CN101249070A - 2-methoxy estradiol vena nano emulsions - Google Patents
2-methoxy estradiol vena nano emulsions Download PDFInfo
- Publication number
- CN101249070A CN101249070A CNA2008100494650A CN200810049465A CN101249070A CN 101249070 A CN101249070 A CN 101249070A CN A2008100494650 A CNA2008100494650 A CN A2008100494650A CN 200810049465 A CN200810049465 A CN 200810049465A CN 101249070 A CN101249070 A CN 101249070A
- Authority
- CN
- China
- Prior art keywords
- phospholipid
- injection
- vena
- methoxyestradiol
- oil
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a 2-methoxyestradiol nano-emulsion for intravenous injection. The nano-emulsion contains 0.05-0.5 w/v% of 2-methoxyestradiol, 5-50 w/v% of oil for injection, 0.05-0.5 w/v% of emulsifier, 2-6 w/v% of isoosmotic adjusting agent, pH regulators and water for injection in balance, wherein 2-methoxyestradiol and emulsifier are dissolved with organic solvents and then evaporated under reduced pressure to remove organic solvents completely, so as to obtain a crystalline or solid dispersion of emulsifier; the oil for injection is filtered and then added in the dispersion or water phase is filtered and then added in the dispersion, followed by stirring, to obtain a primary emulsion; the primary emulsion is subjected to a high-pressure homogenizer, the pH regulator is added to regulate the pH value and the water for water is added; and the resulting mixture is further filtered, sealed, sterilized and cooled down to room temperature. The nano-emulsion is suitable for intravenous injection and has properties of sustained release and target drug delivery in vivo. The nano-emulsion has no problems of oral preparations and has high safety and reliability. The invention is an innovation in the medicine field and has significant social and economic benefits.
Description
One, technical field
The present invention relates to field of medicaments, the nano emulsion composition that particularly a kind of slightly water-soluble anticarcinogen 2-methoxyestradiol and vein can be constituted by the adjuvant that physiology is accepted: 2-methoxy estradiol vena nano emulsions.
Two, background technology
2-methoxyestradiol (1,3,5-triolefin-2,3,17 β-trihydroxy-2-methyl ether sterol) be an estradiol physiology metabolite (.J Cancer Res ClinOncol.127:405～410 such as Schumacher G in vivo, (2001)), has tangible anti-tumor activity, its anticancer mechanism may be induced tumor and endothelial cell apoptosis .Cancer.92:500～509 (2001) such as () Lin HL, also have antineoplastic vascular form .Invest New Drug.20:183～194 (2002) such as () Figg WD with and can suppress the hypertrophy of tumor cell relevant .Carcinog.31:111～124 (2001) such as () Kumar AP.It is to suppress cell proliferation in dose-dependent mode of time at research 2-methoxyestradiol to myeloma cell's the 2-methoxyestradiol of also having found on that the scholar is arranged, its inhibitory action when 10 μ mol/L the strongest (.Clin Cancer Res.8:3948～3954 (2002) such as Dingli D), this just requires the 2-methoxyestradiol being used for reaching an effective blood drug level when clinical on the one hand, requires simultaneously can keep an effective blood drug level for a long time in vivo.But the I phase clinical research result of 2-methoxyestradiol shows that the 2-methoxyestradiol is oral irregular, lacks dependency (James J etc., Invest New Drugs, 25:41-48 (2006)) between pharmacokinetic parameter and the dosage.So 2-methoxyestradiol drug administration by injection form can solve the defective of its oral formulations.
The 2-methoxyestradiol is an insoluble drug in a kind of water, dissolubility is less than 5mg/L in the water, injection one to such medicine is to adopt injection suspension, this injection requires medicine to have higher pharmacologically active, less dosage is promptly arranged, and can only intramuscular and subcutaneous injection, but the conventional dosage of 2-methoxyestradiol need reach more than the 400mg; The 2nd, be that solvent or employing ethanol are that solvent adding polyoxyethylene hydrogenated Oleum Ricini is that solubilizing agent is formed with the organic solvent, the critical defect that with an organic solvent reaches the injection of surface active agent solubilization is to cause haemolysis and anaphylaxis easily, and lack slow release and targeting, as the product that goes on the market
Clearly being defined in needs to use the processing of desensitizing earlier of 17-hydroxy-11-dehydrocorticosterone, antihistaminic before the clinical use, even like this
Higher clinical anaphylaxis in use still occurs, make the poor compliance of clinical treatment.
Three, summary of the invention
At above-mentioned situation, for overcoming its deficiency, but the present invention's purpose is exactly that poorly water soluble drugs 2-methoxyestradiol and biological acceptable auxiliary are constituted the 2-methoxy estradiol vena nano emulsions injection for intravenous administration, that have better biocompatibility, that certain capacity of slow release and targeting are arranged together.The technical scheme of its solution is: the present invention is by the 2-methoxyestradiol 0.05%～0.5% (W/V) of w/v, oil for injection 5%～50%, emulsifying agent 0.05%～5%, isoosmotic adjusting agent 2%～6%, pH regulator agent and surplus be water for injection make [w/v be meant solids with the gram (g) meter, liquids is counted with milliliter (ml), be W/V, as follows], wherein get 2-methoxyestradiol 0.05%～0.5% earlier and emulsifying agent 0.05%～5% is used organic solvent dissolution, evaporated under reduced pressure eliminates organic solvent again, obtain the liquid crystal state or the solid dispersion of pharmaceutical emulsifier, (aqueous mixture is by the emulsifying agent 0.05%～5% of w/v to add the oil for injection 5%～50% of 0.22 μ m filtering with microporous membrane or the aqueous mixture 5%～50% of 0.22 μ m filtering with microporous membrane again, isoosmotic adjusting agent 2%～6%, surplus is that water for injection mixes composition) disperse, stir and obtain colostrum; By high pressure dispersing emulsification machine more than three times (number of times by the high pressure dispersing emulsification machine is relevant with uniformity with the nano-emulsion size that obtains at last), operating pressure 5k～18k psi is 5.5～8.0 with pH regulator agent adjust pH, adds to the full amount of water for injection at last again; Again through 0.45 μ m filtering with microporous membrane, nitrogen purge gas stream protection filling encapsulation, 121 ℃ of autoclavings 20 minutes progressively are cooled to room temperature towards hot water, promptly get the present invention.The present invention the results showed it is having of a kind of suitable intravenous administration nano emulsion composition slow-release capability, that have the targeting ability in the body, can overcome the defective of oral formulations, safety, reliably, it is succeeded in developing, and is an innovation greatly medically, has huge social and economic benefit.
Four, the specific embodiment
Below in conjunction with embodiment the specific embodiment of the present invention is elaborated.
Present composition nano-emulsion is by the 2-methoxyestradiol 0.05%～0.5% (W/V) of w/v (W/V), oil for injection 5%～50%, emulsifying agent 0.05%～5%, isoosmotic adjusting agent 2%～6%, pH regulator agent and surplus are that water for injection is made, wherein get 2-methoxyestradiol 0.05%～0.5% earlier and emulsifying agent 0.05%～5% is used organic solvent dissolution, evaporated under reduced pressure eliminates organic solvent again, obtain the liquid crystal state or the solid dispersion of pharmaceutical emulsifier, add the oil for injection 5%～50% of 0.22 μ m filtering with microporous membrane or the aqueous mixture 5%～50% of 0.22 μ m filtering with microporous membrane again and disperse, stir and obtain colostrum; By high pressure dispersing emulsification machine more than three times (number of times by the high pressure dispersing emulsification machine is relevant with uniformity with the nano-emulsion size that obtains at last), operating pressure 5k～18k psi is 5.5～8.0 with pH regulator agent adjust pH, adds to the full amount of water for injection at last again; Through 0.45 μ m filtering with microporous membrane, nitrogen purge gas stream protection filling encapsulation with 121 ℃ of rotation autoclaves, was sterilized 20 minutes again, and sterilization finishes, and progressively is cooled to room temperature towards hot water, promptly gets the present invention.
Said oil for injection can be that soybean oil, olive oil, Oleum Sesami, safflower oil, Oleum Gossypii semen, safranine caul-fat, Semen Maydis oil, Oleum Fructus Bruceae, some medium chain wet goods can be the mixture of any in the acceptable oil of intravenous injection physiology or its two kinds, three kinds among the present invention, its content in compositions is 5%～50% of compositions cumulative volume, preferred 15%～30%.
Said emulsifying agent can be phospholipid or poloxamer or the mixture of the two among the present invention, content in compositions is 0.05%～5% of bulking value, preferred 0.5%～4%, wherein phospholipid content in the compositions cumulative volume is 0.05%～5%, preferred 0.5%～3%; The content of poloxamer in the compositions cumulative volume is 0.05%～5%, preferred 0.1%～1%; If the two mixture, the weight ratio of its phospholipid and poloxamer are 10: 1～1: 5, preferred 5: 1～2: 1, content was 0.05%～5% of compositions cumulative volume.
Said phospholipid comprises natural phospholipid among the present invention, semi-synthetic phospholipid and artificial complete synthesis phospholipid, it can be soybean phospholipid, Ovum Gallus domesticus Flavus lecithin, the Semen sojae atricolor hydrogenated phospholipid, hydrogenated yolk lecithin, two palmityl phospholipid, DSPE, Polyethylene Glycol-distearyl ethanolamine etc. are any, and the phospholipid by special modification, phospholipid as single (many) clonal antibodies modification, the phospholipid that galactosyl is modified, the phospholipid of expressing polypeptide shed repair decorations etc. any, it also can be the mixture of two or more phospholipid of different nature, as the mixture of soybean phospholipid with the Polyethylene Glycol-distearyl ethanolamine of long circulatory function, the mixture of the Polyethylene Glycol-distearyl ethanolamine of Semen sojae atricolor hydrogenated phospholipid and long circulatory function.
The phospholipid ratio of said phospholipid and long circulatory function is 1%～99%: 1%～99%, and with 80%～98%: 20%～2% is better, preferred 90%～95%: 10%～5%.
Said poloxamer comprises multiple model, can be used as the acceptable model of vein physiology as poloxamer-188, poloxamer-338, poloxamer-407 etc., wherein with the poloxamer-188 optimum.
Said 2-methoxyestradiol is a drug target in the invention, and the amount in compositions is 0.05%～0.5% (W/V) of bulking value, preferred 0.1%～0.3% (W/V).
Said isoosmotic adjusting agent can be any in glucose, sorbitol, glycerol and the kind can intravenous injection accepted by physiology among the present invention, its used in amounts is mediated according to the osmotic pressure size in the compositions, and with compositions cumulative volume weight percent meter: the consumption of glucose is generally 3%～5%, the consumption of sorbitol is generally 3%～6%, the glycerol consumption is generally 2%～3%.
Said pH regulator agent is the soda acid that vein can be accepted by physiology among the present invention, can be hydrochloric acid or sodium hydroxide, is used to regulate the pH value of compositions nano-emulsion, and consumption is so that its pH value reaches 5.5-8.0 is as the criterion.
Said organic solvent among the present invention can be chloroform or acetone, and consumption is advisable to dissolve 2-methoxyestradiol and emulsifying agent fully.
Contain phospholipid in the compositions of the present invention, owing to well-known reason, this compositions preferably all has the protection of nitrogen purge gas stream in preparation process, and sterilising temp is low as far as possible, sterilization time is short as far as possible.
The emulsifying agent consumption of compositions nano-emulsion size of the present invention and employing, kind and relevant by the number of times of high pressure dispersing emulsification machine, the general mean diameter of high pressure dispersing emulsification machine of passing through is about 600nm, mean diameter is less than 300nm after passing through three times continuously, the finished product mean diameter that obtains is less than 300nm, less than 1%, do not detect particle greater than the particle of 1 μ m greater than 5 μ m; This compositions has according to the consumption that uses emulsifying agent is different with kind-5mV～-50mV surface potential (claiming Zeta potential again); This compositions room temperature placement emulsion droplet size is stable, Zeta potential is stable, and 4 ℃～10 ℃ placements of this compositions emulsion droplet size, Zeta potential are stablized, and places the emulsion droplet particle diameter under 0 ℃～-20 ℃ conditions of this compositions and becomes big, Zeta potential reduction; The pH value size of this compositions is different with consumption slightly variant according to the kind of the kind of using oil for injection and consumption, emulsifying agent, but generally in 5.5～8.0 scope, is fit to intravenous injection, and the highest pH value also must not surpass 9.0.
The present invention also can be provided by following examples, but is not limited only to embodiment.
Embodiment 1
Take by weighing 2-methoxyestradiol 200mg; soybean lecithin 2.0g; dissolve with the 5m1 chloroform; eliminate chloroform with rotating thin film evaporation evaporated under reduced pressure; form the medicine liquid crystal film; add soybean oil 20g again through 0.22 μ m filtering with microporous membrane; jolting disperses liquid crystal film; adding through 4% glucose solution of 0.22 μ m filtering with microporous membrane to 100ml; stir and form colostrum; spare three times through microjet high pressure dispersing emulsification machine breast again; operating pressure 17k psi, reconciling pH value with 0.1Mol/L hydrochloric acid or 0.1Mol/L sodium hydroxide is the filtering with microporous membrane of 5.5～8.0,0.45 μ m; nitrogen purge gas stream protection filling encapsulation; with 121 ℃ of rotation autoclaves; sterilized 20 minutes, and progressively be cooled to room temperature towards hot water, promptly.
The present embodiment product is measured mean diameter 240nm, Zeta potential-35mV through laser light scattering fine grain measurement instrument; Cavia porcellus carries out whole body initiative allergometry, vein low dose group 3ml/kg, high dose group 9ml/kg, and measurement result is all negative; Measure its hemolytic with red cell suspension, test sample there is no erythrocyte hemolysis and red blood cell condensation phenomenon in 3 hours; Release in vitro the results are shown in Table 1, shows to have slow-release capability; Distribution results sees Table 2 in the mice body, shows to have the targeting ability.
Embodiment 2
Take by weighing 2-methoxyestradiol 150mg; poloxamer-188 0.9g; dissolve with the 5ml chloroform; eliminate chloroform with rotating thin film evaporation evaporated under reduced pressure; form the solid dispersion of 2-methoxyestradiol and poloxamer; add olive oil 20g again through 0.22 μ m filtering with microporous membrane; jolting disperses solid dispersion; adding through 2.5% glycerite of 0.22 μ m filtering with microporous membrane to 100ml; stir and form colostrum; spare three times through microjet high pressure dispersing emulsification machine breast again; operating pressure 15k psi is with the filtering with microporous membrane of 0.1Mol/L hydrochloric acid or 0.1Mol/L sodium hydroxide conciliation pH 5.5～8.0,0.45 μ m; nitrogen purge gas stream protection filling encapsulation; 121 ℃ of rotation autoclaves; sterilized 20 minutes, and progressively be cooled to room temperature towards hot water, promptly.
The present embodiment product is measured mean diameter 290nm, Zeta potential-38mV through laser light scattering fine grain measurement instrument; Cavia porcellus carries out whole body initiative allergometry, vein low dose group 4ml/kg, high dose group 12ml/kg, and measurement result is all negative; Measure its hemolytic with red cell suspension, test sample there is no erythrocyte hemolysis and red blood cell condensation phenomenon in 3 hours; Release in vitro the results are shown in Table 1, shows to have slow-release capability; Distribution results sees Table 2 in the mice body, shows to have the targeting ability.
Embodiment 3
Take by weighing 2-methoxyestradiol 250mg; Ovum Gallus domesticus Flavus lecithin 2.0g; dissolve with the 5ml chloroform; eliminate chloroform with rotating thin film evaporation evaporated under reduced pressure; form the medicine liquid crystal film; add soybean oil 30g again through 0.22 μ m filtering with microporous membrane; jolting disperses liquid crystal film; adding through the solution that includes 0.5%% poloxamer and 5% sorbitol of 0.22 μ m filtering with microporous membrane to 100ml; stir and form colostrum; spare three times through microjet high pressure dispersing emulsification machine breast again; operating pressure 16k psi is with the filtering with microporous membrane of 0.1Mol/L hydrochloric acid or 0.1Mol/L sodium hydroxide adjusting pH 5.5～8.0,0.45 μ m; nitrogen purge gas stream protection filling encapsulation; 121 ℃ of rotation autoclaves; sterilized 20 minutes, and progressively be cooled to room temperature towards hot water, promptly.
The present embodiment product is measured mean diameter 190nm, Zeta potential-41mV through laser light scattering fine grain measurement instrument; Cavia porcellus carries out whole body initiative allergometry, vein low dose group 2.4ml/kg, high dose group 7.2ml/kg, and measurement result is all negative; Measure its hemolytic with red cell suspension, test sample there is no erythrocyte hemolysis and red blood cell condensation phenomenon in 3 hours; Release in vitro the results are shown in Table 1, shows to have slow-release capability; Distribution results sees Table 2 in the mice body, shows to have the targeting ability.
Embodiment 4
Take by weighing 2-methoxyestradiol 300mg; Semen sojae atricolor hydrogenated phospholipid 2.0g; dissolve with the 5ml chloroform; eliminate chloroform with rotating thin film evaporation evaporated under reduced pressure; form the medicine liquid crystal film; add olive oil 30g again through 0.22 μ m filtering with microporous membrane; jolting disperses liquid crystal film; adding through the solution that includes 0.5% poloxamer and 2.5% glycerol of 0.22 μ m filtering with microporous membrane to 100ml; stir and form colostrum; spare three times through microjet high pressure dispersing emulsification machine breast again; operating pressure 18k psi is with the filtering with microporous membrane of 0.1Mol/L hydrochloric acid or 0.1Mol/L sodium hydroxide conciliation pH 5.5～8.0,0.45 μ m; nitrogen purge gas stream protection filling encapsulation; 121 ℃ of rotation autoclaves; sterilized 20 minutes, and progressively be cooled to room temperature towards hot water, promptly.
The present embodiment product is measured mean diameter 180nm, Zeta potential-42mV through laser light scattering fine grain measurement instrument; Cavia porcellus carries out whole body initiative allergometry, vein low dose group 2ml/kg, high dose group 6ml/kg, and measurement result is all negative; Measure its hemolytic with red cell suspension, test sample there is no erythrocyte hemolysis and red blood cell condensation phenomenon in 3 hours; Release in vitro the results are shown in Table 1, shows to have slow-release capability; Distribution results sees Table 2 in the mice body, shows to have the targeting ability.
The foregoing description is listed as follows:
Each embodiment release in vitro result (%) of table 1
Distribution targeting evaluation in each embodiment mice body of table 2
Embodiment 5
Take by weighing 2-methoxyestradiol 50mg; Semen sojae atricolor hydrogenated phospholipid 0.5g; dissolve with the 3ml chloroform; eliminate chloroform with rotating thin film evaporation evaporated under reduced pressure; form the medicine liquid crystal film; add soybean oil 5g again through 0.22 μ m filtering with microporous membrane; jolting disperses liquid crystal film; adding through the solution that includes 2.5% glycerol of 0.22 μ m filtering with microporous membrane to 100ml; stir and form colostrum; spare three times through microjet high pressure dispersing emulsification machine breast again; operating pressure 17k psi is with the filtering with microporous membrane of 0.1Mol/L hydrochloric acid or 0.1Mol/L sodium hydroxide conciliation pH5.5～8.0,0.45 μ m; nitrogen purge gas stream protection filling encapsulation; 121 ℃ of rotation autoclaves; sterilized 20 minutes, and progressively be cooled to room temperature towards hot water, promptly.
Measure mean diameter 290nm, Zeta potential-37mV through laser light scattering fine grain measurement instrument; Product is placed stable for 4 ℃～10 ℃; Cavia porcellus carries out whole body initiative allergometry, vein low dose group 2ml/kg, high dose group 6ml/kg, and measurement result is all negative; Measure its hemolytic with red cell suspension, test sample there is no erythrocyte hemolysis and red blood cell condensation phenomenon in 3 hours.
Embodiment 6
Take by weighing 2-methoxyestradiol 500mg; Semen sojae atricolor hydrogenated phospholipid 5g; dissolve with the 10ml chloroform; eliminate chloroform with rotating thin film evaporation evaporated under reduced pressure; form the medicine liquid crystal film; add soybean oil 50g again through 0.22 μ m filtering with microporous membrane; jolting disperses liquid crystal film; adding through the solution that includes 3% glucose of 0.22 μ m filtering with microporous membrane to 100ml; stir and form colostrum; spare three times through microjet high pressure dispersing emulsification machine breast again; operating pressure 17k psi is with the filtering with microporous membrane of 0.1Mol/L hydrochloric acid or 0.1Mol/L sodium hydroxide conciliation pH5.5～8.0,0.45 μ m; nitrogen purge gas stream protection filling encapsulation; 121 ℃ of rotation autoclaves; sterilized 20 minutes, and progressively be cooled to room temperature towards hot water, promptly.
Measure mean diameter 260nm, Z eta current potential-37mV through laser light scattering fine grain measurement instrument; Product is placed for 4 ℃～10 ℃ and is stablized, and the product viscosity is higher; Cavia porcellus carries out whole body initiative allergometry, vein low dose group 1ml/kg, high dose group 3ml/kg, and measurement result is all negative; Measure its hemolytic with red cell suspension, test sample there is no erythrocyte hemolysis and red blood cell condensation phenomenon in 3 hours.
Embodiment 7
Take by weighing 2-methoxyestradiol 50mg; Semen sojae atricolor hydrogenated phospholipid 0.5g; dissolve with the 3ml chloroform; eliminate chloroform with rotating thin film evaporation evaporated under reduced pressure; form the medicine liquid crystal film; add soybean oil 5g again through 0.22 μ m filtering with microporous membrane; jolting disperses liquid crystal film; adding through the solution that includes 0.1% poloxamer and 3% glycerol of 0.22 μ m filtering with microporous membrane to 100ml; stir and form colostrum; spare three times through microjet high pressure dispersing emulsification machine breast again; operating pressure 16k psi is with the filtering with microporous membrane of 0.1Mol/L hydrochloric acid or 0.1Mol/L sodium hydroxide conciliation pH 5.5～8.0,0.45 μ m; nitrogen purge gas stream protection filling encapsulation; 121 ℃ of rotation autoclaves; sterilized 20 minutes, and progressively be cooled to room temperature towards hot water, promptly.
Measure mean diameter 220nm, Z eta current potential-39mV through laser light scattering fine grain measurement instrument; Product is placed stable for 4 ℃～10 ℃; Cavia porcellus carries out whole body initiative allergometry, vein low dose group 3ml/kg, high dose group 9ml/kg, and measurement result is all negative; Measure its hemolytic with red cell suspension, test sample there is no erythrocyte hemolysis and red blood cell condensation phenomenon in 3 hours.
Embodiment 8
Take by weighing 2-methoxyestradiol 500mg; Semen sojae atricolor hydrogenated phospholipid 4.5g; dissolve with the 15ml chloroform; eliminate chloroform with rotating thin film evaporation evaporated under reduced pressure; form the medicine liquid crystal film; add olive oil 5g again through 0.22 μ m filtering with microporous membrane; jolting disperses liquid crystal film; adding through the solution that includes 0.5% poloxamer and 3% sorbitol of 0.22 μ m filtering with microporous membrane to 100ml; stir and form colostrum; spare three times through microjet high pressure dispersing emulsification machine breast again; operating pressure 17k psi is with the filtering with microporous membrane of 0.1Mol/L hydrochloric acid or 0.1Mol/L sodium hydroxide conciliation pH 5.5～8.0,0.45 μ m; nitrogen purge gas stream protection filling encapsulation; 121 ℃ of rotation autoclaves; sterilized 20 minutes, and progressively be cooled to room temperature towards hot water, promptly.
Measure mean diameter 205nm, Z eta current potential-40mV through laser light scattering fine grain measurement instrument; Product is placed stable for 4 ℃～10 ℃; The product viscosity is higher; Cavia porcellus carries out whole body initiative allergometry, vein low dose group 3ml/kg, high dose group 9ml/kg, and measurement result is all negative; Measure its hemolytic with red cell suspension, test sample there is no erythrocyte hemolysis and red blood cell condensation phenomenon in 3 hours.
The Cavia porcellus that utilizes of the present composition carries out in the irritated research of whole body initiative, and its high low dose group anaphylaxis of wonderful discovery is all negative.Its medium-sized vein low dose group dosage is 6mg/kg, and the vein high dose group is 18mg/kg.
The present composition is also obtained desired result in the research of rabbit erythrocyte hemolytic reaction, press the new drug research guideline, get the rabbit erythrocyte suspension, test sample is diluted to medicine 0.5mg/ml with 0.9% normal saline and tests, and test sample was not seen haemolysis and red blood cell condensation phenomenon in 3 hours.
The present composition is a release medium with 0.9% normal saline, test sample is placed bag filter, commentaries on classics blue laws with Chinese Pharmacopoeia carries out release in vitro research, and the result shows that release in vitro has slow-release capability, can just satisfy the time dose kinetics treatment demand of 2-methoxyestradiol.
The present composition carries out the research that distributes in the tail intravenously administrable body with white mice, and the polyoxyethylene hydrogenated Oleum Ricini alcoholic solution that adopts the 2-methoxyestradiol is used relative uptake ratio for contrast
Estimate its targeting rate (r
eThe ratio of expression sample target organ area under the drug-time curve and control sample target organ area under the drug-time curve), the result shows that the 2-methoxyestradiol easily concentrates in organs such as liver, spleen, lung, kidney, mammary gland, bone marrow.
The present invention the results showed it is the nano emulsion composition that has the targeting ability in a kind of body with slow-release capability of suitable intravenous administration, can overcome the defective of oral formulations, safety, reliably, solved the practical technique difficult problem that people thirst for the 2-methoxyestradiol 400mg heavy dose that solves always, the present invention is a kind of anticancer active constituent, also comprise to contain the 2-methoxyestradiol and constitute this invention compositions and be used for other medical purpose, the 2-methoxyestradiol can also be by the certain structure transformation, the noval chemical compound that has similar physicochemical property with the 2-methoxyestradiol that obtains.It is succeeded in developing, and is an innovation greatly medically, has huge social and economic benefit.
Claims (10)
1. 2-methoxy estradiol vena nano emulsions, it is characterized in that, 2-methoxyestradiol 0.05%～0.5% by w/v, oil for injection 5%～50%, emulsifying agent 0.05%～5%, isoosmotic adjusting agent 2%～6%, pH regulator agent and surplus are that water for injection is made, wherein get 2-methoxyestradiol 0.05%～0.5% earlier and emulsifying agent 0.05%～5% is used organic solvent dissolution, evaporated under reduced pressure eliminates organic solvent again, obtain the liquid crystal state or the solid dispersion of pharmaceutical emulsifier, add the oil for injection 5%～50% of 0.22 μ m filtering with microporous membrane or the aqueous mixture 5%～50% of 0.22 μ m filtering with microporous membrane again and disperse, stir and obtain colostrum; Pass through the high pressure dispersing emulsification machine again more than three times, operating pressure 5k～18k psi is 5.5～8.0 with pH regulator agent adjust pH, adds to the full amount of water for injection at last; Through 0.45 μ m filtering with microporous membrane, nitrogen purge gas stream protection filling encapsulation with 121 ℃ of rotation autoclaves, was sterilized 20 minutes, progressively was cooled to room temperature towards hot water again.
2. 2-methoxy estradiol vena nano emulsions according to claim 1 is characterized in that, said aqueous mixture is by emulsifying agent 0.05%～5%, the isoosmotic adjusting agent 2%～6% of w/v, and surplus is that water for injection mixes composition.
3. 2-methoxy estradiol vena nano emulsions according to claim 1, it is characterized in that, said oil for injection can be that soybean oil, olive oil, Oleum Sesami, safflower oil, Oleum Gossypii semen, safranine caul-fat, Semen Maydis oil, Oleum Fructus Bruceae, some medium chain wet goods can be the mixture of any in the acceptable oil of intravenous injection physiology or its two kinds, three kinds, and its content is preferably 15%～30% of compositions cumulative volume.
4. 2-methoxy estradiol vena nano emulsions according to claim 1 is characterized in that, said emulsifying agent can be phospholipid or poloxamer or the mixture of the two, and wherein phospholipid content in the compositions cumulative volume is preferably 0.5%～3%; Poloxamer content in the compositions cumulative volume is preferably 0.1%～1%; If emulsifying agent is the two mixture, the weight ratio of its phospholipid and poloxamer is 10: 1～1: 5, is preferably 5: 1～2: 1, and content is preferably 0.05%～5% of compositions cumulative volume.
5. 2-methoxy estradiol vena nano emulsions according to claim 4, it is characterized in that, said phospholipid is that soybean phospholipid, Ovum Gallus domesticus Flavus lecithin, Semen sojae atricolor hydrogenated phospholipid, hydrogenated yolk lecithin, two palmityl phospholipid, DSPE, Polyethylene Glycol-distearyl ethanolamine are any, also can be the phospholipid modified of list or polyclonal antibody, the phospholipid of phospholipid that galactosyl is modified, expressing polypeptide shed repair decorations any, or the mixture of two or more phospholipid of different nature.
6. 2-methoxy estradiol vena nano emulsions according to claim 4 is characterized in that, said poloxamer is any of poloxamer-188, poloxamer-338, poloxamer-407, and optimum is a poloxamer-188.
7. 2-methoxy estradiol vena nano emulsions according to claim 1 is characterized in that, said 2-methoxyestradiol optimum content is 0.1%～0.3% of a compositions cumulative volume.
8. 2-methoxy estradiol vena nano emulsions according to claim 1, it is characterized in that, said isoosmotic adjusting agent is any in glucose, sorbitol, glycerol and the kind can intravenous injection accepted by physiology, and in the compositions total volume percent: the consumption of glucose is 3%～5%, the consumption of sorbitol is 3%～6%, the glycerol consumption is 2%～3%.
9. 2-methoxy estradiol vena nano emulsions according to claim 1 is characterized in that, said pH regulator agent is hydrochloric acid or the sodium hydroxide that vein can be accepted by physiology.
10. 2-methoxy estradiol vena nano emulsions according to claim 1 is characterized in that, said organic solvent is chloroform or acetone.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008100494650A CN101249070B (en) | 2008-04-02 | 2008-04-02 | 2-methoxy estradiol vena nano emulsions |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2008100494650A CN101249070B (en) | 2008-04-02 | 2008-04-02 | 2-methoxy estradiol vena nano emulsions |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101249070A true CN101249070A (en) | 2008-08-27 |
| CN101249070B CN101249070B (en) | 2010-07-21 |
Family
ID=39952784
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2008100494650A Expired - Fee Related CN101249070B (en) | 2008-04-02 | 2008-04-02 | 2-methoxy estradiol vena nano emulsions |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101249070B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105748425A (en) * | 2016-02-29 | 2016-07-13 | 北京颐诺赛医药科技有限公司 | 2-methoxyestradiol solubilization medicinal preparation |
| CN107184587A (en) * | 2017-05-22 | 2017-09-22 | 河南科技大学 | A kind of 2 methoxyestradiol combination of oral medication and preparation method thereof, 2 methoxyestradiol soft capsules |
| CN107412161A (en) * | 2017-05-22 | 2017-12-01 | 河南科技大学 | A kind of methoxyestradiol intravenous injection of self-emulsifying 2 and preparation method thereof |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3225706C2 (en) * | 1982-07-09 | 1984-04-26 | A. Nattermann & Cie GmbH, 5000 Köln | Liquid active ingredient formulations in the form of concentrates for microemulsions |
| DE19825856A1 (en) * | 1998-06-10 | 1999-12-16 | Labtec Gmbh | New topical formulation which includes active agent as liquid lipid nanoparticles in an oil-in-water emulsion |
| BRPI0407667A (en) * | 2003-02-20 | 2006-03-01 | Univ Pittsburgh | estradiol metabolites for the treatment of pulmonary hypertension |
| MX2008001687A (en) * | 2005-08-12 | 2008-02-19 | Drugtech Corp | Estrogen compositions and therapeutic methods of use thereof. |
| US20070128289A1 (en) * | 2005-12-07 | 2007-06-07 | Zhao Jonathon Z | Nano-and/or micro-particulate formulations for local injection-based treatment of vascular diseases |
-
2008
- 2008-04-02 CN CN2008100494650A patent/CN101249070B/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105748425A (en) * | 2016-02-29 | 2016-07-13 | 北京颐诺赛医药科技有限公司 | 2-methoxyestradiol solubilization medicinal preparation |
| CN107184587A (en) * | 2017-05-22 | 2017-09-22 | 河南科技大学 | A kind of 2 methoxyestradiol combination of oral medication and preparation method thereof, 2 methoxyestradiol soft capsules |
| CN107412161A (en) * | 2017-05-22 | 2017-12-01 | 河南科技大学 | A kind of methoxyestradiol intravenous injection of self-emulsifying 2 and preparation method thereof |
| CN107184587B (en) * | 2017-05-22 | 2021-05-18 | 河南科技大学 | 2-methoxyestradiol oral pharmaceutical composition, preparation method thereof and 2-methoxyestradiol soft capsule |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101249070B (en) | 2010-07-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Gao et al. | Preparation and characterization of Pluronic/TPGS mixed micelles for solubilization of camptothecin | |
| Sarisozen et al. | Long-circulating PEG-PE micelles co-loaded with paclitaxel and elacridar (GG918) overcome multidrug resistance | |
| CN101909614B (en) | Nanodispersion | |
| CN101524330B (en) | Micro emulsion drug carrying system and manufacturing method thereof | |
| CN101366697A (en) | Novel nano-lipid carrier for injection embodying paclitaxel series substances and preparation method thereof | |
| CN102048688B (en) | Taxol submicroemulsion taking cholesterol complex as intermediate carrier | |
| WO2022160971A1 (en) | Concentrate containing poorly soluble drug, and emulsion prepared therefrom | |
| CN106420610A (en) | Ionic liquid microemulsion and application thereof | |
| WO2016177346A1 (en) | Cabazitaxel fat emulsion injection, and preparation method and use thereof | |
| CN109730998A (en) | Miboplatin albumin nano granular composition and its preparation method | |
| CN108578356B (en) | Artemether oral microemulsion in-situ gel and preparation method thereof | |
| CN101524329B (en) | Bicyclo-ethanol submicron emulsion and preparation method thereof | |
| CN101249070B (en) | 2-methoxy estradiol vena nano emulsions | |
| CN109718228A (en) | The antitumor Lymph Node Metastasis of mitoxantrone acts on and its pharmaceutical preparation | |
| CN100998592B (en) | Microemulsion containing matrine | |
| CN102552134B (en) | Fat emulsion containing vitamin K1 | |
| Sabri et al. | Comparison between conventional and supersaturable self-nanoemulsion loaded with nebivolol: preparation and in-vitro/ex-vivo evaluation | |
| Shi et al. | Arginine-glycine-aspartic acid-anchored curcumin-based nanotherapeutics inhibit pyroptosis-induced cytokine release syndrome for in vivo and in vitro sepsis applications | |
| CN102641245A (en) | Chitosan-chitosan derivative nanosphere for loading indissoluble medicament, preparation method of nanosphere, and application of nanosphere serving as oral prepration | |
| WO2019004338A1 (en) | Pharmaceutical composition and tumor immunoactivity promoter | |
| CN114028324B (en) | Uncaria base temperature-sensitive gel nasal administration preparation and preparation method thereof | |
| CN105919974B (en) | Salmon calcitonin phosphatide complexes and its lipid nano particle and preparation method | |
| Liu et al. | A comprehensive preclinical evaluation of intravenous etoposide lipid emulsion | |
| CN107802600B (en) | Icariin bone targeting nano liposome as well as preparation method and application thereof | |
| Zhang et al. | Phytoestrogen-derived multifunctional ligands for targeted therapy of breast cancer |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20100721 Termination date: 20130402 |