CN1895224A - Polyvinyl-phosphorylcholine elaioplast preparation and its making method - Google Patents
Polyvinyl-phosphorylcholine elaioplast preparation and its making method Download PDFInfo
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- CN1895224A CN1895224A CN 200610088099 CN200610088099A CN1895224A CN 1895224 A CN1895224 A CN 1895224A CN 200610088099 CN200610088099 CN 200610088099 CN 200610088099 A CN200610088099 A CN 200610088099A CN 1895224 A CN1895224 A CN 1895224A
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Abstract
A polyene phosphatidylcholine liposome with high curative effect is prepared through dissolving polyene phosphatifylcholine, phosphatide and cholesterol in organic solvent, constant-temp drying for removing solvent, filming, adding vitamin, stabilizer and mannitol or glucose solution, dissolving, ultrasonic vibration or homogenizing, filtering by membrane for removing bacteria, loading in containers, filling N2 or H2 and sealing.
Description
Technical field
The present invention relates to a kind of polyvinyl-phosphorylcholine elaioplast preparation and preparation method thereof, be used for cholestasis; Poison; The recurrence of prevention cholelithiasis; Gestosis; Treatment of diseases such as psoriasis, neurodermatitis, radiation syndrome belong to field of medicine preparing technology.
Background technology
The various hepatopaths of China are up to more than 3500 people at present, and the hepatitis virus carrier is hundreds of millions of, and are annual because of the about hundreds of thousands people of the number of hepatopathy death.The task of preventing and treating of hepatopathy is very arduous.The medicine of preventing and treating hepatopathy at present has a variety of, but good effect, the low medicine of side effect but seldom, especially all effectively broad-spectrum medicinal is just still less to various hepatopathys.The Main Ingredients and Appearance of injection polyene phosphatidylcholine is the essential phospholipid class, its chemical constitution is suitable with endogenous phospholipid, promptly exist the phospholipid of liver plasma membrane suitable with those, because of containing a large amount of polyunsaturated fatty acid, its function can be excellent than endogenous phospholipid, in vivo, mainly build up at liver, with the film system combination of whole molecule and liver plasma membrane and organelle thereof, the hepatocyte structure of destroyed is carried out the physiology reparation, created prerequisite for recovering normal liver function; It also has the adjusting immunologic process in addition, stablizes liver plasma membrane, suppresses the lipid peroxidation that free radical causes, the liver plasma membrane that damaged by the immunopathology process is recovered and stablizes; It is again biliary main emulsifying agent, can promote bile emulsifying to drain, so the effect of promoting the function of the gallbladder to alleviate jaundice effect and the formation of prevention cholelithiasis is arranged: this series products is applied to acute clinically or chronic hepatitis, hepatic necrosis, liver cirrhosis, hepatic coma (comprising forerunner's hepatic coma); Fatty liver (also seeing the diabetes patient); Cholestasis; Poison; The prevention recurrence of hepatolithiasis; Perioperative treatment, especially hepatobiliary surgery; Also can be used to prevent the formation and the radiation treatment syndrome of cholelithiasis.
The polyene phosphatidylcholine dosage form of having used clinically at present has injection, capsule.Because the easy oxidation of polyene phosphatidylcholine, all responsive to light and heat, its properties of Aqueous Solution is difficult for stable.The Polyene Phosphatidylcholine injection liquid that uses clinically contains benzyl alcohol at present.Benzyl alcohol is known from experience generation stimulation, irritated effect to the people, can cause damage to liver simultaneously.Point out in the description of Polyene Phosphatidylcholine injection liquid: " patient may produce anaphylaxis to benzyl alcohol contained in this product ", " owing to contain benzyl alcohol in this product; neonate and premature infant's forbidding ", " intravenous injection needs slowly; dilution is used as need; can only can not add other medicines in syringe with the dilution in 1: 1 of venous patient blood ", " drip liquid must be used with no electrolyte injection dilution back ".Therefore, limit the use crowd, can't satisfy the needs of clinical use.
Summary of the invention
The objective of the invention is to overcome above-mentioned weak point, thereby a kind of medicine stability that can improve polyene phosphatidylcholine is provided, do not use benzyl alcohol to make solvent, do not produce anaphylaxis and haemolysis, intravenous injection is to the blood vessel nonirritant; Employing lecithin adds cholesterol, aminoacid and gelatin used as stabilizers, vitamin C is made antioxidant, has the effect of certain slow release and targeting, and lecithin and aminoacid can produce good synergism to strengthen the curative effect of product with polyene phosphatidylcholine simultaneously; Can directly instil or intravenous injection during use, can satisfy polyvinyl-phosphorylcholine elaioplast preparation of clinical needs easy to use and preparation method thereof with 5% glucose injection dissolving posterior vein.
Main solution of the present invention is achieved in that
Polyvinyl-phosphorylcholine elaioplast preparation of the present invention, its formula proportion are in weight ratio:
The present invention mainly adopts 1～50 part of 1～50 part of polyene phosphatidylcholine, 1～10 part of vitamin, phosphatidase 11～100 part, 1～30 part in cholesterol, 1～20 part of stabilizing agent, mannitol or glucose solution;
The present invention adopts polyene phosphatidylcholine, phospholipid, cholesterol to be dissolved in chloroform or ether or benzyl alcohol or isopropyl alcohol or the ethanol, evaporation drying under constant temperature, and removing desolvates makes film forming; Carry out vacuum drying treatment again; Add vitamin, stabilizing agent, mannitol or D/W dissolving film then; With ultrasonic echography vibration or the processing of high-pressure homogenization pump particle diameter is diminished, the degerming of reuse membrane filtration divides in the container of packing into, and lyophilization off-white color or faint yellow bulk are sealed behind logical at last nitrogen or the hydrogen or gland gets final product.
Stabilizing agent of the present invention can be one or more of ornithine or Aspartic Acid or taurine or cysteine or threonine or methionine or gelatin.
Phospholipid of the present invention is lecithin or soybean phospholipid.
Vitamin of the present invention is vitamin B1 3mg: vitamin B2 3mg: vitamin B6 3mg: vitamin B12 100ug: Vitamin E acetate 33mg: one or more compound vitamines of vitamin C 100mg ratio.
It is as follows that the present invention treats the preparation method processing step of Liposomal formulation of polytype hepatopathy:
Feature is that its medicine is the composition of raw materials ratio in weight ratio:
1, get 1～50 part of polyene phosphatidylcholine, phosphatidase 11～100 part, cholesterol is dissolved in chloroform or ether or benzyl alcohol or isopropyl alcohol or the ethanol for 1～30 part, be dissolved into clear and bright solution fully, the rotation evaporation drying was removed to desolvate and is made film forming in 10 minutes～10 hours under constant temperature, carried out vacuum drying treatment then 1～10 hour, thermostat temperature: 50～60 ℃, the rotation rotating speed: 30～100 rev/mins, the vacuum drying temperature: 20～60 ℃, vacuum: 0.08-0.095Mpa;
3, add 1～20 part of 1～10 part of vitamin, stabilizing agent, mannitol or 1～50 part of solution dissolving film of glucose that regulates pH value; PH value: 3～10;
4, handled 20 minutes～7 hours with ultrasonic echography processing 15 minutes～6 hours or high-pressure homogenization pump, homogenate pump rotating speed: 500～10000 rev/mins, particle diameter is diminished to 0.1～8um, the degerming of reuse 0.20～0.22um membrane filtration, divide in the container of packing into, lyophilization 1～24 hour promptly gets off-white color or faint yellow bulk, ultrasonic frequency: 20～30KHZ, ultrasonic power: 100～3000W;
5, seal behind logical nitrogen or the hydrogen or gland gets final product.
Compared with the prior art the present invention has the following advantages:
1, the present invention does not contain benzyl alcohol, does not produce blood vessel irritation and anaphylaxis, directly instil or intravenous injection with 5% glucose injection dissolving posterior vein, so product is safer, uses more convenient.
2, because employing lecithin adds cholesterol, aminoacid and gelatin used as stabilizers, vitamin C is made antioxidant; Lecithin and aminoacid (as ornithine and Aspartic Acid) are all and good physiologically active arranged, ornithine and Aspartic Acid can activate two crux enzymes in the liver detoxification function, assist to remove harmful free radical, strengthen the functions of expelling toxin of liver, promote reparation and the regeneration of hepatocyte self, improve liver function; Taurine can with cholic acid in conjunction with increasing the bile permeability, so can remove cholestasis, be choleretic effect; Cysteine is the aminoacid that contains sulfydryl, participates in the phospholipid metabolism in cell reduction process and the liver, can protect hepatocyte to be without prejudice, to impel the vigorous effect of liver function; Lecithin is the patron saint of liver: the lecithin deficiency can cause fat to gather in a large number in liver in the body, forms fatty liver, causes inflammation swelling, stops blood circulation, causes hepatic necrosis; Lecithin helps hepatocellular regeneration, promotes fat acid decomposition, reduces the cholesterol level in the blood, and therefore polyvinyl-phosphorylcholine elaioplast preparation of the present invention more is better than similar preparation on curative effect.
3, gelatin forms microsphere in cryodesiccated process, with the vitamin parcel, thereby has the effect of slow release and targeting; Can make the liposome particle diameter be controlled at the 0.1-8um scope by control ultrasound wave or the processing of high-pressure homogenization pump, and have good liver target effect.
4, aminoacid and gelatin are amphiprotic substance, and the technical program can produce charging property under the pH condition, thereby prevent to assemble; Lysate produces clustering phenomena because the gelation of gelatin stops in put procedure, make preparation more stable (table 1); Preparation method of the present invention is simple, and cost is low, and raw material is easy to get, but suitability for industrialized production.
Table 1 polyvinyl-phosphorylcholine elaioplast low temperature (2-10 ℃) stability test data
| Lot number | Time (moon) | Outward appearance | Microscopic examination |
| A | 1 | Off-white color or faint yellow loose block | Do not assemble no crystallization after the dissolving |
| 3 | Off-white color or faint yellow loose block | Do not assemble no crystallization after the dissolving | |
| 6 | Off-white color or faint yellow loose block | Do not assemble no crystallization after the dissolving | |
| 12 | Off-white color or faint yellow loose block | Do not assemble no crystallization after the dissolving | |
| B | 1 | Off-white color or faint yellow loose block | Do not assemble no crystallization after the dissolving |
| 3 | Off-white color or faint yellow loose block | Do not assemble no crystallization after the dissolving | |
| 6 | Off-white color or faint yellow loose block | Do not assemble no crystallization after the dissolving | |
| 12 | Off-white color or faint yellow loose block | Do not assemble no crystallization after the dissolving |
The specific embodiment
To be further described for the embodiment of the invention below:
Embodiment one:
It is as follows that the present invention treats the preparation method processing step of Liposomal formulation of polytype hepatopathy: its composition of filling a prescription: in g/ml:
The present invention takes by weighing polyene phosphatidylcholine 50g, refined lecithin 70g, cholesterol 20g puts in the round-bottomed flask, add the about 350ml of dehydrated alcohol and make to the above-mentioned mixture and be dissolved into clear and bright solution fully, put the water bath with thermostatic control temperature: 60 ℃, Rotary drying made film forming in 0.5～10 hour, carried out vacuum drying treatment then 4 hours, the rotation rotating speed: 30～100 rev/mins, the vacuum drying temperature: 20～60 ℃, vacuum 0.08-0.095Mpa; Add the stabilizing agent that regulates pH value and get Aspartic Acid 3g, gelatin 30g; Vitamin 28g (vitamin B1 3mg: vitamin B2 3mg: vitamin B6 3mg: vitamin B12 100ug: Vitamin E acetate 33mg: the compound vitamin of vitamin C 100mg ratio); The solution 1000ml dissolving film of mannitol 50g, pH value: 3～10; With ultrasonoscope supersound process 20 minutes～5 hours, particle diameter is diminished to 0.1～8um, ultrasonic frequency: 20～30KHZ, ultrasonic power: 1000W, the degerming of reuse 0.22um membrane filtration, be sub-packed in the ampoule bottle, make every bottle to contain polyene phosphatidylcholine 250mg, carried out lyophilization 1～24 hour; Logical noble gas seals and promptly gets polyvinyl-phosphorylcholine elaioplast preparation.
Embodiment two:
It is as follows that the present invention treats the preparation method processing step of Liposomal formulation of polytype hepatopathy: its composition of filling a prescription: in g/ml:
The present invention takes by weighing polyene phosphatidylcholine 30g, refined lecithin 60g, cholesterol 10g puts in the round-bottomed flask, about 250ml that adds diethyl ether makes to the above-mentioned mixture is dissolved into clear and bright solution fully, puts the water bath with thermostatic control temperature: 55 ℃, and 0.5～10 hour film forming of Rotary drying, carried out vacuum drying treatment then 4 hours, the rotation rotating speed: 30～100 rev/mins, the vacuum drying temperature: 20～60 ℃, vacuum: 0.08-0.095Mpa; Add regulate pH value contain cysteine 2.5g, gelatin 40g; Vitamin 15g (vitamin B1 3mg: vitamin B2 3mg: vitamin B6 3mg: vitamin B12 100ug: the compound vitamin of vitamin C 100mg ratio); The solution 1000ml dissolving film of glucose 50g, pH value: 3～10; With ultrasonoscope supersound process 20 minutes～2 hours, reuse high-pressure homogenization pump carried out homogenate 10 minutes～2.5 hours, made particle diameter diminish to 0.1～8um ultrasonic frequency: 20～30KHZ, ultrasonic power: 1000W, homogenate pump rotating speed: 500～10000 rev/mins; The degerming of reuse 0.22um membrane filtration is sub-packed in cillin bottle, makes every bottle to contain polyene phosphatidylcholine 250mg, carries out lyophilization 1～24 hour; Logical noble gas seals and promptly gets polyvinyl-phosphorylcholine elaioplast preparation.
Embodiment three:
It is as follows that the present invention treats the preparation method processing step of Liposomal formulation of polytype hepatopathy: its composition of filling a prescription: in g/ml:
The present invention takes by weighing polyene phosphatidylcholine 50g, refining soybean lecithin 80g, cholesterol 15g puts in the round-bottomed flask, adding the about 400ml of chloroform makes to the above-mentioned mixture and is dissolved into clear and bright solution fully, put the water bath with thermostatic control temperature: 50 ℃ of Rotary dryings made film forming in 0.5～10 hour, carried out vacuum drying treatment then 4 hours, rotation rotating speed: 30～100 rev/mins, the vacuum drying temperature: 20～60 ℃, vacuum 0.08-0.095Mpa; Add regulate pH value contain ornithine 5g, gelatin 20g, vitamin 20g (Vitamin E acetate 33mg: the compound vitamin of vitamin C 100mg ratio); The solution 1000ml dissolving film of mannitol 50g, pH value: 3～10; Carried out homogenate 30 minutes～5 hours with the high-pressure homogenization pump, the homogenate pump rotating speed: 500～10000 rev/mins, particle diameter is diminished to 0.1～8um, the degerming of reuse 0.22um membrane filtration, be sub-packed in the ampoule bottle, make every bottle to contain polyene phosphatidylcholine 250mg, carried out lyophilization 1～24 hour; Logical noble gas seals and promptly gets polyvinyl-phosphorylcholine elaioplast preparation.
The raw material that uses among the present invention is purchased by market, and equipment is conventional equipment.
Claims (5)
1, a kind of polyvinyl-phosphorylcholine elaioplast preparation is characterized in that formula proportion is in weight ratio: get polyene phosphatidylcholine: 1～50 part, vitamin: 1～10 part, phospholipid: 1～100 part, cholesterol: 1～30 part, stabilizing agent: 1～20 part, mannitol or glucose solution: 1～50 part;
Earlier polyene phosphatidylcholine, phospholipid, cholesterol are dissolved in chloroform or ether or benzyl alcohol or isopropyl alcohol or the ethanol, evaporation drying under constant temperature, removing desolvates makes film forming; Carry out vacuum drying treatment again; Add vitamin, stabilizing agent, mannitol or glucose solution dissolving film then; Handle that with ultrasonic echography vibration or high-pressure homogenization pump particle diameter is diminished, the degerming of reuse membrane filtration divides lyophilization in the container of packing into, seals behind logical at last nitrogen or the hydrogen or gland gets final product.
2, polyvinyl-phosphorylcholine elaioplast preparation according to claim 1 is characterized in that described stabilizing agent is one or more of ornithine or Aspartic Acid or taurine or cysteine or threonine or methionine or gelatin.
3, polyvinyl-phosphorylcholine elaioplast preparation according to claim 1 is characterized in that described phospholipid is lecithin or soybean phospholipid.
4, polyvinyl-phosphorylcholine elaioplast preparation according to claim 1 is characterized in that described vitamin is vitamin B1 3mg: vitamin B2 3mg: vitamin B6 3mg: vitamin B12 100ug: Vitamin E acetate 33mg: one or more compound vitamines of vitamin C 100mg.
5, a kind of preparation method processing step by the described polyvinyl-phosphorylcholine elaioplast preparation of claim 1 is as follows:
(1), get polyene phosphatidylcholine: 1～50 part, phospholipid: 1～100 part, cholesterol: 1～30 part is dissolved in chloroform or ether or benzyl alcohol or isopropyl alcohol or the ethanol, is dissolved into clear and bright solution;
(2), under constant temperature, rotate evaporation drying: removed to desolvate in 10 minutes～10 hours and make film forming, carry out vacuum drying treatment then: 1～10 hour, thermostat temperature: 50～60 ℃, rotation rotating speed: 30～100 rev/mins, the vacuum drying temperature: 20～60 ℃, vacuum: 0.08-0.095Mpa;
(3), add the vitamin regulate pH value: 1～10 part, stabilizing agent: 1～20 part, mannitol or glucose solution: 1～50 part of solution dissolving film; PH value: 3～10;
(4), handled 20 minutes～7 hours with ultrasonic echography processing 15 minutes～6 hours or high-pressure homogenization pump, homogenate pump rotating speed: 500～10000 rev/mins, particle diameter is diminished to 0.1～8um, the degerming of reuse 0.20～0.22um membrane filtration, divide in the container of packing into, lyophilization 1～24 hour promptly gets off-white color or faint yellow bulk, ultrasonic frequency: 20～30KHZ, ultrasonic power: 100～3000W;
(5), seal behind logical nitrogen or the hydrogen or gland gets final product.
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| CN 200610088099 CN1895224A (en) | 2006-06-26 | 2006-06-26 | Polyvinyl-phosphorylcholine elaioplast preparation and its making method |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103705446A (en) * | 2012-10-08 | 2014-04-09 | 正大天晴药业集团股份有限公司 | Polyene phosphatidyl choline injection, and preparation method thereof |
| CN104666246A (en) * | 2007-09-28 | 2015-06-03 | Sdg公司 | Orally Bioavailable Lipid-based Constructs |
| CN106916841A (en) * | 2017-03-02 | 2017-07-04 | 江苏省农业科学院 | A kind of method for determining duck Hsp90 α protein binding phosphatid ylcholines region |
| US10751418B2 (en) | 2007-09-28 | 2020-08-25 | Sdg, Inc. | Orally bioavailable lipid-based constructs |
| US11071715B2 (en) | 2017-03-13 | 2021-07-27 | Sdg, Inc. | Lipid-based nanoparticles and methods using same |
| US11077173B2 (en) | 2017-03-13 | 2021-08-03 | Sdg, Inc. | Lipid-based nanoparticles and methods using same |
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2006
- 2006-06-26 CN CN 200610088099 patent/CN1895224A/en active Pending
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104666246A (en) * | 2007-09-28 | 2015-06-03 | Sdg公司 | Orally Bioavailable Lipid-based Constructs |
| US10568835B2 (en) | 2007-09-28 | 2020-02-25 | Sdg, Inc. | Orally bioavailable lipid-based constructs |
| US10751418B2 (en) | 2007-09-28 | 2020-08-25 | Sdg, Inc. | Orally bioavailable lipid-based constructs |
| US11517529B2 (en) | 2007-09-28 | 2022-12-06 | Sdg, Inc. | Orally bioavailable lipid-based constructs |
| CN103705446A (en) * | 2012-10-08 | 2014-04-09 | 正大天晴药业集团股份有限公司 | Polyene phosphatidyl choline injection, and preparation method thereof |
| CN106916841A (en) * | 2017-03-02 | 2017-07-04 | 江苏省农业科学院 | A kind of method for determining duck Hsp90 α protein binding phosphatid ylcholines region |
| US11071715B2 (en) | 2017-03-13 | 2021-07-27 | Sdg, Inc. | Lipid-based nanoparticles and methods using same |
| US11077173B2 (en) | 2017-03-13 | 2021-08-03 | Sdg, Inc. | Lipid-based nanoparticles and methods using same |
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