CN103536532A - Alprostadil composition as well as preparation method thereof - Google Patents
Alprostadil composition as well as preparation method thereof Download PDFInfo
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Abstract
The invention relates to an alprostadil composition which comprises alprostadil, oil for injection, phospholipid and water for injection, wherein the concentration of alprostadil in the formula is 6-11 micrograms/ml, preferably 7-9 micrograms/ml, the concentration of oil for injection is 100mg/ml and the concentration of phospholipid is 18mg/ml. The encapsulation efficiency of the alprostadil injection prepared by the invention is over 95%.
Description
Technical field
The present invention relates to a kind of Alprostadil composition and preparation method thereof, be specifically related to alprostadil injection of a kind of high envelop rate and preparation method thereof.
Background technology
Alprostadil, claims again prostaglandin E
1(PGE
1), be the extremely strong biological active substances of a kind of activity, there is anticoagulant, thromboxane A
2the effect of generation, the formation of tremulous pulse medicated porridge sample Lipid Plaque and immune complex, and can expand the pharmacological action of periphery and arteria coronaria blood vessel, be mainly used in treating the extremity tranquillization pain that extremity ulcer that chronic arteria occlusion disease (thromboangiitis obliterans, Arteriosclerosis obliterans etc.) causes and tiny blood vessels circulatory disturbance cause, improve the auxiliary treatment of cardiovascular and cerebrovascular microcirculation disturbance and chronic hepatitis.
In clinical use procedure, there is larger zest in free Alprostadil, as cause local pain, swelling sense, serious appearance is rubescent and occur red line along vein trend.Therefore, alprostadil injection has adopted lipoid microsphere (Lipid Microsphere) drug delivery technologies to reduce the zest of free Alprostadil.Lipoid microsphere is a kind of microsome dispersion that fatty oil sealed by immobilized artificial membrane as soft substrate of take, its preparation method is that medicine is dissolved in fatty oil, take exquisite lecithin as emulsifying agent, through high pressure homogenize, make O/W type medicine carrying fat milk, breast grain mean diameter 200nm, lipoid microsphere also claims fat milk (Fat/Lipid Emulsion).
The formation theory of lipoid microsphere is not yet ripe at present, and according to Interfacial Adsorption membrane theory, emulsifying agent is when reducing two-phase interface tension force, and emulsifying agent aligns around drop, forms adsorbed film.
Existing alprostadil injection specification has 1ml and 2ml, and concentration is 5 μ g/ml, why does not make the Alprostadil of high concentration, and tracing it to its cause may be relevant with drug loading or envelop rate.According to the molecular structure of Alprostadil, infer that the affinity of Alprostadil and phospholipid is greater than its dissolubility in oil, Alprostadil is mainly dispersed in oil-water interfaces place.PGE1 lipoid microsphere of a kind of charge and preparation method thereof is disclosed as patent application 200910010165.6, its adjuvant used is oil for injection, emulsifying agent, co-emulsifier, isoosmotic adjusting agent, antioxidant, and pH adjusting agent, drug main in its lipoid microsphere lipoid microsphere of preparing will be distributed in oil-water interfaces, the pharmaceutical pack of 90% left and right can be wrapped in oil phase and oil-water interfaces.But because the adhesion between Alprostadil and phospholipid is still inadequate, the 10% even more Alprostadil of still can having an appointment is distributed in water, causes certain safety hidden danger.Therefore, according to the enlightenment of prior art, under the fixing prerequisite of the consumption of phospholipid, if the consumption of Alprostadil increases, will cause envelop rate to decline, therefore, be difficult to improve the concentration of Alprostadil.
Summary of the invention
Technical problem to be solved by this invention is the prejudice that overcomes prior art, do not increasing under the prerequisite of emulsifying agent, alprostadil injection of the high envelop rate of a kind of high concentration and preparation method thereof is provided, by optimizing preparation technology, makes the constant product quality of preparation better.
Technical scheme of the present invention is as follows:
, comprise Alprostadil, oil for injection, phospholipid, water for injection, in its prescription, the concentration of Alprostadil is 6-11 μ g/ml, is preferably 7-9 μ g/ml, and the concentration of oil for injection is 100mg/ml, and phospholipid concentration is 18mg/ml.
Described oil for injection is selected from refined soybean oil, Oleum Arachidis hypogaeae semen, safflower oil, Oleum Gossypii semen, olive oil, Oleum Cocois, Oleum Sesami, fish oil, medium chain monoglyceride, medium chain glycerol dibasic acid esters, medium chain triglyceride, ethyl oleate, acetylated monoglyceride, propylene glycol dibasic acid esters, glyceryl linoleate, Polyethylene Glycol glyceryl laurate ester or its combination.Be preferably refined soybean oil and medium chain triglyceride, both weight ratios are 1: 1.
The preferred Ovum Gallus domesticus Flavus lecithin of described phospholipid, wherein the content of phosphatidylcholine is more than 96%.
Above-mentioned composition also comprises oleic acid, glycerol, and oleic acid prescription concentration is 2.4mg/ml; Glycerol prescription concentration is 22.1mg/ml, and pH adjusting agent is sodium hydroxide, and adjusting pH value is 5.0-6.0.
The preparation method of alprostadil injection, comprises the following steps:
(1) preparation of water: glycerol is added to the water, stirs it is dissolved, as water;
(2) preparation of oil phase: add phospholipid in oil for injection, oleic acid and Alprostadil, stir it is dissolved, as oil phase;
(3) preparation of colostrum: step (2) oil phase is added in step (1) water, and high speed shear is disperseed, and forms colostrum;
(4) high pressure homogenize: step (3) colostrum is adjusted to pH to 5.0～6.0, and high pressure homogenize, obtains smart breast;
(5) fill: step (4) essence is newborn through 0.22 μ m filtering with microporous membrane degerming, aseptic embedding;
(6) moist heat sterilization (F
0> 8)
(7) step (1) to (5) all operates under nitrogen protection.
The described high speed shear jitter time of step (3) is 10～60 minutes, and shear rate is 3000～10000rpm, 55～70 ℃ of temperature; The described high pressure homogenize pressure of step (4) is 600～2000bar, homogenize number of times 3～6 times.The described sterilising temp of step (6) is 126 ± 1 ℃, F
0value is more than or equal to 8.
The envelop rate of the alprostadil injection that the present invention is prepared is more than 95%.
Specific embodiment
Embodiment 1:
Prescription:
| Prescription | 1 | 2 | 3 | 4 |
| Alprostadil inventory | 5.07mg | 7.03mg | 9.10mg | 11.13mg |
| Refined soybean oil | 100g | 100g | 100g | 100g |
| Ovum Gallus domesticus Flavus lecithin | 18g | 18g | 18g | 18g |
| Oleic acid | 2.4g | 2.4g | 2.4g | 2.4g |
| Glycerol | 22.1g | 22.1g | 22.1g | 22.1g |
| 0.1M?NaOH | In right amount | In right amount | In right amount | In right amount |
| Water for injection adds to | 1000ml | 1000ml | 1000ml | 1000ml |
Technique:
(1) preparation of water: recipe quantity glycerol is added to the water to dissolving, is heated to 60 ℃, standby;
(2) preparation of oil phase: recipe quantity refined soybean oil is heated to 60 ℃, adds recipe quantity Ovum Gallus domesticus Flavus lecithin, oleic acid and Alprostadil, stir and make its dissolving;
(3) preparation of colostrum: step (2) oil phase is added in step (1) water, temperature 60 C, high speed shear is disperseed, and shear rate 10000rpm, forms colostrum at 15 minutes time
(4) high pressure homogenize: step (3) colostrum is adjusted to pH5.4～5.6 with 0.1M NaOH, through microjet instrument high pressure homogenize 3 times, pressure 1000～1200bar;
(5) fill: step (4) essence is newborn through 0.22 μ m filtering with microporous membrane degerming, aseptic embedding;
(6) 126 ± 1 ℃ of moist heat sterilization (F
0> 8)
(7) step (1) to (5) all operates under nitrogen protection.
Entrapment efficiency determination:
Utilize ultrafiltration centrifugal determination to measure envelop rate
1. select the ultra-filtration centrifuge tube of 10K, centrifugal 5 minutes of 3000rpm, in the particle size distribution of mensuration upper strata thickness part and lower clear liquid, whether there is particle to occur, if centrifugal rear lower floor sees through without microgranule and upper strata distributes substantially unchanged,, according to method under assay item, measure the content of clear liquid Chinese medicine under ultra-filtration centrifuge tube.
2. the mensuration of medicine total content
According to the algoscopy under assay item, measure, result is the medicine total content of this product.
Chromatographic condition:
Chromatographic column: C
18post
Mobile phase: 0.0067mol/L phosphate buffer (is got potassium dihydrogen phosphate 9.07g, adding water makes to dissolve, make 1000ml, separately get disodium hydrogen phosphate,anhydrous 9.46g, add water and make to dissolve, make 1000ml, the latter is added in the former, until pH is 6.3, gets this liquid 100ml and add water to 1000ml, shake up, obtain)-acetonitrile (3: 1).
Sample size: 20 μ l; Flow velocity: 1.0ml/min; Detect wavelength: 278nm; Column temperature: 60 ℃
Past column reaction pipe: polyfluortetraethylene pipe
Past column reaction liquid: 1mol/L potassium hydroxide solution
Past column reaction flow velocity: 0.5ml/min
3. the mensuration of envelop rate
The envelop rate of this product is as shown in the formula calculating and get final product.
| Prescription | 1 | 2 | 3 | 4 |
| Envelop rate (%) | 89.5 | 96.8 | 96.5 | 93.1 |
Embodiment 2
Prescription:
| Prescription | 5 | 6 |
| Alprostadil inventory | 6.23mg | 8.16mg |
| Refined soybean oil | 50g | 50g |
| Medium chain triglyceride | 50g | 50g |
| Ovum Gallus domesticus Flavus lecithin | 18g | 18g |
| Oleic acid | 2.4g | 2.4g |
| Glycerol | 22.1g | 22.1g |
| 0.1M?NaOH | In right amount | In right amount |
| Water for injection adds to | 1000ml | 1000ml |
Technique:
(1) preparation of water: glycerol is added to the water to dissolving, is heated to 55 ℃, standby;
(2) preparation of oil phase: refined soybean oil and medium chain triglyceride are heated to 55 ℃, add Ovum Gallus domesticus Flavus lecithin, oleic acid and Alprostadil, stir and make its dissolving;
(3) preparation of colostrum: step (2) oil phase is added in step (1) water, 55 ℃ of temperature, high speed shear is disperseed, and shear rate 8000rpm, forms colostrum at 20 minutes time
(4) high pressure homogenize: step (3) colostrum is adjusted to pH5.4～5.6, through microjet instrument high pressure homogenize 3 times, pressure 600～1000bar;
(5) fill: step (4) essence is newborn through 0.22 μ m filtering with microporous membrane degerming, aseptic embedding;
(6) 126 ± 1 ℃ of moist heat sterilization (F
0> 8)
(7) step (1) to (5) all operates under nitrogen protection.
Entrapment efficiency determination (carrying out with reference to method in embodiment 1):
| Prescription | 5 | 6 |
| Envelop rate (%) | 93.3 | 97.6 |
Embodiment 3
Prescription:
| Prescription | 7 | 8 |
| Alprostadil inventory | 70.61mg | 70.76mg |
| Refined soybean oil | 500g | 1000g |
| Medium chain triglyceride | 500g | 0g |
| Ovum Gallus domesticus Flavus lecithin | 180g | 180g |
| Oleic acid | 24g | 24g |
| Glycerol | 221g | 221g |
| 0.1M?NaOH | In right amount | In right amount |
| Water for injection adds to | 10000ml | 10000ml |
Technique:
(1) preparation of water: glycerol is added to the water to dissolving, is heated to 70 ℃, standby;
(2) preparation of oil phase: oil is heated to 70 ℃, adds Ovum Gallus domesticus Flavus lecithin, oleic acid and Alprostadil, stir and make its dissolving;
(3) preparation of colostrum: step (2) oil phase is added in step (1) water, temperature 70 C, high speed shear is disperseed, and shear rate 3000rpm, forms colostrum at 60 minutes time;
(4) high pressure homogenize: step (3) colostrum is adjusted to pH5.4～5.6, through microjet instrument high pressure homogenize 3 times, pressure 1000～1400bar;
(5) fill: step (4) essence is newborn through 0.22 μ m filtering with microporous membrane degerming, aseptic embedding;
(6) 126 ± 1 ℃ of moist heat sterilization (F
0> 8)
(7) step (1) to (5) all operates under nitrogen protection.
Entrapment efficiency determination (carrying out with reference to method in embodiment 1):
| Prescription | 7 | 8 |
| Envelop rate (%) | 98.0 | 95.6 |
Claims (10)
1. an Alprostadil composition, comprises Alprostadil, oil for injection, and phospholipid, water for injection, in its prescription, the concentration of Alprostadil is 6-11 μ g/ml, and the concentration of oil for injection is 100mg/ml, and phospholipid concentration is 18mg/ml.
2. Alprostadil composition according to claim 1, is characterized in that, in prescription, the concentration of Alprostadil is 7-9 μ g/ml.
3. Alprostadil composition according to claim 1; it is characterized in that, described oil for injection is selected from refined soybean oil, Oleum Arachidis hypogaeae semen, safflower oil, Oleum Gossypii semen, olive oil, Oleum Cocois, Oleum Sesami, fish oil, medium chain monoglyceride, medium chain glycerol dibasic acid esters, medium chain triglyceride, ethyl oleate, acetylated monoglyceride, propylene glycol dibasic acid esters, glyceryl linoleate, Polyethylene Glycol glyceryl laurate ester or its combination.
4. Alprostadil composition according to claim 3, is characterised in that, described oil for injection is refined soybean oil and medium chain triglyceride, and both weight ratios are 1: 1.
5. Alprostadil composition according to claim 1, is characterized in that, described phospholipid is Ovum Gallus domesticus Flavus lecithin, and wherein the content of phosphatidylcholine is more than 96%.
6. Alprostadil composition according to claim 1, is characterized in that, contains oleic acid, glycerol, and pH value is 5.0～6.0.
7. a preparation method for the arbitrary described Alprostadil composition of claim 1～6, is characterized in that, comprises the following steps:
(1) preparation of water: recipe quantity glycerol is added to the water, stirs it is dissolved, as water;
(2) preparation of oil phase: add recipe quantity phospholipid in recipe quantity oil for injection, oleic acid and Alprostadil, stir it is dissolved, as oil phase;
(3) preparation of colostrum: step (2) oil phase is added in step (1) water, and high speed shear is disperseed, and forms colostrum;
(4) high pressure homogenize: step (3) colostrum is adjusted to pH to 5.0～6.0, and high pressure homogenize, obtains smart breast;
(5) fill: step (4) essence is newborn through 0.22 μ m filtering with microporous membrane degerming, aseptic embedding;
(6) moist heat sterilization;
(7) step (1) to (5) all operates under nitrogen protection.
8. the preparation method of Alprostadil composition according to claim 7, is characterized in that, the described high speed shear jitter time of step (3) is 10～60 minutes, and shear rate is 3000～10000rpm, 55～70 ℃ of temperature.
9. the preparation method of Alprostadil composition according to claim 8, is characterized in that, the described high pressure homogenize pressure of step (4) is 600～2000bar, homogenize number of times 3～6 times.
10. the preparation method of Alprostadil composition according to claim 9, is characterized in that, the described moist heat sterilization temperature of step (6) is 126 ± 1 ℃, F
0value is more than or equal to 8.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104490776A (en) * | 2014-12-26 | 2015-04-08 | 北京蓝丹医药科技有限公司 | Alprostadil injection and preparation method thereof |
| CN105012248A (en) * | 2014-04-29 | 2015-11-04 | 北京蓝丹医药科技有限公司 | Injection alprostadil fat emulsion and preparing method thereof |
| CN105310976A (en) * | 2014-06-04 | 2016-02-10 | 北京蓝丹医药科技有限公司 | Stable alprostadil composition |
| CN107884529A (en) * | 2016-09-29 | 2018-04-06 | 辽宁远大诺康生物制药有限公司 | A kind of method and its application for determining fat emulsion formulation entrapment efficiency |
| CN104173301B (en) * | 2014-08-29 | 2018-08-10 | 北京蓝丹医药科技有限公司 | A kind of Alprostadil freeze-dried breast and preparation method thereof |
| CN108653208A (en) * | 2017-03-30 | 2018-10-16 | 北京蓝丹医药科技有限公司 | A kind of alprostadil injection |
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| CN105012248A (en) * | 2014-04-29 | 2015-11-04 | 北京蓝丹医药科技有限公司 | Injection alprostadil fat emulsion and preparing method thereof |
| CN105012248B (en) * | 2014-04-29 | 2018-01-02 | 北京蓝丹医药科技有限公司 | A kind of injection prostadil fatty breast and preparation method thereof |
| CN105310976A (en) * | 2014-06-04 | 2016-02-10 | 北京蓝丹医药科技有限公司 | Stable alprostadil composition |
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| CN104173301B (en) * | 2014-08-29 | 2018-08-10 | 北京蓝丹医药科技有限公司 | A kind of Alprostadil freeze-dried breast and preparation method thereof |
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| CN104490776B (en) * | 2014-12-26 | 2017-06-16 | 本溪恒康制药有限公司 | Alprostadil injection and preparation method thereof |
| CN107884529A (en) * | 2016-09-29 | 2018-04-06 | 辽宁远大诺康生物制药有限公司 | A kind of method and its application for determining fat emulsion formulation entrapment efficiency |
| CN107884529B (en) * | 2016-09-29 | 2020-12-08 | 辽宁远大诺康生物制药有限公司 | Method for measuring drug encapsulation efficiency of fat emulsion preparation and application thereof |
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Address after: 250013 room 2, building 34-1, No. 418 Jiefang East Road, Lixia District, Shandong, Ji'nan Applicant after: JINAN LANDAN MEDICINE SCIENCE & TECHNOLOGY CO., LTD. Address before: 250013 Building 2, No. 34-1, Jiefang East Road, Lixia District, Ji'nan, Shandong, 418 Applicant before: Ji'nan Maijier Medical Technology Development Co Ltd |
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Application publication date: 20140129 |