CN1493289A - Hydroxy camptothecin emulsion and its preparation method - Google Patents
Hydroxy camptothecin emulsion and its preparation method Download PDFInfo
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- CN1493289A CN1493289A CNA031528341A CN03152834A CN1493289A CN 1493289 A CN1493289 A CN 1493289A CN A031528341 A CNA031528341 A CN A031528341A CN 03152834 A CN03152834 A CN 03152834A CN 1493289 A CN1493289 A CN 1493289A
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Abstract
A hydroxycamptothecin emulsion is prepared from hydroxycamptothecin 0.01-2.2 %, emulsifier 0.3-8%, triglyceride 2-30%, glycerine for injection 2.0-3.0 % and water for injection through dissolving the 10-hydroxycamptothecin in the oil phase containing triglyceride and emulsifier, adding water phase, mixing, and ultrasonic or homogeneous emulsifying. Its advantages are high curative effect and stability, and good target to tissue.
Description
Technical field
The present invention relates to a kind of Emulsion and preparation method thereof, especially hydroxycamptothecin Emulsion and preparation method thereof belongs to medical technical field.
Background technology
Discover that separating the 10-hydroxycamptothecine (10-HCPT) that obtains from Fructus seu radix camptothecae acuminatae (Fructus Camptothecae Acuminatae) is the highest active chemical compound in all natural or synthetic camptothecin analogues.
Because HCPT can select to suppress the activity of DNA topoisomerase I, disturb the enzymatic DNA of topoisomerase to cut off the link reaction, make enzyme and DNA chain rupture stable composite, and suppress the joint again of incision, therefore have the DNA of causing chain rupture, disturb dna replication dna, have antineoplastic action.Medically, HCPT mainly acts on the S phase, to G as cell cycle specific agents
2Also there is retarding action on-M border, and the primary hepatocarcinoma effective percentage is reached 56.2%, and the tumor of head and neck effective percentage reaches 64.3%, and the gastric cancer effective percentage reaches 47%.From clinical practice, hydroxycamptothecin sodium-salt parenteral solution anticancer spectrum is wide, and curative effect is better.But its water solublity is little, causes hydroxycamptothecin E ring opening in the process of dissolving formation sodium salt in alkali liquor, thus active the reduction, and side reaction increases.The clinical gastrointestinal reaction that mainly shows as, bone marrow depression, urinary tract reaction.{ referring to (1), Dong Xiyu etc., Chinese herbal medicine, 199627 (4): 243～245; (2) Yang Shicheng etc., Acta Pharmaceutica Sinica, 1999,34 (2): 146～150; (3) Gu Dexin, Chinese Medicine information, 1995:1 (6): 340～344}
Summary of the invention
The technical problem to be solved in the present invention is that research is a kind of as intravenous hydroxycamptothecin Emulsion; it should be able to protect the E ring in the hydroxycamptothecin structure; make medicine composition hydroxycamptothecin stable, reduce the side reaction that produces owing to E ring breakage structural degradation, thereby improve curative effect.
But the present invention also comprises the preparation method of hydroxycamptothecin Emulsion industrializing implementation.
For addressing the above problem, the invention provides following technical scheme.
A kind of hydroxycamptothecin injectable emulsion, it comprises hydroxycamptothecin 0.01～2.2%, emulsifying agent 0.3～8%, triglyceride compounds 2～30%, isotonic agent glycerol for injection 2.0～3.0% by weight percentage, all the other are water for injection.
Described injectable emulsion, its preferably percentage by weight be: hydroxycamptothecin is 0.05～2%, emulsifying agent is 0.6～5%, the triglyceride compounds is 5～20%, isotonic agent 2.2～2.5%.Wherein: emulsifying agent is selected from fabaceous lecithin, lecithin or non-ionic surface active agent Planck Buddhist nun 188F
68In a kind of or two kinds; The triglyceride compounds is selected from a kind of of long chain triglyceride and/or medium chain triglyceride or two kinds.Long chain triglyceride is selected from a kind of in soybean oil, safflower oil, Semen Maydis oil, Oleum Cocois, the Oleum Ricini or two kinds.
The preparation method of described injectable emulsion comprises the following steps:
A) it is standby to get hydroxycamptothecin, emulsifying agent, triglyceride compounds, isotonic agent glycerol for injection, water for injection;
B) hydroxycamptothecin, emulsifying agent, triglyceride compound are formed oil phase B;
C) the isotonic agent glycerol for injection is mixed formation water C with water for injection;
D) oil phase B is mixed with water C, ultrasonic or homogenizing forms Emulsion.
Aforementioned injectable emulsion, proportioning is preferably: stabilizing agent oleic acid, cholesterol and/or the enuatrol of adding 0.1～4%; 0.5～5% co-emulsifier polyvinylpyrrolidone; 0.01-0.5% antioxidant V
E0.5～7% cosolvent Polyethylene Glycol
200, Polyethylene Glycol
300, Polyethylene Glycol
400, benzyl benzoate or 1, the 2-propylene glycol.
The preparation method of described injectable emulsion comprises the steps:
A) it is standby to get hydroxycamptothecin, emulsifying agent, triglyceride compounds, isotonic agent glycerol for injection, water for injection, stabilizing agent, co-emulsifier, antioxidant, cosolvent;
B) hydroxycamptothecin, emulsifying agent, triglyceride compounds are mixed formation oil phase B with stabilizing agent;
C) isotonic agent glycerol for injection, co-emulsifier are mixed formation water C with water for injection;
D) oil phase B is mixed with water C, ultrasonic or homogenizing forms Emulsion; Perhaps,
B) with ethanol hydroxycamptothecin and/or cosolvent are dissolved, form hydroxycamptothecin ethanol liquid B1; Emulsifying agent, triglyceride compounds are mixed formation oil phase B2 with stabilizing agent; Again hydroxycamptothecin ethanol liquid B1 is mixed with oil phase B2 and form oil phase B;
C) isotonic agent glycerol for injection, co-emulsifier are mixed formation water C with water for injection;
D) oil phase B is mixed with water C, ultrasonic or homogenizing forms Emulsion; Perhaps,
B) with ethanol hydroxycamptothecin and/or cosolvent are dissolved, form hydroxycamptothecin ethanol liquid B1; With triglyceride compound formation oil phase B2; Again hydroxycamptothecin ethanol liquid B1 is mixed with oil phase B2 and form oil phase B;
C) isotonic agent glycerol for injection, co-emulsifier, emulsifying agent, stabilizing agent are mixed formation water C with water for injection;
D) oil phase B is mixed with water C, ultrasonic or homogenizing forms Emulsion.The preparation method of described injectable emulsion, all right:
C) excipient sorbitol, glucose, mannitol, NaCl, lactose and/or the dextran of adding 0.5-3% in water C get water D;
D) oil phase B is mixed with water D, after ultrasonic or homogenizing formed Emulsion, lyophilized preparation was made in lyophilization.
The preparation method preferably of described injectable emulsion comprises the steps:
A) get hydroxycamptothecin 0.05%, Polyethylene Glycol
2001%, ethanol is an amount of, and ultrasonic dissolution is made pastille solution B 1;
B) get soybean oil 10%, medium chain triglyceride 10%, fabaceous lecithin 0.6%, cholesterol 0.4% forms oil phase B2;
C) in oil phase B2, add pastille solution B 1, the ultrasonic mixing that impels, ethanol is removed in decompression, gets oil phase B;
D) get glycerol 2.5%, polyvinylpyrrolidone 4% adds injection water to 100%, gets water C;
E),, form Emulsion through ultrasound wave or the emulsifying of homogenizing instrument with water C and oil phase B mixing.
The another kind of described injectable emulsion is preparation method preferably, comprises the steps:
A) get hydroxycamptothecin 2%, Polyethylene Glycol
2006% is an amount of with ethanol, and ultrasonic dissolution is made pastille solution B 1;
B) get soybean oil 5%, medium chain triglyceride 5%, fabaceous lecithin 2% and mix, form oil phase B2 with cholesterol 0.6%;
C) add pastille solution B 1 in oil phase B2, the ultrasonic medicinal liquid that makes is scattered in oil phase, and ethanol is removed in decompression, gets oil phase B;
D) get glycerol 2.2% and polyvinylpyrrolidone 4%, add injection water to 100%, form water C;
E),, form Emulsion through ultrasound wave or the emulsifying of homogenizing instrument with water C, oil phase D mixing.
Hydroxycamptothecin emulsion composition of the present invention be a kind of be the preparation of carrier with oil/aqueous emulsion, comprise
---hydroxycamptothecin;
---emulsifying agent
---the triglyceride oil phase;
---contain the water of isotonic agent;
Described hydroxycamptothecin is dissolved in the described oil phase, forms stable sub-micro (particle diameter 100～500 nanometers) breast or nanometer (particle diameter 10～100 nanometers) Emulsion in described aqueous phase again.
Hydroxycamptothecin weight percent content of the present invention is 0.01～2%, and emulsifying agent is 0.3～8%, triglyceride 2～20%, and all the other are water.In addition, can also add co-emulsifier, stabilizing agent, cosolvent, antioxidant as required.
Above triglyceride can be a kind of in the long chain triglyceride such as soybean oil, safflower oil Semen Maydis oil, Oleum Cocois, Oleum Ricini, also can be medium chain triglyceride (MCT); Emulsifying agent can be fabaceous lecithin, lecithin or non-ionic surface active agent Planck Buddhist nun (Poloxamer) 188F
68Isotonic agent is a glycerol for injection; Co-emulsifier is polyvinylpyrrolidone (PVP); Stabilizing agent is oleic acid, cholesterol, enuatrol; Antioxidant is V
ECosolvent is PEG
200, PEG
300, PEG
400, benzyl benzoate, or 1, the 2-propylene glycol.
Hydroxycamptothecin injectable emulsion compositions of the present invention can be produced by the preparation method of following steps:
1), hydroxycamptothecin is dispersed in the triglyceride oil phase that contains emulsifying agent;
2) add water, mixing is made colostrum;
3) ultrasonic emulsification or emulsifying make hydroxycamptothecin be dissolved in oil phase and form stable dispersion, make submicron or nano-emulsion.
Above step 1 can realize by following three kinds of methods:
Method one
1-1) hydroxycamptothecin is dissolved in the organic solvent;
1-2) will dissolve the liquid adding contains in the triglyceride oil phase of emulsifying agent;
1-3) decompression rotation, organic solvent is removed in evaporation, forms the hydroxycamptothecin oil phase.
Method two
2-1) hydroxycamptothecin is added the triglyceride oil phase that contains emulsifying agent;
2-2) heating makes hydroxycamptothecin be dissolved in oil phase.
Method three
3-1) hydroxycamptothecin is mixed with the triglyceride oil phase that contains emulsifying agent;
3-2) grind, make hydroxycamptothecin be dispersed in oil phase.
Above Emulsion can act on intravenous fluid, transfusion, also can add excipient such as mannitol, NaCl, lactose, dextran at the aqueous phase before forming Emulsion, make Emulsion after, lyophilized preparation is made in lyophilization again.
Be not difficult to find out that the Emulsion and the preparation method of pharmaceutical carrier of the present invention are practical, realize commercialization easily.And experiment shows, as carrier, has not only solved the E ring opening problem that causes because of the pH value height with fat milk, has also increased the chemical stability of manufactured goods, and the distribution in vivo of altered medicine has the tissue target tropism, thereby has improved the curative effect of medicine.
The specific embodiment
The present invention is further illustrated below in conjunction with embodiment.
Raw material sources and specification:
The U.S. Hydrargyri Oxydum Rubrum industry of hydroxycamptothecin Hubei Mei Erya (group) company limited product batch number: 030201...... content: 98.9% meets standard under the WS1-XG-014-2001 corresponding entry
The U.S. Hydrargyri Oxydum Rubrum industry of reference substance hydroxycamptothecin injection Hubei Mei Erya (group) company limited product batch number: 030623
North Area, soybean oil Tieling medicinal oil company limited meets the Chinese Pharmacopoeia standard
Medium chain triglyceride Shanghai higher-dimension Industrial Co., Ltd. meets the European Pharmacopoeia standard
Fabaceous lecithin Shanghai Taiwei Pharmaceutical Co., Ltd. meets the Chinese Pharmacopoeia standard
Polyvinylpyrrolidone (Shanghai) BASF Co., Ltd meets the European Pharmacopoeia standard
Embodiment one
Shown in table 1 first row, take by weighing hydroxycamptothecin 0.05 gram (be Emulsion gross weight 0.005%) by the Emulsion percentage by weight, add Polyethylene Glycol 1.0 grams (1%), it is an amount of to add ethanol, and ultrasonic dissolution is made and is contained drug solns.
Take by weighing each 10 gram (10%) of soybean oil and MCT, fabaceous lecithin 0.6 gram (0.6%), cholesterol 0.4 gram (0.4%) forms oil phase.
Add in oil phase and contain drug solns, the ultrasonic phospholipid that makes dissolves, and medicine is scattered in oil phase.The decompression rotary evaporation is removed organic solvent.
Take by weighing glycerol 2.5 grams (2.5%), PVP4 restrains (4%), adds injection water to 100g
Water, oil phase mixing form colostrum, press the preparation routine through ultrasonic emulsification, form Emulsion.
Using method: quiet notes 5mg/100ml/d was a course of treatment in continuous 5 days
The preparation stability test and the antitumor drug effect of Emulsion of the present invention are tested referring to embodiment eight, nine.
Embodiment two
Shown in table 1 secondary series, take by weighing hydroxycamptothecin 0.05 gram by weight percentage, add soybean oil 2 grams, the MCT4 gram, fabaceous lecithin 1.2 grams, cholesterol 3 grams, heating and melting, temperature is controlled at 80 ℃, forms oil phase.
Take by weighing glycerol 2.5 grams, add injection water to 100 gram.
Water, oil phase mixing form colostrum, pulverizing through ultrasound wave or homogenizing instrument, form Emulsion.
Embodiment three
Shown in table 1 the 3rd row, take by weighing hydroxycamptothecin 0.05g by weight percentage, add Polyethylene Glycol 6g, soybean oil 2.5g, MCT2.5g, fabaceous lecithin 1.2g, cholesterol 4g grinds, and makes principal agent be scattered in oil phase.
Take by weighing glycerol 2.2g, add injection water to 100g.
Water, oil phase mixing form colostrum, pulverizing through ultrasound wave or homogenizing instrument, form Emulsion.
It was a course of treatment in continuous 5 days that the Emulsion of using method: embodiment two, three adopts 5% glucose or 0.9% sodium chloride to be diluted to the quiet notes of 500ml 10mg/d.
Embodiment four
Shown in table 1 the 4th row, take by weighing hydroxycamptothecin 2g by the Emulsion percentage by weight, add Polyethylene Glycol 6g, it is an amount of to add ethanol, and ultrasonic dissolution is made and is contained drug solns.
Take by weighing soybean oil 5g and MCT5g, fabaceous lecithin 2g, cholesterol 0.6g forms oil phase.
Add in oil phase and contain drug solns, the ultrasonic phospholipid that makes dissolves, and medicine is scattered in oil phase.The decompression rotary evaporation is removed organic solvent.
Take by weighing glycerol 2.2g, PVP4g adds injection water to 100g
Water, oil phase mixing form colostrum, through ultrasound wave or the emulsifying of homogenizing instrument, form Emulsion.
Embodiment five
Shown in table 1 the 5th row, take by weighing hydroxycamptothecin 1g by weight percentage, add Polyethylene Glycol 1g, soybean oil 4g, MCT2g, fabaceous lecithin 5g, heating and melting, temperature is controlled at 150 ℃, forms oil phase.
Take by weighing glycerol 2.5g, PVP4g adds injection water to 100g.
Water, oil phase mixing form colostrum, pulverizing through ultrasound wave or homogenizing instrument, form Emulsion.
Embodiment six
Shown in table 1 the 6th row, take by weighing hydroxycamptothecin 1g by weight percentage, add Polyethylene Glycol 1g, soybean oil 3g, MCT3g, fabaceous lecithin 2g, cholesterol 0.4g grinds, and makes principal agent be scattered in oil phase.
Take by weighing glycerol 2.5g, PVP4g adds injection water to 100g.
Water, oil phase mixing form colostrum, pulverizing through ultrasound wave or homogenizing instrument, form Emulsion.
Embodiment seven
Aqueous phase at above embodiment one adds dextran 0.5 gram (0.5%); Perhaps, the aqueous phase at embodiment two adds sorbitol 1.5 grams (1.5%); Perhaps, the aqueous phase at embodiment three adds glucose 3.0 grams (3%); And then emulsifying, it is conventional through lyophilization that the Emulsion of formation is pressed the lyophilized preparation preparation, makes lyophilized preparation.Add 0.9%NaCl or the dilution of 5% glucose during clinical use, injection for intravenous is used.
The Emulsion of using method: embodiment five, six, seven adopts 5% glucose or 0.9% sodium chloride to be diluted to the quiet notes of 500ml 20mg/d, and four times is a course of treatment.
The list of references of embodiment one to embodiment seven: (1) flat its energy, modern medicinal agents;
(2)M.Jayne?Lawrence：Advanced?Drug?Delivery?Reviews?2000(45)：89～121；(3)Tstsuo?Yamaguch，et.PharmaceuticalResearch，vol12，1995(9)：1273～1278；(4)Christian?VonCorswant，et.Joumal?of?Pharmaceutial?Sciences.Vol871998(2)：200～208。
Embodiment eight
6 prescriptions are made 10 days, 60 ℃ Experimental Investigation on Factors of Affecting respectively in the his-and-hers watches 1, and the study on the stability index comprises: medicament contg, total related substance, particle diameter, surface potential, pH value, viscosity, result such as table 2.
Table 1, Emulsion proportioning raw materials of the present invention
Emulsion 123456
Soybean phosphatide 0.6% 1.2% 1.2% 2% 5% 2%
Soybean oil 10% 2% 2.5% 5% 4% 3%
Medium chain triglycerides 10% 4% 2.5% 5% 2% 3%
Cholesterol 0.4% 3% 4% 0.6% 0 0.4%
Polyethylene Glycol 1% 0 6% 6% 1% 1%
Glycerol 2.5% 2.5% 2.2% 2.2% 2.2% 2.5%
Polyethylene arsenic pyrrolidone 4% 000 4% 4%
10-hydroxycamptothecine 0.005% 0.005% 0.005% 2% 1% 1%
The stability test of table 2, Emulsion of the present invention
Emulsion 1 10 days 5 days 10 days
Concentration (μ g/ml) 49.8 49.8 49.8
Total related substance (%) 2.33 2.57 2.55
Mean diameter (nm) 323.9 339.4 347.9
Surface potential (mv)-31.2-34.2-31.5
PH value 4.72 4.77 4.72
Viscosity (cp) 1.72 1.80 1.79
Emulsion 20 days 5 days 10 days
Concentration (μ g/ml) 48.7 48.5 48.0
Total related substance (%) 2.40 2.41 2.71
Mean diameter (nm) 185.3 182.3 201.8
Surface potential (mv)-37.6-38.2-41.6
PH value 4.80 4.78 4.78
Viscosity (cp) 1.59 1.55 1.67
Emulsion 30 days 5 days 10 days
Concentration (μ g/ml) 48.7 48.8 48.0
Total related substance (%) 2.55 2.58 2.70
Mean diameter (nm) 170.1 172.6 178.8
Surface potential (mv)-43.6-40.1-46.9
PH value 4.70 4.71 4.77
Viscosity (cp) 1.43 1.55 1.67
Emulsion 40 days 5 days 10 days
Concentration (mg/ml) 19.63 19.58 19.55
Total related substance (%) 2.70% 2.77% 2.79%
Mean diameter (nm) 241.9 293.5 298.1
Surface potential (mv)-35.8-36.0-38.1
PH value 4.83 4.80 4.80
Viscosity (cp) 2.03 2.13 2.29
Emulsion 50 days 5 days 10 days
Concentration (mg/ml) 9.93 9.79 9.71
Total related substance (%) 2.77 2.83 2.90
Mean diameter (nm) 160.4 159.5 167.6
Surface potential (mv)-41.1-41.0-43.4
PH value 4.73 4.73 4.69
Viscosity (cp) 1.66 1.74 1.73
Emulsion 60 days 5 days 10 days
Concentration (mg/ml) 9.83 9.71 9.73
Total related substance (%) 2.71 2.73 2.88
Mean diameter (nm) 147.3 149.7 154.5
Surface potential (mv)-37.5-36.9-35.4
PH value 4.74 4.74 4.66
Viscosity (cp) 1.77 1.80 1.79
4 ℃, 25 ℃ accelerated test researchs done by 1,6 liang of prescription of his-and-hers watches 1 and the room temperature experimentation was done quantitative check, result such as table 3 (unit such as preceding) in the time of 1,2,3,6 month:
The accelerated test of table 3, Emulsion of the present invention and room temperature experiment
Emulsion 1
1 month 2 months 3 months 6 months
4 ℃ of 25 ℃ of room temperatures of 4 ℃ of 25 ℃ of room temperatures of 4 ℃ of 25 ℃ of room temperatures of 4 ℃ of 25 ℃ of room temperatures
Concentration 49.6 49.8 49.1 48.9 49.1 48.7 49.7 47.5 47.9 48.0 47.3 47.4
Total related substance 2.51 2.66 2.59 2.55 2.61 2.56 2.64 2.75 2.76 2.66 2.79 2.65
Mean diameter 249.6 249.3 231.7 226.1 226.8 229.4 227.3 245.0 239.1 227.9 282.3 212.0
Surface potential-28.5-36.9-31.1-37.5-42.0-39.0-35.4-34.8-39.6-32.8-35.8-38.2
PH value 4.70 4.74 4.73 4.71 4.74 4.69 4.79 4.66 4.70 4.73 4.72 4.68
Viscosity 1.77 1.79 1.71 1.76 1.87 1.74 1.73 1.88 1.79 1.72 1.821.85
Emulsion 6
1 month 2 months 3 months 6 months
4 ℃ of 25 ℃ of room temperatures of 4 ℃ of 25 ℃ of room temperatures of 4 ℃ of 25 ℃ of room temperatures of 4 ℃ of 25 ℃ of room temperatures
Concentration (mg/ml) 9.71 9.83 9.77 9.75 9.70 9.69 9.81 9.82 9.74 9.72 9.669.74
Total related substance 2.60 2.63 2.55 2.57 2.73 2.66 2.58 2.74 2.64 2.59 2.76 2.62
Mean diameter 131.1 159.1 141.5 128.6 150.3 149.8 144.7 166.4 159.3 154.1 160.5 161.6
Surface potential-30.5-33.1-38.0-38.2-35.8-38.8-40.0-37.6-31.5-43.1-42.4-42.0
PH value 4.73 4.70 4.69 4.77 4.72 4.76 4.76 4.68 4.72 4.79 4.68 4.71
Viscosity 1.72 1.80 1.72 1.75 1.82 1.77 1.71 1.80 1.74 1.76 1.831.73
The simulation clinical trial
For this product of clinical practice, Emulsion 6 usefulness, 5% glucose or 0.9%NaCl dilute (1: 9) in the table 1, sample is put at room temperature placed 12 hours, and the observation sample outward appearance is measured drug level, the drug degradation product, and result such as table 4 (unit such as preceding):
The stability test of table 4, Emulsion of the present invention 6 and 5% glucose diluent
Time (h) 02468 10 12
Outward appearance is even, and white evenly
Emulsion does not have layering, the nothing precipitation is the same the same
Concentration (mg/ml) 9.94 9.93 9.94 9.9 9.91 9.9 9.93
Total related substance 2.70 2.66 2.67 2.71 2.65 2.70 2.72
The stability test of table 5, Emulsion of the present invention 6 and 0.9%NaCl diluent
Time (h) 02468 10 12
Outward appearance is even, and white evenly
Emulsion does not have layering, the nothing precipitation is the same the same
Concentration (mg/ml) 9.94 9.90 9.97 9.90 9.86 9.83 9.88
Total related substance 2.70 2.74 2.88 2.85 2.91 2.99 2.95
60 ℃ of influence factors, quicken under 4 ℃, the 25 ℃ situations, the data that draw through high performance liquid chromatogram, the analysis of Ma Erwen particle diameter instrument, whole process, hydroxycamptothecin content does not have significant change, and total related substance obviously increases, and particle diameter keeps relative stability during studying, simulation clinical administration test specimen keeps stable, has proved that hydroxycamptothecin Emulsion physics, chemical stability are better.
This experimental technique list of references: Chinese Pharmacopoeia (two ones) national drug standards WS-XG-2002
Embodiment nine
The test of pesticide effectiveness to C26 solid tumor (intestinal cancer)
Adopt 10 one group of kunming mice, divide 6 groups, each three groups of commercially available hydroxycamptothecin injection and hydroxycamptothecin Emulsions of the present invention, three dosage group administrations respectively, continuous quiet notes 7 days were checked tumour inhibiting rate after 7 days, the result is as follows:
Tumour inhibiting rate (%)
HCPT Emulsion 2mg/Kg 63.23
1mg/Kg 47.42
0.5mg/kg 37.80
Commercially available 2mg/kg 51.55
1mg/kg 40.21
0.5mg/Kg 29.55
HCPT Emulsion group of the present invention obviously is better than commercially available similar drug group.
Glioma brain tumour (intracranial inoculation) clinical trial
Adopt the G422 mice, 10 of every compositions divide 6 groups, and each three groups of commercially available hydroxycamptothecin injection and hydroxycamptothecin Emulsions of the present invention compare test, and the dead mouse situation is observed in continuous quiet note sky, and the result is as follows:
Average natural law (my god) T-C/C (%)
HCPT Emulsion 2mg/Kg 16.3 ± 4.8 79.12
1mg/Kg 15.0±4.6 64.8
0.5mg/kg 13.4±2.9 47.25
Commercially available liquid drugs injection 2mg/Kg 15.1+3.7 65.9
1mg/Kg 13.7±3.8 50.55
0.5mg/kg 12.2±3.2 34.0
HCPT Emulsion of the present invention obviously prolongs the life span of glioma Mus than commercially available liquid drugs injection.
The Lewis lung cancer test of pesticide effectiveness
Adopt kunming mice, 10 of every compositions divide 6 groups, and commercially available liquid drugs injection and hydroxycamptothecin Emulsion of the present invention are compared its tumour inhibiting rate (continuous quiet notes 7 days), and the result is as follows:
Tumour inhibiting rate (%)
HCPT Emulsion 2mg/kg 64.44
1mg/Kg 50.63
0.5mg/Kg 38.49
Commercially available liquid drugs injection 2mg/kg 53.14
1mg/Kg 42.26
0.5mg/Kg 32.64
The more commercially available liquid drugs injection of HCPT Emulsion of the present invention suppresses the lung ratio of outflow and obviously improves.
HCPT Emulsion toxicity test of the present invention
20 of HCPT Emulsion kunming mices, male female half and half, maximum concentration (1mg/ml), maximum dosage-feeding (0.5ml), the tail vein is continuous, and administration is after 7 days, and body weight increases, no overt toxicity.The mice maximum tolerated dose is 40mg/kg.
The inferior acute toxicity test of HCPT Emulsion of the present invention quiet notes administration in continuous 7 days, male female each 3 groups of kunming mice, 10 every group, the result is as follows:
Male mouse of kunming
HCPT Emulsion LD50=3.64mg/Kg 95%--105% credibility interval
Be 3.3--4.03mg/kg
Female kunming mice
HCPT Emulsion LD50=3.76mg/Kg, the 95%--105% credibility interval is 3.26--4.35mg/Kg
This LD
50Numerical value is better than literature value.
Above experimental data fully shows, the present invention has avoided making solvent with sodium hydroxide solution, thereby prevented the E ring opening, improved curative effect of medication, reduced toxic and side effects, therefore the scope of application broadens (common liquid drugs injection should not mix use with 5% glucose), is expected to become a kind of antineoplastic new preparation of safe and reliable, determined curative effect.
The list of references of this implementation method has: (1) Zhang.D Cancer ChemotherPhermaco1998,41 (4); (2) pharmacological experiment and the guidances such as jade of money.
Claims (10)
1, a kind of hydroxycamptothecin injectable emulsion, it comprises hydroxycamptothecin 0.01～2.2%, emulsifying agent 0.3～8%, triglyceride compounds 2～30%, isotonic agent glycerol for injection 2.0～3.0% by weight percentage, all the other are water for injection.
2, according to the described injectable emulsion of claim 1, it is characterized in that: hydroxycamptothecin is 0.05～2%, emulsifying agent is 0.6～5%, the triglyceride compounds is 5～20%, isotonic agent glycerol for injection 2.2～2.5%.
3, according to claim 1 or 2 described injectable emulsions, it is characterized in that: emulsifying agent is selected from fabaceous lecithin, lecithin or non-ionic surface active agent Planck Buddhist nun 188F
68In a kind of or two kinds; The triglyceride compounds is selected from a kind of of long chain triglyceride and/or medium chain triglyceride or two kinds.
4, according to the described injectable emulsion of claim 3, it is characterized in that: long chain triglyceride is selected from a kind of in soybean oil, safflower oil, Semen Maydis oil, Oleum Cocois, the Oleum Ricini or two kinds.
5, the preparation method of claim 1 or 2 described injectable emulsions comprises the following steps:
A) it is standby to get hydroxycamptothecin, emulsifying agent, triglyceride compounds, isotonic agent glycerol for injection, water for injection;
B) hydroxycamptothecin, emulsifying agent, triglyceride compound are formed oil phase B;
C) the isotonic agent glycerol for injection is mixed formation water C with water for injection;
D) oil phase B is mixed with water C, ultrasonic or homogenizing forms Emulsion.
6, according to the described injectable emulsion of claim 1, it is characterized in that: stabilizing agent oleic acid, cholesterol and/or the enuatrol of adding 0.3～4%; 0.5～5% co-emulsifier polyvinylpyrrolidone; 0.01-0.5% antioxidant V
E0.5～7% cosolvent Polyethylene Glycol
200, Polyethylene Glycol
300, Polyethylene Glycol
400, benzyl benzoate or 1, the 2-propylene glycol.
7, the preparation method of the described injectable emulsion of claim 6 comprises the steps:
A) it is standby to get hydroxycamptothecin, emulsifying agent, triglyceride compounds, isotonic agent glycerol for injection, water for injection, stabilizing agent, co-emulsifier, antioxidant, cosolvent;
B) hydroxycamptothecin, emulsifying agent, triglyceride compounds are mixed formation oil phase B with stabilizing agent;
C) isotonic agent glycerol for injection, co-emulsifier are mixed formation water C with water for injection;
D) oil phase B is mixed with water C, ultrasonic or homogenizing forms Emulsion; Perhaps,
B) with ethanol hydroxycamptothecin and/or cosolvent are dissolved, form hydroxycamptothecin ethanol liquid B1; Emulsifying agent, triglyceride compounds are mixed formation oil phase B2 with stabilizing agent; Again hydroxycamptothecin ethanol liquid B1 is mixed with oil phase B2 and form oil phase B;
C) isotonic agent glycerol for injection, co-emulsifier are mixed formation water C with water for injection;
D) oil phase B is mixed with water C, ultrasonic or homogenizing forms Emulsion;
Perhaps,
B) with ethanol hydroxycamptothecin and/or cosolvent are dissolved, form hydroxycamptothecin ethanol liquid B1; With triglyceride compound formation oil phase B2; Again hydroxycamptothecin ethanol liquid B1 is mixed with oil phase B2 and form oil phase B;
C) isotonic agent glycerol for injection, co-emulsifier, emulsifying agent, stabilizing agent are mixed formation water C with water for injection;
D) oil phase B is mixed with water C, ultrasonic or homogenizing forms Emulsion.
8, according to the preparation method of the described injectable emulsion of claim 7, it is characterized in that:
C) excipient sorbitol, glucose, mannitol, NaCl, lactose and/or the dextran of adding 0.5-3% in water C get water D;
D) oil phase B is mixed with water D, after ultrasonic or homogenizing formed Emulsion, lyophilized preparation was made in lyophilization.
9, according to the preparation method of claim 7 or 8 described injectable emulsions, it is characterized in that comprising the steps:
A) get hydroxycamptothecin 0.05%, Polyethylene Glycol
2001%, ethanol is an amount of, and ultrasonic dissolution is made pastille solution B 1;
B) get soybean oil 10%, medium chain triglyceride 10%, fabaceous lecithin 0.6%, cholesterol 0.4% forms oil phase B2;
C) in oil phase B2, add pastille solution B 1, the ultrasonic mixing that impels, ethanol is removed in decompression, gets oil phase B;
D) get glycerol 2.5%, polyvinylpyrrolidone 4% adds injection water to 100%, gets water C;
E),, form Emulsion through ultrasound wave or the emulsifying of homogenizing instrument with water C and oil phase B mixing.
10, according to the preparation method of claim 7 or 8 described injectable emulsions, it is characterized in that comprising the steps:
A) get hydroxycamptothecin 2%, Polyethylene Glycol
2006% is an amount of with ethanol, and ultrasonic dissolution is made pastille solution B 1;
B) get soybean oil 5%, medium chain triglyceride 5%, fabaceous lecithin 2% and mix, form oil phase B2 with cholesterol 0.6%;
C) add pastille solution B 1 in oil phase B2, the ultrasonic medicinal liquid that makes is scattered in oil phase, and ethanol is removed in decompression, gets oil phase B;
D) get glycerol 2.2% and polyvinylpyrrolidone 4%, add injection water to 100%, form water C;
E),, form Emulsion through ultrasound wave or the emulsifying of homogenizing instrument with water C, oil phase D mixing.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN100333722C (en) * | 2005-03-11 | 2007-08-29 | 江苏正大天晴药业股份有限公司 | Stable oil-in-water emulsion of propyl gallate for vein and its preparing method |
| CN100349570C (en) * | 2004-11-26 | 2007-11-21 | 复旦大学 | 10-hydoxy camptothecin self micro emulsifieation composition |
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| CN1951367B (en) * | 2006-08-08 | 2012-05-30 | 沈阳药科大学 | Fat emulsion containing hydroxycamptothecine and preparation method thereof |
| CN102988366A (en) * | 2012-12-31 | 2013-03-27 | 成都中医药大学 | Use and nasal administration medicine of hydroxycamptothecine |
| CN103462892A (en) * | 2007-11-28 | 2013-12-25 | 联邦科学和工业研究组织 | Nanoemulsions |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN100349570C (en) * | 2004-11-26 | 2007-11-21 | 复旦大学 | 10-hydoxy camptothecin self micro emulsifieation composition |
| CN100333722C (en) * | 2005-03-11 | 2007-08-29 | 江苏正大天晴药业股份有限公司 | Stable oil-in-water emulsion of propyl gallate for vein and its preparing method |
| CN100367951C (en) * | 2005-12-16 | 2008-02-13 | 石药集团恩必普药业有限公司 | Butyl benzene phthalein vein emulsion and its application |
| US10463614B2 (en) | 2005-12-16 | 2019-11-05 | Shijiazhuang Pharma Group Nbp Pharmaceutical Co. | Butylphthalide intravenous emulsion and application thereof |
| CN1951367B (en) * | 2006-08-08 | 2012-05-30 | 沈阳药科大学 | Fat emulsion containing hydroxycamptothecine and preparation method thereof |
| CN103462892A (en) * | 2007-11-28 | 2013-12-25 | 联邦科学和工业研究组织 | Nanoemulsions |
| US9649275B2 (en) | 2007-11-28 | 2017-05-16 | Commonwealth Scientific And Industrial Research Organisation | Nanoemulsions |
| CN102988366A (en) * | 2012-12-31 | 2013-03-27 | 成都中医药大学 | Use and nasal administration medicine of hydroxycamptothecine |
| CN102988366B (en) * | 2012-12-31 | 2014-07-02 | 成都中医药大学 | Use and nasal administration medicine of hydroxycamptothecine |
| CN108824063A (en) * | 2016-12-03 | 2018-11-16 | 潍坊恒联特种纸有限公司 | A kind of coating process of single side Blue Engineering paper |
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