CN101006992A - Propofol freeze-dried emulsion and its preparing method - Google Patents
Propofol freeze-dried emulsion and its preparing method Download PDFInfo
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Abstract
The invention relates to a medicinal composition containing propofol and process for preparation, wherein each 1kg of the freeze-dried product comprises propofol 1g, oil for injection 0-20g, emulsifying agent 0.1-10g, auxiliary emulsifying agent 0.001-5g, other stabilizing agent 0-2g, freeze-drying protective agent 1-40g, and right amount of pH modifier. The invention can achieve better constancy.
Description
Invention field
The present invention relates to a kind of pharmaceutical composition that contains propofol, and the preparation method of said composition.
Background of invention
Propofol, chemistry is called 2, and the 6-diisopropyl phenol is a kind of injectable anesthetis, can induce and keep general anesthesia, and be used for calmness in care unit.Propofol uses as anesthetis and applies for a patent in many countries and regions, is 1472793 British patent as the patent No., U.S. Pat P4056635, USP4452817, USP4798846 etc.
Although propofol is a kind of preferred anesthetis, it is a kind of water-insoluble drug, is difficult to it directly is mixed with injection for intravenous behind the solution.For solving the administration problem of propofol, the medicament scholar has carried out big quantity research.The non-ionic surface active agent Cremophor EL that initial use injectable is used prepares the aqueous solution of 1% propofol to its solubilising, still, has shown at intravenous injection CremophorEL to have some side effect, wherein most importantly anaphylaxis.
People such as G.Trapani have studied propofol have been prepared into clathrate with hydroxypropyl B-cyclodextrin with 1: 1 molar ratio enclose, to improve its dissolubility in water; In WO96/32135, describe the Pharmaceutical composition that comprises propofol and hydroxypropyl B-cyclodextrin clathrate compounds equally, be prepared into the injection of clear solution shape.Domestic also have CN1625414A and two pieces of similar patent applications of CN1454085A openly.Hydroxypropyl B-cyclodextrin has good water-solubility and solubilizing effect as pharmaceutic adjuvant, there is some safety issues (2-Hydroxypropyl-β-Cyclodextrin as being directly used in intravenous administration hydroxypropyl B-cyclodextrin, Part II:Safety and ManufacturingIssues.Pharmaceutical Techology, Feb, 1992).
The dosage form of the product of propofol listing at present is mainly Emulsion.By using vegetable oil, emulsifying agent, supplementary element and toxicity improver etc. propofol to be prepared into Emulsion, external many patents (USP5714520; USP5731355; USP5731356 and USP5908869) report all arranged.The propofol emulsion commodity that success is gone on the market ' Diprivan ' by name, its prescription is:
Propofol 10mg/ml
Oleum Glycines 100mg/ml
Glycerol 22.5mg/ml
Lecithin 12mg/ml
EDTA-2Na 0.005％
Common Emulsion is heterogeneous liquid preparation, belongs to the thermodynamics and kinetics Unstable Systems, and common Emulsion Chinese medicine, Oleum Glycines and lecithin high-temperature process and the liquid form long term store in the course of processing is easy to generate degraded and oxidation; The emulsion droplet particle is easy to merge and phenomenon such as particle diameter increase occurs in the long-term put procedure.Usually the posterior vein injectable emulsion particle size range that is uniformly dispersed is between 0.1～0.5 μ m.Should be below 1 μ m by country to the requirement overwhelming majority of Emulsion particle diameter.
Fatty matter in the Emulsion is the good substrate of growth of microorganism under liquid environment simultaneously, patent WO0023050, described among US6469069 and the US5714520 by adding EDTA, antibacterial such as pentaacetic acid and sulphite realize suppressing the purpose of accidental pollution growth of microorganism.In addition, product can not stand violent jolting and high low tempertaure storage (the commercially available prod description requires 2～25 ℃ of storages, must not be freezing), and these all make this product make troubles in production, transportation and use.
Freeze-dried emulsion is to add cryoprotective agent in Emulsion; the method of employing frozen drying is prepared into Emulsion in a kind of preparation of solid forms; medicine makes it be recovered to liquid emulsion facing with aquation media such as preceding adding water for injection or normal saline, uses for injection.Patent EP0211257, JP602398417, ZA8604032, but US005882684 has described composition and the preparation method of difference injection for intravenous with the medicine freeze-dried emulsion respectively, US005977172, US5612058 and US005882684 have described and have used preparation prescription and the technology that cryodesiccated method prepares the PGE1 freeze-dried emulsion, and the result shows that these freeze-dried emulsions all show higher stability.
Usually freeze-dry process comprises the following steps: 1) with lyophilizing solution or Emulsion degerming packing, place freeze dryer; 2) low temperature pre-freeze; 3) sublimation drying, wherein sublimation drying often is divided into several stages by different temperatures again.
Reach Emulsion is prepared into freeze-dried emulsion stable, that recovery effect is good, key is to select proper supplementary material and proportioning thereof.And the key of freeze-dry process is the character according to lyophilizing solution or Emulsion, selects the temperature and the processing time in each stage.
Summary of the invention
In the propofol freeze-dried emulsion provided by the invention, be equivalent to contain in the unit mass dried frozen aquatic products of propofol 1g and contain:
Propofol 1g
Oil for injection 0～20g
Emulsifying agent 0.1～10g
Coemulsifier 0.001～5g
Other stabilizing agent 0～2g
Freeze drying protectant 1～40g
The pH regulator agent is an amount of
Described oil for injection can be vegetable oil, animal oil, the chemical modification of any kind of and makes oily a kind of or its mixture, is Oleum Glycines, Semen Lini oil, Oleum Camelliae, safflower oil, Oleum Gossypii semen, Semen Maydis oil, Oleum Arachidis hypogaeae semen, Oleum Ricini as vegetable oil; Animal oil is fish oil, pilchardine, trout oil, tunny fish oil or anchovy oil; The oil of described chemical modification manufacturing is medium chain triglyceride, monoglyceride, diglyceride, ethyl oleate, isopropyl myristate, isopropyl palmitate, poly-oxyl castor oil hydrogenated, long-chain or medium-chain fatty acid or fatty acid alcohol.
Described emulsifying agent comprises, but is not restricted to, phospholipid, and natural phospholipid for example is as Ovum Gallus domesticus Flavus lecithin; Synthesize or semisynthetic phospholipid, as phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE and phosphatidyl glycerol; The phospholipid of ethoxylation; Glycolipid; Sterol such as cholesterol and cholesterol ester; Nonionic surfactant, as HS15, Tweens, polyoxypropylene-polyoxyethylene block copolymer such as poloxamer and poloxamines; Or its mixture; Preferred surfactants is phospholipid or phospholipid and above-mentioned one or more surfactant mixtures.
Said coemulsifier comprises the saturated or unsaturated fatty acid of straight or branched C6～18, as stearic acid, oleic acid, Palmic acid, myristic acid and its esters; The primary amine of C2～18, secondary amine such as ethanolamine, oleyl amine, 18-amine.; Aminoacid such as lysine, histidine, arginine; Steroid such as cholesterol or its ester, cholic acid and sodium salt thereof, dehydrocholic acid and sodium salt thereof, deoxycholic acid and sodium salt thereof, glycocholic acid and sodium salt thereof; Nonionic surfactant is as tween and poloxamer; Phosphatidic acid and charged lipid such as PA, PG, DPPA, DPPG; Polyhydroxy compounds such as glycerol, PVP, PEG, xylitol.
Other stabilizing agent comprises metal ion chelation agent such as edetate; Growth of microorganism inhibitor such as pentaacetic acid, sulphite; Antioxidant is as nitrogen, sodium sulfite, sodium sulfite, vitamin C, alpha-tocopherol.These stabilizing agents all can add in right amount.
The pH regulator agent is one or more mixture of hydrochloric acid, sodium hydroxide, acetic acid, sodium acetate, phosphate, citric acid, citrate.
Freeze drying protectant is mainly glucide, one or more of glucose, dextran, fructose, lactose, galactose, sucrose, maltose, trehalose, mannitol, sorbitol, xylitol.
The preparation method of freeze-dried emulsion is divided into two parts.
1, preparation propofol emulsion
It is biphase that medicine and adjuvant thereof are prepared into profit, with biphase mixing, shears in the time of 20～80 ℃, forms colostrum, regulates pH value 4～9, crosses homogenizer, with emulsion homogenize repeatedly, obtains finely dispersed Emulsion.
Oil for injection concentration is 0～20% (w/v) in the preferred Emulsion, and more preferably consumption is 1%～10% (w/v).
Emulsifier concentration is 0.1%～10% (w/v) in the preferred Emulsion, and more preferably consumption is 0.5%～3% (w/v).
Coemulsifier concentration is 0.001～5% (w/v) in the preferred Emulsion, and more preferably consumption is 0.005%～2% (w/v).
The concentration of preferred other stabilizing agent is 0～2% (w/v).
The consumption of freeze drying protectant is 1%～40% (w/v) in the preferred Emulsion, and more preferably consumption is 2～30%, and most preferred quantities is 5～20%.
Preferred pH value is 6.0～8.0.
Homogenization pressure is at 5000～15000psi, and the particle size range of Emulsion is 50nm～300nm.
2, the preparation of freeze-dried emulsion
For propofol emulsion, be prepared into freeze-dried emulsion, can not realize under the conventional lyophilisation condition.The Emulsion freeze-dry process of reporting in the prior art also differs and realizes surely.Therefore, the applicant obtains following preferred lyophilisation condition through research.
In the above-mentioned even Emulsion that obtains, add freeze drying protectant, dissolve complete after-filtration degerming, packing, the Emulsion that branch installs is put into freeze dryer, in subzero pre-freeze 2～4h below 40 ℃, be warming up to subzero 30～subzero 20 ℃ and keep more than the 20h, vacuum decompression is removed moisture, be warming up to 0 ℃, keep 8～10h continuation vacuum decompression and remove moisture; Be warming up to 25 ℃, continue vacuum decompression and remove moisture, get exsiccant freeze-dried emulsion.
The freeze-dried emulsion that makes is measured on demand and is added water, makes it be recovered to Emulsion after the reconstruction, and the particle size range of institute's antigalactic is 50nm～0.5 μ m, but injection for intravenous.
The assay of propofol adopts the HPLC method.The relevant particle size determination of freeze-dried emulsion adopts Brookhaven 90plus particle size analyzer laser granulometry to measure.
According to the prescription and the prepared propofol freeze-dried emulsion of preparation technology thereof of propofol freeze-dried emulsion provided by the invention, compare with existing propofol emulsion, under high temperature (40 ℃) and low temperature (20 ℃), all have good stability; Particle diameter does not have significant change before and after the Emulsion lyophilizing.
The specific embodiment
Embodiment 1:
＜1〉composition of propofol freeze-dried emulsion is: propofol 1g, and Oleum Glycines 20g, the Ovum Gallus domesticus Flavus lecithin 1.2g of purification, cholesterol 0.2g, Tween-80 0.5g, EDTA-2Na 0.01g, sucrose 8g, sodium hydroxide is an amount of, and all the other are water for injection, altogether 100ml.
＜2〉propofol freeze-dried emulsion preparation technology is as follows:
Ovum Gallus domesticus Flavus lecithin and cholesterol shear agitation with purification under 40 ℃ are dissolved in the Oleum Glycines, add the propofol mix homogeneously again and make oil phase; Tween-80, EDTA-2Na are dissolved in the water for injection, make water; Water joined in the oil phase stir 10min and get colostrum, regulate pH value 7.0～8.0, colostrum is crossed high pressure homogenizer, at first regulate homogenizer pressure and be 5000psi homogenize 3 times repeatedly, re-adjustment homogenizer pressure is 15000psi, and homogenize gets even Emulsion 3～5 times repeatedly.Add freeze drying protectant sucrose mix homogeneously,, with the packing of gained Emulsion, remove moisture through lyophilization and get propofol freeze-dried emulsion then with 0.22 μ m filtering with microporous membrane.
＜3〉the lyophilizing breast that makes is measured the adding sterilized water for injection on demand, after the hydration vibration, is recovered to Emulsion, can use for intravenous drip.
Embodiment 2:
＜1〉composition of propofol freeze-dried emulsion is: propofol 2g, Oleum Glycines 8g, injection Ovum Gallus domesticus Flavus lecithin 2.0g, Poloxamer 1.0g, oleic acid 0.05g, EDTA-2Na 0.005g, sucrose 10g, mannitol 5g, sodium hydroxide is an amount of, and all the other are water for injection, altogether 100ml.
＜2〉propofol freeze-dried emulsion preparation technology is as follows:
With Oleum Glycines, oleic acid mixing, add the propofol mix homogeneously again and make oil phase under 60 ℃; The injection Ovum Gallus domesticus Flavus lecithin is scattered in the water for injection that contains EDTA-2Na and Poloxamer, makes water; Under 40 ℃ water joined and shear 10min in the oil phase and get colostrum, regulate pH value 6.5～8.0, colostrum is crossed high pressure homogenizer, at first regulate homogenizer pressure and be 5000psi homogenize 3 times repeatedly, re-adjustment homogenizer pressure is 15000psi, and homogenize gets even Emulsion 3～5 times repeatedly.Add freeze drying protectant sucrose and mannitol mix homogeneously, with 0.22 μ m filtering with microporous membrane, with the packing of gained Emulsion, remove moisture through lyophilization then, inflated with nitrogen gets propofol freeze-dried emulsion.
＜3〉the lyophilizing breast that makes is measured the adding sterilized water for injection on demand, after the hydration vibration, is recovered to Emulsion, can use for intravenous drip.
Embodiment 3:
＜1〉composition of propofol freeze-dried emulsion is: propofol 1g, and Oleum Glycines 15g, the soybean lecithin 2.4g of purification, oleyl amine 0.05g, EDTA-2Na 0.005g, lactose 10g, glycerol 2.25g, sodium hydroxide is an amount of, and all the other are water for injection, altogether 100ml.
＜2〉propofol freeze-dried emulsion preparation technology is as follows:
Soybean lecithin with purification under 40 ℃ is scattered in the Oleum Glycines, adds oleyl amine again, the propofol mix homogeneously makes oil phase; Glycerol and EDTA-2Na are dissolved in the water for injection, make water; Water joined in the oil phase shear 10min and get colostrum, regulate pH value 7.0～8.0, colostrum is crossed high pressure homogenizer, at first regulate homogenizer pressure and be 5000psi homogenize 2 times repeatedly, re-adjustment homogenizer pressure is 10000～15000psi, and homogenize gets even Emulsion 3～5 times repeatedly.Add the freeze drying protectant lactose to dissolving fully even Emulsion, cross 0.22 μ m microporous filter membrane, with the even Emulsion packing of gained, remove moisture then through lyophilization, inflated with nitrogen gets propofol freeze-dried emulsion.
＜3〉the lyophilizing breast that makes is measured the adding sterilized water for injection on demand, after the hydration vibration, is recovered to Emulsion, can use for intravenous drip.
Embodiment 4:
＜1〉composition of propofol freeze-dried emulsion is: propofol 2g, and Oleum Glycines 12g, injection Ovum Gallus domesticus Flavus lecithin 0.6g, poloxamer 2g, glycerol 0.5g, trehalose 8g, sodium hydroxide is an amount of, and all the other are water for injection, altogether 100ml.
＜2〉propofol freeze-dried emulsion preparation technology is as follows:
Under 40 ℃ Oleum Glycines and propofol mix homogeneously are made oil phase; The injection Ovum Gallus domesticus Flavus lecithin is scattered in 40 ℃ of waters for injection that contain poloxamer, makes water; Water joined in the oil phase stir 15min and get colostrum, regulate pH value 7.0～8.0, colostrum is crossed high pressure homogenizer, at first regulate homogenizer pressure and be 5000psi homogenize 2 times repeatedly, re-adjustment homogenizer pressure is 15000psi, repeatedly homogenize 3 times even Emulsion.Add the freeze drying protectant trehalose to dissolving fully even Emulsion, cross 0.22 μ m microporous filter membrane, with the even Emulsion packing of gained, remove moisture then through lyophilization, inflated with nitrogen gets propofol freeze-dried emulsion.
＜3〉the lyophilizing breast that makes is measured the adding sterilized water for injection on demand, after the hydration vibration, is recovered to Emulsion, can use for intravenous drip.
Embodiment 5:
＜1〉composition of propofol freeze-dried emulsion is: propofol 2g, Oleum Glycines 2g, the soybean lecithin 2.0g of purification, DPPG 0.1g, poloxamer1.5g, HS-15 0.5g, alpha-tocopherol 0.02g, PVPC300.5g, sucrose 20g, sodium hydroxide is an amount of, and all the other are water for injection, altogether 100ml.
＜2〉propofol freeze-dried emulsion preparation technology is as follows:
Soybean lecithin and DPPG with purification under 40 ℃ are scattered in the Oleum Glycines, add alpha-tocopherol, add the propofol mix homogeneously again and make oil phase; PVPC30, poloxamer and HS-15 are dissolved in the water for injection, make water; Water joined in the oil phase stir 10min and get colostrum, regulate pH value 6.5～7.5, colostrum is crossed high pressure homogenizer, at first regulate homogenizer pressure and be 5000psi homogenize 3 times repeatedly, re-adjustment homogenizer pressure is 15000psi, and homogenize gets even Emulsion 3～5 times repeatedly.Add freeze drying protectant sucrose to dissolving fully even Emulsion, cross 0.22 μ m microporous filter membrane, with the even Emulsion packing of gained, remove moisture then through lyophilization, inflated with nitrogen gets propofol freeze-dried emulsion.
＜3〉the lyophilizing breast that makes is measured the adding sterilized water for injection on demand, after the hydration vibration, is recovered to Emulsion, can use for intravenous drip.
Embodiment 6:
＜1〉composition of propofol freeze-dried emulsion is: propofol 2g, Oleum Glycines 10g, the soybean lecithin 1.8g of purification, poloxamer 0.5g, oleic acid 0.03g, PVPC30 0.5g, EDTA-2Na 0.01g, mannitol 10g, sodium hydroxide is an amount of, and all the other are water for injection, altogether 100ml.
＜2〉propofol freeze-dried emulsion preparation technology is as follows:
Soybean lecithin with purification under 50 ℃ is scattered in the Oleum Glycines, adds oleic acid, adds the propofol mix homogeneously again and makes oil phase; Poloxamer, PVPC30 and EDTA-2Na be dissolved in 40 ℃ the water for injection, make water; Water joined in the oil phase stir 15min and get colostrum, regulate pH value 7.0～8.0, colostrum is crossed high pressure, at first regulate homogenizer pressure and be 5000psi homogenize 2 times repeatedly, re-adjustment homogenizer pressure is 10000～15000psi, and homogenize gets even Emulsion 4 times repeatedly.Add freeze drying protectant mannitol to dissolving fully even Emulsion, cross 0.22 μ m microporous filter membrane, with the even Emulsion packing of gained, remove moisture then through lyophilization, inflated with nitrogen gets propofol freeze-dried emulsion.
＜3〉the lyophilizing breast that makes is measured the adding sterilized water for injection on demand, after the hydration vibration, is recovered to Emulsion, can use for intravenous drip.
Embodiment 7:
＜1〉composition of propofol freeze-dried emulsion is: propofol 1g, and midchain oil 10g, Tween-800.5g, sodium cholate 0.005g, EDTA-2Na 0.005g, glycerol 1.0g, sucrose 10g, mannitol 5g, sodium hydroxide is an amount of, and all the other are water for injection, altogether 100ml.
＜2〉propofol freeze-dried emulsion preparation technology is as follows:
Under 60 ℃ propofol added that mix homogeneously makes oil phase in the midchain oil; Tween-80, sodium cholate, glycerol and EDTA-2Na are dissolved in the water for injection, make water; Water joined in the oil phase stir 15min and get colostrum, regulate pH value 6.5～8.0, colostrum is crossed high pressure homogenizer, at first regulate homogenizer pressure and be 5000psi homogenize 2 times repeatedly, re-adjustment homogenizer pressure is 15000psi, repeatedly homogenize 5 times even Emulsion.Add freeze drying protectant sucrose and mannitol to dissolving fully even Emulsion, cross 0.22 μ m microporous filter membrane, with the even Emulsion packing of gained, remove moisture then through lyophilization, inflated with nitrogen gets propofol freeze-dried emulsion.
＜3〉the lyophilizing breast that makes is measured the adding sterilized water for injection on demand, after the hydration vibration, is recovered to Emulsion, can use for intravenous drip.
Embodiment 8:
＜1〉composition of propofol freeze-dried emulsion is: propofol 2g, midchain oil 12g, the Ovum Gallus domesticus Flavus lecithin 1.8g of purification, poloxamer 1g, oleic acid 0.05g, alpha-tocopherol 0.02g, EDTA-2Na 0.005g, sucrose 10g, lactose 2g, sodium hydroxide is an amount of, and all the other are water for injection, altogether 100ml.
＜2〉propofol freeze-dried emulsion preparation technology is as follows:
With midchain oil, oleic acid, alpha-tocopherol mix homogeneously, add propofol again and make oil phase under 60 ℃; The Ovum Gallus domesticus Flavus lecithin of purification is scattered in the water for injection that contains poloxamer and EDTA-2Na, makes water; Water joined in the oil phase shear 10min and get colostrum, regulate pH value 6.0～7.5, colostrum is crossed high pressure homogenizer, at first regulate homogenizer pressure and be 5000psi homogenize 2 times repeatedly, re-adjustment homogenizer pressure is 15000psi, repeatedly homogenize 5 times even Emulsion.Add freeze drying protectant sucrose and lactose and extremely get even Emulsion after the dissolving fully, cross 0.22 μ m microporous filter membrane, with the even Emulsion packing of gained, remove moisture through lyophilization then, inflated with nitrogen gets propofol freeze-dried emulsion.
＜3〉the lyophilizing breast that makes is measured the adding sterilized water for injection on demand, after the hydration vibration, is recovered to Emulsion, can use for intravenous drip.
Embodiment 9:
＜1〉composition of propofol freeze-dried emulsion is: propofol 1g, and the Ovum Gallus domesticus Flavus lecithin 1.2g of purification, NaGC 0.5g, EDTA-2Na 0.005g, glycerol 1g, mannitol 10g, sodium hydroxide is an amount of, and all the other are water for injection, altogether 100ml.
＜2〉propofol freeze-dried emulsion preparation technology is as follows:
Propofol is as oil phase; The Ovum Gallus domesticus Flavus lecithin of purification is scattered in the water for injection that contains NaGC, glycerol and EDTA-2Na, makes water; 40 ℃ join water in the oil phase and to shear 10min and get colostrum, regulate pH value 6.0～7.5, colostrum is crossed high pressure homogenizer, at first regulate homogenizer pressure and be 5000psi homogenize 2 times repeatedly, re-adjustment homogenizer pressure is 15000psi, repeatedly homogenize 2 times even Emulsion.Add frozen-dried protective mannitol and extremely get even Emulsion after the dissolving fully, cross 0.22 μ m microporous filter membrane, with the even Emulsion packing of gained, remove moisture through lyophilization then, inflated with nitrogen gets propofol freeze-dried emulsion.
＜3〉the lyophilizing breast that makes is measured the adding sterilized water for injection on demand, after the hydration vibration, is recovered to Emulsion, can use for intravenous drip.
Embodiment 10
Stability experiment:
Table 1: change of size before and after the Emulsion lyophilizing
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Embodiment 5 | Embodiment 6 | Embodiment 7 | Embodiment 8 | Embodiment 9 | |
| Before the lyophilizing (nm) | 352.3 | 220.5 | 285.2 | 270.8 | 219.5 | 372.4 | 212.5 | 195.4 | 100.4 |
| After the lyophilizing (nm) | 406.4 | 237.1 | 318.7 | 372.1 | 253.2 | 431.1 | 231.2 | 212.3 | 150.5 |
Table 1 shows that particle diameter does not have significant change before and after the Emulsion lyophilizing
Table 2: freeze-dried emulsion compares with listing Emulsion low temperature (20 ℃) freeze-stable
| Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | Commercially available Emulsion | |
| Particle diameter (nm) before freezing | 340.4 | 230.7 | 315.9 | 270.7 | 242.4 |
| Freezing back particle diameter (nm) | 364.1 | 236.1 | 320.2 | 297.2 | 381.5 |
According to table 2 as can be known, freeze-dried emulsion has better stability than commercially available Emulsion under the freezing condition.
Table 3: high temperature is placed preparation stability relatively for 40 ℃
| Sample | Time | The preparation outward appearance | Medicament contg | Emulsion mean diameter (nm) | The bacterium inspection |
| Self-control lyophilizing breast (embodiment 2) | 0 day | The white loose solid | 99.8％ | 221nm | Qualified |
| January | The white loose solid | 100.2％ | 219nm | Qualified | |
| February | The white loose solid | 99.3％ | 230nm | Qualified | |
| March | The white loose solid | 99.5％ | 245nm | Qualified | |
| The Emulsion injection | 0 day | White emulsion | 99.7％ | 247nm | Qualified |
| January | White emulsion | 98.1％ | 264nm | Qualified | |
| February | White emulsion | 97.7％ | 310nm | Qualified | |
| March | White emulsion | 97.3％ | 376nm | Qualified |
As known from Table 3, freeze-dried emulsion at high temperature medicament contg keeps stable, and emulsion particles changes little, and stability in the large is higher.
Claims (13)
1, propofol freeze-dried emulsion is equivalent to contain in the unit mass dried frozen aquatic products of propofol 1g and contains:
Propofol 1g
Oil for injection 0～20g
Emulsifying agent 0.1～10g
Coemulsifier 0.001～5g
Other stabilizing agent 0～2g
Freeze drying protectant 1～40g
The pH regulator agent is an amount of.
2, propofol freeze-dried emulsion according to claim 1 is characterized in that described oil for injection can be a kind of or its mixture of the vegetable oil of any kind of, animal oil, chemical modification manufacturing oil.
3, propofol freeze-dried emulsion according to claim 2 is characterized in that said vegetable oil is selected from Oleum Glycines, Semen Lini oil, Oleum Camelliae, safflower oil, Oleum Gossypii semen, Semen Maydis oil, Oleum Arachidis hypogaeae semen, Oleum Ricini; Animal oil is selected from fish oil, pilchardine, trout oil, tunny fish oil or anchovy oil; The grease separation that described chemical modification is made is from medium chain triglyceride, monoglyceride, diglyceride, ethyl oleate, isopropyl myristate, isopropyl palmitate, poly-oxyl castor oil hydrogenated, long-chain or medium-chain fatty acid or fatty acid alcohol.
4, propofol freeze-dried emulsion according to claim 1 is characterized in that described emulsifying agent is selected from natural phospholipid; Synthesize or semisynthetic phospholipid; Glycolipid; Nonionic surfactant; Or its mixture.
5, propofol freeze-dried emulsion according to claim 4 is characterized in that described emulsifying agent is phospholipid or phospholipid and above-mentioned one or more surfactant mixtures.
6, propofol freeze-dried emulsion according to claim 1 is characterized in that described coemulsifier is selected from straight or branched C
6～18Saturated or unsaturated fatty acid; C
2～18Primary amine, secondary amine; Aminoacid; Steroid or its ester, cholic acid and sodium salt thereof, dehydrocholic acid and sodium salt thereof, deoxycholic acid and sodium salt thereof, glycocholic acid and sodium salt thereof; Nonionic surfactant; Phosphatidic acid and charged lipid; The polyhydroxy compounds.
7, propofol freeze-dried emulsion according to claim 1 is characterized in that described other stabilizing agent comprises metal ion chelation agent; The growth of microorganism inhibitor; Antioxidant.
8, propofol freeze-dried emulsion according to claim 1 is characterized in that described pH regulator agent is one or more mixture of hydrochloric acid, sodium hydroxide, acetic acid, sodium acetate, phosphate, citric acid, citrate.
9, propofol freeze-dried emulsion according to claim 1 is characterized in that freeze drying protectant is selected from one or more of glucose, dextran, fructose, lactose, galactose, sucrose, maltose, trehalose, mannitol, sorbitol, xylitol.
10, a kind of method for preparing the propofol freeze-dried emulsion of one of claim 1 to 9 comprises that propofol emulsion prepares and two steps of preparation of freeze-dried emulsion, it is characterized in that:
It is biphase that medicine and adjuvant thereof are prepared into profit, with biphase mixing, shears in the time of 20～80 ℃, forms colostrum, regulates pH value 6～8, crosses homogenizer, with emulsion homogenize repeatedly, obtains finely dispersed Emulsion; Wherein
Oil for injection concentration is 0～20% (w/v) in the Emulsion; Emulsifier concentration is 0.1%～10% (w/v); Coemulsifier concentration is 0.001～5% (w/v); The concentration of other stabilizing agent is 0～2% (w/v); The consumption of freeze drying protectant is 2%～30% (w/v).
11, the preparation method of propofol freeze-dried emulsion according to claim 10, it is characterized in that in the Emulsion oil for injection concentration more preferably consumption be 1%～10% (w/v); Emulsifying agent is 0.5%～3% (w/v) more preferably; Coemulsifier concentration is 0.005%～2% (w/v) more preferably; Freeze drying protectant more preferably concentration is 5～20%.
12, according to the preparation method of claim 10 or 11 described propofol freeze-dried emulsions, it is characterized in that homogenization pressure at 5000～15000psi, the particle size range of Emulsion is 50nm～300nm.
13,, it is characterized in that in said freeze-dried emulsion preparation process the pre-freeze temperature is subzero below 40 ℃, 2～4 hours time according to the preparation method of claim 10 or 11 described propofol freeze-dried emulsions; The sublimation drying parameter is kept more than 20 hours when temperature is subzero 30～subzero 20 ℃ respectively, keeps in the time of 0 ℃ 8～10 hours, is maintained until in the time of 25 ℃ and obtains exsiccant freeze-dried emulsion.
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| CN2006100312051A CN101006992B (en) | 2006-01-27 | 2006-01-27 | Propofol freeze-dried emulsion and its preparing method |
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| CN101006992A true CN101006992A (en) | 2007-08-01 |
| CN101006992B CN101006992B (en) | 2011-08-17 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102366404A (en) * | 2011-10-20 | 2012-03-07 | 四川百利药业有限责任公司 | Propofol medium-long-chain fatty emulsion |
| CN104490780A (en) * | 2015-01-16 | 2015-04-08 | 河北一品制药有限公司 | Preparation method of propofol fat emulsion injection |
| CN104523591A (en) * | 2014-12-19 | 2015-04-22 | 西安力邦肇新生物科技有限公司 | Formula and preparation method of non-allergenic and painless novel propofol fatty microemulsion freeze-drying preparation |
| CN114129578A (en) * | 2021-09-28 | 2022-03-04 | 瑞普（天津）生物药业有限公司 | Application of fospropofol disodium in preparation of pet anesthesia and sedation drugs |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1106192C (en) * | 1995-03-17 | 2003-04-23 | 曾尼卡有限公司 | Oil in water emulsions containing 2, 6 -diisopropyl phenic and ehtylenedinamine-tetra acetic salt |
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2006
- 2006-01-27 CN CN2006100312051A patent/CN101006992B/en not_active Expired - Fee Related
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102366404A (en) * | 2011-10-20 | 2012-03-07 | 四川百利药业有限责任公司 | Propofol medium-long-chain fatty emulsion |
| CN102366404B (en) * | 2011-10-20 | 2015-10-07 | 四川百利药业有限责任公司 | A kind of Propofol medium-long-chain fatty emulsion |
| CN104523591A (en) * | 2014-12-19 | 2015-04-22 | 西安力邦肇新生物科技有限公司 | Formula and preparation method of non-allergenic and painless novel propofol fatty microemulsion freeze-drying preparation |
| CN104523591B (en) * | 2014-12-19 | 2019-01-18 | 西安力邦肇新生物科技有限公司 | Without sensitization, painless propofol fat micro emulsion frozen preparation formula and preparation method |
| CN104490780A (en) * | 2015-01-16 | 2015-04-08 | 河北一品制药有限公司 | Preparation method of propofol fat emulsion injection |
| CN104490780B (en) * | 2015-01-16 | 2017-04-19 | 河北一品制药有限公司 | Preparation method of propofol fat emulsion injection |
| CN114129578A (en) * | 2021-09-28 | 2022-03-04 | 瑞普（天津）生物药业有限公司 | Application of fospropofol disodium in preparation of pet anesthesia and sedation drugs |
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| CN101006992B (en) | 2011-08-17 |
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