CN1593417A - Lipid emulsions of camptothecin derivative and its preparation - Google Patents
Lipid emulsions of camptothecin derivative and its preparation Download PDFInfo
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- CN1593417A CN1593417A CN 200410041190 CN200410041190A CN1593417A CN 1593417 A CN1593417 A CN 1593417A CN 200410041190 CN200410041190 CN 200410041190 CN 200410041190 A CN200410041190 A CN 200410041190A CN 1593417 A CN1593417 A CN 1593417A
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Abstract
The invention provides a Hydroxy camptothecin derivative fat emulsion suitable for industrial production, which comprises oil for injection, emulsifying agent, polyethylene glycol or polyvidone or hydroxypropyl beta-cyclodextrin assolubilising agent, The emulsion can improve the Hydroxy camptothecin derivative in fatty grease oil phase.
Description
Technical field
The present invention relates to a kind of camptothecin derivative lipomul and preparation method thereof, be specially intravenous injection fatty emulsion that contains the camptothecine or derivatives thereof and preparation method thereof.
Background technology
Camptothecin derivative has the broad-spectrum anti-tumor effect as selective d NA topoisomerase enzyme inhibitor.The derivant that studies show that camptothecine and many camptothecines is unstable in aqueous solution and blood (PH=7.4), and lactonic ring E-ring ring opening hydrolysis becomes hydroxyl to contract hydrochlorate and loses activity.But because camptothecine and derivant dissolubility in aqueous solution thereof are low, existing injection can only be with its hydrolysis under the alkaline pH condition, and this just greatly reduces its anti-tumor in vivo effect.On the other hand, biopharmaceutics studies show that the camptothecin derivative half-life is short, and effect is held time shorter, will certainly increase the toxic reaction that is directly proportional with dosage and increase dosage.In addition, similar to other cancer therapy drugs, 10-hydroxycamptothecine is all very big to tumor cell and Normocellular lethality, and patient's body constitution sharply descends in chemotherapy process, does not often adhere to several courses of treatment and is forced to drug withdrawal.
The conventional preparation method of fat milk system adds emulsifying agent with refined plant oil and water for injection is fully emulsified and oil/water type that make does not have bacterial emulsion, and its modal problem is a poor stability, places back generation layering.When camptothecin derivative was prepared into lipomul, because medicine dissolubility in the fat milk oil phase is extremely low, the fat milk that obtains of formulation produced precipitation owing to medicine that can't dissolution treatment dosage routinely.The reaction of the gastrointestinal toxicity of camptothecin derivative such as 10-hydroxycamptothecine is big in addition.
Summary of the invention
The technical problem to be solved in the present invention is how to increase camptothecin derivative dissolubility in the fat milk oil phase, and it stably is encapsulated in the fat milk oil phase.Make the lipomul good stability of making, place the back medicine and do not separate out, and do not produce layering.Also wish improvement, under the prerequisite that camptothecin derivative activity and drug effect all are significantly increased, reduce or reduce the toxic and side effects of camptothecin derivative as much as possible by dosage form and adjuvant.
For addressing the above problem, the invention provides following technical proposals.
A kind of lipomul comprises camptothecin derivative, oil for injection, emulsifying agent, solubilizing agent.
In the described lipomul, camptothecin derivative is selected from 10-hydroxycamptothecine, topology is for agreeing, irinotecan, 7-ethyl-10-hydroxycamptothecine, 9-amino-20 (S) camptothecine, 9-nitro-20 (S) camptothecine, 10,11-methylene dioxy base camptothecine, 10,11-ethylidene dioxy base camptothecine, the 7-ethyl-camptothecin, 9-chloro-10,11-methylene dioxy base camptothecine, 9,10-dichloro-camptothecine, 7-trimethyl silicane ethyl-10-hydroxycamptothecine, 7-tert-butyl group first wane-camptothecine, 7-(4-methyl isophthalic acid-piperazine methyl)-10, one or more mixture in 11-ethylidene dioxy base camptothecine and the high camptothecin derivant; Oil for injection is selected from one or more mixture in soybean oil, Oleum Ricini, Oleum Camelliae, Oleum Sesami, safflower oil, Oleum Gossypii semen, middle long-chain fatty acid ester, the olive oil; Emulsifying agent is selected from one or two or more kinds mixture among phospholipid, the general sieve stream Buddhist nun; Solubilizing agent is selected from Polyethylene Glycol, polyvidone and/or hydroxypropyl; Also comprise antioxidant.It contains camptothecin derivative 0.001%-0.05%, oil for injection 5-20%, emulsifying agent 2-9%, solubilizing agent is selected from Polyethylene Glycol 5-20%, polyvidone 1-6% or hydroxypropyl 1-6% by weight; Antioxidant is selected vitamin E for use; High camptothecin derivant is BN-80915.
Lipomul preferably, by weight, contain camptothecin derivative 0.002%-0.04%, oil for injection 6-18%, phosphatidase 11-5%, general sieve stream Buddhist nun 1-4%, solubilizing agent are selected from Polyethylene Glycol 6-18% or hydroxypropyl 2-5%, antioxidant 0.01-0.03%; Water for injection adds to 100%.
Lipomul by weight, contains camptothecin derivative 0.003%-0.03%, oil for injection 8-16%, phosphatidase 12-4% preferably, and general sieve stream Buddhist nun 2-3%, solubilizing agent are selected from hydroxypropyl 2-5% or polyvidone 2-5%.
Phospholipid in the aforementioned lipomul is soybean lecithin, Ovum Gallus domesticus Flavus lecithin and/or synthetic phospholipid; Other also comprises isoosmotic adjusting agent, and water for injection adds to 100%.
The preparation method of aforementioned lipomul comprises the steps:
Get oil for injection, camptothecin derivative in 50-200 ℃ of mixing, temperature adds phospholipid during to 50-80 ℃, mixes forming mixed liquor (1);
Water for injection, emulsifying agent, isoosmotic adjusting agent are mixed with solubilizing agent, form water (2);
Water (2) is mixed with mixed liquor (1), make colostrum, behind pH regulator agent adjusting pH to 4-8, carry out homogenize again; Make the lipomul that contains camptothecin derivative.
Lipomul is preparation method preferably: get oil for injection, camptothecin derivative in 100-180 ℃ of mixing, be cooled to 50-80 ℃, add phospholipid, antioxidant mixing, form mixed liquor (1); The water for injection of emulsifying agent with 50-80 ℃ is mixed, mix with the water liquid that contains isoosmotic adjusting agent and solubilizing agent again, form water (2); Water (2) is poured in the mixed liquor (1), after high speed dispersion under the 50-80 ℃ of condition, made colostrum in mechanical agitation 2-3 hour, regulate pH to 4-8 with the pH regulator agent; Carry out homogenize again, make the lipomul that contains camptothecin derivative.
Lipomul is appropriate preparation method more: oil for injection, camptothecin derivative, phospholipid and antioxidant are equaled 50-80 ℃ of mixing, form mixed liquor (1); The water for injection of emulsifying agent with 50-80 ℃ is mixed, mix with the water liquid that contains isoosmotic adjusting agent and solubilizing agent again, form water (2); Water (2) is poured in the mixed liquor (1), after high speed dispersion under the 50-80 ℃ of condition, made colostrum in mechanical agitation 2-3 hour, regulate pH to 4-8 with the pH regulator agent; Carry out homogenize again, make the lipomul that contains camptothecin derivative.
The present invention has not only increased camptothecin derivative dissolubility in the fat milk oil phase, and it stably is encapsulated in the fat milk oil phase owing to screened specific solubilizing agent.Make the lipomul good stability of making, place the back medicine and do not separate out, and lipomul does not produce layering.Can solve camptothecin derivative in the problem aspect galenic pharmacy and the biopharmaceutics two with fat milk as carrier.Because camptothecin derivative also stably is encapsulated in the fat milk oil phase with the closed loop solubilising, before arriving target site, can keep activity form, strengthen its drug effect, in addition, because the drug slow that is encapsulated in the Emulsion inner phase discharges the residence time of possible prolong drug in blood.Camptothecin derivative fat milk of the present invention is compared with normal injection, and activity and drug effect all are significantly increased, and toxic and side effects significantly descends.The Nutrition of fat milk has also improved the life quality of mice with tumor.
Summarize preparation method of the present invention below:
Method one
Used for intravenous injection oil (5%-20%) is dropped into container later with 0.2 μ m membrane filtration, camptothecin derivative (0.001%-0.05%) is put in the container, after high temperature (100-200 ℃) mechanical agitation treats that medicine disperses, being cooled to (50-80 ℃) drops into phospholipid (1%-5%), can add or not add antioxidant, continue mechanical agitation and treat the phospholipid dissolving, mix homogeneously forms mixed liquor;
An amount of water for injection is placed another container, be heated to (50-80 ℃), add emulsifying agent such as phospholipid (1%-5%), general sieve stream Buddhist nun dispersed with stirring such as (1%-8%), with isoosmotic adjusting agent glycerol (2.5%), water dissolution such as solubilizing agent such as Polyethylene Glycol, polyvidone or hydroxypropyl beta cyclodextrin (1%-10%) adds wherein later with 0.2 μ m membrane filtration.
Water is under agitation poured in the mixing oil phase, after high speed dispersion under the 50-80 ℃ of condition, made colostrum in mechanical agitation 2-3 hour, regulate pH to 4-8 with the pH regulator agent;
The colostrum that makes is moved into high pressure homogenization machine, secondary homogenize;
Through filtering with microporous membrane, logical nitrogen, fill, gland.
The fat milk that fill is good places the rotation high-pressure sterilizing pot to sterilize.
Wherein oil for injection can be selected one or more mixture in soybean oil, Oleum Ricini, Oleum Camelliae, Oleum Sesami, safflower oil, Oleum Gossypii semen, middle long-chain fatty acid ester, the olive oil, emulsifying agent can be selected soybean lecithin, Ovum Gallus domesticus Flavus lecithin, synthetic phospholipid, general sieve stream Buddhist nun etc., and solubilizing agent can be selected Polyethylene Glycol, polyvidone, hydroxypropyl etc.
Method two
(1) used for intravenous injection oil (5%-20%) drops into container later through 0.2 μ m membrane filtration, camptothecin derivative (0.001%-0.05%) is also put in the container, be heated to 50-80 ℃ and stir, add phospholipid (1%-5%), can add or not add antioxidant, continue mechanical agitation and treat the phospholipid dissolving, mix homogeneously forms mixed liquor.(2) in another preparing tank, add suitable quantity of water, be heated to 50-80 ℃, add emulsifying agent such as phospholipid (1%-10%), general sieve stream Buddhist nun (1%-8%) dispersed with stirring.Water dissolution such as isoosmotic adjusting agent glycerol and solubilizing agent such as Polyethylene Glycol, polyvidone or hydroxypropyl beta cyclodextrin (1%-10%) also adds in the jar later with 0.2 μ m membrane filtration.(3) water that step (2) is obtained is under agitation poured in the mixed phase that step (1) obtains, and makes colostrum in mechanical agitation 2-3 hour after high speed dispersion under the 50-80 ℃ of condition, regulates pH to 4-8 with the pH regulator agent.Finely dispersed colostric fluid filters with 40 μ m filter membranes, carries out twice emulsifying through the high pressure dispersing emulsification machine then.Under agitation add water to capacity, transfer pH to check semi-finished product.Through the filtration of 10 μ m filter membranes, fill.Fill nitrogen, add rubber stopper and jewelling lid.Carry out 121 ℃ with the rotation autoclave, F0 sterilizes under 20 the condition.After sterilization finishes, cooling gradually.
Characteristics of the present invention and effect are that preparation method is simple, and not high and do not have specific (special) requirements to the equipment requirements used in the preparation process, the time is short, and cost is low, is beneficial to production in enormous quantities.
The specific embodiment
Intravenous injection level soybean oil (Tieling medicinal oil company limited); Injection fabaceous lecithin (Shanghai Taiwei Pharmaceutical Co., Ltd.); General sieve stream Buddhist nun (BASF AG); Middle long-chain fatty acid ester (Colorcon company).
Embodiment 1
Injection soybean oil 20g, 10-hydroxycamptothecine 20mg are put in the container, this container is placed oil bath, be heated to about 150 ℃, be stirred to medicine and disperse, be cooled to 80 ℃, drop into lecithin 1.5g, vitamin E 100mg and be stirred to the evenly mixed phase of phospholipid dissolving formation.Water for injection 80ml is placed another container, add general sieve stream Buddhist nun 4g, polyvidone 4g, glycerol 2.5g and lecithin 3.5g and form water in 80 ℃ of stirring and dissolving; The mixed liquid that will contain 10-hydroxycamptothecine, soybean oil and lecithin mixes with the water that contains general sieve stream Buddhist nun, glycerol, polyvidone (PVP) and lecithin under 80 ℃, mechanical agitation, and continue down mechanical agitation at 80 ℃ and made colostrum in 1 hour, and with citron acid for adjusting pH value to 6; The colostrum that makes is disperseed through high speed dispersor, move into high pressure homogenizer, homogenize arrives till the emulsion droplet particle diameter passed examination; Again with the colostrum emulsion through filtering with microporous membrane, fill, logical nitrogen, gland; Carry out 121 ℃ with the rotation autoclave, F0 sterilizes under 20 the condition.After sterilization finishes, cooling gradually.Store down at 4-10 ℃.Promptly make the 10-hydroxycamptothecine fat emulsion intravenous fluid injection formulation of 20mg/100ml.
4stability determination system takes the fat milk of prepared fresh, places tool plug centrifuge tube, behind the centrifugal 15min of 4000rpm, does not find layering, does not see that also xanchromatic drug precipitation separates out.The shady and cool place of room temperature stores half a year, and significant change does not all take place for physicochemical property such as Emulsion outward appearance, particle diameter, Zeta potential and content, shows that Emulsion is stable.
Embodiment 2
Injection soybean oil 10g, medium chain fatty acid ester 5g, 10-hydroxycamptothecine 2mg are put in the container, this container is placed oil bath, be heated to about 120 ℃, being stirred to medicine disperses, be cooled to 70 ℃, drop into lecithin 2.5g, vitamin e1 00mg and be stirred to the evenly mixed phase of phospholipid dissolving formation.Water for injection 85ml is placed another container, add general sieve stream Buddhist nun 5g, Polyethylene Glycol 5g, glycerol 2.5g and lecithin 4.5g and form water in 70 ℃ of stirring and dissolving; The mixed liquid that will contain 10-hydroxycamptothecine, soybean oil and lecithin is mixed with the water that contains general sieve stream Buddhist nun, glycerol, Polyethylene Glycol and lecithin under 70 ℃, mechanical agitation, and continues mechanical agitation down at 70 ℃ and made colostrum in 1 hour.The colostrum that makes is disperseed through high speed dispersor, move into high pressure homogenizer, homogenize arrives till the emulsion droplet particle diameter passed examination; Again with the colostrum emulsion through filtering with microporous membrane, fill, logical nitrogen, sealing by fusing; Carry out 121 ℃ with the rotation autoclave, F0 sterilizes under 20 the condition.After sterilization finishes, cool off gradually towards hot water.Store down at 4-10 ℃.Promptly make the 10-hydroxycamptothecine fat emulsion intravenous fluid injection formulation of 2mg/100ml.
4stability determination system takes the fat milk of prepared fresh, places tool plug centrifuge tube, behind the centrifugal 15min of 4000rpm, does not find layering, does not see that also xanchromatic drug precipitation separates out.The shady and cool place of room temperature stores half a year, and significant change does not all take place for physicochemical property such as Emulsion outward appearance, particle diameter, Zeta potential and content, shows that Emulsion is stable.
Embodiment 3
Injection soybean oil 15g, 10-hydroxycamptothecine 8mg are put in the container, this container is placed oil bath, be heated to about 150 ℃, be stirred to medicine and disperse, be cooled to 70 ℃, input 1.5g lecithin, vitamin E 100mg are stirred to the phospholipid dissolving and form evenly mixed phase.Water for injection 85ml is placed another container, add general sieve stream Buddhist nun 5g, hydroxypropyl beta cyclodextrin 3g, glycerol 2.5g and lecithin 2.5g and form water in 70 ℃ of stirring and dissolving.The mixed liquid that will contain 10-hydroxycamptothecine, soybean oil and lecithin is mixed with the water that contains general sieve stream Buddhist nun, glycerol, hydroxypropyl beta cyclodextrin and lecithin under 70 ℃, mechanical agitation, and continues mechanical agitation down at 70 ℃ and made colostrum in 1 hour.The colostrum that makes is disperseed through high speed dispersor, move into high pressure homogenizer, homogenize arrives till the emulsion droplet particle diameter passed examination; Again with the colostrum emulsion through filtering with microporous membrane, fill, logical nitrogen, sealing by fusing; Carry out 121 ℃ with the rotation autoclave, F0 sterilizes under 20 the condition.After sterilization finishes, cool off gradually towards hot water.Store down at 4-10 ℃.Promptly make the 10-hydroxycamptothecine fat emulsion intravenous fluid injection formulation of 8mg/100ml.
4stability determination system takes the fat milk of prepared fresh, places tool plug centrifuge tube, behind the centrifugal 15min of 4000rpm, does not find layering, does not see that also xanchromatic drug precipitation separates out.The shady and cool place of room temperature stores half a year, and significant change does not all take place for physicochemical property such as Emulsion outward appearance, particle diameter, Zeta potential and content, shows that Emulsion is stable.
Embodiment 4
Injection soybean oil 10g, 9-nitro-20 (S) camptothecine 6mg are put in the container, this container is placed oil bath, be heated to about 120 ℃, be stirred to medicine and disperse, be cooled to 80 ℃, input 2.5g lecithin, vitamin E 100mg are stirred to the phospholipid dissolving and form evenly mixed phase.Water for injection 90ml is placed another container, add general sieve stream Buddhist nun 4g, glycerol 2.5g, hydroxypropyl 4g, reach lecithin 4.5g in 80 ℃ of stirring and dissolving formation waters.The mixed liquid that will contain 9-nitro-20 (S) camptothecine, soybean oil and lecithin is mixed with above-mentioned water under 80 ℃ of mechanical agitation, and continues mechanical agitation down at 80 ℃ and made colostrum in 1 hour.The colostrum that makes is disperseed through high speed dispersor, move into high pressure homogenizer, homogenize arrives till the emulsion droplet particle diameter passed examination; Again with the colostrum emulsion through filtering with microporous membrane, fill, logical nitrogen, sealing by fusing; Carry out 121 ℃ with the rotation autoclave, F0 sterilizes under 20 the condition.After sterilization finishes, cool off gradually towards hot water.Store down at 4-10 ℃.Promptly make 9-nitro-20 (S) the camptothecine fat emulsion intravenous fluid injection formulation of 6mg/100ml.
4stability determination system takes the fat milk of prepared fresh, places tool plug centrifuge tube, behind the centrifugal 15min of 4000rpm, does not find layering, does not see that also xanchromatic drug precipitation separates out.The shady and cool place of room temperature stores half a year, and significant change does not all take place for physicochemical property such as Emulsion outward appearance, particle diameter, Zeta potential and content, shows that Emulsion is stable.
Embodiment 5
Injection soybean oil 10g, middle long-chain fatty acid ester 5g are put in the container, this container is placed oil bath, be heated to 80 ℃, add 9-nitro-20 (S) camptothecine 1mg, be stirred to and be uniformly dispersed, adding 2.5g lecithin, (can add also not vitaminize E 100mg) then is stirred to the phospholipid dissolving and forms evenly mixed phase.Water for injection 85ml is placed another container, add general sieve stream Buddhist nun 4g, polyvidone 3g, glycerol 2.5g, reach lecithin 4.5g in 80 ℃ of stirring and dissolving formation waters.The mixed liquid that will contain 9-nitro-20 (S) camptothecine, soybean oil and lecithin is mixed with above-mentioned water under 80 ℃ of mechanical agitation, and continues mechanical agitation down at 80 ℃ and made colostrum in 1 hour.The colostrum that makes is disperseed through high speed dispersor, move into high pressure homogenizer, homogenize arrives till the emulsion droplet particle diameter passed examination; Again with the colostrum emulsion through filtering with microporous membrane, fill, logical nitrogen, sealing by fusing; Carry out 121 ℃ with the rotation autoclave, F0 sterilizes under 20 the condition.After sterilization finishes, cool off gradually towards hot water.Store down at 4-10 ℃.Promptly make 9-nitro-20 (S) the camptothecine fat emulsion intravenous fluid injection formulation of 1mg/100ml.
4stability determination system takes the fat milk of prepared fresh, places tool plug centrifuge tube, behind the centrifugal 15min of 4000rpm, does not find layering, does not see that also xanchromatic drug precipitation separates out.The shady and cool place of room temperature stores half a year, and significant change does not all take place for physicochemical property such as Emulsion outward appearance, particle diameter, Zeta potential and content, shows that Emulsion is stable.
Embodiment 6
Pharmacodynamic study;
S180 ascites tumor model mice is made: get well-grown S180 ascites tumor under aseptic condition, with the normal saline dilution, make 1.0 * 106/ml tumor cell suspension, be inoculated in 90 mouse peritoneals, every is respectively 0.2ml.
Laboratory animal and grouping: 90 of male closed colony Kunming mouses, body weight 18-22g, make the EAC model mouse, be divided into A, B, C group at random, 30 every group are respectively A: normal saline matched group B:10-alkyl camptothecine injection treatment group C:10-hydroxy camptothecin fat milk treatment group
Every mouse tail vein injection of experimental technique: A group normal saline matched group 0.9% normal saline 0.2ml., inject once every day, injected continuously 8 days
B organizes 10-hydroxycamptothecine injection for treating group every mouse tail vein injection 10-hydroxycamptothecine injection (0.8mg/kg), and inject once every day, injected continuously 8 days.
C organizes 10-hydroxycamptothecine fat milk treatment group every mouse tail vein injection 0.08mg/ml 10-hydroxycamptothecine fat milk of the present invention (0.8mg/kg), and inject once every day, injected continuously 8 days.
The mice standing feedstuff of standing feedstuff of feeding in the administration cycle, normal drinking-water.Disconnected awl is put to death mice after 8 days, isolates the ascites tumor body, removes epidermal tissue and accurately weighs, and calculate tumour inhibiting rate.
Tumour inhibiting rate=(A-B)/A * 100% (A is that the average tumor of physiology saline control group is heavy, and B is that the average tumor of treatment group is heavy)
Relatively whether the tumour inhibiting rate of 10-hydroxycamptothecine injection for treating group and 10-hydroxycamptothecine fat milk treatment group exists significant difference.
Experimental result: after injecting 8 days continuously, the average tumor of normal saline matched group heavily is 2.9 grams, and the average tumor of 10-hydroxycamptothecine injection for treating group heavily is 2.6 grams, and suppression ratio is 10.34%; It heavily is 1.5 grams that average tumor is organized in the treatment of 10-hydroxycamptothecine fat milk, and suppression ratio is 48.27%.There is significant difference (p＜0.01) in the tumour inhibiting rate of 10-hydroxycamptothecine injection for treating group and 10-hydroxycamptothecine fat milk treatment group.10-hydroxycamptothecine fat milk tumour inhibiting rate is 5 times of injection approximately, because 10-hydroxycamptothecine is encapsulated in closed loop in the emulsion droplet of fat milk, activity and drug effect all are significantly increased.
In addition, 10-hydroxycamptothecine injection for treating group appetite during administration descends, and average weight alleviates 10-40% after 8 days, and dead mouse is arranged, and becomes celestial to see that gastrointestinal has the petechia, and this is relevant to the digestive tract toxic reaction with 10-hydroxycamptothecine.But 10-hydroxycamptothecine fat milk treatment group average weight increases 5-10%, and none death, and, gastrointestinal tract is dissected and do not seen that the petechia is arranged.Show that further 10-hydroxycamptothecine is solubilized in the fat milk with the lactone closed loop, toxic and side effects significantly descends.The Nutrition of fat milk has also improved the life quality of mice with tumor.
Claims (10)
1, a kind of lipomul comprises camptothecin derivative, oil for injection, emulsifying agent, solubilizing agent.
2, the lipomul of claim 1, described camptothecin derivative is selected from 10-hydroxycamptothecine, topology is for agreeing, irinotecan, 7-ethyl-10-hydroxycamptothecine, 9-amino-20 (S) camptothecine, 9-nitro-20 (S) camptothecine, 10,11-methylene dioxy base camptothecine, 10,11-ethylidene dioxy base camptothecine, the 7-ethyl-camptothecin, 9-chloro-10,11-methylene dioxy base camptothecine, 9,10-dichloro-camptothecine, 7-trimethyl silicane ethyl-10-hydroxycamptothecine, 7-tert-butyl group first wane-camptothecine, 7-(4-methyl isophthalic acid-piperazine methyl)-10, one or more mixture in 11-ethylidene dioxy base camptothecine and the high camptothecin derivant; Oil for injection is selected from one or more mixture in soybean oil, Oleum Ricini, Oleum Camelliae, Oleum Sesami, safflower oil, Oleum Gossypii semen, middle long-chain fatty acid ester, the olive oil; Emulsifying agent is selected from one or two or more kinds mixture among phospholipid, the general sieve stream Buddhist nun; Solubilizing agent is selected from Polyethylene Glycol, polyvidone and/or hydroxypropyl; Also comprise antioxidant.
3, the lipomul of claim 2 by weight, contains camptothecin derivative 0.001%-0.05%, oil for injection 5-20%, emulsifying agent 2-9%, solubilizing agent is selected from Polyethylene Glycol 5-20%, polyvidone 1-6% or hydroxypropyl 1-6%; Antioxidant is selected vitamin E for use; High camptothecin derivant is BN-80915.
4, the lipomul of claim 3, by weight, contain camptothecin derivative 0.002%-0.04%, oil for injection 6-18%, phosphatidase 11-5%, general sieve stream Buddhist nun 1-4%, solubilizing agent are selected from Polyethylene Glycol 6-18% or hydroxypropyl 2-5%, antioxidant 0.01-0.03%; Water for injection adds to 100%.
5, the lipomul of claim 4 by weight, contains camptothecin derivative 0.003%-0.03%, oil for injection 8-16%, phosphatidase 12-4%, and general sieve stream Buddhist nun 2-3%, solubilizing agent are selected from hydroxypropyl 2-5% or polyvidone 2-5%.
6, the lipomul of claim 5, wherein phospholipid is soybean lecithin, Ovum Gallus domesticus Flavus lecithin and/or synthetic phospholipid.
7, the lipomul of claim 6 also comprises isoosmotic adjusting agent, and water for injection adds to 100%.
8, the preparation method of claim 1-7 lipomul comprises the steps:
Get oil for injection, camptothecin derivative in 50-200 ℃ of mixing, temperature adds phospholipid during to 50-80 ℃, mixes forming mixed liquor (1);
Water for injection, emulsifying agent, isoosmotic adjusting agent are mixed with solubilizing agent, form water (2);
Water (2) is mixed with mixed liquor (1), make colostrum, behind pH regulator agent adjusting pH to 4-8, carry out homogenize again; Make the lipomul that contains camptothecin derivative.
9, the preparation method of the lipomul of claim 8 is characterized in that: get oil for injection, camptothecin derivative in 100-180 ℃ of mixing, be cooled to 50-80 ℃, add phospholipid, antioxidant mixing, form mixed liquor (1); The water for injection of emulsifying agent with 50-80 ℃ is mixed, mix with the water liquid that contains isoosmotic adjusting agent and solubilizing agent again, form water (2); Water (2) is poured in the mixed liquor (1), after high speed dispersion under the 50-80C condition, made colostrum in mechanical agitation 2-3 hour, regulate pH to 4-8 with the pH regulator agent; Carry out homogenize again, make the lipomul that contains camptothecin derivative.
10, the preparation method of the lipomul of claim 8 is characterized in that: oil for injection, camptothecin derivative, phospholipid and antioxidant are equaled 50-80 ℃ of mixing, form mixed liquor (1); The water for injection of emulsifying agent with 50-80 ℃ is mixed, mix with the water liquid that contains isoosmotic adjusting agent and solubilizing agent again, form water (2); Water (2) is poured in the mixed liquor (1), after high speed dispersion under the 50-80 ℃ of condition, made colostrum in mechanical agitation 2-3 hour, regulate pH to 4-8 with the pH regulator agent; Carry out homogenize again, make the lipomul that contains camptothecin derivative.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100349570C (en) * | 2004-11-26 | 2007-11-21 | 复旦大学 | 10-hydoxy camptothecin self micro emulsifieation composition |
| CN1951367B (en) * | 2006-08-08 | 2012-05-30 | 沈阳药科大学 | Fat emulsion containing hydroxycamptothecine and preparation method thereof |
| CN106619509A (en) * | 2016-12-21 | 2017-05-10 | 山东大学 | Oxaliplatin-and-irinotecan jointly loading lipid emulsion and preparing method thereof |
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2004
- 2004-07-06 CN CN 200410041190 patent/CN1593417A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100349570C (en) * | 2004-11-26 | 2007-11-21 | 复旦大学 | 10-hydoxy camptothecin self micro emulsifieation composition |
| CN1951367B (en) * | 2006-08-08 | 2012-05-30 | 沈阳药科大学 | Fat emulsion containing hydroxycamptothecine and preparation method thereof |
| CN106619509A (en) * | 2016-12-21 | 2017-05-10 | 山东大学 | Oxaliplatin-and-irinotecan jointly loading lipid emulsion and preparing method thereof |
| CN106619509B (en) * | 2016-12-21 | 2020-02-18 | 山东大学 | Oxaliplatin and irinotecan co-loaded drug-loaded fat emulsion and preparation method thereof |
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