CN107049942A - A kind of alprostadil injection - Google Patents

A kind of alprostadil injection Download PDF

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Publication number
CN107049942A
CN107049942A CN201611270909.4A CN201611270909A CN107049942A CN 107049942 A CN107049942 A CN 107049942A CN 201611270909 A CN201611270909 A CN 201611270909A CN 107049942 A CN107049942 A CN 107049942A
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phosphatidyl
phosphatide
alprostadil
oil
injection
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林静文
马莹
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Beijing Pudekangli Pharmaceutical Technology Development Co Ltd
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Beijing Pudekangli Pharmaceutical Technology Development Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles

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  • Dispersion Chemistry (AREA)
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Abstract

The present invention provides a kind of alprostadil injection, containing Alprostadil, as the phosphatide of emulsifying agent, oil for injection, water for injection, wherein, the phosphatide contains following components：The phosphatidyl choline that phosphatide percentage by weight is 96.71% 99.90%w/w is accounted for, the phosphatidyl-ethanolamine that phosphatide percentage by weight is 0.10% 3.00%w/w is accounted for, the phosphatidyl glycerol that phosphatide percentage by weight is less than 0.30%w/w is accounted for.Wherein, each component is preferably in phosphatide, and phosphatidyl choline accounts for phosphatide percentage by weight for 97.75 98.90%w/w, and phosphatidyl-ethanolamine accounts for phosphatide percentage by weight for 1.00 2.00%w/w, and the percentage by weight that phosphatidyl glycerol accounts for phosphatide is 0.10 0.25%w/w.The alprostadil injection that the present invention is provided can reduce anisidine value, and its unknown auxiliary material peak energy is enough kept low when carrying out content detection using high performance liquid chromatography.

Description

A kind of alprostadil injection
Technical field
The present invention relates to technical field of pharmaceuticals, and in particular to a kind of alprostadil injection.
Background technology
Alprostadil, also known as prostaglandin E1 (PGE1), are a kind of extremely strong physiological activators of activity, with suppression blood Platelet aggregation, thromboxane A2 generation, the athero- Lipid Plaque formation of artery and the effect of immune complex, and periphery and hat can be expanded The pharmacological action of arteries and veins blood vessel, is mainly used in treating chronic arterial occlusion disease (Buerger's disease, Arteriosclerosis obliterans Deng) caused by four control four limbs tranquillization pain caused by ulcer and tiny blood vessels dyshaemia, improve cardiovascular and cerebrovascular microcirculation disorder And the auxiliary treatment of chronic hepatitis.
The Alprostadil preparation listed at present has Alprostadil powder pin (cyclodextrin inclusion compound) and alprostadil injection (fat Fat emulsion formulation).There is larger excitant in free Alprostadil, such as cause local pain, swelling during Clinical practice Feel, serious appearance is rubescent and red line occurs along vein trend.Therefore alprostadil injection employs lipid microspheres drug delivery technologies To reduce the excitant of free Alprostadil.Lipid microspheres are a kind of using fat oil as soft matrix, and phosphatide is emulsifying agent microsome point Granular media system, its preparation method is that medicine is dissolved in fat oil, using refined lecithin as emulsifying agent, through high-pressure homogeneous into O/W types Drug-loaded emulsion.
Wherein, phosphatide has significant impact as emulsifying agent to the stability of alprostadil injection.Patent CN101511367B provides a kind of prostaglandin of stabilization (i.e. Alprostadil) fat emulsion, and it is using containing phosphatidyl choline The ratio between PC and phosphatidyl glycerol PG phosphatide, wherein PC and PG are 95:5~99.7:0.3, preferably 97:3~99.5:0.5, should Phosphatidyl-ethanolamine PE is substantially free of in the phosphatide of fat emulsion.The standby alprostadil injection of the patent system can be at 5 DEG C Under the conditions of store 2 years, it is ensured that the residual rate and average grain diameter of Alprostadil meet the requirements.
CN201410246450.9 provides a kind of Alprostadil composition of stabilization, comprising Alprostadil, oil for injection, Phosphatidyl choline, phosphatidylinositols, without phosphatidyl-ethanolamine, its weight proportion is as follows, and the weight of Alprostadil is 1 part, note It is 5000~30000 parts to penetrate with the weight of oil, and the weight of phosphatidyl choline is 1200-4000 parts, and the weight of phosphatidylinositols is 12-48 parts, prepared product has more preferable safety and stability.
A kind of Alprostadil compositions of CN201410664852.0, comprising Alprostadil, oil for injection, egg yolk lecithin, The weight of Alprostadil is 1 part, and the weight of oil for injection is 2000~20000 parts, the weight of egg yolk lecithin for 1200~ 3600 parts, in the egg yolk lecithin content of phosphatidyl choline more than 96%, the content of phosphatidylinositols for 0.3~ 1.0%, and without phosphatidyl-ethanolamine.
In summary, prior art is for phosphatide and defined not when solving alprostadil injection stability problem PE containing phosphatidyl-ethanolamine.
For alprostadil injection, except the stability of medicine in itself, wherein also containing 10% lubricant component, it is in system In standby and sterilization process may oxidation Decomposition into aldehyde, ketone, acid etc., because aldoketones material has certain toxicity, can cause The potential safety hazard of clinical application, therefore the anisidine value in fat emulsion injection is controlled.Component in phosphatide Anisidine value how is influenceed, the technical inspiration of correlation is not provided in the prior art.
The content of the invention
It is an object of the invention to the defect for overcoming prior art, there is provided a kind of relatively low Alprostadil of anisidine value Parenteral solution, it was unexpectedly determined that the alprostadil injection that the present invention is provided is contained in preservation using high performance liquid chromatography During amount detection, its unknown auxiliary material peak energy is enough kept low.
The present invention provides a kind of alprostadil injection, containing Alprostadil, phosphatide, oil for injection, water for injection, its In, the phosphatide contains following components：The phosphatidyl choline that phosphatide percentage by weight is 96.71%-99.90%w/w is accounted for, phosphorus is accounted for Fat percentage by weight is 0.10%-3.00%w/w phosphatidyl-ethanolamine, accounts for phosphatide percentage by weight and is less than 0.30%w/w's Phosphatidyl glycerol.
In above-mentioned alprostadil injection, described phosphatidyl choline accounts for phosphatide percentage by weight for 97.75-98.90% W/w, phosphatidyl-ethanolamine accounts for phosphatide percentage by weight for 1.00-2.00%w/w, and phosphatidyl glycerol accounts for the percentage by weight of phosphatide For 0.10-0.25%w/w.
In above-mentioned alprostadil injection, the concentration of Alprostadil is 5 μ g/ml, and the concentration of phosphatide is 6-18mg/ml, note It is 100-300mg/ml to penetrate with the concentration of oil.
Described phosphatidyl choline is selected from the phosphatidyl choline and its salt of natural origin, the phosphatidyl choline and its salt of synthesis Or its combination；The phosphatidyl choline of the synthesis is selected from DSPC, dioleyl phosphatidyl choline, two palm fibres Palmitic acid phosphatidyl choline, L-Dimyristoylphosphatidylcholine, DDPC, dilauroyl phosphatidyl courage Alkali, two mustard phosphatidyl cholines, 1- stearyl -2- oleolyl phosphatidyl cholines, 1- palmityl -2- oleolyl phosphatidyls Choline, 1- myristoyl -2- oleolyl phosphatidyl cholines, 1- stearyl -2- palmityl phosphatidyl cholines, 1- stearoyls Base -2- myristoyl phosphatidyl cholines, 1- palmityl -2- stearoyl phosphatidyl choline, 1- palmityl -2- nutmegs Phosphatidyl choline, 1- myristoyl -2- stearoyl phosphatidyl choline, 1- myristoyl -2- palmityl phosphatide Phatidylcholine or its combination.
Described phosphatidyl glycerol is selected from the phosphatidyl glycerol and its salt of natural origin, the phosphatidyl glycerol and its salt of synthesis Or its combination；The phosphatidyl glycerol of the synthesis is selected from DSPG, DOPG, two Palmityl phosphatidyl glycerol, DMPG, 1- palmityl -2- oleolyl phosphatidyl glycerine, two mustard Acyl phosphatidyl glycerol, PE or its combination.
Described phosphatidyl-ethanolamine is selected from the phosphatidyl-ethanolamine and its salt that the phosphatidyl-ethanolamine is natural origin, The phosphatidyl-ethanolamine and its salt or their any combination of synthesis；The phosphatidyl-ethanolamine of the synthesis is selected from distearyl acyl group Phosphatidyl-ethanolamine, DOPE, DPPE, two myristoyl phosphatidyl second Hydramine, two mustard acyl phosphatidyl-ethanolamines, two lauroyl phosphatidyl-ethanolamines or its combination.
Described oil for injection be selected from refined soybean oil, safflower oil, cottonseed oil, olive oil, coconut oil, castor oil, fish oil, Medium chain mono, medium chain triglyceride dibasic acid esters, medium chain triglyceride, ethyl oleate, acetylated monoglyceride, propane diols dibasic acid esters, Asia Olein, polyethylene glycol glyceryl laurate ester or its combination.
Also include isotonic regulator in above-mentioned alprostadil injection, the isotonic regulator is selected from glycerine, glucose, sweet Reveal sugar alcohol or its combination.
PH adjusting agent is also included in above-mentioned alprostadil injection, described pH adjusting agent is selected from sodium hydroxide, hydrochloric acid, phosphorus Acid, phosphate, citric acid, citrate, acetic acid, acetate or its combination.
A kind of preparation method for preparing above-mentioned alprostadil injection, is comprised the steps of：
(1) preparation of aqueous phase：Glycerine is added in recipe quantity water for injection, stirring dissolves it, is used as aqueous phase；
(2) preparation of oil phase：Phosphatide, Alprostadil are added in soybean oil, stirring dissolves it, is used as oil phase；
(3) oil phase is added in aqueous phase, high speed shear is disperseed, forms colostrum；
(4) it is colostrum is high-pressure homogenising, obtain smart breast；
(5) it is filling, sterilizing, thus obtaining the product.
The present invention is found surprisingly that the enlightenment with prior art is on the contrary, contain a small amount of phosphatidyl-ethanolamine, no in phosphatide The stability of Alprostadil is not only interfered with, and helps to reduce the anisidine value of product, is more found surprisingly that, helps The impurity peaks produced in reduction auxiliary material, can preferably control the quality of alprostadil injection product.
Brief description of the drawings
Fig. 1：The automatic pretreatment apparatus used in test case 2.
Embodiment
Comparative example 1
Prescription Consumption
Alprostadil 5mg
Phosphatide 18g
Soybean oil 100g
Glycerine 22.1g
0.1M NaOH In right amount
Phosphatide includes phosphatidyl choline 17.946g, phosphatidyl glycerol 0.054g in above-mentioned prescription.
Preparation method：
(1) preparation of aqueous phase：Glycerine is added to the water, stirring dissolves it, is used as aqueous phase；
(2) preparation of oil phase：Phosphatide, Alprostadil are added in soybean oil, stirring dissolves it, is used as oil phase；
(3) oil phase is added in aqueous phase, it is 1000ml to make total amount, high speed shear is disperseed, and forms colostrum；
(4) it is colostrum is high-pressure homogenising, obtain smart breast；
(5) it is filling, sterilizing, thus obtaining the product.
Comparative example 2
Prescription Consumption
Alprostadil 5mg
Phosphatide 18g
Soybean oil 100g
Glycerine 22.1g
0.1M NaOH In right amount
Phosphatide includes phosphatidyl choline 17.325g, phosphatidyl-ethanolamine 0.63g, phosphatidyl glycerol in above-mentioned prescription 0.045g。
Preparation method：
(1) preparation of aqueous phase：Glycerine is added to the water, stirring dissolves it, is used as aqueous phase；
(2) preparation of oil phase：Phosphatide, Alprostadil are added in soybean oil, stirring dissolves it, is used as oil phase；
(3) oil phase is added in aqueous phase, it is 1000ml to make total amount, high speed shear is disperseed, and forms colostrum；
(4) it is colostrum is high-pressure homogenising, obtain smart breast；
(5) it is filling, sterilizing, thus obtaining the product.
Comparative example 3
Prescription Consumption
Alprostadil 5mg
Phosphatide 18g
Soybean oil 100g
Glycerine 22.1g
0.1M NaOH In right amount
Phosphatide includes phosphatidyl choline 17.766g, phosphatidyl-ethanolamine 0.18g, phosphatidyl glycerol in above-mentioned prescription 0.054g。
Preparation method：
(1) preparation of aqueous phase：Glycerine is added to the water, stirring dissolves it, is used as aqueous phase；
(2) preparation of oil phase：Phosphatide, Alprostadil are added in soybean oil, stirring dissolves it, is used as oil phase；
(3) oil phase is added in aqueous phase, it is 1000ml to make total amount, high speed shear is disperseed, and forms colostrum；
(4) it is colostrum is high-pressure homogenising, obtain smart breast；
(5) it is filling, sterilizing, thus obtaining the product.
Embodiment 1
Prescription Consumption
Alprostadil 5mg
Phosphatide 18g
Soybean oil 100g
Glycerine 22.1g
0.1M NaOH In right amount
Phosphatide includes phosphatidyl choline 17.937g, phosphatidyl-ethanolamine 0.018g, phosphatidyl glycerol in above-mentioned prescription 0.045g。
Preparation method：
(1) preparation of aqueous phase：Glycerine is added to the water, stirring dissolves it, is used as aqueous phase；
(2) preparation of oil phase：Phosphatide, Alprostadil are added in soybean oil, stirring dissolves it, is used as oil phase；
(3) oil phase is added in aqueous phase, it is 1000ml to make total amount, high speed shear is disperseed, and forms colostrum；
(4) it is colostrum is high-pressure homogenising, obtain smart breast；
(5) it is filling, sterilizing, thus obtaining the product.
Embodiment 2
Prescription Consumption
Alprostadil 5mg
Phosphatide 18g
Soybean oil 100g
Glycerine 22.1g
0.1M NaOH In right amount
Phosphatide includes phosphatidyl choline 17.775g, phosphatidyl-ethanolamine 0.18g, phosphatidyl glycerol in above-mentioned prescription 0.045g。
Preparation method：
(1) preparation of aqueous phase：Glycerine is added to the water, stirring dissolves it, is used as aqueous phase；
(2) preparation of oil phase：Phosphatide, Alprostadil are added in soybean oil, stirring dissolves it, is used as oil phase；
(3) oil phase is added in aqueous phase, it is 1000ml to make total amount, high speed shear is disperseed, and forms colostrum；
(4) it is colostrum is high-pressure homogenising, obtain smart breast；
(5) it is filling, sterilizing, thus obtaining the product.
Embodiment 3
Phosphatide includes phosphatidyl choline 17.595g, phosphatidyl-ethanolamine 0.36g, phosphatidyl glycerol in above-mentioned prescription 0.045g。
Preparation method：
(1) preparation of aqueous phase：Glycerine is added to the water, stirring dissolves it, is used as aqueous phase；
(2) preparation of oil phase：Phosphatide, Alprostadil are added in soybean oil, stirring dissolves it, is used as oil phase；
(3) oil phase is added in aqueous phase, it is 1000ml to make total amount, high speed shear is disperseed, and forms colostrum；
(4) it is colostrum is high-pressure homogenising, obtain smart breast；
(5) it is filling, sterilizing, thus obtaining the product.
Embodiment 4
Prescription Consumption
Alprostadil 5mg
Phosphatide 18g
Soybean oil 100g
Glycerine 22.1g
0.1M NaOH In right amount
Phosphatide includes phosphatidyl choline 17.415g, phosphatidyl-ethanolamine 0.54g, phosphatidyl glycerol in above-mentioned prescription 0.045g。
Preparation method：
(1) preparation of aqueous phase：Glycerine is added to the water, stirring dissolves it, is used as aqueous phase；
(2) preparation of oil phase：Phosphatide, Alprostadil are added in soybean oil, stirring dissolves it, is used as oil phase；
(3) oil phase is added in aqueous phase, it is 1000ml to make total amount, high speed shear is disperseed, and forms colostrum；
(4) it is colostrum is high-pressure homogenising, obtain smart breast；
(5) it is filling, sterilizing, thus obtaining the product.
7 days under the conditions of comparative example 1-3 and embodiment 1-4 sample are respectively placed in into 40 DEG C, according to test case 1 and test The method and index of example 2 are detected.
The measure of the anisidine value of test case 1
According to《Fat emulsion injection (C14-C24) quality standard》Method is recorded in (exposure draft) to be detected.Inspection Survey method：Lucifuge fast operating.Precision measures this product 10ml (V), puts in 250ml round-bottomed flasks, adds absolute ethyl alcohol 20ml, 60 DEG C of water-bath rotary evaporation in vacuo are to almost no liquid；Again plus absolute ethyl alcohol 20ml, repeat twice.Residue with isopropanol- Isooctane (20:80) solution is dissolved, and full dose is transferred in 25ml measuring bottles, with isopropanol-isooctane (20:80) solution is diluted to quarter Degree, shakes up, and takes 12ml accurately to add 2.0g anhydrous sodium sulfates and removes remaining traces of moisture.Solution with 15000rpm speed from The heart 3 minutes, takes supernatant as need testing solution.According to ultraviolet-visible spectrophotometer (Chinese Pharmacopoeia two annex of version in 2010 IV A), at 350nm wavelength, with isopropanol-isooctane (20:80) solution determines the absorbance of need testing solution as blank (A1).Precision measures need testing solution and isopropanol-isooctane (20:80) each 5ml of solution, puts in a tool plug test tube, respectively respectively The 4- aminoanisoles glacial acetic acid solution that precision adds 0.25% (faces and uses brand-new) 1ml, and closed shaking, lucifuge accurately places 10 points Clock.With isopropanol-isooctane (20:80) solution conduit solution makees blank, and the extinction of need testing solution pipe is determined at 350nm wavelength Spend (A2).It is calculated as follows.
Calculation formula：
V：The sampling amount (ml) of test sample
1.2：The solution dilution gfactor added after the glacial acetic acid solution of 4- aminoanisoles
Testing result is as shown in the table：
According to above-mentioned testing result it can be found that 1-4 of embodiment of the present invention anisidine value is when preserving 7 days for 40 DEG C Anisidine value can be maintained at less than 1.0, and the anisidine value of comparative example 1 and comparative example 3 is more than 1.0.Comparative example 2 Anisidine value although disclosure satisfy that requirement, but the degraded of its Alprostadil is substantially greater than embodiment 1-4.Therefore can See that prostadil fatty breast prepared by the present invention can not only ensure the stabilization of active ingredient Alprostadil, and first can be obtained The relatively low fat emulsion of epoxide aniline value, with more preferable safety and stability.
Test case 2
Efficient liquid phase detection is carried out to alprostadil injection prepared by embodiment 1-4 and comparative example 1-3.Detection method is as follows：
Chromatographic condition is filler with octadecylsilane chemically bonded silica with system suitability, with 0.0067mol/L Phosphate buffer (pH is 6.3) (takes potassium dihydrogen phosphate 9.07g, adding water makes dissolving, 1000ml is made, separately take anhydrous phosphoric acid hydrogen Disodium 9.46g, adding water makes dissolving, and 1000ml is made, and the latter is added in the former, until pH is 6.3, takes this liquid 100ml to add water to 1000ml, shakes up, and produces)-acetonitrile (3:1) it is mobile phase；Regulation flow velocity makes Alprostadil about 15min appearances；Past column reaction liquid For 1mol/L potassium hydroxide solutions, flow velocity is 1.0ml/min, and past column reaction pipe is polyfluortetraethylene pipe 60 DEG C of column temperature；Detection wavelength 278nm.Number of theoretical plate is calculated by Alprostadil peak should be not less than 5000, Alprostadil and prostate Plain A1Separating degree should be greater than 10, prostaglandin A12.0 are should be greater than with interior target separating degree.
The preparation of inner mark solution takes alpha-Naphthol about 62.5mg, accurately weighed, puts in 25ml measuring bottles, plus absolute ethyl alcohol dissolving is simultaneously Scale is diluted to, precision measures 3ml, put in 100ml measuring bottles, plus mobile phase is diluted to scale, shakes up, and is used as inner mark solution.
The preparation of reference substance solution takes Alprostadil reference substance about 10mg, accurately weighed, puts in 100ml measuring bottles, plus anhydrous Ethanol dissolves and is diluted to scale, shakes up, as reference substance stock solution, and precision measures reference substance stock solution 5ml, puts 100ml amounts In bottle, plus mobile phase is diluted to scale, and precision measures 1ml, then accurate addition 1ml inner mark solutions, is used as reference substance solution.
The preparation precision of need testing solution measures this product 1ml, then the accurate inner mark solution for adding 1ml, shakes up, as trying Product solution.(being used after preparation in 2 hours)
Determination method precision measures need testing solution and each 20 μ l injections liquid chromatograph of reference substance solution, records chromatogram, By internal standard method with calculated by peak area, produce.
Automatic pretreatment apparatus：By a pretreatment column, the pump of a flushing pretreatment column, two six-way valve compositions
Pretreatment column：C18Column length 3cm × 4mm；5μm
Pretreatment column flushing liquor：Absolute ethyl alcohol
Irrigation flow rate：2ml/min
Stream working condition：It is as shown in the table
* 1) after internal standard elution completely
* 2) * 1) after 0.1min
The alprostadil injection prepared by embodiment 1-4 and comparative example 1-3 is detected using the above method, found A unknown auxiliary material peak (Alprostadil retention time is 13min), after being preserved 7 days under the conditions of 40 DEG C, the peak occurs in 28min Peak area can increase.Following table have recorded when being calculated according to area normalization method, the % at the unknown auxiliary material peak that 28min occurs Area.
According to above-mentioned result of the test it can be found that after 40 DEG C store 7 days, the Alprostadil prepared by comparative example 1-3 is noted The % peak areas for penetrating liquid 28min unknown auxiliary material peak are dramatically increased, and the alprostadil injection prepared by 1-4 of the embodiment of the present invention The % peak area increases at the unknown auxiliary material peaks of liquid 28min are smaller.
Embodiment 5
Prescription Consumption
Alprostadil 5mg
Phosphatide 6g
Olive oil 100g
Medium chain triglyceride 100g
Glycerine 22.1g
0.1M NaOH In right amount
Phosphatide includes phosphatidyl choline 5.82g, phosphatidyl-ethanolamine 0.18g in above-mentioned prescription.
Preparation method：
(1) preparation of aqueous phase：Glycerine is added to the water, stirring dissolves it, is used as aqueous phase；
(2) preparation of oil phase：Phosphatide, Alprostadil are added in olive oil and medium chain triglyceride, stirring dissolves it, It is used as oil phase；
(3) oil phase is added in aqueous phase, it is 1000ml to make total amount, high speed shear is disperseed, and forms colostrum；
(4) it is colostrum is high-pressure homogenising, obtain smart breast；
(5) it is filling, sterilizing, thus obtaining the product.
After testing, the alprostadil injection indices obtained by embodiment 5 meet the requirements.
Embodiment 6
Phosphatide includes phosphatidyl choline 11.605g, phosphatidyl-ethanolamine 0.36g, phosphatidyl glycerol in above-mentioned prescription 0.035g。
Preparation method：
(1) preparation of aqueous phase：Glycerine is added to the water, stirring dissolves it, is used as aqueous phase；
(2) preparation of oil phase：Phosphatide, Alprostadil are added in soybean oil, stirring dissolves it, is used as oil phase；
(3) oil phase is added in aqueous phase, it is 1000ml to make total amount, high speed shear is disperseed, and forms colostrum；
(4) it is colostrum is high-pressure homogenising, obtain smart breast；
(5) it is filling, sterilizing, thus obtaining the product.
After testing, the alprostadil injection indices obtained by embodiment 6 meet the requirements.
Embodiment 7
Prescription Consumption
Alprostadil 5mg
Phosphatide 15g
Soybean oil 300g
Glycerine 22.1g
0.1M NaOH In right amount
Phosphatide includes phosphatidyl choline 14.985g, phosphatidyl-ethanolamine 0.015g in above-mentioned prescription.
Preparation method：
(1) preparation of aqueous phase：Glycerine is added to the water, stirring dissolves it, is used as aqueous phase；
(2) preparation of oil phase：Phosphatide, Alprostadil are added in soybean oil, stirring dissolves it, is used as oil phase；
(3) oil phase is added in aqueous phase, it is 1000ml to make total amount, high speed shear is disperseed, and forms colostrum；
(4) it is colostrum is high-pressure homogenising, obtain smart breast；
(5) it is filling, sterilizing, thus obtaining the product.
After testing, the alprostadil injection indices obtained by embodiment 7 meet the requirements.
Embodiment 8
Prescription Consumption
Alprostadil 5mg
Phosphatide 18g
Soybean oil 200g
Glycerine 22.1g
0.1M NaOH In right amount
Phosphatide includes phosphatidyl choline 17.955g, phosphatidyl-ethanolamine 0.027g, phosphatidyl glycerol in above-mentioned prescription 0.018g。
Preparation method：
(1) preparation of aqueous phase：Glycerine is added to the water, stirring dissolves it, is used as aqueous phase；
(2) preparation of oil phase：Phosphatide, Alprostadil are added in soybean oil, stirring dissolves it, is used as oil phase；
(3) oil phase is added in aqueous phase, it is 1000ml to make total amount, high speed shear is disperseed, and forms colostrum；
(4) it is colostrum is high-pressure homogenising, obtain smart breast；
(5) it is filling, sterilizing, thus obtaining the product.
After testing, the alprostadil injection indices obtained by embodiment 8 meet the requirements.
The preferred embodiment of the present invention is described in detail in the above.But, the present invention is not limited to above-mentioned embodiment party Detail in formula, in the range of the technology design of the present invention, can carry out a variety of simple changes to technical scheme Type, these simple variants belong to protection scope of the present invention.
It is further to note that each particular technique feature described in above-mentioned embodiment, in not lance In the case of shield, it can be combined by any mode.In order to avoid unnecessary repetition, the present invention is to various possible groups Conjunction mode no longer separately illustrates.
In addition, various embodiments of the present invention can be combined randomly, without departing from this hair Bright thought, it should equally be considered as content disclosed in this invention.

Claims (10)

1. a kind of alprostadil injection, contains Alprostadil, phosphatide, oil for injection, water for injection, it is characterised in that described Phosphatide contains following components：The phosphatidyl choline that phosphatide percentage by weight is 96.71%-99.90%w/w is accounted for, phosphatide weight hundred is accounted for Divide than the phosphatidyl-ethanolamine for 0.10%-3.00%w/w, account for the phosphatidyl glycerol that phosphatide percentage by weight is less than 0.30%w/w.
2. alprostadil injection according to claim 1, it is characterised in that described phosphatidyl choline accounts for phosphatide weight Percentage is 97.75-98.90%w/w, and phosphatidyl-ethanolamine accounts for phosphatide percentage by weight for 1.00-2.00%w/w, and phosphatidyl is sweet The percentage by weight that oil accounts for phosphatide is 0.10-0.25%w/w.
3. the alprostadil injection according to claim 1-2, it is characterised in that the concentration of described Alprostadil is 5 μ G/ml, the concentration of phosphatide is 6-18mg/ml, and the concentration of oil for injection is 100-300mg/ml.
4. alprostadil injection according to claim 1, it is characterised in that described phosphatidyl choline is selected from natural next The phosphatidyl choline and its salt in source, the phosphatidyl choline and its salt of synthesis or its combination；The phosphatidyl choline of the synthesis is selected from DSPC, dioleyl phosphatidyl choline, Dioctonoyl pnosphotidyl choline, two myristoyl phosphatide Phatidylcholine, DDPC, DLPC, two mustard phosphatidyl cholines, 1- stearyls- 2- oleolyl phosphatidyl cholines, 1- palmityl -2- oleolyl phosphatidyl cholines, 1- myristoyl -2- oleolyl phosphatidyls Choline, 1- stearyl -2- palmityl phosphatidyl cholines, 1- stearyl -2- myristoyl phosphatidyl cholines, 1- palms Acyl group -2- stearoyl phosphatidyl choline, 1- palmityl -2- myristoyl phosphatidyl cholines, 1- myristoyls -2- is hard Fatty acyl group phosphatidyl choline, 1- myristoyls -2- palmityls phosphatidyl choline or its combination.
5. alprostadil injection according to claim 1, it is characterised in that described phosphatidyl glycerol is selected from natural next The phosphatidyl glycerol and its salt in source, the phosphatidyl glycerol and its salt of synthesis or its combination；The phosphatidyl glycerol choosing of the synthesis From DSPG, DOPG, DPPG, two myristoyl phosphorus Phosphatidyl glycerol, 1- palmityl -2- oleolyl phosphatidyl glycerine, two mustard acyl phosphatidyl glycerols, PE or It is combined.
6. alprostadil injection according to claim 1, it is characterised in that described phosphatidyl-ethanolamine is selected from described Phosphatidyl-ethanolamine is the phosphatidyl-ethanolamine and its salt of natural origin, the phosphatidyl-ethanolamine and its salt of synthesis or their times Meaning combination；The phosphatidyl-ethanolamine of the synthesis be selected from DSPE, DOPE, DPPE, two myristoyl phosphatidyl-ethanolamines, two mustard acyl phosphatidyl-ethanolamines, two lauroyl phosphorus Acyl monoethanolamine or its combination.
7. florfenicol residues according to claim 1, it is characterised in that described oil for injection is selected from refined big Soya-bean oil, safflower oil, cottonseed oil, olive oil, coconut oil, castor oil, fish oil, medium chain mono, medium chain triglyceride dibasic acid esters, middle chain are sweet Oily three esters, ethyl oleate, acetylated monoglyceride, propane diols dibasic acid esters, glyceryl linoleate, polyethylene glycol glyceryl laurate ester or It is combined.
8. the alprostadil injection according to claim 1-7, it is characterised in that also comprising isotonic regulator, described etc. Ooze conditioning agent and be selected from glycerine, glucose, mannitol or its combination.
9. alprostadil injection according to claim 1, it is characterised in that also comprising pH adjusting agent, described pH is adjusted Save agent and be selected from sodium hydroxide, hydrochloric acid, phosphoric acid, phosphate, citric acid, citrate, acetic acid, acetate or its combination.
10. a kind of preparation method for preparing the alprostadil injection described in claim 1-9, is comprised the steps of：
（1）The preparation of aqueous phase：Glycerine is added in recipe quantity water for injection, stirring dissolves it, is used as aqueous phase；
（2）The preparation of oil phase：Phosphatide, Alprostadil are added in oil for injection, stirring dissolves it, is used as oil phase；
（3）Oil phase is added in aqueous phase, high speed shear is disperseed, form colostrum；
（4）Colostrum is high-pressure homogenising, obtain smart breast；
（5）It is filling, sterilizing, thus obtaining the product.
CN201611270909.4A 2016-12-30 2016-12-30 A kind of alprostadil injection Withdrawn CN107049942A (en)

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CN107137351A (en) * 2017-06-05 2017-09-08 辅必成（上海）医药科技有限公司 A kind of Alprostadil emulsions parenteral solution of stabilization
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CN110045034A (en) * 2019-04-30 2019-07-23 江苏东南纳米材料有限公司 A kind of method that high performance liquid chromatography measures two mustard phosphatidyl choline contents

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Application publication date: 20170818