CN101756895A - Polyene phosphatidyl choline intravenous preparation and preparation method thereof - Google Patents
Polyene phosphatidyl choline intravenous preparation and preparation method thereof Download PDFInfo
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- CN101756895A CN101756895A CN200910079855A CN200910079855A CN101756895A CN 101756895 A CN101756895 A CN 101756895A CN 200910079855 A CN200910079855 A CN 200910079855A CN 200910079855 A CN200910079855 A CN 200910079855A CN 101756895 A CN101756895 A CN 101756895A
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Abstract
The invention relates to a polyene phosphatidyl choline intravenous preparation (comprising infusion and freeze-drying) and a preparation method thereof. The raw materials of the polyene phosphatidyl choline intravenous preparation comprise polyene phosphatidyl choline, sodium cholate and xylitol which can accept the adjustment osmotic pressure. The process comprises the following steps: preparing a colloidal dispersion system from the polyene phosphatidyl choline and the sodium cholate according to the prescription under the conditions required by the process; carrying out active carbon decoloration on the colloidal dispersion system, then carrying out rough filtration on the obtained product under the condition of adding nitrogen, adding the xylitol according to the prescription into the obtained solution to prepare concentrated solution for later use; and adding water for injection to make up to volume, and preparing the infusion by the processing procedures of filtering, filling, adding the stopper, pressing the cover, sterilizing, detecting leakage and the like, or preparing the freeze-drying preparation by the processing procedures of filtering, filling, freeze-drying, adding the stopper, pressing the cover and sterilizing. The prepared infusion solution finished product has convenient clinical use, better stability on low temperature storage or clinical use, no turbidity or emulsification phenomenon, and better safety performance.
Description
Technical field
The present invention relates to the polyene phosphatidylcholine is the intravenous formulations (transfusion and lyophilizing) of primary raw material, especially a kind of polyene phosphatidylcholine Xylitol injection and preparation method thereof.
Background technology
Polyene phosphatidylcholine is the further extract of soybean extract-soybean phospholipid, and is consistent with important endogenous phospholipid on chemical constitution.
Modern pharmacological research shows that polyene phosphatidylcholine enough reduces hepatocellular fatty infiltration; Reduce inflammatory reaction; Promote liver cell regeneration by increasing RNA and proteinic synthesizing with glycogen content; By suppressing collagenation, reducing collagen/DNA ratio and the formation of liver hydroxyproline generation reduction connective tissue; Polyene phosphatidylcholine can be protected sinusoidal endothelial cell regulating liver-QI cell biological film to avoid damage, repair membrane damage, promote film regeneration.This product can make the liver plasma membrane tissue regeneration, coordinates the function between phospholipid and the cell membrane tissue, thereby can make lipid metabolism, synthetic protein and the function of detoxification etc. of liver recover normal effectively.This product has good lipotropy; its effective ingredient structure and cell membrane phospholipid are basic identical, and contain a large amount of unsaturated fatty acids, and energy the liver protecting cellularity reaches has dependent enzyme system to phospholipid; prevent hepatic necrosis and new connective tissue hypertrophy, promote hepatopathy rehabilitation.Be applicable to various types of hepatopathys, as: hepatitis, chronic hepatitis, hepatic necrosis, liver cirrhosis, hepatic coma (comprising forerunner's hepatic coma), fatty liver (also seeing the diabetes patient), cholestasis, poisoning, the recurrence of prevention cholelithiasis, perioperative treatment (especially hepatobiliary surgery), gestosis (comprising vomiting), psoriasis, neurodermatitis and radiation syndrome.
Because polyene phosphatidylcholine is originally as a kind of amphiphatic molecule, room temperature is semi-solid state down, and the pure product of polyene phosphatidylcholine are white cured shape solid, and are crystallizable under the low temperature, are insoluble to acetone, ethyl acetate.Dissolve in methanol, ethanol, EC.Polyene phosphatidylcholine is exposed to easily oxidation in the air, color and luster becomes brown deeply, easy oxidation scission of link under its high temperature, acidity, the illumination condition, therefore making of the clear and bright solution of homogeneous phase is the research emphasis of intravenous injection preparation, here selecting with polyene phosphatidylcholine compatibility relevant auxiliary materials good and that safety is good is the key of prescription composition, is the key of appropriate process technology shaped preparation.
At present, commercially available relevant injection has only liquid drugs injection, its preparation prescription is generally formed with adjuvant such as different solubilizing agents, secondary solubilizer, surfactant and certain amount of solvent, should be used for making clear liquor by what adopt " colloidal dispersion technology of preparing ", makes corresponding dosage form afterwards.Wherein solubilizing agent generally has cholic acid salt etc., and surfactant is a phospholipid itself etc., and the secondary solubilizer and the agent that relieves the pain have benzyl alcohol, and solvent has water for injection etc.
Here, may produce haemolysis during the benzyl alcohol large usage quantity, and muscle is had zest, and callosity cicatrix, certain toxicity and the bibliographical information of lethal are arranged.Therefore, there is the application of safety issue adjuvant in former prescription, and forbids in child hepatopath.
In addition, though finished product itself has fine solubility and stability, in its use, there is following problem in commercially available relevant aqueous injection:
The one, liquid drugs injection need face can intravenous troublesome operation link, the liquid medicine contamination that easily produces thus with preceding dilution.
The 2nd, liquid drugs injection is when making diluent with glucose solution, because of its metabolism utilization needs the participation of insulin, though can be the hepatopath provides heat, the side effect of the hyperglycemia that can bring but then on the one hand.
In sum, the injection technology of preparing and the method that find a kind of safer polyene phosphatidylcholine prescription to form and better be more suitable for are very necessary to guaranteeing data for clinical drug use.
At the solution of polyene phosphatidylcholine water solublity difficult point, the domestic related application that several pieces of distinct methods are arranged.All the seeing of at present relevant patent situation retrieval, application number: 200710050223.9, the invention compositions contains polyene phosphatidylcholine, benzyl alcohol, glycocholic acid or cholic acid or tween 80, ethanol or propylene glycol or glycerol, sodium hydroxide or sodium carbonate, 2,6 ditertiary butyl p cresol, tertiary butyl-4-hydroxy methoxybenzene, vitamin E is formed; Application number: 200610009780.1, compositions is made up of alkaline matter, cosolvent, excipient that polyene phosphatidylcholine, pharmacology allow; Application number: 200510124422.0, it is characterized in that forming by polyene phosphatidylcholine, solubilizing agent, water for injection, antiseptic and antioxidant; Application number: 200510030631.9, compositions comprises polyene phosphatidylcholine, cholate and caffolding agent composition; Application number: 200610088099.0, compositions is made up of polyene phosphatidylcholine, phospholipid, cholesterol, vitamin, stabilizing agent, mannitol or glucose; Application number: 200510021089.0, compositions polyene phosphatidylcholine and pharmaceutically acceptable solubilizing agent, caffolding agent and other supplementary elements are formed; Application number: 200610003436.1, compositions is by cosolvent, pH regulator agent, polyene phosphatidylcholine, antioxidant, an amount of excipient; Application number: 200510105183.4, compositions is made up of cosolvent, pH regulator agent, polyene phosphatidylcholine, antioxidant, the nutrient solution of formula ratio, cosolvent, isotonic agent, several vitamins; Application number: 200510094998.7, compositions is made up of polyene phosphatidylcholine and solubilizing agent; Application number: 200510037429.9, compositions is made up of polyene phosphatidylcholine and pharmaceutically acceptable carrier (cosolvent); Application number: 200510021636.5, compositions is made up of interior polyene phosphatidylcholine, solubilizing agent and freeze drying protectant; Application number: 200510057457.7, compositions is made up of polyene phosphatidylcholine, pharmaceutic adjuvant; Application number: 200410056865.6, compositions is made up of polyene phosphatidylcholine, solubilizing agent, water for injection.
In a word, show, there is no the identical content report of the present invention through relevant patent and prior art literature search result.
Summary of the invention
One of purpose of the present invention is to overcome the deficiency of the existing prescription of polyene phosphatidylcholine injection, for the use of this class medicine clinically provides a kind of good effect and safer, more reliable injection prescription; Two be to provide more convenient, the more stable polyene phosphatidylcholine transfusion of clinical use and freeze-dried formulation and preparation method thereof.
The present invention is achieved by the following technical solutions: polyene phosphatidylcholine transfusion prescription is made up of principal agent polyene phosphatidylcholine, cosolvent, isoosmotic adjusting agent, makes lyophilized formulations according to routine preparation transfusion or through lyophilization.
Polyene phosphatidylcholine is insoluble in water, considers to add cosolvent, and the selection of cosolvent is chosen as sodium cholate through testing in many ways to investigate, and sodium cholate and polyene phosphatidylcholine form colloidal dispersion system.The consumption of sodium cholate is selected and the mass ratio of principal agent is 0.1～2.5: 1, is preferably 0.5～2: 1.
Isoosmotic adjusting agent or lyophilizing proppant are selected xylitol, and xylitol better heat stability, pH scope are than the pH wide ranges (4.5～7.0) of glucose injection, and chemical property is also stable than glucose.
Preparation method of the present invention is: polyene phosphatidylcholine, sodium cholate place in the high-speed tissue mashing machine, add 3/5 water for injection, stir under nitrogen current until becoming uniform translucent colloidal dispersion.Add activated carbon adsorption 15min, under nitrogen current with No. 3 incipient fusion filter coarse filtration.Add xylitol and an amount of water for injection, the circulation homogenize is mended and is added water to capacity for several times, and the circulation homogenize is even.With the microporous filter membrane of 0.45 μ m filter (taking a sample to check) qualified after, nitrogen is filled in fill, sealing by fusing, 121 ℃, sterilization in 15 minutes, check, packing are made transfusion; Or fill, conventional lyophilizing, check, packing is made lyophilizing.
The present invention has following advantage: component of the present invention adopts xylitol to make isoosmotic adjusting agent, makes that prescription is formed more rationally, clinical practice is safer.The contained xylitol of gained finished product preparation is converted into hepatic glycogen in blood rapid than glucose, so easily absorb than glucose in vivo; And its metabolism utilization does not need the participation of insulin, and on the one hand can be the hepatopath provides heat, has avoided adopting the side effect of the hyperglycemia that the glucose solution diluent brings on the other hand; Replace the benzyl alcohol of former commercially available liquid drugs injection with xylitol, avoided the many side effect that bring because of benzyl alcohol; Simultaneously infusion solution solved that liquid drugs injection need face can intravenous troublesome operation link with preceding dilution, thereby stopped consequent liquid medicine contamination; Gained infusion solution finished product is clinical easy to use, and the stability during in cryopreservation or in clinical use better, muddiness or emulsion can not occur, and the product safety performance is better; The lyophilized preparation convenient transportation, good stability only need add the water for injection dilution when facing with use and get final product.
The specific embodiment
Embodiment 1 (specification 100ml:232.5mg)
Polyene phosphatidylcholine 250g, sodium cholate 500g place in the high-speed tissue mashing machine, add 60000ml water for injection, stir under nitrogen current until becoming uniform translucent colloidal dispersion.Add activated carbon adsorption 15min, under nitrogen current with No. 3 incipient fusion filter coarse filtration.Add xylitol 5000g and 20000ml water for injection, the circulation homogenize is mended and is added water to capacity 100000ml for several times, and the circulation homogenize is even.With the microporous filter membrane of 0.22 μ m filter (taking a sample to check) qualified after, nitrogen is filled in fill, sealing by fusing, 121 ℃, sterilization in 15 minutes.Check, packing.
Embodiment 2 (specification 250ml:465.0mg)
Polyene phosphatidylcholine 250g, sodium cholate 350g place in the high-speed tissue mashing machine, add 150000ml water for injection, stir under nitrogen current until becoming uniform translucent colloidal dispersion.Add activated carbon adsorption 15min, under nitrogen current with No. 3 incipient fusion filter coarse filtration.Add xylitol 12500g and 50000ml water for injection, the circulation homogenize is mended and is added water to capacity 250000ml for several times, and the circulation homogenize is even.With the microporous filter membrane of 0.22 μ m filter (taking a sample to check) qualified after, nitrogen is filled in fill, sealing by fusing, 121 ℃, sterilization in 15 minutes.Check, packing.
Embodiment 3 (specification 500ml:1162.5mg)
Polyene phosphatidylcholine 250g, sodium cholate 250g place in the high-speed tissue mashing machine, add 300000ml water for injection, stir under nitrogen current until becoming uniform translucent colloidal dispersion.Add activated carbon adsorption 15min, under nitrogen current with No. 3 incipient fusion filter coarse filtration.Add xylitol 25000g and 125000ml water for injection, the circulation homogenize is mended and is added water to capacity 500000ml for several times, and the circulation homogenize is even.With the microporous filter membrane of 0.22 μ m filter (taking a sample to check) qualified after, nitrogen is filled in fill, sealing by fusing, 121 ℃, sterilization in 15 minutes.Check, packing.
Embodiment 4 (specification l00ml:232.5mg)
Polyene phosphatidylcholine 250g, sodium cholate 400g place in the high-speed tissue mashing machine, add 60000ml water for injection, stir under nitrogen current until becoming uniform translucent colloidal dispersion.Add activated carbon adsorption 15min, under nitrogen current with No. 3 incipient fusion filter coarse filtration.Add xylitol 5000g and 20000ml water for injection, the circulation homogenize is mended and is added water to capacity 100000ml for several times, and the circulation homogenize is even.With the microporous filter membrane of 0.22 μ m filter (taking a sample to check) qualified after, nitrogen is filled in fill, sealing by fusing, 121 ℃, sterilization in 15 minutes.Check, packing.
Embodiment 5 (specification 232.5mg/ bottle (in polyene phosphatidylcholine))
Polyene phosphatidylcholine 250g, sodium cholate 400g place in the high-speed tissue mashing machine, add 60000ml water for injection, stir under nitrogen current until becoming uniform translucent colloidal dispersion.Add activated carbon adsorption 15min, under nitrogen current with No. 3 incipient fusion filter coarse filtration.Add xylitol 5000g and 20000ml water for injection, the circulation homogenize is mended and is added water to capacity 100000ml for several times, and the circulation homogenize is even.With the microporous filter membrane of 0.22 μ m filter (taking a sample to check) qualified after, nitrogen is filled in fill, places in the freeze dryer ,-30 ℃ of pre-freezes 6 hours were warming up to 30 ℃, dry 4 hours in 20 hours.Jump a queue, gland, the check, the packing.
The continuous three batch samples detection data that obtain according to embodiment 1 and 5 are as follows.
1, finished product leading indicator testing result
Assay is mainly polyene phosphatidylcholine PC, and related substance is hemolytic phospholipid LPC, and testing result sees Table 1.
Table 1 finished product leading indicator testing result
Conclusion: the index of correlation testing result is all up to specification.
2, the lyophilizing finished product adds every index testing result in the diluent (water for injection)
Method: get continuous three batches of lyophilizing samples, place behind the adding diluent to observe after 12 hours and detect, content results was 100% calculating with 0 hour, the results are shown in Table 2.
Table 2 lyophilizing finished product adds every index testing result in the diluent (water for injection)
Conclusion: after the lyophilizing finished product added water for injection, solution kept clarification in 12 hours, and content decreases, and related substance increases to some extent, but all in acceptability limit.
3, crystalline polamer observed result in the unlike material intravenous transfusion device dropping process
Method: get continuous three batch samples, drip the back with the unlike material intravenous transfusion device and observe.The results are shown in Table 3.
Phenomenon observed result in the table 3 unlike material intravenous transfusion device dropping process
Conclusion: no muddiness or emulsifying situation in the unlike material intravenous transfusion device dropping process.
Claims (5)
1. a polyene phosphatidyl choline intravenous preparation (transfusion and lyophilizing) and preparation thereof is characterized in that with the polyene phosphatidylcholine being principal agent, comprise adjuvants compositions such as cosolvent sodium cholate and xylitol.
2. according to described a kind of polyene phosphatidyl choline intravenous preparation (transfusion and lyophilizing) of claim 1, it is characterized in that cosolvent sodium cholate and polyene phosphatidylcholine mass ratio are 0.1～2.5: 1, are preferably 0.5～2: 1.
3. according to described a kind of polyene phosphatidyl choline intravenous preparation (transfusion and lyophilizing) of claim 1, it is characterized in that the transfusion isoosmotic adjusting agent is selected xylitol, xylitol can be used as the proppant of lyophilized preparation again.
4. according to described a kind of polyene phosphatidylcholine infusion preparation of claim 1, it is characterized in that preparation method is: polyene phosphatidylcholine, sodium cholate are placed in the high-speed tissue mashing machine, add 3/5 water for injection, under nitrogen current, stir until becoming uniform translucent colloidal dispersion.Add activated carbon adsorption 15min, under nitrogen current with No. 3 incipient fusion filter coarse filtration.Add xylitol and an amount of water for injection, the circulation homogenize is mended and is added water to capacity for several times, and the circulation homogenize is even.With the microporous filter membrane of 0.22 μ m filter (taking a sample to check) qualified after, nitrogen is filled in fill, sealing by fusing, 121 ℃, sterilization in 15 minutes.Check, packing.
5. according to described a kind of polyene phosphatidylcholine lyophilized formulations of claim 1, it is characterized in that preparation method is: polyene phosphatidylcholine, sodium cholate are placed in the high-speed tissue mashing machine, add 3/5 water for injection, under nitrogen current, stir until becoming uniform translucent colloidal dispersion.Add activated carbon adsorption 15min, under nitrogen current with No. 3 incipient fusion filter coarse filtration.Add xylitol and an amount of water for injection, the circulation homogenize is mended and is added water to capacity for several times, and the circulation homogenize is even.With the microporous filter membrane of 0.22 μ m filter (taking a sample to check) qualified after, nitrogen is filled in fill, conventional lyophilizing, check, packing.
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| CN2009100798557A CN101756895B (en) | 2009-03-13 | 2009-03-13 | Polyene phosphatidyl choline intravenous preparation and preparation method thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102631313A (en) * | 2011-11-10 | 2012-08-15 | 上海天氏利医药科技有限公司 | Polyene phosphatidyl choline intravenous administration preparation and preparation method thereof |
| CN112957477A (en) * | 2021-02-07 | 2021-06-15 | 中国药科大学 | Nano-carrier for regulating and controlling liver sinus endothelial cells and preparation method and application thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1602878A (en) * | 2004-08-26 | 2005-04-06 | 北京瑞伊人科技发展有限公司 | Preparation process of polyene phosphatidylcholine injection |
| CN100366238C (en) * | 2005-10-25 | 2008-02-06 | 江苏正大天晴药业股份有限公司 | Freeze dried polyene lecithin powder for injection and its prepn |
| CN101244070A (en) * | 2007-02-13 | 2008-08-20 | 桂勇 | Polyene phosphatidylcholine high-capacity injection |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102631313A (en) * | 2011-11-10 | 2012-08-15 | 上海天氏利医药科技有限公司 | Polyene phosphatidyl choline intravenous administration preparation and preparation method thereof |
| CN112957477A (en) * | 2021-02-07 | 2021-06-15 | 中国药科大学 | Nano-carrier for regulating and controlling liver sinus endothelial cells and preparation method and application thereof |
| CN112957477B (en) * | 2021-02-07 | 2024-04-26 | 中国药科大学 | Nanocarrier for regulating and controlling liver sinusoidal endothelial cells, and preparation method and application thereof |
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