CN102631313A - Polyene phosphatidyl choline intravenous administration preparation and preparation method thereof - Google Patents
Polyene phosphatidyl choline intravenous administration preparation and preparation method thereof Download PDFInfo
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Abstract
The invention relates to the technical field of medicine preparation aims to overcome the deficiency of poor stability of the polyene phosphatidyl choline injection preparation, and provides a polyene phosphatidyl choline intravenous administration preparation. The polyene phosphatidyl choline intravenous administration preparation is composed of a medicine solution and an auxiliary solution, wherein the medicine solution is composed of polyene phosphatidyl choline and proper organic solvent, is the organic solvent solution of the polyene phosphatidyl choline and can contain a proper stabilizing agent; and the auxiliary solution has the main ingredients of a solubilizer and injection water and can contain a pH conditioning agent, an isoosmotic adjusting agent and the like. When the polyene phosphatidyl choline intravenous administration preparation is used, the auxiliary solution is added into the medicine solvent to be evenly mixed, and the mixture is dipped after the mixture is subjected to intravenous injection or diluted by glucose injection. The polyene phosphatidyl choline intravenous administration preparation which has a definite curative effect and is safer and more reliable is provided for the clinics.
Description
Technical field
The invention belongs to technical field of medicine, be specifically related to a kind of polyene phosphatidyl choline intravenous drug-delivery preparation and preparation method thereof.
Background technology
Polyene phosphatidylcholine is the further extract of soybean phospholipid, and is consistent with some important endogenous phospholipid of human body on chemical constitution.Polyene phosphatidylcholine is applicable to treatments such as various types of hepatopathys clinically.
Pharmacological research shows that polyene phosphatidylcholine can reduce hepatocellular fatty infiltration; Reduce inflammatory reaction; Through increase RNA and proteinic synthetic, and increase glycogen content, promote liver cell regeneration; And pass through to suppress collagenation, reduction collagen/DNA ratio and liver hydroxyl and assist the formation of propylhomoserin generation minimizing connective tissue; Polyene phosphatidylcholine can protect sinusoidal endothelial cell and hepatocyte to avoid damage, and can repair damage, the regeneration of promotion film.Polyene phosphatidylcholine also can impel the liver plasma membrane tissue regeneration, coordinates the function between the cell membrane tissue, thereby can impel lipid metabolism, protein synthesis and the function of detoxification etc. of liver to recover normal effectively.In addition, polyene phosphatidylcholine has stronger lipotropy, and chemical constitution and cell membrane phospholipid are basic identical; And contain a large amount of unsaturated fatty acids; Ability the liver protecting cellularity reaches has dependent enzyme system to phospholipid, prevents hepatic necrosis and new connective tissue hypertrophy, promotes 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 (comprising the diabetes fatty liver), cholestasis, poisoning, the recurrence of prevention cholelithiasis, perioperative treatment (especially hepatobiliary surgery), gestosis (comprising vomiting), psoriasis, neurodermatitis and radiation syndrome etc.
Polyene phosphatidylcholine is originally as a kind of amphiphatic molecule, and for semi-solid, pure article are white cured shape solid to room temperature, and are crystallizable under the low temperature, are insoluble to acetone, ethyl acetate, dissolve in lower alcohol, rudimentary ether, Polyethylene Glycol, propylene glycol, glycerol, chloroform etc. down.Polyene phosphatidylcholine is exposed to and is prone to oxidation in the air, and easy oxidative cleavage under high temperature, Acidity of Aikalinity and illumination condition shows as color and luster and deepens, and peroxide value raises, and medicine irritation increases, and toxicity increases.Therefore polyene phosphatidylcholine will be processed intravenous administration formulation and has poor stability, the technical difficulty of aspects such as peroxide that easy toxigenicity is bigger and lysophosphatide.
In order to increase the stability of pharmaceutical preparation, common idea is that polyene phosphatidylcholine is processed injectable powder at present, like one Chinese patent application CN200510077503.X, polyenic phosphatidylcholine powder injection and preparation method thereof; One Chinese patent application CN200610003436.1, polyene phosphatidyl choline powder injection and preparation method thereof; One Chinese patent application CN200510021636.5, polyenic phosphatide acylcholine freeze-dried powder injecta medicine; One Chinese patent application CN200510021089.0, a kind of polyenic phosphatide acylcholine freeze-dried powder injecta and preparation method thereof; One Chinese patent application CN201010264516.9, a kind of high security injection polyene phosphatidylcholine and method for preparing; One Chinese patent application CN200510094998.7, a kind of polyenylphosphatidylfreezee freezee-dried powder injection for injecting and preparation method thereof; One Chinese patent application CN200610009780.1, polyenylphosphatidylfreezee freezee-dried powder injection for injecting and preparation method thereof; One Chinese patent application CN200510037429.9, polyene phosphatidyl choline lyophilized powdered injection; One Chinese patent application CN200510057457.7, injection is polyene phosphatidylcholine freeze-dried and preparation method thereof; One Chinese patent application CN200510030631.9 is used for the composition and method of making the same of injection polyene phosphatidyl choline powder injection, and waiting multinomial patent application all is that polyene phosphatidylcholine is processed injectable powder.At first; Though injectable powder can partly increase stability of formulation; But injectable powder (comprising lyophilized injectable powder) can not thoroughly be stopped moisture content, and the trace water of existence still can make and be in alkaline environment Chinese medicine polyene phosphatidylcholine hydrolysis oxidation, can not tackle the problem at its root.Secondly, the injectable powder manufacturing process is complicated, and energy consumption is huge, and commercial production has inconvenience.The 3rd, injectable powder need could be injected or instiled with after the appropriate solvent dissolving when clinical use, has increased the workload of clinical medical and nursing.
In addition, because polyene phosphatidylcholine is water insoluble,, need to add appropriate solubilizing agent for making the injection that is fit to clinical use.At present; Commercially available Essentiale N/Essentiale Forte N
Polyene Phosphatidylcholine injection liquid liquid drugs injection; Its preparation prescription is by adjuvant and solvent compositions such as solubilizing agent, secondary solubilizer; So-called through adopting " colloidal dispersion technology of preparing " makes clear liquor, makes corresponding preparation then.Wherein solubilizing agent is a deoxycholic acid, and is adjusted to alkalescence with sodium hydroxide.Because the medicine polyene phosphatidylcholine is in the weakly alkaline environment; There is following deficiency in the preparation Essentiale N/Essentiale Forte N
of therefore German Sanofi-Aventis pharmaceutical Co. Ltd: 1. in transportation, storage process, be prone to take place chemical reactions such as hydrolysis oxidation; Most typical is to show as peroxide value to raise; Hemolytic phospholipid increases; The zest of medicine increases, and toxicity increases; 2. in order to reduce medicine at transportation, hydrolysis oxidation in the storage process, then must be in refrigerator cryopreservation, increased inconvenience and cost for transportation and storage; 3. even more serious is: possibly be in order to increase stability of formulation; Added the secondary solubilizer benzyl alcohol in the Essentiale N/Essentiale Forte N
; Benzyl alcohol has bigger toxicity; Can cause fatal " syndrome of panting " etc., so Essentiale N/Essentiale Forte N
is forbidden in neonate and premature infant.4. the solubilizing agent NaTDC is that the polyene phosphatidylcholine injection produces toxic and side effects, especially causes the downright bad main cause of injection site tissue.
In sum, still there is not polyene phosphatidyl choline intravenous drug-delivery preparation a kind of stable type, safe and reliable at present.
Summary of the invention
The objective of the invention is to overcome the deficiency of Polyene Phosphatidylcholine injection liquid preparation stability, be clinical a kind of determined curative effect, safer, the more reliable polyene phosphatidyl choline intravenous drug-delivery preparation of providing.
The present invention faces and uses preceding remix through medicine polyene phosphatidylcholine and relevant solubilizing agent being made, separated packing respectively and storing, and has obtained stable intravenous administration formulation unexpectedly.
The invention provides a kind of intravenous administration formulation of polyene phosphatidylcholine, form by drug solution agent and assisted solution agent two parts, the component and the proportioning that it is characterized in that drug solution agent and assisted solution agent respectively as follows:
(1) drug solution agent:
Wherein, the injection organic solvent is selected from one or more in Macrogol 200, Liquid Macrogol, PEG400, Macrogol 600, propylene glycol, glycerol, the dehydrated alcohol, preferred dehydrated alcohol or propylene glycol;
Stabilizing agent is selected from one or more among vitamin E, vitamin E Nicotinate, hydroxy toluene butyl ester (BHT), Butylated hydroxyanisole (BHA), tertiarybutylhydroquinone (TBHQ) and citric acid (sodium), the EDTA-2Na, preferred vitamin E, vitamin E Nicotinate or citric acid (sodium);
(2) assisted solution agent:
Wherein, Solubilizing agent is selected from one or more in cholic acid (sodium), deoxycholic acid (sodium), hyodeoxycholic acid (sodium), ursodeoxycholic acid (sodium), chenodeoxy cholic acid (sodium), dehydrocholic acid (sodium), the oleic acid (sodium), preferred cholic acid (sodium), deoxycholic acid (sodium) or hyodeoxycholic acid (sodium);
The pH regulator agent is selected from one or more in sodium hydroxide, hydrochloric acid, citric acid (sodium), phosphoric acid and inorganic salt thereof, malic acid, acetic acid, sodium carbonate, the sodium bicarbonate;
Isoosmotic adjusting agent is selected from one or more in glycerol, sorbitol, mannitol, glucose, xylose, the sodium chloride.
The invention provides the preparation technology of the intravenous administration formulation of above-mentioned polyene phosphatidylcholine, comprising:
(1) preparation of drug solution agent:
Polyene phosphatidylcholine and stabilizing agent etc. is dissolved in suitable injection organic solvent, presses the injection technological requirement,, make the drug solution agent through activated carbon adsorption, filtration, embedding, sterilization etc.
The concrete operations step is following: polyene phosphatidylcholine, stabilizing agent are dissolved in the injection organic solvent through appropriate formulations technology, add 0.05%～1% needle-use activated carbon absorption, with after No. 3 incipient fusion filter coarse filtration; Microporous filter membrane fine straining with 0.22 μ m; In the sampling inspection qualified after, fill is sealed; Sterilization promptly gets;
(2) preparation of assisted solution agent:
With solubilizing agent, isoosmotic adjusting agent, pH regulator agent etc. and water for injection, process another agent by injection technology equally---the assisted solution agent;
The concrete operations step is following: solubilizing agent, isoosmotic adjusting agent etc. are dissolved with an amount of water for injection, regulate pH value with the pH regulator agent, water for injection adds to total amount; Add 0.05%～1% needle-use activated carbon absorption, with after No. 3 incipient fusion filter coarse filtration, with the microporous filter membrane fine straining of 0.22 μ m; Fill; Seal, sterilization promptly gets.
The inventor finds under study for action; When being solubilizing agent with the NaTDC, when polyene phosphatidylcholine directly is dissolved in water for injection, by weight; The used in amounts of NaTDC adds to the over half of principal agent polyene phosphatidylcholine, just can obtain more clarifying injection solution; And make us feeling surprised be; After polyene phosphatidylcholine is with suitable injectable solvent (like dehydrated alcohol) dissolving; When being added in the water for injection again; The consumption of NaTDC can be reduced to 1/10～1/5 (referring to embodiment 17) of principal agent polyene phosphatidylcholine, and the zest of preparation and toxicity are obviously reduced.Schuller Petrovic S etc. (Dermatol Surg.2008,34 (4): 529-42) report, Polyene Phosphatidylcholine injection liquid have certain toxicity to body tissue, and especially vascular tissue can cause the necrosis to rat and people's vascular tissue.And we discover that Polyene Phosphatidylcholine injection liquid maybe be relevant with NaTDC to the zest of blood vessel; The Mus endnote is penetrated test and is shown; Behind the consumption that reduces NaTDC, injection all obviously reduces (referring to embodiment 18) to the zest and the toxicity of Mus tail.
The present invention is facing polyene phosphatidylcholine and solubilizing agent preparation, packing and storage respectively with preceding just mixing, and have following characteristics: 1. preparation stability is high, owing to not contacting with alkaline solution in production, transportation, the storage process, has improved stability of drug; 2. preparation security is good; The present invention has reduced lysophosphatide generation and peroxide value rising on the one hand, and the use amount that has reduced solubilizing agent under the polyene phosphatidylcholine situation is measured equally at solubilising in the aspect in addition, in addition; Avoid the use of benzyl alcohol, thereby greatly improve the safety of preparation; 3. made things convenient for to store and transportation, because the stability raising, need be in refrigerator storage; 4. preparation technology is simple, adapts to suitability for industrialized production, because the present invention adopts the injectable organic solvent, in the preparation process, polyene phosphatidylcholine more is prone to dissolving, makes preparation easier; 5. save energy cost, the present invention avoids adopting Freeze Drying Technique to prepare stable polyene phosphatidylcholine injection, thereby has practiced thrift energy cost.
The specific embodiment
Combine embodiment that the present invention is described in detail, but enforcement of the present invention is not limited only to this at present.
Embodiment 1:
A kind of intravenous administration formulation of polyene phosphatidylcholine is made up of drug solution agent and assisted solution agent,
The drug solution agent:
Polyene phosphatidylcholine 250g, vitamin E Nicotinate 25g, citric acid 7.5g are dissolved among the 4000mlPEG400, add activated carbon adsorption 15min, with after No. 3 incipient fusion filter coarse filtration; With the microporous filter membrane fine straining of 0.22 μ m, in the sampling inspection qualified after, every 4ml fill; Seal 121 ℃ of sterilizations in 15 minutes.
The assisted solution agent:
Sodium cholate 250g adds the about 400ml dissolving of injection water, regulates pH value to 7.5～10.0 with sodium hydroxide solution or dilute hydrochloric acid solution, uses water for injection to add to cumulative volume and is 500ml; Add activated carbon adsorption 15min; With after No. 3 incipient fusion filter coarse filtration, with the microporous filter membrane fine straining of 0.22 μ m, every 0.5ml fill; Seal 121 ℃ of sterilizations in 15 minutes.
Embodiment 2:
A kind of intravenous administration formulation of polyene phosphatidylcholine is made up of drug solution agent and assisted solution agent,
The drug solution agent:
Polyene phosphatidylcholine 600g, citric acid 6g are dissolved among 2000ml PEG200 and the 2000ml PEG600, add activated carbon adsorption 15min, with after No. 3 incipient fusion filter coarse filtration; With the microporous filter membrane fine straining of 0.22 μ m, in the sampling inspection qualified after, every 4ml fill; Fill nitrogen, seal, 121 ℃ of sterilizations in 15 minutes.
The assisted solution agent:
Sodium cholate 300g adds the about 400ml dissolving of injection water, regulates pH value to 7.5～10.0 with sodium hydroxide solution or dilute hydrochloric acid solution, uses water for injection to add to cumulative volume and is 500ml; Add activated carbon adsorption 15min; With after No. 3 incipient fusion filter coarse filtration, with the microporous filter membrane fine straining of 0.22 μ m, every 0.5ml fill; Seal 121 ℃ of sterilizations in 15 minutes.
Embodiment 3:
A kind of intravenous administration formulation of polyene phosphatidylcholine is made up of drug solution agent and assisted solution agent,
The drug solution agent:
Polyene phosphatidylcholine 250g is dissolved in the 1000ml dehydrated alcohol, adds activated carbon adsorption 15min, with after No. 3 incipient fusion filter coarse filtration, with the microporous filter membrane fine straining of 0.22 μ m, in the sampling inspection qualified after, every 1ml fill is sealed, 121 ℃ of sterilizations in 15 minutes.
The assisted solution agent:
Deoxycholic acid 130g, sodium hydroxide 35g dissolve with an amount of water for injection, regulate pH value to 7.5～10.0 with sodium hydroxide solution or dilute hydrochloric acid solution, use water for injection to add to cumulative volume and are 4000ml; Add activated carbon adsorption 15min; With after No. 3 incipient fusion filter coarse filtration, with the microporous filter membrane fine straining of 0.22 μ m, every 4ml fill; Seal 121 ℃ of sterilizations in 15 minutes.
Embodiment 4:
A kind of intravenous administration formulation of polyene phosphatidylcholine is made up of drug solution agent and assisted solution agent,
The drug solution agent:
Polyene phosphatidylcholine 250g is dissolved in the 2000ml dehydrated alcohol, adds activated carbon adsorption 15min, with after No. 3 incipient fusion filter coarse filtration, with the microporous filter membrane fine straining of 0.22 μ m, in the sampling inspection qualified after, every 2ml fill is sealed, 121 ℃ of sterilizations in 15 minutes.
The assisted solution agent:
Deoxycholic acid 100g, sodium hydroxide 27g dissolve with an amount of water for injection, regulate pH value to 7.5～10.0 with citric acid or sodium citrate solution, use water for injection to add to cumulative volume and are 3000ml; Add activated carbon adsorption 15min; With after No. 3 incipient fusion filter coarse filtration, with the microporous filter membrane fine straining of 0.22 μ m, every 3ml fill; Seal 121 ℃ of sterilizations in 15 minutes.
Embodiment 5:
A kind of intravenous administration formulation of polyene phosphatidylcholine is made up of drug solution agent and assisted solution agent,
The drug solution agent:
Polyene phosphatidylcholine 250g, EDTA-2Na 1g are dissolved in the 3000ml dehydrated alcohol, add activated carbon adsorption 15min, with after No. 3 incipient fusion filter coarse filtration; With the microporous filter membrane fine straining of 0.22 μ m, in the sampling inspection qualified after, every 3ml fill; Seal 121 ℃ of sterilizations in 15 minutes.
The assisted solution agent:
Deoxycholic acid 80g, sodium hydroxide 18g dissolve with an amount of water for injection, regulate pH value to 7.5～10.0 with phosphoric acid solution, use water for injection to add to cumulative volume and are 2000ml; Add activated carbon adsorption 15min; With after No. 3 incipient fusion filter coarse filtration, with the microporous filter membrane fine straining of 0.22 μ m, every 2ml fill; Seal 121 ℃ of sterilizations in 15 minutes.
Embodiment 6:
A kind of intravenous administration formulation of polyene phosphatidylcholine is made up of drug solution agent and assisted solution agent,
The drug solution agent:
Polyene phosphatidylcholine 250g, citric acid 7.5g are dissolved in the 4000ml dehydrated alcohol, add activated carbon adsorption 15min, with after No. 3 incipient fusion filter coarse filtration; With the microporous filter membrane fine straining of 0.22 μ m, in the sampling inspection qualified after, every 4ml fill; Seal 121 ℃ of sterilizations in 15 minutes.
The assisted solution agent:
Deoxycholic acid 500g, sodium hydroxide 9g dissolve with an amount of water for injection, regulate pH value to 7.5～10.0 with sodium carbonate liquor, use water for injection to add to cumulative volume and are 1000ml; Add activated carbon adsorption 15min; With after No. 3 incipient fusion filter coarse filtration, with the microporous filter membrane fine straining of 0.22 μ m, every 1ml fill; Seal 121 ℃ of sterilizations in 15 minutes.
Embodiment 7:
A kind of intravenous administration formulation of polyene phosphatidylcholine is made up of drug solution agent and assisted solution agent,
The drug solution agent:
Polyene phosphatidylcholine 600g is dissolved in the 1000ml dehydrated alcohol, adds activated carbon adsorption 15min, with after No. 3 incipient fusion filter coarse filtration, with the microporous filter membrane fine straining of 0.22 μ m, in the sampling inspection qualified after, every 1ml fill is sealed, 121 ℃ of sterilizations in 15 minutes.
The assisted solution agent
NaTDC 120g, sodium bicarbonate 15g, sodium chloride 900g dissolve with an amount of water for injection, regulate pH value to 7.5～10.0 with sodium hydroxide solution or dilute hydrochloric acid solution, and using water for injection to add to cumulative volume is 100; 000ml adds activated carbon adsorption 15min, with after No. 3 incipient fusion filter coarse filtration; Microporous filter membrane fine straining with 0.22 μ m; Every 100ml fill is sealed, 121 ℃ of sterilizations in 15 minutes.
Embodiment 8:
A kind of intravenous administration formulation of polyene phosphatidylcholine is made up of drug solution agent and assisted solution agent,
The drug solution agent:
Polyene phosphatidylcholine 250g, vitamin E 1.5g are dissolved in the 10000ml dehydrated alcohol, add activated carbon adsorption 15min, with after No. 3 incipient fusion filter coarse filtration; With the microporous filter membrane fine straining of 0.22 μ m, in the sampling inspection qualified after, every 10ml fill; Seal 121 ℃ of sterilizations in 15 minutes.
The assisted solution agent:
NaTDC 120g, sodium bicarbonate 2.5g dissolve with an amount of water for injection, regulate pH value to 7.5～10.0 with sodium hydroxide solution or dilute hydrochloric acid solution, use water for injection to add to cumulative volume and are 10000ml; Add activated carbon adsorption 15min; With after No. 3 incipient fusion filter coarse filtration, with the microporous filter membrane fine straining of 0.22 μ m, every 10ml fill; Seal 121 ℃ of sterilizations in 15 minutes.
Embodiment 9:
A kind of intravenous administration formulation of polyene phosphatidylcholine is made up of drug solution agent and assisted solution agent,
The drug solution agent:
Polyene phosphatidylcholine 50g, vitamin E 0.5g are dissolved in 100, in the 000ml dehydrated alcohol, add activated carbon adsorption 15min; With after No. 3 incipient fusion filter coarse filtration, with the microporous filter membrane fine straining of 0.22 μ m, in the sampling inspection qualified after; Every 100ml fill is sealed, 121 ℃ of sterilizations in 15 minutes.
The assisted solution agent:
NaTDC 10g, sodium chloride 900g dissolve with an amount of water for injection, regulate pH value to 7.5～10.0 with sodium hydroxide solution or dilute hydrochloric acid solution, and using water for injection to add to cumulative volume is 100; 000ml adds activated carbon adsorption 15min, with after No. 3 incipient fusion filter coarse filtration; Microporous filter membrane fine straining with 0.22 μ m; Every 100ml fill is sealed, 121 ℃ of sterilizations in 15 minutes.
Embodiment 10:
A kind of intravenous administration formulation of polyene phosphatidylcholine is made up of drug solution agent and assisted solution agent,
The drug solution agent:
Polyene phosphatidylcholine 250g is dissolved in the 500ml propylene glycol, adds activated carbon adsorption 15min, with after No. 3 incipient fusion filter coarse filtration, with the microporous filter membrane fine straining of 0.22 μ m, in the sampling inspection qualified after, every 0.5ml fill is sealed, 121 ℃ of sterilizations in 15 minutes.
The assisted solution agent:
Hyodeoxycholic acid 130g, sodium hydroxide 3.4g, sodium chloride 900g dissolve with an amount of water for injection, regulate pH value to 7.5～10.0 with sodium carbonate liquor, and using water for injection to add to cumulative volume is 100; 000ml adds activated carbon adsorption 15min, with after No. 3 incipient fusion filter coarse filtration; Microporous filter membrane fine straining with 0.22 μ m; Every 100ml fill is sealed, 121 ℃ of sterilizations in 30 minutes.
Embodiment 11:
A kind of intravenous administration formulation of polyene phosphatidylcholine is made up of drug solution agent and assisted solution agent,
The drug solution agent:
Polyene phosphatidylcholine 250g, vitamin E 1.5g are dissolved in the 1000ml propylene glycol, add activated carbon adsorption 15min, with after No. 3 incipient fusion filter coarse filtration; With the microporous filter membrane fine straining of 0.22 μ m, in the sampling inspection qualified after, every 1ml fill; Seal 121 ℃ of sterilizations in 15 minutes.
The assisted solution agent:
Hyodeoxycholic acid 250g, sodium hydroxide 3.4g, sodium chloride 90g dissolve with an amount of water for injection, regulate pH value to 7.5～10.0 with sodium hydroxide solution or dilute hydrochloric acid solution, and using water for injection to add to cumulative volume is 10; 000ml adds activated carbon adsorption 15min, with after No. 3 incipient fusion filter coarse filtration; Microporous filter membrane fine straining with 0.22 μ m; Every 10ml fill is sealed, 121 ℃ of sterilizations in 30 minutes.
Embodiment 12:
A kind of intravenous administration formulation of polyene phosphatidylcholine is made up of drug solution agent and assisted solution agent,
The drug solution agent:
Polyene phosphatidylcholine 250g, vitamin E 10g are dissolved in 500ml propylene glycol+500ml dehydrated alcohol, add activated carbon adsorption 15min, with after No. 3 incipient fusion filter coarse filtration; With the microporous filter membrane fine straining of 0.22 μ m, in the sampling inspection qualified after, every 1ml fill; Seal 121 ℃ of sterilizations in 15 minutes.
The assisted solution agent:
Deoxycholic acid 120g, sodium hydroxide 1.7g, glycerol 22.4g dissolve with an amount of water for injection, regulate pH value to 7.5～10.0 with sodium hydroxide solution or dilute hydrochloric acid solution, use water for injection to add to cumulative volume and are 4000mL; Add activated carbon adsorption 15min; With after No. 3 incipient fusion filter coarse filtration, with the microporous filter membrane fine straining of 0.22 μ m, every 4ml fill; Seal 121 ℃ of sterilizations in 15 minutes.
Embodiment 13:
A kind of intravenous administration formulation of polyene phosphatidylcholine is made up of drug solution agent and assisted solution agent,
Drug solution agent: with embodiment 3
The assisted solution agent:
Ursodeoxycholic acid 100g, sodium hydroxide 1.2g, sodium chloride 35g dissolve with an amount of water for injection, regulate pH value to 7.5～10.0 with sodium hydroxide solution or dilute hydrochloric acid solution, use water for injection to add to cumulative volume and are 4000mL; Add activated carbon adsorption 15min; With after No. 3 incipient fusion filter coarse filtration, with the microporous filter membrane fine straining of 0.22 μ m, every 4ml fill; Seal 121 ℃ of sterilizations in 15 minutes.
Embodiment 14:
A kind of intravenous administration formulation of polyene phosphatidylcholine is made up of drug solution agent and assisted solution agent,
Drug solution agent: with embodiment 3
The assisted solution agent:
Chenodeoxy cholic acid 80g, sodium hydroxide 1.0g, sodium chloride 35g dissolve with an amount of water for injection, regulate pH value to 7.5～10.0 with sodium hydroxide solution or dilute hydrochloric acid solution, use water for injection to add to cumulative volume and are 4000mL; Add activated carbon adsorption 15min; With after No. 3 incipient fusion filter coarse filtration, with the microporous filter membrane fine straining of 0.22 μ m, every 4ml fill; Seal 121 ℃ of sterilizations in 15 minutes.
Embodiment 15:
A kind of intravenous administration formulation of polyene phosphatidylcholine is made up of drug solution agent and assisted solution agent,
Drug solution agent: with embodiment 3
The assisted solution agent:
Enuatrol 50g, sodium bicarbonate 4g dissolve with an amount of water for injection, regulate pH value to 7.5～10.0 with sodium hydroxide solution or dilute hydrochloric acid solution, use water for injection to add to cumulative volume and are 4000mL; Add activated carbon adsorption 15min; With after No. 3 incipient fusion filter coarse filtration, with the microporous filter membrane fine straining of 0.22 μ m, every 4ml fill; Seal 121 ℃ of sterilizations in 15 minutes.
Embodiment 16:
A kind of intravenous administration formulation of polyene phosphatidylcholine is made up of drug solution agent and assisted solution agent,
The drug solution agent:
Polyene phosphatidylcholine 250g is dissolved in the 2000ml dehydrated alcohol, adds activated carbon adsorption 15min, with after No. 3 incipient fusion filter coarse filtration, with the microporous filter membrane fine straining of 0.22 μ m, in the sampling inspection qualified after, every 2ml fill is sealed, 121 ℃ of sterilizations in 15 minutes.
The assisted solution agent:
Dehydrocholic acid 100g, sodium hydroxide 1.2g, sodium chloride 27g dissolve with an amount of water for injection, regulate pH value to 7.5～10.0 with sodium hydroxide solution or dilute hydrochloric acid solution, use water for injection to add to cumulative volume and are 3000mL; Add activated carbon adsorption 15min; With after No. 3 incipient fusion filter coarse filtration, with the microporous filter membrane fine straining of 0.22 μ m, every 3ml fill; Seal 121 ℃ of sterilizations in 15 minutes.
Embodiment 17: NaTDC is to the solubilization experiment of polyene phosphatidylcholine
Use NaTDC to be solubilizing agent, preparation polyene phosphatidylcholine ultimate density is 5% aqueous solution.Referring to table 1.
Table 1 NaTDC is to the solubilization of polyene phosphatidylcholine
(1) polyene phosphatidylcholine directly is dissolved in water for injection, when polyene phosphatidylcholine: during NaTDC (1: 0.5), just can obtain settled solution;
(2) with polyene phosphatidylcholine with anhydrous alcohol solution after, be dissolved in water for injection again, when polyene phosphatidylcholine: during NaTDC (1: 0.1), show muddy slightly; When polyene phosphatidylcholine: during NaTDC (1: 0.2), can obtain the settled solution that supply to inject.
Embodiment 18: the zest of rat tails injectable drug and toxicity test
Settled solution among the rat tails injection effect embodiment 1, the zest and the toxicity of observing medicine.Referring to table 2.
The zest and the toxicity of table 2 rat tails injectable drug
Medicine 1: polyene phosphatidylcholine: NaTDC (1: 0.5) directly is dissolved in water for injection, contains polyene phosphatidylcholine 5g in every 100ml solution;
Medicine 2: polyene phosphatidylcholine is dissolved in a little ethanol earlier, is dissolved in the aqueous solution of NaTDC again.Polyene phosphatidylcholine in the final solution: NaTDC is 1: 0.2, contains polyene phosphatidylcholine 5g in every 100ml solution.
Press 5ml/kg and give rat tails injectable drug 1 or medicine 2.Because the deoxycholic acid sodium content is high in the medicine 1, medicine irritation and toxicity are big, are injected rat tic, agitation, and the injection site is red and swollen, red purple; And the deoxycholic acid sodium content is lower in the medicine 2, and zest and toxicity are all little, is injected calmness of rat, and the injection site does not have redness yet.Accompanying drawing is seen in rat tails injection polyene phosphatidylcholine solution local excitation sex expression.
Embodiment 19: the Polyene Phosphatidylcholine injection liquid stability experiment
Drug solution agent and assisted solution agent with embodiment 3 preparations experimentize.Experiment divides three groups; Be respectively drug solution agent group, drug solution agent+assisted solution agent group and Essentiale N/Essentiale Forte N
group (lot number: 091409; Valid until 2012 01 month), placed 6 days in 60 ℃.6 days same day to the of placing, respectively organize polyene phosphatidylcholine, related substance hemolytic phospholipid and peroxide value with high effective liquid chromatography for measuring every day respectively.
Polyene phosphatidylcholine content with the 1st day is 100%, and the medicament contg of each day draws medicament contg and changes percentage rate by comparison with other, and every group is repeated three batches, and average result is seen table 3; The average percentage composition of related substance hemolytic phospholipid is seen table 4; Peroxide value is seen table 5.
The content of table 3 polyene phosphatidylcholine compares, n=3
The average percentage composition of table 4 related substance hemolytic phospholipid, n=3
Table 5 peroxide value, n=3
Experimental result shows, polyene phosphatidylcholine and solubilizing agent preparation, packing and storage respectively faced with preceding just mixing; Can increase stability; Minimizing hydrolysis, oxidation, the especially variation of related substance hemolytic phospholipid and peroxide value reduce greatly, have increased the safety of preparation.
Claims (7)
1. the intravenous administration formulation of a polyene phosphatidylcholine is characterized in that this intravenous administration formulation is made up of drug solution agent and assisted solution agent two parts, the component of drug solution agent and assisted solution agent and proportioning respectively as follows:
(1) drug solution agent:
Wherein, the injection organic solvent is selected from one or more in Macrogol 200, Liquid Macrogol, PEG400, Macrogol 600, propylene glycol, glycerol, the dehydrated alcohol;
Stabilizing agent is selected from one or more among vitamin E, vitamin E Nicotinate, hydroxy toluene butyl ester, Butylated hydroxyanisole, tertiarybutylhydroquinone, citric acid, sodium citrate, the EDTA-2Na;
(2) assisted solution agent:
Wherein, solubilizing agent is selected from one or more in cholic acid, sodium cholate, deoxycholic acid, NaTDC, hyodeoxycholic acid, hyodeoxycholic acid sodium, ursodeoxycholic acid, ursodeoxycholic acid sodium, chenodeoxy cholic acid, chenodeoxy cholic acid sodium, dehydrocholic acid, sodium dehydrocholate, oleic acid, the enuatrol;
The pH regulator agent is selected from one or more in sodium hydroxide, hydrochloric acid, citric acid, sodium citrate, phosphoric acid and inorganic salt thereof, malic acid, acetic acid, sodium carbonate, the sodium bicarbonate;
Isoosmotic adjusting agent is selected from one or more in glycerol, sorbitol, mannitol, glucose, xylose, the sodium chloride.
2. the intravenous administration formulation of a kind of polyene phosphatidylcholine according to claim 1 is characterized in that, polyene phosphatidylcholine wherein is 2.5～50%.
3. the intravenous administration formulation of a kind of polyene phosphatidylcholine according to claim 1 and 2 is characterized in that, solubilizing agent wherein is 0.13～50%.
4. the intravenous administration formulation of a kind of polyene phosphatidylcholine according to claim 1 and 2 is characterized in that, injection organic solvent wherein is dehydrated alcohol or propylene glycol; Stabilizing agent wherein is vitamin E, vitamin E Nicotinate, citric acid or sodium citrate; Solubilizing agent wherein is cholic acid, sodium cholate, deoxycholic acid, NaTDC, hyodeoxycholic acid or hyodeoxycholic acid sodium.
5. the intravenous administration formulation of a kind of polyene phosphatidylcholine according to claim 1 and 2 is characterized in that, faces the time spent drug solution agent to be added in the assisted solution agent directly intravenous injection behind the mixing by clinical administration dosage; Or, be used for instiling with after the glucose injection dilution.
6. the intravenous administration formulation of a kind of polyene phosphatidylcholine according to claim 1 and 2 is characterized in that, a drug solution agent and an assisted solution agent of packing are packaged in the same packing box separately.
7. the preparation technology of the intravenous administration formulation of a polyene phosphatidylcholine may further comprise the steps:
(1) preparation of drug solution agent:
Polyene phosphatidylcholine, stabilizing agent are dissolved in the injection organic solvent through appropriate formulations technology, add 0.05%～1% needle-use activated carbon absorption, with after No. 3 incipient fusion filter coarse filtration; With the microporous filter membrane fine straining of 0.22 μ m, in the sampling inspection qualified after, fill; Seal, sterilization promptly gets;
(2) preparation of assisted solution agent:
Solubilizing agent, isoosmotic adjusting agent etc. are dissolved with an amount of water for injection, regulate pH value with the pH regulator agent, water for injection adds to total amount, adds the absorption of 0.05%～1% needle-use activated carbon; With after No. 3 incipient fusion filter coarse filtration, with the microporous filter membrane fine straining of 0.22 μ m, fill; Seal, sterilization promptly gets.
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| CN2012100397125A CN102631313A (en) | 2011-11-10 | 2012-02-21 | Polyene phosphatidyl choline intravenous administration preparation and preparation method thereof |
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Cited By (1)
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| CN108653204A (en) * | 2018-08-01 | 2018-10-16 | 辽宁海思科制药有限公司 | A kind of Polyene Phosphatidylcholine injection liquid pharmaceutical composition and preparation method thereof |
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| CN101152189A (en) * | 2007-10-12 | 2008-04-02 | 成都翰朗生物科技有限公司 | Polyene phosphatidyl choline injection and method for preparing the same |
| CN101244070A (en) * | 2007-02-13 | 2008-08-20 | 桂勇 | Polyene phosphatidylcholine high-capacity injection |
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| CN101756895A (en) * | 2009-03-13 | 2010-06-30 | 北京瑞伊人科技发展有限公司 | Polyene phosphatidyl choline intravenous preparation and preparation method thereof |
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| CN1951389A (en) * | 2005-10-18 | 2007-04-25 | 上海医药工业研究院 | Composition of Essentiale Phospholipids injection and preparation method thereof |
| CN101244070A (en) * | 2007-02-13 | 2008-08-20 | 桂勇 | Polyene phosphatidylcholine high-capacity injection |
| CN101152189A (en) * | 2007-10-12 | 2008-04-02 | 成都翰朗生物科技有限公司 | Polyene phosphatidyl choline injection and method for preparing the same |
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