount of
Glucose 25
Water for injection adds to 100ml
Preparation technology:
Take by weighing the injection soybean phospholipid (containing the 93%3-sn-phosphatidylcholine) of recipe quantity, use an amount of dissolve with ethanol, add water for injection 60ml and disperse phospholipid solution, add an amount of injection deoxycholic acid and regulate pH value 7.0, after the stirring and dissolving, add the 25g glucose for injection with sodium hydroxide, stirring and dissolving, add water for injection to 100ml, mixing, 0.22um microporous filter membrane degerming excessively, packing, every 10ml, lyophilization, inflated with nitrogen gets product.
Embodiment 9, " essentiale " " lyophilized injectable powder "
Composition weight (gram)
Injection soybean phospholipid 2.5
Cholic acid is an amount of
Ethanol is an amount of
Vitamin B2 is an amount of
Sodium chloride is an amount of
Lactose 50
Water for injection adds to 250ml
Preparation technology:
Take by weighing the injection soybean phospholipid (containing the 93%3-sn-phosphatidylcholine) of recipe quantity, use an amount of dissolve with ethanol, add water for injection 100ml and disperse phospholipid solution, add an amount of injection cholic acid and regulate pH value 7.5, after the stirring and dissolving, add 50g injection lactose, vitamin B2, sodium chloride with sodium hydroxide, stirring and dissolving, add water for injection to 250ml, mixing, 0.22um microporous filter membrane degerming excessively, packing, every 25ml, lyophilization, inflated with nitrogen gets product.
Embodiment 1～9 is carried out hemolytic test, the results are shown in Table 8.
The external hemolytic test result of table 8.
| Haemolysis situation in the time of 4 hours | Test tube number | ||||||
| ??1 | ??2 | ??3 | ??4 | ??5 | ??6 | ??7 | |
| Prescription 1 | ??+ | ??- | ??- | ??- | ??- | ||
| Prescription 2 | ??- | ??- | ??- | ??- | ??- | ||
| Prescription 3 | ??- | ??- | ??- | ??- | ??- | ||
| Prescription 4 | ??- | ??- | ??- | ??- | ??- | ||
| Prescription 5 | ??- | ??- | ??- | ??- | ??- | ??- | ??+ |
| Prescription 6 | ??- | ??- | ??- | ??- | ??- | ||
| Prescription 7 | ??- | ??- | ??- | ??- | ??- | ||
| Prescription 8 | ??- | ??- | ??- | ??- | ??- | ||
| Prescription 9 | ??- | ??- | ??- | ??- | ??- | ||
With prescription preparation of the present invention, can suppress the external haemolysis of " essentiale ".
Embodiment 10, do not produce " essentiale " injection composition of haemolysis
Adopt 50% glucose injection as the tissue dewatering hyperosmotic solution clinically, usage is quick intravenous injection 20～50ml, and its effect is of short duration.And 25% glucose injection is used for replenishing heat energy and additional body fluid because of some reason feed reduces the patient that maybe can not take food.In view of above-mentioned result of the test, we consider commercially available " essentiale " injection and commercially available or homemade 50% glucose injection are combined, during clinical practice in 1: 1～1: 3 ratio with behind " essentiale " and 50% glucose injection or the 25% glucose injection mix homogeneously, slowly intravenous administration avoids producing haemolysis.The results are shown in Table 9, table 10.
Table 9. " essentiale " injection: 50% glucose injection=1: 1 external hemolytic test result
| Time (hour) | Test tube number | ||||||
| ??1 | ??2 | ??3 | ??4 | ??5 | ??6 | ??7 | |
| ??0.25 | ??± | ??- | ??- | ??- | ??- | ??- | ??+ |
| ??0.5 | ??± | ??- | ??- | ??- | ??- | ??- | ??+ |
| ??0.75 | ??± | ??- | ??- | ??- | ??- | ??- | ??+ |
| ??1.0 | ??± | ??- | ??- | ??- | ??- | ??- | ??+ |
| ??2.0 | ??± | ??- | ??- | ??- | ??- | ??- | ??+ |
| ??3.0 | ??± | ??- | ??- | ??- | ??- | ??- | ??+ |
| ??4.0 | ??± | ??- | ??- | ??- | ??- | ??- | ??+ |
±: part haemolysis
Table 10. " essentiale " injection: 50% glucose injection=1: 3 external hemolytic test result
| Time (hour) | Test tube number | ||||||
| ??1 | ??2 | ??3 | ??4 | ??5 | ??6 | ??7 | |
| ??0.25 | ??- | ??- | ??- | ??- | ??- | ??- | ??+ |
| ??0.5 | ??- | ??- | ??- | ??- | ??- | ??- | ??+ |
| ??1.0 | ??- | ??- | ??- | ??- | ??- | ??- | ??+ |
| ??2.0 | ??- | ??- | ??- | ??- | ??- | ??- | ??+ |
| ??3.0 | ??- | ??- | ??- | ??- | ??- | ??- | ??+ |
2, hemolytic test in the body
, standby in 1: 1～1: 3 ratio with behind " essentiale " and the 25% glucose injection mix homogeneously.
Get 2 of rabbit, the slow intravenous injection 2mL/kg of oneself rabbit ear vein of administration group, matched group intravenous injection 25% glucose injection is pressed 0.5mL/ and is divided at the uniform velocity slowly injection.Inject and got blood 3mL from ear vein in back 1 hour, put centrifuge 2000rpm centrifugal 10 minutes, draw medicine group serum and matched group serum compares, perusal has or not haemolysis.Conclusion: administration group serum is the same with matched group serum not to have haemolysis.
Claims (7)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510046281 CN1698622A (en) | 2005-04-19 | 2005-04-19 | "Gandejian" injection without hemolysis and its composition |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510046281 CN1698622A (en) | 2005-04-19 | 2005-04-19 | "Gandejian" injection without hemolysis and its composition |
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| Publication Number | Publication Date |
|---|---|
| CN1698622A true CN1698622A (en) | 2005-11-23 |
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| Application Number | Title | Priority Date | Filing Date |
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