CN1846712A - Cinobufagin emulsion for injection and its prepn process - Google Patents
Cinobufagin emulsion for injection and its prepn process Download PDFInfo
- Publication number
- CN1846712A CN1846712A CNA2006100328774A CN200610032877A CN1846712A CN 1846712 A CN1846712 A CN 1846712A CN A2006100328774 A CNA2006100328774 A CN A2006100328774A CN 200610032877 A CN200610032877 A CN 200610032877A CN 1846712 A CN1846712 A CN 1846712A
- Authority
- CN
- China
- Prior art keywords
- injection
- oil
- acid
- emulsion
- cinobufagin
- 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
- 238000002347 injection Methods 0.000 title claims abstract description 85
- 239000007924 injection Substances 0.000 title claims abstract description 85
- 239000000839 emulsion Substances 0.000 title claims abstract description 84
- SCULJPGYOQQXTK-OLRINKBESA-N Cinobufagin Chemical compound C=1([C@@H]2[C@@]3(C)CC[C@@H]4[C@@]5(C)CC[C@H](O)C[C@H]5CC[C@H]4[C@@]43O[C@@H]4[C@@H]2OC(=O)C)C=CC(=O)OC=1 SCULJPGYOQQXTK-OLRINKBESA-N 0.000 title claims abstract description 66
- SCULJPGYOQQXTK-UHFFFAOYSA-N Cinobufagin Natural products CC(=O)OC1C2OC22C3CCC4CC(O)CCC4(C)C3CCC2(C)C1C=1C=CC(=O)OC=1 SCULJPGYOQQXTK-UHFFFAOYSA-N 0.000 title claims abstract description 66
- 238000000034 method Methods 0.000 title description 3
- 238000002360 preparation method Methods 0.000 claims abstract description 25
- 230000001804 emulsifying effect Effects 0.000 claims abstract description 21
- 239000003995 emulsifying agent Substances 0.000 claims abstract description 10
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 9
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 9
- 239000006184 cosolvent Substances 0.000 claims abstract description 9
- 239000003921 oil Substances 0.000 claims description 60
- 235000019198 oils Nutrition 0.000 claims description 60
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 45
- 239000012071 phase Substances 0.000 claims description 28
- 239000000203 mixture Substances 0.000 claims description 22
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 19
- -1 nicotiamide Substances 0.000 claims description 17
- 239000003795 chemical substances by application Substances 0.000 claims description 16
- 210000003022 colostrum Anatomy 0.000 claims description 16
- 235000021277 colostrum Nutrition 0.000 claims description 16
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 15
- 238000004945 emulsification Methods 0.000 claims description 13
- 238000004659 sterilization and disinfection Methods 0.000 claims description 11
- 239000008215 water for injection Substances 0.000 claims description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 claims description 8
- 241000269417 Bufo Species 0.000 claims description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 8
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- 238000012856 packing Methods 0.000 claims description 8
- 230000001105 regulatory effect Effects 0.000 claims description 8
- 210000000582 semen Anatomy 0.000 claims description 8
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical group 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 claims description 7
- 241001415432 Duttaphrynus melanostictus Species 0.000 claims description 7
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 7
- 239000008347 soybean phospholipid Substances 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 6
- 229930006000 Sucrose Natural products 0.000 claims description 6
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- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 claims description 6
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 6
- 239000005720 sucrose Substances 0.000 claims description 6
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 claims description 5
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 5
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 5
- CFWRDBDJAOHXSH-SECBINFHSA-N 2-azaniumylethyl [(2r)-2,3-diacetyloxypropyl] phosphate Chemical compound CC(=O)OC[C@@H](OC(C)=O)COP(O)(=O)OCCN CFWRDBDJAOHXSH-SECBINFHSA-N 0.000 claims description 5
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 5
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 5
- SRBFZHDQGSBBOR-IOVATXLUSA-N D-xylopyranose Chemical compound O[C@@H]1COC(O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-IOVATXLUSA-N 0.000 claims description 5
- 235000003935 Hippophae Nutrition 0.000 claims description 5
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- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 5
- 239000005642 Oleic acid Substances 0.000 claims description 5
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 5
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 5
- 229920001030 Polyethylene Glycol 4000 Polymers 0.000 claims description 5
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 claims description 5
- 235000019197 fats Nutrition 0.000 claims description 5
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 5
- 239000000787 lecithin Substances 0.000 claims description 5
- 235000010445 lecithin Nutrition 0.000 claims description 5
- 229940067606 lecithin Drugs 0.000 claims description 5
- 229930182817 methionine Natural products 0.000 claims description 5
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 5
- 229960000502 poloxamer Drugs 0.000 claims description 5
- 229920001983 poloxamer Polymers 0.000 claims description 5
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 5
- 235000012424 soybean oil Nutrition 0.000 claims description 5
- 239000003549 soybean oil Substances 0.000 claims description 5
- 230000001954 sterilising effect Effects 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- DTOSIQBPPRVQHS-PDBXOOCHSA-N alpha-linolenic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC(O)=O DTOSIQBPPRVQHS-PDBXOOCHSA-N 0.000 claims description 4
- 239000004202 carbamide Substances 0.000 claims description 4
- 235000013877 carbamide Nutrition 0.000 claims description 4
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 4
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- 210000004185 liver Anatomy 0.000 claims description 4
- ACVYVLVWPXVTIT-UHFFFAOYSA-N phosphinic acid Chemical compound O[PH2]=O ACVYVLVWPXVTIT-UHFFFAOYSA-N 0.000 claims description 4
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- PYMYPHUHKUWMLA-UHFFFAOYSA-N 2,3,4,5-tetrahydroxypentanal Chemical compound OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 claims description 3
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Landscapes
- Medicinal Preparation (AREA)
Abstract
The present invention provides one kind of cinobufagin emulsion for injection and its preparation process. Cinobufagin is dissolved with one or several kinds of injection oil and compounded with proper amount of emulsifier, cosolvent, antioxidant, isoosmotic regulator, pH regulator and other medicinal supplementary material to prepare the cinobufagin emulsion for injection. The preparation process includes mixing, heating, emulsifying, high pressure homogenizing and other steps. The cinobufagin emulsion for injection is stable, can inhibit tumor, has no obvious stimulation and may be used for injection directly or after being diluted. It serves as the carrier of anticarcinogen cinobufagin and the energy replenisher.
Description
Technical field
The present invention relates to the preparation method of cinobufagin emulsion for injection, belong to the production and the processing of pharmaceutical preparation.
Background technology
Cinobufacin is the ethanol extraction of Bufonidae animal Bufo siccus (Bufo bufogargarizans Cantor) or Bufo melanostictus (Bufo melanostictus Schneider) skin.The effective ingredient that mainly contains indoles alkaloid such as the plain lactone of toad is (referring to Zhang Aiping, Liu Mingrui, Kang Jianli etc., the clinical care of cinobufacin intravenous applications, medical forum impurity, 2004,25 (23): 75～76).In dry product, fat Venenum Bufonis aglucon contained in the cinobufacin must not be less than 4%, and cinobufagin must not be less than 5%.
HUACHANSU ZHUSHEYE is the water formulation of Bufo siccus skin.Basic pharmacology studies show that: HUACHANSU ZHUSHEYE has direct killing action to hepatocarcinoma, gastric cancer and colon cancer cell; Clinical research proof HUACHANSU ZHUSHEYE cures mainly malignant tumor, and is particularly remarkable to digestive system tumor, pulmonary carcinoma, cervical cancer and breast carcinoma curative effect; Chronic hepatitis B and chronic HBV carrier also there is obvious curative effects.Hydro-acupuncture preparation when clinical practice, the excessive or twice shorter sufferer of medication interval time of consumption heating phenomenon that occurs feeling cold, local excitation appears in a few patients, even phlebitis.(referring to: season Haining, Li Chengjian.The untoward reaction of cinobufacin, the medicine Leader, 2002,5 (21): 157), the incidence rate of adverse reaction of these product up to 43.28% (referring to Gong Aiping, Liu Jinxiu, Ni Bei etc., the untoward reaction of cinobufacin (attached 201 routine clinical observation), Xuzhou Medical College's journal, 1998,18 (3): 418～421), this untoward reaction may be the allergy of the quality of the pharmaceutical preparations due to not good enough.
Summary of the invention
The technical problem that quasi-solution of the present invention is determined works out a kind of cinobufagin emulsion for injection at the more weak deficiency of drug targeting due to the cinobufacin hydro-acupuncture preparation, reduces simultaneously or avoids its allergy in its drug effect of performance.The invention provides that a kind of preparation technology is simple, easy to use, zest is low, the cinobufagin emulsion for injection of good stability, to satisfy on the market demand to this medicine.
With one or more oil for injection dissolving cinobufacin, and the pharmaceutic adjuvants such as injection emulsifying agent, cosolvent, antioxidant, isoosmotic adjusting agent and pH regulator agent that optionally add one or more are prepared into and meet the Emulsion that injection requires in cinobufagin emulsion for injection of the present invention.
Cinobufagin emulsion for injection prescription of the present invention is as follows:
| Form | Parts by weight |
| Cinobufacin | 0.5～70 |
| Oil for injection | 200～600 (preferred 100～500) |
| Emulsifying agent | 0～90 (preferred 1～90) |
| Cosolvent | 0～90 |
| Antioxidant | 0～10 (preferred 0.05～10) |
| Isoosmotic adjusting agent | (preferred 1～20) in right amount |
| The pH regulator agent | (preferred 0.01～20) in right amount |
| Water for injection | 700～1000 |
Cinobufagin emulsion for injection of the present invention is made up of cinobufacin, oil for injection, emulsifying agent, cosolvent, antioxidant isoosmotic adjusting agent, pH regulator agent and water for injection.
The used cinobufacin of the present invention is the extract of Bufonidae animal Bufo siccus (Bufo bufogargarizansCantor) or Bufo melanostictus (Bufo melanostictus Schneider) skin.Be located in temperate zone to subtropical zone on the south the preferred the Changjiang river and produce Bufo siccus or Bufo melanostictus.In dry product, contained fat Venenum Bufonis aglucon must not be less than 4% (preferred fat Venenum Bufonis aglucon content is greater than 7%) in the cinobufacin, and cinobufagin must not be less than 5% (preferred cinobufagin content is greater than 7.5%).
The oil for injection that adopts in the Emulsion of the present invention is selected from soybean oil, fish oil, Semen Lini oil, Oleum Helianthi, Radix Oenotherae erythrosepalae oil, Oleum Hippophae, Oleum Arachidis hypogaeae semen, refine Testa oryzae oil, Semen Tritici aestivi germ oil, Oleum sesami, perilla oil, safflower oil, Princepia utilis oil, one or more mixture in bathypelagic fish oil, oleic acid, Petiolus Trachycarpi oil, stearic acid, alpha-linolenic acid, gamma-Linolenic acid, deoxycholic acid, sodium pantothenate, nicotiamide, oleic acid, polyunsaturated fatty acid, EPA and ester thereof, 26 carbon 5 alkene acids and ester, glycerol or the coix seed oil.Preferably from soybean oil, one or more mixture of fish oil, Semen Lini oil, Oleum Helianthi, Radix Oenotherae erythrosepalae oil, Oleum Hippophae, Oleum Arachidis hypogaeae semen, refine Testa oryzae oil, Semen Tritici aestivi germ oil, Oleum sesami.
The emulsifying agent that adopts in the Emulsion of the present invention is selected from one or more mixture of soybean phospholipid, egg yolk lecithin, poloxamer, lecithin, cephalin, xanthan gum, sucrose ester, low methoxyl pectin, arabic gum, ginsenoside, Radix Panacis Quinquefolii saponin, arasaponin, gypenoside, glyceryl monooleate.Preferably from one or more mixture of soybean phospholipid, egg yolk lecithin, poloxamer, lecithin, cephalin.
The cosolvent that adopts in the Emulsion of the present invention is selected from one or more mixture of carbamide, nicotiamide, ethanolamine, propylene glycol, PEG4000, glycyrrhizic acid, salicylic acid, sodium succinate, sodium phosphate, methionine, acetate, PEG 4000, glycinate.Be preferable over one or more mixture of carbamide, nicotiamide, ethanolamine, propylene glycol, PEG4000.
The antioxidant that adopts in the Emulsion of the present invention is selected from one or more mixture of tocopherol, dibenzylatiooluene, D-xylose, hypophosphorous acid, paddy Guang liver peptide, methionine, Gardenia Yellow, L-tartaric acid, hydroquinone, polyacrylic acid, gallic acid, phytic acid, succinic acid (sodium), Oleum thymi vulgaris.Be preferable over one or more mixture of tocopherol, dibenzylatiooluene, D-xylose, hypophosphorous acid, paddy Guang liver peptide.
The isoosmotic adjusting agent that adopts in the Emulsion of the present invention is selected from one or more mixture of glycerol, sorbitol, sodium chloride, potassium chloride, sucrose, mannitol, glucose.
The pH regulator agent of adopting in the Emulsion of the present invention is preferably selected from the mineral acid of variable concentrations and comprises hydrochloric acid, rare nitric acid, phosphoric acid, dilute sulfuric acid, NH4Cl etc., or organic acid comprises acetic acid, succinic acid, oxalic acid etc., preferred hydrochloric acid, rare nitric acid, dilute sulfuric acid; Or the inorganic base of variable concentrations comprises NaOH, KOH etc., or organic base comprises basic amino acid, sodium acetate, sodium lactate, ethylenediamine etc.; Or the buffer solution of the phosphate of different pH, acetate, ammonia.
The preparation method of cinobufagin emulsion for injection of the present invention comprises the following steps: (please distinguishing one from the other, which is necessary, and which is preferred)
1. the preparation of oil phase: measure cinobufacin, oil for injection and selectable cosolvent by prescription,, get oil phase 10～95 ℃ of heated and stirred dissolvings.
2. the preparation of water: measure water for injection and selectable isoosmotic adjusting agent by prescription,, get water 10～95 ℃ of heated and stirred dissolvings.
3. optionally add emulsifying agent or antioxidant at oil phase or at aqueous phase.
4. the preparation of cinobufacin Emulsion: oil phase and water are mixed (50～70 ℃ of preferred mixing temperatures) 10～95 ℃ of temperature, with emulsification pretreatment or stirring and emulsifying 1～200 minute (preferred emulsifying 30～200 minutes), rotating speed is 20～8000 rev/mins (preferred rotating speed is 100～8000 rev/mins), makes oil phase and water mix homogeneously.Regulating its pH with the pH regulator agent is 3.0～11.0 (preferred pH is 4.0～10.0), gets colostrum.With the further emulsifying of colostrum, further emulsifying is to be selected from the emulsifying of high pressure homogenization machine homogenize (pressure is 500～25000psi, preferred 1000～25000psi, temperature is 10～95 ℃, preferred 50～95 ℃), (temperature is 20～95 ℃ to ultrasonic emulsification, preferred 30～95 ℃, emulsification times 1～200 minute, preferred 20～200 minutes), mechanical agitation emulsifying, (rotating speed is 500～50000 rev/mins, preferred 1000～50000 rev/mins in perhaps colloid mill emulsifying, emulsification times 1～200 minute, preferred 20～200 minutes), packing, sterilization, the mean diameter of Emulsion is 10nm～5 μ m (preferred 10nm～2 μ m), gets cinobufacin Emulsion product.
This Emulsion is colourless, white or off-white color emulsion liquid, has opalescence to occur sometimes, and the preferred content of cinobufacin in Emulsion is 0.03～8%, preferred content is 0.03～8%, mean diameter is 10nm～5 μ m (preferred 10nm～2 μ m), and pH is 3.0～11.0, and preferred pH is 4.0～11.0.
Cinobufagin emulsion for injection drug loading provided by the invention is big, good stability, and shelf time can reach more than 2 years.Utilize technical scheme of the present invention can prepare the Emulsion of different cinobufacin content, described Emulsion can be directly used in injection, also can dilute back intramuscular injection or instillation, and is easy to use, both improve the administration targeting of cinobufacin, ensured the medicine stability in transfusion transportation and the use again.The said preparation toxic and side effects is low, and zest is low, has good bioavailability.Emulsion preparation technology method of the present invention is simple, is applicable to a large amount of preparations and suitability for industrialized production cinobufagin emulsion for injection.
Intravenous drip dosage according to cinobufagin emulsion for injection of the present invention is 0.01～1mg/kg body weight, is preferably 0.04～0.5mg/kg body weight, 1～3 time on the 1st; Or intramuscular injection, 1～3 time on the 1st.Children's subtracts slightly.
The specific embodiment
Embodiment 1 preparation contains the cinobufagin emulsion for injection of 0.03% cinobufacin
Get cinobufacin 0.5g, soybean oil 600g, soybean phospholipid 90g, heating in water bath to 75 ℃, stirring and dissolving, oil phase.Measure water for injection 1000ml, add glycerol 20g, be heated to 75 ℃ of stirring and dissolving, get water.75 ℃ of mixing, emulsification pretreatment 50 minutes (8000 rev/mins of rotating speeds) mixes oil phase and water with oil phase and water.Regulating its pH with sodium hydroxide solution (0.1mol/ml) is 11.0, gets colostrum.With colostrum with high pressure homogenization machine homogenize emulsifying (pressure 1000psi, 75 ℃ of temperature) packing, fill nitrogen, disinfection with high pressure steam, 115 ℃ of sterilizations 30 minutes, product cinobufagin emulsion for injection 1625ml.This Emulsion mean diameter 200.6nm, cinobufacin content be 0.0028% for the sign amount 93.3%.0.5mg/kg slowly instils by body weight, 3 times on the 1st.Children's subtracts slightly.
Embodiment 2 preparations contain the cinobufagin emulsion for injection of 0.1% cinobufacin
Take by weighing cinobufacin 1.0g, each 200g of Radix Oenotherae erythrosepalae oil and Oleum sesami, hydroquinone 10g, heating in water bath to 45 ℃, stirring and dissolving gets oil phase.Measure water for injection 770ml, add sucrose and each 10g of sodium chloride, egg yolk lecithin 50g and acetate 50g are heated to 45 ℃ of dissolvings and stir, and get water.Oil phase and water are mixed down at 45 ℃, and emulsification pretreatment 90 minutes (20 rev/mins of rotating speeds) makes oil phase and water mixing.Regulating its pH value with ethylenediamine solution (5%) is 7.5, gets colostrum.With mechanical agitation emulsifying (rotating speed is 2000 rev/mins) 100 minutes, nitrogen was filled in packing with colostrum, disinfection with high pressure steam, 115 ℃ of sterilizations 30 minutes, product cinobufagin emulsion for injection 1050ml.This Emulsion mean diameter 3.0 μ m, cinobufacin content is 0.095%, is 95% of sign amount.1.0mg/kg slowly instils by body weight, 1 time on the 1st.Children's subtracts slightly.
Embodiment 3 preparations contain the cinobufagin emulsion for injection of 1.0% cinobufacin
Take by weighing cinobufacin 10g, safflower oil 400g, soybean phospholipid 12g and ginsenoside 46g and Gardenia Yellow 4.5g and D-xylose 0.5g, heating in water bath to 25 ℃, stirring and dissolving gets oil phase.Measure water for injection 870ml, add propylene glycol 0.9g and sorbitol 8g, be heated to 25 ℃ of stirrings, get water.Oil phase and water are mixed down at 25 ℃, and agitator emulsifying 40 minutes (2000 rev/mins of rotating speeds) makes oil phase and water mixing.Regulating its pH value with sodium lactate solution (2.0mol/ml) is 8.0, gets colostrum.Colostrum is used ultrasonic emulsification 50 minutes.Nitrogen is filled in packing, and disinfection with high pressure steam was sterilized 30 minutes for 115 ℃, got product cinobufagin emulsion for injection 1010ml.This Emulsion mean diameter 9.5 μ m, cinobufacin content is 0.0099%, is 99.0% of sign amount.By slow intramuscular injection of body weight 0.6mg/kg or intravenous injection, 2 times on the 1st.Children's subtracts slightly.
Embodiment 4 preparations contain the cinobufagin emulsion for injection of 2% cinobufacin
Take by weighing cinobufacin 20g, oleic acid 290g, bathypelagic fish oil 190g and Timnodonic Acid 10g, PEG40000 80g and methionine 0.50g, and dibenzylatiooluene 0.5g, heating in water bath to 95 ℃, stirring and dissolving gets oil phase.Measure water for injection 670ml, add each 5g of Pyrusussuriensis alcohol and glucose, poloxamer 5g, gypenoside 5g and arabic gum 6g are heated to 95 ℃ of dissolvings and stir, and get water.Oil phase and water are mixed down at 95 ℃, and emulsification pretreatment 200 minutes (6000 rev/mins of rotating speeds) makes oil phase and water mixing.Regulating its pH value with phosphate buffer solution (pH=3.0) is 3.9, gets colostrum.With colloid mill emulsifying 4 minutes (rotating speed is 50 000 rev/mins), nitrogen is filled in packing with colostrum, disinfection with high pressure steam, 115 ℃ of sterilizations 30 minutes, product cinobufagin emulsion for injection 990ml.This Emulsion mean diameter 10nm, cinobufacin content is 2.02%, is 101.0% of sign amount.Slowly instil or intravenous injection 3 times on the 1st by body weight 0.8mg/kg.Children's subtracts slightly.
Embodiment 5 preparations contain the cinobufagin emulsion for injection of 5% cinobufacin
Take by weighing cinobufacin 5.0g, fish oil 5g, Oleum Helianthi 5g, Princepia utilis oil 5g, after the dried peptide 0.9g of sucrose ester 10g, cephalin 1.0g and paddy Guang is mixed together, heating in water bath to 65 ℃, stirring and dissolving gets oil phase.Measure water for injection 75ml, add glycerol 2.5g, glycyrrhizic acid 1.5g and salicylic acid 6.0g, low methoxyl pectin 10g are heated to 65 ℃ of dissolvings and stir, and get water.Oil phase and water are mixed down at 65 ℃, and agitator emulsifying 30 minutes (5000 rev/mins of rotating speeds) makes oil phase and water mixing.Regulating its pH value with NH4Cl solution (1.5mol/ml) is 6.5, gets colostrum.Colostrum was stirred 30 minutes with high pressure homogenization machine homogenize emulsifying (pressure 50psi, 65 ℃ of temperature), and nitrogen is filled in packing, and disinfection with high pressure steam was sterilized 30 minutes for 115 ℃, got product cinobufagin emulsion for injection 101ml.This Emulsion mean diameter 489.1nm, cinobufacin content is 4.95%, is 99.0% of sign amount.Slowly instil or intravenous injection 1 time on the 1st by body weight 1.0mg/kg.Children's subtracts slightly.
Embodiment 6 preparations contain the cinobufagin emulsion for injection of 8.0% cinobufacin
Take by weighing cinobufacin 70g, Oleum Hippophae 20g, perilla oil 1.6g, soybean phospholipid 1.5g, lecithin 9.0g mixture heating in water bath to 37 ℃, stirring and dissolving gets oil phase.Measure water for injection 700ml, add sodium chloride 18g and potassium chloride 1.9g, glycinate 6.0g, gallic acid 0.5g and Oleum thymi vulgaris 2.9g are heated to 37 ℃ of dissolvings and stir, and get water.Oil phase and water are mixed down at 37 ℃, and stirring and emulsifying 30 minutes (200 rev/mins of rotating speeds) makes oil phase and water mixing.It is 10.0 that sodium acetate (3.0mol/ml) is regulated its pH value, gets colostrum.Colostrum is used ultrasonic emulsification (90 ℃ of temperature) 30 minutes, and nitrogen is filled in packing, and disinfection with high pressure steam was sterilized 100 minutes for 100 ℃, got product cinobufagin emulsion for injection 875ml.This Emulsion mean diameter 147.7nm, cinobufacin content is 7.91%, is 98.9% of sign amount.By slow muscle of body weight 0.01mg/kg or intravenous injection, 3 times on the 1st.Children's subtracts slightly.
Experimental example: cinobufagin emulsion for injection quality investigation
1, cinobufagin emulsion for injection ambient stable test in 18 months
According to Chinese Pharmacopoeia 2005 editions, investigate cinobufagin emulsion for injection 25 ℃ ± 2 ℃ of room temperatures, placed 18 months under relative humidity 60% ± 10% condition, in the sampling in 1,3,6,9,12,18 month of placing once, investigate outward appearance, particle diameter and the content of sample respectively.Outward appearance, particle diameter and content three be eligible all, and it is qualified to be recorded as, otherwise is recorded as defective.The results are shown in Table 1.
Table 1, cinobufagin emulsion for injection ambient stable test in 18 months
| Sample | The cinobufagin emulsion for injection outward appearance, particle diameter, content (moon) | |||||
| 1 | 3 | 6 | 9 | 12 | 18 | |
| Embodiment 1 embodiment 2 embodiment 3 embodiment 4 embodiment 5 embodiment 6 | Qualified qualified | Qualified qualified | Qualified qualified | Qualified qualified | Qualified qualified | Qualified qualified |
Annotate: the cinobufacin concentration of the cinobufagin emulsion for injection of embodiment 1～6 is respectively: 0.028%～7.91%.
The result shows: the stability according to the prepared cinobufagin emulsion for injection of the foregoing description is better.Product is stable.
2, cinobufagin emulsion for injection is to the inhibitory action of H22 hepatocarcinoma sarcoma
Get 84 of ICR mices at random, unisexuality is other, right front axil subcutaneous vaccination H22 mouse ascites, and every Mus 0.2ml, cell concentration are 1 * 107 ml-1.Inoculate and be divided into 6 groups by the body weight stratified random after 24 hours, except that 24 of matched groups, all the other every group 12: 1. matched group (distilled water), 2. 5-Fu 15mgkg-1 group, 3.～6. cinobufagin emulsion for injection (embodiment 1,3,4 and 5) is 0.028%, 0.095%, 2.02% and 7.91% group.Every day 1 time, continuous 7 days, volume was 10mlkg-1.The results are shown in Table 2.
The data that cinobufacin injection liquid drugs injection is preferably arranged
The result shows that 0.028%～7.91% pair of H22 solid tumor of cinobufagin emulsion for injection has significant inhibitory effect, compares with matched group, and cinobufagin emulsion for injection is respectively organized tumor representation work and reduced (P＜0.05 or P＜0.01), and tumour inhibiting rate increases with dosage.
Table 2, cinobufagin emulsion for injection are transplanted the therapeutical effect (x ± s) of H22 solid tumor to mice
| Group | Dosage | Number of animals | Average weight (g) | Tumor heavy (g) | Tumour inhibiting rate (%) | |
| Beginning/last | Beginning | At last | ||||
| Contrast 5-Fu cinobufagin emulsion for injection | 15mg·kg-1 0.028％ 0.095％ 2.02％ 7.91％ | 24/21 12/8 12/10 12/10 12/10 12/10 | 21±2 19±1 200±1 19±2 19±2 20±2 | 22±2 16±4 ** 20±2 19±2 21±2 20±2 | 1.31±0.38 0.40±0.19 ** 1.03±0.28 1.00±0.35 0.85±0.45 * 0.84±0.15 ** | - 69.8 21.7 23.7 35.1 35.9 |
The t check is compared with matched group,
*P＜0.05,
*P＜0.01
3, the irritant test of cinobufagin emulsion for injection
Get 4 of rabbit, body weight 2.0～2.5kg, male and female half and half, be divided into two groups, make left and right sides lower limb quadriceps femoris injection cinobufagin emulsion for injection 1ml (embodiment 6, and concentration is 7.91%) at it respectively, 48h behind the medicine, the inspection quadriceps femoris is cutd open in execution, vertically cuts and observes injection site muscular irritation reaction, presses table 3 conversion response rank.
Table 3, injection muscular irritation reaction and reaction rank
| Order of reaction | Irritant reaction |
| 1 2 3 4 5 | No significant change mild hyperaemia, its scope is less than the hyperemia of 0.5～1.0cm moderate, its scope is less than the hyperemia of 0.5～1.0cm severe, it is downright bad to accompany right myodegeneration to occur, and has the brown degeneration popularity necrosis to occur |
Perusal shows that 7.91% cinobufagin emulsion for injection irritant reaction is 0 grade.It is nonirritant.
4, the hypersensitive test of cinobufagin emulsion for injection
Get 12 of Cavia porcelluss, by the sterile working, 6 are the administration group, the next day every lumbar injection cinobufagin emulsion for injection (embodiment 6, concentration is 7.91%) 0.5ml, totally 3 times, after it is divided equally two groups, one group in injection the last first the 14th day, the cinobufagin emulsion for injection 2ml/ of the same concentration of intravenous injection only attacks; Another 21 days of organizing after injection are first attacked with method.Every Ovum Gallus domesticus album 0.5ml that lumbar injection concentration is (1: the 5) next day of 6 Cavia porcelluss of Ovum Gallus domesticus album positive controls, totally 3 times, after divide two groups at random with it, in first after (last) injection the 14th day and the 21st day, intravenous injection concentration is that the Ovum Gallus domesticus album 2ml/ that dilutes at 1: 5 only attacks.In the 15min of injection back, observe anaphylactic reaction whether occurs, and press table 4 and determine anaphylaxis progression.
The anaphylaxis of table 4,7.91% cinobufagin emulsion for injection Cavia porcellus and the order of reaction
| Reaction symptom | The order of reaction |
| No significant reaction is slightly grabbed nose, tremble or the cough of perpendicular approximate number sound, grab nose, tremble or the repeatedly cough continuously of perpendicular hair, with dyspnea or spasm, spasm such as tic, twitch, gatism, shock death | 0 1 2 3 4 |
The intravenous injection result shows that 7.91% cinobufagin emulsion for injection sensitivity test is qualified.
Claims (9)
1, the invention provides a kind of cinobufagin emulsion for injection and preparation method thereof.Be a kind ofly to dissolve cinobufacin and be prepared into the Emulsion that meets injection requirement with pharmaceutic adjuvants such as suitable emulsifying agents with oil for injection.
Cinobufagin emulsion for injection of the present invention is made up of following prescription:
Form content (parts by weight)
Cinobufacin 0.5～70
Oil for injection 200～600 (preferred 100～500)
Emulsifying agent 0～90 (preferred 1～90)
Cosolvent 0～90
Antioxidant 0～10 (preferred 0.05～10)
Isoosmotic adjusting agent an amount of (preferred 1～20)
PH regulator agent an amount of (preferred 0.01～20)
Water for injection 700～1000
2, cinobufagin emulsion for injection as claimed in claim 1 is characterized in that described cinobufacin is the extract of Bufonidae animal Bufo siccus (Bufo bufogargarizans Cantor) or Bufo melanostictus (Bufo melanostictusSchneider) skin.Be located in temperate zone to subtropical zone on the south the preferred the Changjiang river and produce Bufo siccus or Bufo melanostictus.In dry product, contained fat Venenum Bufonis aglucon must not be less than 4% (preferred fat Venenum Bufonis aglucon content is greater than 7%) in the cinobufacin, and cinobufagin must not be less than 5% (preferred cinobufagin content is greater than 7.5%).
3, cinobufagin emulsion for injection as claimed in claim 1, it is characterized in that described oil for injection is to be selected from soybean oil, fish oil, Semen Lini oil, Oleum Helianthi, Radix Oenotherae erythrosepalae oil, Oleum Hippophae, Oleum Arachidis hypogaeae semen, the refine Testa oryzae oil, Semen Tritici aestivi germ oil, Oleum sesami, perilla oil, safflower oil, Princepia utilis oil, bathypelagic fish oil, oleic acid, Petiolus Trachycarpi oil, stearic acid, alpha-linolenic acid, gamma-Linolenic acid, deoxycholic acid, sodium pantothenate, nicotiamide, oleic acid, polyunsaturated fatty acid, EPA and ester thereof, 26 carbon 5 alkene acids and ester thereof, one or more mixture in glycerol or the coix seed oil.Preferably from soybean oil, one or more mixture of fish oil, Semen Lini oil, Oleum Helianthi, Radix Oenotherae erythrosepalae oil, Oleum Hippophae, Oleum Arachidis hypogaeae semen, refine Testa oryzae oil, Semen Tritici aestivi germ oil, Oleum sesami.
4, cinobufagin emulsion for injection as claimed in claim 1 is characterized in that described emulsifying agent is one or more the mixture that is selected from soybean phospholipid, egg yolk lecithin, poloxamer, lecithin, cephalin, xanthan gum, sucrose ester, low methoxyl pectin, arabic gum, ginsenoside, Radix Panacis Quinquefolii saponin, arasaponin, gypenoside or the glyceryl monooleate.Preferably from one or more mixture of soybean phospholipid, egg yolk lecithin, poloxamer, lecithin, cephalin.
5, cinobufagin emulsion for injection as claimed in claim 1 is characterized in that described cosolvent is one or more the mixture that is selected from carbamide, nicotiamide, ethanolamine, propylene glycol, glycyrrhizic acid, salicylic acid, sodium succinate, sodium phosphate, methionine, acetate, PEG 4000, the glycinate.Preferably from one or more mixture of carbamide, nicotiamide, ethanolamine, propylene glycol, PEG 4000.
6, cinobufagin emulsion for injection as claimed in claim 1 is characterized in that described antioxidant is one or more the mixture in tocopherol, dibenzylatiooluene, D-xylose, hypophosphorous acid, paddy Guang liver peptide, methionine, Gardenia Yellow, L-tartaric acid, hydroquinone, polyacrylic acid, gallic acid, phytic acid, succinic acid (sodium) and the Oleum thymi vulgaris.Preferably from one or more mixture of tocopherol, dibenzylatiooluene, D-xylose, hypophosphorous acid, paddy Guang liver peptide.
7, cinobufagin emulsion for injection as claimed in claim 1 is characterized in that described isoosmotic adjusting agent is to be selected from a kind of in glycerol, sorbitol, sodium chloride, potassium chloride, sucrose, mannitol, the glucose or more than one mixture.
8, cinobufagin emulsion for injection as claimed in claim 1 is characterized in that described pH regulator agent is to be selected from not that the mineral acid of variable concentrations comprises hydrochloric acid, rare nitric acid, phosphoric acid, dilute sulfuric acid, NH
4Cl etc. or organic acid comprise acetic acid, succinic acid, oxalic acid etc.; Or, the inorganic base of variable concentrations comprises basic amino acid, sodium acetate, sodium lactate, ethylenediamine etc. for comprising NaOH, KOH etc. or organic base; Or be phosphate, the acetate of different pH, the buffer solution of ammonia.
9, the preparation method of cinobufagin emulsion for injection as claimed in claim 1 is characterized in that comprising the following steps:
1. the preparation of oil phase is measured cinobufacin, oil for injection, cosolvent by prescription and is dissolved 10～95 ℃ of heated and stirred, oil phase.
2. the preparation of water is measured water for injection and isoosmotic adjusting agent by prescription, 10～95 ℃ of heated and stirred dissolvings, gets water.
3. emulsifying agent or antioxidant can add at oil phase or aqueous phase at the same time or separately.
4. the preparation of cinobufagin emulsion for injection mixes oil phase and water 10～95 ℃ of temperature, and with emulsification pretreatment or stirring and emulsifying 1～200 minute, rotating speed was 20～8000 rev/mins, makes oil phase and water mix homogeneously.Regulating its pH with the pH regulator agent is 3.0～11.0, gets colostrum.With the further emulsifying of colostrum, further emulsifying is to be selected from the emulsifying of high pressure homogenize (pressure is 500～25000psi, temperature is 10～95 ℃), (temperature is 20～95 ℃ to ultrasonic emulsification, emulsification times 1～200 minute), (rotating speed is 500～50000 rev/mins for mechanical agitation emulsifying or colloid mill emulsifying, emulsification times 1～200 minute), packing, sterilization, the mean diameter of Emulsion is 10nm～10 μ m, gets cinobufacin Emulsion product.
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