CN1771968A - Ursolic acid fat emulsion injection and its prepn - Google Patents
Ursolic acid fat emulsion injection and its prepn Download PDFInfo
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- CN1771968A CN1771968A CN 200510114817 CN200510114817A CN1771968A CN 1771968 A CN1771968 A CN 1771968A CN 200510114817 CN200510114817 CN 200510114817 CN 200510114817 A CN200510114817 A CN 200510114817A CN 1771968 A CN1771968 A CN 1771968A
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Abstract
The present invention relates to one kind of ursolic acid fat emulsion injection and its preparation. The fat emulsion consists of ursolic acid as active component and medicinal supplementary material, and consists of ursolic acid 0.01-0.15 wt%, oil for injection 5-30 wt%, emulsifier 1-9 wt%, solubilizer 1-6 wt%, isosmotic agent 2-2.5 wt%, and antioxidant 0.01-0.03 wt%, except water for injection. The present invention has simple preparation process, and the injection may be used clinically in intravenous injection, and has high bioavailability, high stability, raised treating effect, slow releasing and targeting effect, and energy providing effect.
Description
Technical field
The present invention relates to a kind of medicine fat milk injection, particularly a kind of ursolic acid fat emulsion injection and preparation method thereof.
Background technology
Ursolic acid is a kind of pentacyclic triterpenoid that is present in the natural plants, form with episome and glycocide is present in many plants, ursolic acid (Ursolic acid) has another name called maloic acid, ursolic acid, mainly be present in the plants such as phragmites communis, Herba Plantaginis, Folium Crataegi, Fructus Ligustri Lucidi (leaf), rhododendron leaves, in Chinese medicine Fructus Corni, Spica Prunellae, Fructus Crataegi etc., also exist, be one of active ingredient of these Chinese medicines.At present, domestic ursolic acid raw material mainly is to extract to obtain from plants such as the Folium Ligustri Lucidi, Folium Crataegi and Fructus Corni.Highly purified ursolic acid composition is a kind of absinthe-green powder, has special characteristic odor, and is water insoluble, dissolve in the ethanol, and the no foreign body in dissolving back, its molecular structural formula is as follows:
Ursolic acid has various biological effects such as calmness, antiinflammatory, antibiotic, anti-diabetic, antiulcer, blood sugar lowering.Recent study personnel find that ursolic acid has carcinogenesis, anti-promoting, induce differentiation of F9 teratocarcinoma cell and blood vessel formation against function, external day, beautiful, method, English, states such as Korea Spro find that also ursolic acid is to renal carcinoma, melanoma (Z.Naturforsch, 56 (1-2): 45-8,2001), colon cancer, ovarian cancer, central nervous system's cancer, people's nonsmall-cell lung cancer (Planta Med, 66 (5): 485-6,2000), people's epidermoidoma (AnticancerRes.20 (6B): 4563-70,2000), people's hepatocarcinoma, ovarian cancer (Arch Pharm Res, 23 (2): 155-8,2000), people's acute promyelocytic leukemia (Pharmacol Toxicol, 86 (2): 53-8,2000) and teratoma cancerous cell such as (PlantaMed, 64 (5): 468-70,1998) certain cellulotoxic effect is arranged.So ursolic acid might become the new type anticancer medicine.In addition, ursolic acid have to kill and suppress Streptococcus mutans group and periodontal pathogen, oral cavity carcinoma of tongue cell has a significant effect.Therefore, can be used as the medicine that effective ingredient is used to prepare dental care product, oral health care product and preparation treatment oral disease.
At present, the pharmacological action of relevant ursolic acid also rests on breadboard research work, and the research of external relevant ursolic acid also all is the common form of raw material, the not preparation of ursolic acid listing.The domestic in recent years people of having has declared tablet, capsule, the granule of ursolic acid, the Chinese patent (application number is 99126892-X) of oral liquid, is used for the treatment of viral hepatitis.Ursolic acid is the strong-hydrophobicity medicine, water solublity is less, utilize general galenic pharmacy method, can not effectively solve the problem of bioavailability, for this reason, the someone has declared the relevant freeze-dried powder of ursolic acid: ursolic acid cyanoacrylate nano particle freeze-dried powder injection and preparation method (application number is CN02147712.4), ursolic acid fabaceous lecithin nano-granule freeze-dried powder pin and preparation method (application number is CN02147711.6), ursolic acid polylactic acid nano particle freeze-dried powder and preparation method (application number is CN02147713.2).Though freeze-dried powder has solved the problem of bioavailability, in slow release and target administration effect, especially to be behind the tumor operation weakness, need give the patient of certain energy, certain scarce limit is arranged.Therefore, the invention provides a kind of ursolic acid fat emulsion injection, can improve the bioavailability of ursolic acid, certain slow release and target administration effect are arranged again, can also provide certain energy to patient simultaneously.
Summary of the invention
The technical problem to be solved in the present invention just provides a kind of ursolic acid fat emulsion injection and preparation method thereof, prepared injection can be applied to clinical as the dosage form of intravenously administrable, improve the bioavailability of ursolic acid, play slow release, targeting simultaneously and the effect of energy is provided.
Technical scheme provided by the invention is: ursolic acid fat emulsion injection, this lipomul is that active component and pharmaceutic adjuvant are formed with the ursolic acid, its weight portion is formed and comprised: ursolic acid 0.01%-0.15%, oil for injection 5-30%, emulsifying agent 1-9%, solubilizing agent 1-6%, isotonic agent 2-2.5%, antioxidant 0.01-0.03%, all the other are water for injection.The preferable of above-mentioned ursolic acid fat emulsion injection consists of: ursolic acid 0.01%-0.15%, oil for injection 10%, emulsifying agent 1.2%, solubilizing agent 1%, isotonic agent 2.2%, antioxidant 0.01%, all the other are water for injection.
Wherein oil for injection is selected from one or more the mixture in soybean oil, Oleum Camelliae, Oleum Sesami, middle long-chain fatty acid ester, the olive oil; Emulsifying agent is a kind of in soybean lecithin, Ovum Gallus domesticus Flavus lecithin, the synthetic phospholipid.Solubilizing agent is a kind of in Polyethylene Glycol, hydroxypropyl, the polyvidone, and antioxidant is selected vitamin E for use, and isoosmotic adjusting agent is selected glycerol for use.
The present invention also provides the preparation method of above-mentioned fat milk injection, and this method comprises the following steps:
1. ursolic acid is pulverized, the particle diameter that makes ursolic acid is less than 80 μ m;
2. get the ursolic acid pulverized, oil for injection in 50-100 ℃ of mixing, temperature adds phospholipid during to 50-80 ℃, mixes forming mixed liquor (1);
3. water for injection, emulsifying agent, isoosmotic adjusting agent are mixed the back with solubilizing agent and stir, make phospholipid be dissolved as water fully, form water (2);
4. under stirring condition, oil phase (1) is added in the water (2), regulate pH to 6.5-7.0 then, add the injection water again, get the milky colostrum to ormal weight;
5. the colostrum that makes is moved into high pressure homogenization machine, homogenize; Lipomul carries out embedding, sterilization after the homogenize, promptly gets required injection breast.
Gained fat milk injection of the present invention is characterized in that particle diameter is 0.05-1.0 μ m, wherein about 10% Emulsion particle diameter＜0.1 μ m, Emulsion particle diameter＜0.35 μ m of 50%, Emulsion particle diameter＜0.6 μ m of 98%, and the product character is white emulsion liquid.
The advantage of ursolic acid fat emulsion injection provided by the present invention is:
1. can bring into play the effect of ursolic acid pharmacodynamics, add an amount of fatty oil simultaneously, be applicable to critical tumour patient first aid and tumour patient postoperative nutritional supplementation as supplementary.
2. medicine directly enters blood of human body, and is rapid-action, absorbs more complete.Avoid the first pass effect of medicine, improved the bioavailability of ursolic acid, brought into play the curative effect of medicine to greatest extent.Ursolic acid is wrapped in the fatty oil, has effectively increased stability of drug.
3. because the ursolic acid medicine is water insoluble, therefore ursolic acid is as anticancer, anti-metastasis drug preparation, the suitable intravenous injection emulsion that is prepared into, passive oriented the concentrating of medicine is being rich in positions such as cytophagous liver, spleen, lymphsystem, not only can realize target administration, and have potential slow releasing function,, reach the effect of " long circulation " owing to r＜1.0 μ m are difficult for the picked-up by netted cortex system.
4. this kind raw material is easy to get, and technology is simple, the production equipment of available routine and prepared, and batch process is dropped in the pharmaceutical factory that is suitable for tool GMP production injection on a large scale.
Ursolic acid fat emulsion of the present invention, but it is characterized in that both the intravenous injection medication also can be made oral medication.
The specific embodiment
Embodiment 1:
Ursolic acid is pulverized, and the particle diameter that makes ursolic acid takes by weighing the ursolic acid 100mg that has pulverized and puts in the container less than 80 μ m; Add injection soybean oil 50g, this container is placed water-bath, be heated to 100 ℃, be stirred to medicine and disperse, be cooled to 80 ℃, drop into lecithin 25g, vitamin E 100mg and be stirred to the evenly mixed phase of phospholipid dissolving formation.Water for injection 800ml is placed another container, add polyvidone 40g, glycerol 25g and lecithin 25g and form water in 80 ℃ of stirring and dissolving; The mixed liquid that will contain ursolic acid, soybean oil and lecithin is mixed with the water that contains glycerol, polyvidone (PVP) and lecithin under 80 ℃, mechanical agitation, and with 1% sodium hydroxide adjusting pH value to 6.5～7.0; Add the injection water again to 1000ml, and continue 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, gland; With rotating autoclave at 100 ℃, F
0Be to sterilize under 20 the condition.After sterilization finishes, cooling gradually.At room temperature store.Promptly make the ursolic acid fat emulsion intravenous injection liquid formulation of 10mg/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 drug precipitation separates out.The shady and cool place of room temperature stored 1 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.
Check result: fat emulsion intravenous fluid injection pH value: 6.7, the magnitude range of breast grain: 0.05-1.0 μ m.
Embodiment 2:
Ursolic acid is pulverized, and the particle diameter that makes ursolic acid takes by weighing the ursolic acid 100mg that has pulverized and puts in the container less than 80 μ m; Add injection soybean oil 50g, this container is placed water-bath, be heated to 100 ℃, be stirred to medicine and disperse, be cooled to 80 ℃, drop into lecithin 5g, vitamin E 100mg and be stirred to the evenly mixed phase of phospholipid dissolving formation.Water for injection 800ml is placed another container, add polyvidone 10g, glycerol 20g and lecithin 5g and form water in 80 ℃ of stirring and dissolving; The mixed liquid that will contain ursolic acid, soybean oil and lecithin is mixed with the water that contains glycerol, polyvidone (PVP) and lecithin under 80 ℃, mechanical agitation, and with 1% sodium hydroxide adjusting pH value to 6.5～7.0; Add the injection water again to 1000ml, and continue 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, gland; With rotating autoclave at 100 ℃, F
0Be to sterilize under 20 the condition.After sterilization finishes, cooling gradually.At room temperature store.Promptly make the ursolic acid fat emulsion intravenous injection liquid formulation of 10mg/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 drug precipitation separates out.The shady and cool place of room temperature stored 1 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.
Check result: fat emulsion intravenous fluid injection pH value: 6.6, the magnitude range of breast grain: 0.05-1.0 μ m.
Embodiment 3
Ursolic acid is pulverized, and the particle diameter that makes ursolic acid takes by weighing the ursolic acid 100mg that has pulverized and puts in the container less than 80 μ m; Add injection soybean oil 100g, this container is placed water-bath, be heated to 100 ℃, be stirred to medicine and disperse, be cooled to 80 ℃, drop into lecithin 6g, vitamin E 100mg and be stirred to the evenly mixed phase of phospholipid dissolving formation.Water for injection 800ml is placed another container, add Polyethylene Glycol 10g, glycerol 22g and lecithin 6g and form water in 80 ℃ of stirring and dissolving; The mixed liquid that will contain ursolic acid, soybean oil and lecithin is mixed with the water that contains glycerol, Polyethylene Glycol and lecithin under 80 ℃, mechanical agitation, and with 1% sodium hydroxide adjusting pH value to 6.5～7.0; Add the injection water again to 1000ml, and continue 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, gland; With rotating autoclave at 100 ℃, F
0Be to sterilize under 20 the condition.After sterilization finishes, cooling gradually.At room temperature store.Promptly make the ursolic acid fat emulsion intravenous injection liquid formulation of 10mg/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 drug precipitation separates out.The shady and cool place of room temperature stored 1 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.
Check result: fat emulsion intravenous fluid injection pH value: 6.7, the size and the scope of breast grain: less than 1 μ m.See that drug precipitation separates out.The shady and cool place of room temperature stored 1 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.
Check result: fat emulsion intravenous fluid injection pH value: 6.7, the magnitude range of breast grain: 0.05-1.0 μ m.
Embodiment 4
Ursolic acid is pulverized, and the particle diameter that makes ursolic acid takes by weighing the ursolic acid 200mg that has pulverized and puts in the container less than 80 μ m; Add injection soybean oil 75g, medium chain fatty acid ester 25g, put in the container, this container is placed water-bath, be heated to about 90 ℃, being stirred to medicine disperses, be cooled to 70 ℃, drop into lecithin 6g, vitamin e1 00mg is stirred to the phospholipid dissolving and forms evenly mixed phase. water for injection 800ml is placed another container, Polyethylene Glycol 50g, glycerol 22g and lecithin 6g form water in 70 ℃ of stirring and dissolving: will contain ursolic acid, the mixed liquid of soybean oil and lecithin is at 70 ℃, under the mechanical agitation with contain glycerol, the water of Polyethylene Glycol and lecithin is mixed, and regulates pH value to 6.5～7.0 with 1% sodium hydroxide; Add the injection water again to 1000ml, and continue 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; With rotating autoclave at 100 ℃, F
0Be to sterilize under 20 the condition.After sterilization finishes, cool off gradually towards hot water.At room temperature store.Promptly make the ursolic acid fat emulsion intravenous injection liquid 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 drug precipitation separates out.The shady and cool place of room temperature stored 1 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.
Check result: fat emulsion intravenous fluid injection pH value: 6.5, the size and the scope of breast grain: 0.05-1.0 μ m.
Embodiment 5
Ursolic acid is pulverized, and the particle diameter that makes ursolic acid takes by weighing the ursolic acid 400mg that has pulverized and puts in the container less than 80 μ m; Add injection soybean oil 150g, put in the container, this container is placed water-bath, be heated to about 90 ℃, be stirred to medicine and disperse, be cooled to 70 ℃, drop into lecithin 10g, vitamin e1 00mg and be stirred to the evenly mixed phase of phospholipid dissolving formation.Water for injection 800ml is placed another container, hydroxypropyl 30g, glycerol 25g and lecithin 5g form waters in 60 ℃ of stirring and dissolving: the mixed liquid that will contain ursolic acid, soybean oil and lecithin is mixed with the water that contains glycerol, hydroxypropyl and lecithin under 60 ℃, mechanical agitation, and with 1% sodium hydroxide adjusting pH value to 6.5～7.0; Add the injection water again to 1000ml, and continue mechanical agitation down at 60 ℃ 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; With rotating autoclave at 100 ℃, F
0Be to sterilize under 20 the condition.After sterilization finishes, cool off gradually towards hot water.At room temperature store.Promptly make the ursolic acid fat emulsion intravenous injection liquid formulation of 40mg/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 drug precipitation separates out.The shady and cool place of room temperature stored 1 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.
Check result: fat emulsion intravenous fluid injection pH value: 7.0, the magnitude range of breast grain: 0.05-1.0 μ m.
Embodiment 6
Ursolic acid is pulverized, and the particle diameter that makes ursolic acid takes by weighing the ursolic acid 1000mg that has pulverized and puts in the container less than 80 μ m; Add injection Oleum Camelliae 200g, put in the container, this container is placed water-bath, be heated to about 80 ℃, be stirred to medicine and disperse, be cooled to 60 ℃, input 25g synthetic phospholipid, vitamin e1 00mg are stirred to the phospholipid dissolving and form evenly mixed phase.Water for injection 700ml is placed another container, glycerol 25g, hydroxypropyl 40g, and synthetic phospholipid 15g form waters in 60 ℃ of stirring and dissolving.The mixed liquid that will contain ursolic acid, soybean oil and phospholipid is mixed with above-mentioned water under 60 ℃ of mechanical agitation, and regulates pH value to 6.5～7.0 with 1% sodium hydroxide; Add the injection water again to 1000ml, and continue mechanical agitation down at 60 ℃ 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; With rotating autoclave at 100 ℃, F
0Be to sterilize under 20 the condition.After sterilization finishes, cool off gradually towards hot water.At room temperature store.Promptly make the ursolic acid fat emulsion intravenous injection liquid formulation of 100mg/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 drug precipitation separates out.The shady and cool place of room temperature stored 1 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.
Check result: fat emulsion intravenous fluid injection pH value: 6.8, the magnitude range of breast grain: 0.05-1.0 μ m.
Embodiment 7
Ursolic acid is pulverized, and the particle diameter that makes ursolic acid takes by weighing the ursolic acid 1500mg that has pulverized and puts in the container less than 80 μ m; Add injection soybean oil 50g, middle long-chain fatty acid ester 50g, put in the container, this container is placed water-bath, be heated to about 80 ℃, be stirred to medicine and disperse, be cooled to 60 ℃, add 6g lecithin then, vitamin E 100mg is stirred to the phospholipid dissolving and forms evenly mixed phase.Water for injection 650ml is placed another container, add polyvidone 10g, glycerol 22g, reach lecithin 6g in 80 ℃ of stirring and dissolving formation waters.The mixed liquid that will contain ursolic acid, soybean oil and lecithin is mixed with above-mentioned water under 60 ℃ of mechanical agitation, and regulate pH value to 6.5～7.0 with 1% sodium hydroxide, add the injection water again to 1000ml, and continue mechanical agitation down at 60 ℃ 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; With rotating autoclave at 100 ℃, F
0Be to sterilize under 20 the condition.After sterilization finishes, cool off gradually towards hot water.At room temperature store.Promptly make the ursolic acid fat emulsion intravenous injection liquid formulation of 150mg/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 drug precipitation separates out.The shady and cool place of room temperature stored 1 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.
Check result: fat emulsion intravenous fluid injection pH value: 6.8, the magnitude range of breast grain: 0.05-1.0 μ m.
Embodiment 8
Ursolic acid is pulverized, and the particle diameter that makes ursolic acid takes by weighing the ursolic acid 1500mg that has pulverized and puts in the container less than 80 μ m; Add injection olive oil 200g, middle long-chain fatty acid ester 100g, put in the container, this container is placed water-bath, be heated to about 80 ℃, be stirred to medicine and disperse, be cooled to 60 ℃, add 45g lecithin then, vitamin E 300mg is stirred to the phospholipid dissolving and forms evenly mixed phase.Water for injection 650ml is placed another container, add polyvidone 60g, glycerol 25g, reach lecithin 45g in 80 ℃ of stirring and dissolving formation waters.The mixed liquid that will contain ursolic acid, soybean oil and lecithin is mixed with above-mentioned water under 60 ℃ of mechanical agitation, and regulate pH value to 6.5～7.0 with 1% sodium hydroxide, add the injection water again to 1000ml, and continue mechanical agitation down at 60 ℃ 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; With rotating autoclave at 100 ℃, F
0Be to sterilize under 20 the condition.After sterilization finishes, cool off gradually towards hot water.At room temperature store.Promptly make the ursolic acid fat emulsion intravenous injection liquid formulation of 150mg/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 drug precipitation separates out.The shady and cool place of room temperature stored 1 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.
Check result: fat emulsion intravenous fluid injection pH value: 6.7, the magnitude range of breast grain: 0.05-1.0 μ m.
Embodiment 9
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 * 10
6Individual/the 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 makes the EAC model mouse, be divided into A, B, C group at random, 30 every group, be respectively A: the normal saline matched group, B: Sodium ursolate. injection for treating group, C: ursolic acid fat emulsion 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 Sodium ursolate. injection for treating group every mouse tail vein injection ursolic acid injection (10mg/kg), and inject once every day, injected continuously 8 days.
C organizes ursolic acid fat emulsion treatment group every mouse tail vein injection 1mg/ml ursolic acid fat emulsion 0.2ml of the present invention (10mg/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 Sodium ursolate. injection for treating group and ursolic acid fat emulsion treatment group exists significant difference.
Experimental result: after injecting 8 days continuously, the average tumor of normal saline matched group heavily is 3.1 grams, and the average tumor of Sodium ursolate. injection for treating group heavily is 2.5 grams, and suppression ratio is 19.35%: it heavily is 1.4 grams that average tumor is organized in the ursolic acid fat emulsion treatment, and suppression ratio is 54.84%.There is significant difference (p＜0.01) in the tumour inhibiting rate of Sodium ursolate. injection for treating group and fat milk treatment group.The ursolic acid fat emulsion tumour inhibiting rate is 3 times of sodium injection approximately, owing to be encapsulated in the emulsion droplet of fat milk with closed loop, activity and drug effect all are significantly increased.
In addition, Sodium ursolate. injection for treating group after 8 days average weight alleviate 2-7%, but ursolic acid fat emulsion treatment group average weight increases 8-15%, further show, ursolic acid is solubilized in the fat milk with the lactone closed loop, toxic and side effects significantly descends, and the Nutrition of fat milk has also improved the life quality of mice with tumor.
Claims (7)
1. ursolic acid fat emulsion injection, the weight portion that it is characterized in that it consists of: ursolic acid 0.01%-0.15%, oil for injection 5-30%, emulsifying agent 1-9%, solubilizing agent 1-6%, isotonic agent 2-2.5%, antioxidant 0.01-0.03%, and all the other are water for injection; Wherein the Emulsion particle diameter in the fat milk injection is 0.05-1.0 μ m.
2. according to the ursolic acid fat emulsion injection of claim 1, its weight portion consists of: ursolic acid 0.01%-0.15%, oil for injection 10%, emulsifying agent 1.2%, solubilizing agent 1%, isotonic agent 2.2%, antioxidant 0.01%, all the other are water for injection, and wherein the Emulsion particle diameter in the fat milk injection is 0.05-1.0 μ m.
3. according to the ursolic acid fat emulsion injection of claim 1, wherein said oil for injection is one or more mixture in soybean oil, Oleum Camelliae, Oleum Sesami, middle long-chain fatty acid ester, the olive oil.
4. according to the ursolic acid fat emulsion injection of claim 1, wherein said emulsifying agent is a kind of in soybean lecithin, Ovum Gallus domesticus Flavus lecithin, the synthetic phospholipid.
5. according to the ursolic acid fat emulsion injection of claim 1, wherein said solubilizing agent is a kind of in Polyethylene Glycol, hydroxypropyl, the polyvidone; Antioxidant is vitamin E; Isoosmotic adjusting agent is a glycerol.
6. according to the ursolic acid fat emulsion injection of claim 1, its preparation method is:
A. ursolic acid is pulverized, the particle diameter that makes ursolic acid is less than 80 μ m;
B. get the ursolic acid pulverized, oil for injection in 50-100 ℃ of mixing, temperature adds phospholipid during to 50-80 ℃, mixes forming mixed liquor (1);
C. water for injection, emulsifying agent, isoosmotic adjusting agent are mixed the back with solubilizing agent and stir, make phospholipid be dissolved as water fully, form water (2);
D. under stirring condition, oil phase (1) is added in the water (2), regulate pH to 6.5-7.0 then, add the injection water again, get the milky colostrum to ormal weight;
E. the colostrum that makes is moved into high pressure homogenization machine, homogenize; Lipomul carries out embedding, sterilization after the homogenize, promptly gets required injection, and wherein the Emulsion particle diameter in the fat milk injection is 0.05-1.0 μ m.
7. according to claim 1,2 ursolic acid fat emulsion injection, it is characterized in that described lipomul also can make oral medication.
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| CN 200510114817 Pending CN1771968A (en) | 2005-11-14 | 2005-11-14 | Ursolic acid fat emulsion injection and its prepn |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101011442B (en) * | 2006-12-29 | 2010-04-07 | 西北工业大学 | Barrenwort extract fat emulsion composition and its preparing process |
| CN1951367B (en) * | 2006-08-08 | 2012-05-30 | 沈阳药科大学 | Fat emulsion containing hydroxycamptothecine and preparation method thereof |
| CN104688745A (en) * | 2010-05-20 | 2015-06-10 | 爱荷华大学研究基金会 | Methods for inhibiting muscle atrophy |
| EP2774602A4 (en) * | 2011-10-31 | 2015-07-22 | Fujifilm Corp | Aqueous dispersion and method for producing same |
| CN105663282A (en) * | 2016-02-17 | 2016-06-15 | 广州欧化药业有限公司 | Peony seed oil lipid emulsion and preparation method thereof |
| CN110464707A (en) * | 2019-07-19 | 2019-11-19 | 湖南先伟实业有限公司 | A kind of oil-in-water type pickering emulsion and preparation method thereof that ursolic acid is stable |
-
2005
- 2005-11-14 CN CN 200510114817 patent/CN1771968A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1951367B (en) * | 2006-08-08 | 2012-05-30 | 沈阳药科大学 | Fat emulsion containing hydroxycamptothecine and preparation method thereof |
| CN101011442B (en) * | 2006-12-29 | 2010-04-07 | 西北工业大学 | Barrenwort extract fat emulsion composition and its preparing process |
| CN104688745A (en) * | 2010-05-20 | 2015-06-10 | 爱荷华大学研究基金会 | Methods for inhibiting muscle atrophy |
| EP2774602A4 (en) * | 2011-10-31 | 2015-07-22 | Fujifilm Corp | Aqueous dispersion and method for producing same |
| CN105663282A (en) * | 2016-02-17 | 2016-06-15 | 广州欧化药业有限公司 | Peony seed oil lipid emulsion and preparation method thereof |
| CN105663282B (en) * | 2016-02-17 | 2018-03-30 | 广州欧化药业有限公司 | A kind of peony seed oil fat emulsion and preparation method thereof |
| CN110464707A (en) * | 2019-07-19 | 2019-11-19 | 湖南先伟实业有限公司 | A kind of oil-in-water type pickering emulsion and preparation method thereof that ursolic acid is stable |
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