CN105748415A - PGE1 (prostaglandin E1) freeze-dried microemulsion composition and preparation method thereof - Google Patents
PGE1 (prostaglandin E1) freeze-dried microemulsion composition and preparation method thereof Download PDFInfo
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- CN105748415A CN105748415A CN201610157370.5A CN201610157370A CN105748415A CN 105748415 A CN105748415 A CN 105748415A CN 201610157370 A CN201610157370 A CN 201610157370A CN 105748415 A CN105748415 A CN 105748415A
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- composition
- alprostadil
- oil phase
- freeze
- preparation
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- 239000000203 mixture Substances 0.000 title claims abstract description 110
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 title claims abstract description 84
- 238000002360 preparation method Methods 0.000 title claims abstract description 46
- 239000004530 micro-emulsion Substances 0.000 title claims abstract description 24
- GMVPRGQOIOIIMI-UHFFFAOYSA-N (8R,11R,12R,13E,15S)-11,15-Dihydroxy-9-oxo-13-prostenoic acid Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CCCCCCC(O)=O GMVPRGQOIOIIMI-UHFFFAOYSA-N 0.000 claims abstract description 81
- 229960000711 alprostadil Drugs 0.000 claims abstract description 81
- 238000004108 freeze drying Methods 0.000 claims abstract description 39
- -1 anionic phospholipid Chemical class 0.000 claims abstract description 26
- 239000003814 drug Substances 0.000 claims abstract description 19
- 239000012875 nonionic emulsifier Substances 0.000 claims abstract description 16
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 239000003223 protective agent Substances 0.000 claims abstract 3
- 239000012071 phase Substances 0.000 claims description 70
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 59
- 238000002156 mixing Methods 0.000 claims description 52
- 239000008346 aqueous phase Substances 0.000 claims description 47
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 39
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- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical group CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 claims description 16
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- RSWGJHLUYNHPMX-UHFFFAOYSA-N 1,4a-dimethyl-7-propan-2-yl-2,3,4,4b,5,6,10,10a-octahydrophenanthrene-1-carboxylic acid Chemical compound C12CCC(C(C)C)=CC2=CCC2C1(C)CCCC2(C)C(O)=O RSWGJHLUYNHPMX-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 208000005189 Embolism Diseases 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- 206010062717 Increased upper airway secretion Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 241000220324 Pyrus Species 0.000 description 1
- 240000000111 Saccharum officinarum Species 0.000 description 1
- 235000007201 Saccharum officinarum Nutrition 0.000 description 1
- 235000010358 acesulfame potassium Nutrition 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000004931 aggregating effect Effects 0.000 description 1
- 229940070940 alprostadil injection Drugs 0.000 description 1
- 229940016267 alprostadil urethral suppository Drugs 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- ODCCQUXDUXHSBP-UHFFFAOYSA-N decanoic acid;propane-1,2,3-triol Chemical compound OCC(O)CO.CCCCCCCCCC(O)=O ODCCQUXDUXHSBP-UHFFFAOYSA-N 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000009795 derivation Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000003617 erythrocyte membrane Anatomy 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 208000018875 hypoxemia Diseases 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 239000002563 ionic surfactant Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000000593 microemulsion method Methods 0.000 description 1
- JKQOBWVOAYFWKG-UHFFFAOYSA-N molybdenum trioxide Chemical compound O=[Mo](=O)=O JKQOBWVOAYFWKG-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000010606 normalization Methods 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- 150000002889 oleic acids Chemical class 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 235000021017 pears Nutrition 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 208000001297 phlebitis Diseases 0.000 description 1
- 208000026435 phlegm Diseases 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical class CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 description 1
- BGKHCLZFGPIKKU-LDDQNKHRSA-N prostaglandin A1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1C=CC(=O)[C@@H]1CCCCCCC(O)=O BGKHCLZFGPIKKU-LDDQNKHRSA-N 0.000 description 1
- 201000007094 prostatitis Diseases 0.000 description 1
- 238000003908 quality control method Methods 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000005464 sample preparation method Methods 0.000 description 1
- KKCBUQHMOMHUOY-UHFFFAOYSA-N sodium oxide Chemical compound [O-2].[Na+].[Na+] KKCBUQHMOMHUOY-UHFFFAOYSA-N 0.000 description 1
- 229910001948 sodium oxide Inorganic materials 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
Classifications
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides PGE1 (prostaglandin E1) freeze-dried microemulsion composition. The composition is prepared from PGE1, a non-ionic emulsifier, chondroitin sulfate, anionic phospholipid and a freeze-drying protective agent, and raw materials and components comprise, in percentage by mass, 0.001%-0.04% of PGE1, 1%-55% of the non-ionic emulsifier, 0.1%-20% of anionic phospholipid, 0.6%-28% of an oil phase and 5%-98% of the freeze-drying protective agent. The encapsulation efficiency and the stability of the composition are significantly improved, reduction of free drug concentration is facilitated, vascular irritation of a preparation is reduced, and the composition is safer and more stable.
Description
Technical field
The present invention relates to a kind of composition, be specifically related to a kind of Alprostadil freeze-dried micro emulsion composition and
Preparation method.
Background technology
Alprostadil (PGE1) it is a kind of 20 carbon unrighted acids, it is widely present in different genera and feeds
In the tissue of breast animal and body fluid, for one of autacoid.And exogenous Alprostadil is as one
Vasodilator and platelet aggregating agent, pharmacologically active is extensive, the most existing multiple formulation listing, including
Parenteralia (the dry breast of injection Alprostadil powder pin, lipoalprostadil, injection Alprostadil
Agent), external preparation class (Alprostadil urethral suppository, Alprostadil emulsifiable paste), can be used for: treat chronic dynamic
Four limbs ulcer that arteries and veins obliterans (Buerger's disease, Arteriosclerosis obliterans etc.) causes and micro-
The four limbs tranquillization pain that thin vessels dyshaemia causes；Treatment cardiovascular and cerebrovascular microcirculation disorder；Organ transplantation
Postoperative antithrombotic treatments, in order to suppress endovascular thrombosis after transplanting；Treatment Ductal dependence
Congenital heart disease, in order to alleviate hypoxemia, keeps conduit blood flow with operative treatment of awaiting a favorable opportunity；Slowly
Property hepatitis auxiliary treatment；Etc..
The poorly water-soluble of Alprostadil, is heated and is easily generated degradation impurity, and blood vessel is had intense stimulus.Example
As, the Alprostadil freeze-dried powder-injection of common injection has extremely strong blood vessel irritation, easily goes out in lung
Living, its side effect produces bright sample swelling pain in various degree when mainly having drip-feed or phlegm is itched, along vein
Skin it sometimes appear that " red line ", when instiling too fast, pain then increases the weight of.Pain and " red line " are general
Can disappear after stopping injection, but non-infectious phlebitis then occurs in severe patient.
After Alprostadil is scattered in lipid microspheres, it will be substantially reduced free Alprostadil content, thus
Reduce the excitant to blood vessel.Such as, Taide, Beijing pharmaceutical manufacturing alprostadil injection (trade name:
Time triumphant) Alprostadil is wrapped in lipid microspheres, thus suppress medicine to inactivate in lung, reduce medicine
Stimulation to blood vessel, makes time lengthening in drug retention body, and dosing greatly reduces, and curative effect is carried
High.But, this product stability is very poor, and when preserving under 0-5 DEG C of environment, Alprostadil is the easiest
It is degraded to PGA1, its drug standard specifies PGA1It is (the most main that content may not exceed 3 μ g/mL
Medicine content is up to 60%).Alprostadil is disperseed by the injection Alprostadil dried emulsifier that Chongqing medicine friend produces
In lipid microspheres, thus reduce free Alprostadil, reduce the excitant to blood vessel, then by lipid microspheres
By suitable means freeze-drying, thus avoid the high-temperature sterilization negative shadow to Alprostadil stability
Ring.This formulation can be by impurity PGA1Control within 10%, make the stability of Alprostadil significantly carry
Height, however, it was found that its free Alprostadil content is the highest, when Clinical practice, blood vessel irritation is still
So exist, bring unnecessary misery to patient；Meanwhile, can produce more than 5 μm after the lyophilized redissolution of this product
Big emulsion droplet, this can block capillary, cause embolism, there is bigger potential safety hazard.
Have some patent applications at present and disclose the freeze drying microemulsion type of Alprostadil.Chinese patent application
CN201110114324.4 discloses a kind of Alprostadil freeze-dried micro emulsion and preparation method thereof, in said preparation
The short chain alcohol such as use glycerine, PEG400, ethanol, propane diols are as assistant for emulsifying agent, and use oleic acid
Salt or cholate are as stabilizer.But, described assistant for emulsifying agent can increase Alprostadil dissolving in aqueous phase
Degree, so that free Alprostadil concentration increases in the outer aqueous phase of micro emulsion, makes envelop rate reduce；Meanwhile,
Described oleate or cholate are as ionic surfactant, and it has the potential of destruction erythrocyte membrane in vivo
Risk.Chinese patent application CN201310027679.9 discloses a kind of Alprostadil without assistant for emulsifying agent
Lyophilized micro emulsion composition.It is found that while that this formulation can reduce the free drug concentration in aqueous phase, but it wraps
Envelope rate is less than 95%, and when Clinical practice, blood vessel irritation yet suffers from；Meanwhile, because this product is without helping
Emulsifying agent, it need to strictly control the speed that profit mixes mutually, and temperature before forming micro emulsion in preparation process
Need to control more than 50 DEG C, so that some drugs is degraded in preparation process, be unfavorable for medicinal substances
The control of amount.
It is generally acknowledged compared to lipide microsphere injection, the stability of Alprostadil freeze-dried micro emulsion composition
Significantly improve, be conducive to reducing the degraded of Alprostadil during producing and storing, it is possible to extend goods
The frame phase；Meanwhile, micro emulsion is thermodynamic stable system, and its possibility producing big emulsion droplet after redissolving is low,
It is better than Alprostadil dried emulsifier.But, the defect of existing Alprostadil freeze-dried micro emulsion composition is:
Envelop rate is low；Free Alprostadil has excitant to blood vessel, is unfavorable for safe medication；It is in system
During Bei, temperature is higher, affects the stability of product.Therefore, this area remains a need for novel
Safer, stable Alprostadil freeze-dried micro emulsion composition.
Summary of the invention
For the problems referred to above, the present invention provides a kind of safer, more stable Alprostadil freeze-dried micro emulsion
Composition, to solve it to vascular stimulation, problem that degradation impurity content is high.
As follows for realizing the technical scheme of above-mentioned purpose:
The present invention provides a kind of Alprostadil freeze-dried micro emulsion composition, described composition comprise Alprostadil,
Nonionic emulsifier, oil phase, anionic phospholipid, freeze drying protectant；
Wherein, by mass percentage, each raw material of described composition with the amount of composition is: Alprostadil
0.001-0.04%, nonionic emulsifier 1-55%, anionic phospholipid 0.1-20%, oil phase
0.6-28%, freeze drying protectant 5-98%.
By mass percentage, each raw material of described composition with the amount of composition is: Alprostadil
0.002-0.02%, nonionic emulsifier 5-40%, anionic phospholipid 0.5-10%, oil phase 5-25%,
Freeze drying protectant 5-85%；
Preferably, by mass percentage, each raw material of described composition with the amount of composition is: Alprostadil
0.002-0.02%, nonionic emulsifier 10-30%, anionic phospholipid 0.5-5%, oil phase 10-25%,
Freeze drying protectant 30-70%；
Preferably, during described composition also comprises phosphatid ylcholine, phosphatidyl-ethanolamine or pH adjusting agent
One or more；Preferably, by mass percentage, described phosphatid ylcholine 0-16%, phosphatide
Acyl monoethanolamine 0-16%, pH adjusting agent 0-1%.
Described nonionic emulsifier selected from polysorbate, Emulsifier EL-60, PEG-8-
Caprylic/capric glyceride, poloxamer or Solutol HS15 (Macrogol 15
Hydroxystearate) one or more in；
Preferably, described nonionic emulsifier be polyoxyethylene sorbitan monoleate and/or polyethylene glycol 15-hydroxyl hard
Resin acid ester；More preferably Solutol HS15.
Described anionic phospholipid is selected from phosphatidyl glycerol, phosphatidylserine, phosphatidylinositols, phosphorus
Resin acid, DOPS, DOPG, 1-palmityl-2-oleoyl-phosphatidyl
Glycerine, DPPG, DSPG, two myristoyl phosphatidyls are sweet
One or more in oil or DPPA；
Preferably, described anionic phospholipid is selected from phosphatidyl glycerol, phosphatidylserine, phosphatidyl
One or more in inositol or phosphatidic acid；More preferably phosphatidyl glycerol.
Described oil phase is selected from medium chain triglyceride, glyceryl linoleate, glycerol caprylate, capric acid glycerine
One or more in ester, ethyl oleate or isopropyl myristate；
Preferably, described oil phase is in medium chain triglyceride, glycerol caprylate or glycerol decanoate
One or more；More preferably medium chain triglyceride.
Described freeze drying protectant selected from mannitol, lactose, sorbierite, trehalose, sucrose, glucose,
One or more in fructose or maltose；
Preferably, described freeze drying protectant one in mannitol, lactose, sucrose or glucose
Or it is multiple；More preferably glucose.
Preferably, described pH adjusting agent selected from hydrochloric acid, NaOH, potassium hydroxide, acetic acid or its
One or more in salt, phosphoric acid or its salt, citric acid or its salt.
Preferably, described composition is before use through glucose injection, water for injection or physiological saline
Parenteral solution redissolves；After redissolution, pH is 3.0-7.0, preferably 4.5-7.0, further preferred 5.0-6.5.
The present invention also provides for a kind of preparation method according to above-mentioned Alprostadil freeze-dried micro emulsion composition, institute
State preparation method to comprise the steps:
(1) by nonionic emulsifier, anionic phospholipid, oil phase and optional phosphatid ylcholine
With optional phosphatidyl-ethanolamine mixing, stirring, to dissolving, is lowered the temperature, and adds Alprostadil, and stirring is extremely
Dissolve, obtain mixing oil phase；
(2) being added to the water by freeze drying protectant, stirring, to dissolving, obtains aqueous phase；
(3) the aqueous phase mixing that mixing oil phase step (1) obtained and step (2) obtain, appoints
Selection of land adds pH adjusting agent to pH 3.0-7.0；
Preferably, described preparation method is further comprising the steps of:
(4) adding water in the mixture that step (3) obtains, homogeneous processes, and filters, freezing dry
Dry.
Preferably, described preparation method comprises the steps:
(1) by nonionic emulsifier, anionic phospholipid, oil phase and optional phosphatid ylcholine
With optional phosphatidyl-ethanolamine mixing, at 20-80 DEG C, stirring is to dissolving, and is cooled to 2-29 DEG C,
Preferably 20-29 DEG C；Adding Alprostadil, stirring, to dissolving, obtains mixing oil phase；
(2) freeze drying protectant is added to the water, stirring to dissolving, temperature control 2-29 DEG C, preferably 20-29 DEG C,
Obtain aqueous phase；；
(3) the aqueous phase mixing that mixing oil phase step (1) obtained and step (2) obtain, control
Temperature 2-29 DEG C, preferably 20-29 DEG C；Add pH adjusting agent to pH 3.0-7.0；
(4) in the mixture that step (3) obtains, add water to prescription full dose, under 50-1000bar all
Matter processes, the most homogeneous process 1-10 time, preferably 2 times, and temperature control 2-29 DEG C, preferably 2-10 DEG C；
Aseptic filtration, freeze-drying.
The present invention also provides for a kind of Alprostadil freeze-dried micro emulsion composition of the present invention and institute of the present invention
State Alprostadil freeze-dried micro emulsion composition that Alprostadil freeze-dried micro emulsion composition preparation method obtains in system
The four limbs that the treatment four limbs ulcer that causes of CAO disease, the tiny blood vessels dyshaemia of getting everything ready causes
Endovascular thrombosis, Ductal dependence after tranquillization pain, cardiovascular and cerebrovascular microcirculation disorder, transplanting
Purposes in property congenital heart disease, the food of chronic hepatitis effect, medicine or health products；
Preferably, CAO disease includes Buerger's disease or Arteriosclerosis obliterans.
Alprostadil freeze-dried micro emulsion composition of the present invention, its envelop rate and stability are significantly carried
Height, advantageously reduces free drug concentration, reduces the blood vessel irritation of preparation, investigates at 25 DEG C
18 months, related substance is had to be less than prior art；There is higher Zeta potential simultaneously, be conducive to system
Stablizing of agent；Additionally, said composition can be prepared below 30 DEG C, effectively prevent drug degradation, profit
In quality control.
In the preparation method of Alprostadil freeze-dried micro emulsion composition of the present invention, Alprostadil will be added
After preparation temperature control below 30 DEG C, it is to avoid Alprostadil is degraded in preparation process.
Detailed description of the invention
Referring to specific embodiment, the present invention is described.It will be appreciated by those skilled in the art that these
Embodiment is merely to illustrate the present invention, and it limits the scope of the present invention never in any form.
Experimental technique in following embodiment, if no special instructions, is conventional method.Following embodiment
In used raw material, reagent material etc., if no special instructions, be commercially available purchase product.
Various bulk drugs in Chinese medicine composition of the present invention all can be bought from market, " Chinese Pharmacopoeia "
The product quality of the kind recorded meets the regulation of " Chinese Pharmacopoeia ".
Embodiment 1: the preparation of composition of the present invention
Weigh 26g Solutol HS15,2g phosphatidyl glycerol, 25g medium chain triglyceride
Three esters, 4g phosphatid ylcholine, after being stirred to dissolve at about 60 DEG C and mix, temperature reduces
To about 25 DEG C, add 5mg Alprostadil, be stirred to dissolve and mix, obtain miscella
Phase；Weigh 75g glucose, add in 600ml water, be stirred to dissolve, temperature control about 25 DEG C,
To aqueous phase；Under agitation, aqueous phase is mixed with mixing oil phase, temperature control about 25 DEG C；Use 0.5M salt
Acid and 0.5M NaOH regulate pH to 5.2, mend and add water to full dose (1L)；By high-pressure homogeneous
Machine is homogeneous 3 times under the pressure of 400bar, temperature control about 8 DEG C；Through aseptic filtration, filling in XiLin
In Ping, freeze-drying, gland, packaging, to obtain final product.
Embodiment 2: the preparation of composition of the present invention
Weigh 20g polyoxyethylene sorbitan monoleate, 3g phosphatidylserine, 20g medium chain triglyceride, 5g phosphorus
Phosphatidylcholine, is stirred to dissolve at about 50 DEG C and mixes, and temperature is reduced to about 29 DEG C,
Add Alprostadil 5mg, be stirred to dissolve and mix, obtain mixing oil phase；Weigh 75g sugarcane
Sugar, adds in 800ml water, is stirred to dissolve, temperature control about 29 DEG C, obtains aqueous phase；Under agitation,
Aqueous phase is mixed with mixing oil phase, temperature control about 29 DEG C；With 0.5M hydrochloric acid and 0.5M NaOH
Regulation pH to 4.0, mends and adds water to full dose (1L)；By high pressure homogenizer at the pressure of 400bar
Lower homogeneous 2 times, temperature control about 10 DEG C；Through aseptic filtration, filling in cillin bottle, freeze-drying,
Gland, packaging, to obtain final product.
Embodiment 3: the preparation of composition of the present invention
Weigh 15g Solutol HS15,1g phosphatidylinositols, 10g medium chain triglyceride
Three esters, 5g phosphatid ylcholine, be stirred to dissolve at about 65 DEG C and mix, and temperature is reduced to
About 22 DEG C, add 5mg Alprostadil, be stirred to dissolve and mix, obtain mixing oil phase；
Weigh 50g mannitol, add in 500ml water, be stirred to dissolve, temperature control about 22 DEG C, obtain water
Phase；Under agitation, aqueous phase is mixed with mixing oil phase, temperature control about 20 DEG C；With 0.5M hydrochloric acid and
0.5M NaOH regulation pH to 5.0, mends and adds water to full dose (1L)；Existed by high pressure homogenizer
Homogeneous 6 times under the pressure of 100bar, temperature control about 8 DEG C；It is through aseptic filtration, filling in cillin bottle,
Freeze-drying, gland, packaging, to obtain final product.
Embodiment 4: the preparation of composition of the present invention
Weigh 10g Solutol HS15,2g phosphatidic acid, 8g medium chain triglyceride,
3g phosphatidyl-ethanolamine, is stirred to dissolve at about 55 DEG C and mixes, and temperature is reduced to 25 DEG C
Left and right, adds 5mg Alprostadil, is stirred to dissolve and mixes, and obtains mixing oil phase；Weigh
100g glucose, adds in 900ml water, is stirred to dissolve, temperature control about 25 DEG C, obtains aqueous phase；
Under agitation, aqueous phase is mixed with mixing oil phase, temperature control about 25 DEG C；With 0.5M hydrochloric acid and 0.5M
NaOH regulation pH to 3.5, mends and adds water to full dose (1L)；By high pressure homogenizer at 500bar
Pressure under homogeneous 2 times, temperature control about 15 DEG C；Through aseptic filtration, filling in cillin bottle, freezing
It is dried, gland, packaging, to obtain final product.
Embodiment 5: the preparation of composition of the present invention
Weigh 2g Solutol HS15,0.1g phosphatidyl glycerol, 1g medium chain triglyceride three
Ester, 0.5g phosphatid ylcholine, be stirred to dissolve at about 70 DEG C and mix, and temperature is reduced to
About 29 DEG C, add 10mg Alprostadil, be stirred to dissolve and mix, obtain mixing oil phase；
Weigh 20g mannitol, add in 800ml water, be stirred to dissolve, temperature control about 29 DEG C, obtain water
Phase；Under agitation, aqueous phase is mixed with mixing oil phase, temperature control about 29 DEG C；With 0.5M hydrochloric acid and
0.5M potassium hydroxide regulation pH to 7.0, mends and adds water to full dose (1L)；Existed by high pressure homogenizer
Homogeneous 1 time under the pressure of 1000bar, temperature control about 29 DEG C；Through aseptic filtration, filling in cillin bottle
In, freeze-drying, gland, packaging, to obtain final product.
Embodiment 6: the preparation of composition of the present invention
Weigh 2g Solutol HS15,0.5g phosphatidyl glycerol, 1g medium chain triglyceride three
Ester, 0.5g phosphatid ylcholine, be stirred to dissolve at about 50 DEG C and mix, and temperature is reduced to 2 DEG C
Left and right, adds 1.5mg Alprostadil, is stirred to dissolve and mixes, and obtains mixing oil phase；Claim
Take 150g glucose, 1.5g citric acid, add in 800ml water, be stirred to dissolve, 2 DEG C of left sides of temperature control
The right side, obtains aqueous phase；Under agitation, aqueous phase is mixed with mixing oil phase, temperature control about 2 DEG C；Use 0.5M
Hydrochloric acid and 0.5M potassium hydroxide regulation pH to 6.5, mend and add water to full dose (1L)；Equal by high pressure
Matter machine is homogeneous 1 time under the pressure of 700bar, temperature control about 2 DEG C；Through aseptic filtration, filling in west
In woods bottle, freeze-drying, gland, packaging, to obtain final product.
Embodiment 7: the preparation of composition of the present invention
Weigh 50g Solutol HS15,30g phosphatidyl glycerol, 10g medium chain triglyceride
Three esters, are stirred to dissolve at about 60 DEG C and mix, and temperature is reduced to about 25 DEG C, add prostatitis
Ground that 7mg, is stirred to dissolve and mixes, and obtains mixing oil phase；Weigh 50g glucose, add
Enter in 800ml water, be stirred to dissolve, temperature control about 22 DEG C, obtain aqueous phase；Under agitation, by water
Mix with mixing oil phase, temperature control about 22 DEG C；Regulate with 0.5M hydrochloric acid and 0.5M NaOH
PH to 6.8, mends and adds water to full dose (1L)；By high pressure homogenizer homogeneous under the pressure of 900bar
1 time, temperature control about 12 DEG C；Through aseptic filtration, filling in cillin bottle, freeze-drying, gland,
Packaging, to obtain final product.
Embodiment 8: the preparation of composition of the present invention
Weigh 50g Solutol HS15,0.2g phosphatidyl glycerol, 50g medium chain triglyceride
Three esters, 30g phosphatid ylcholine, be stirred to dissolve at about 80 DEG C and mix, and temperature is reduced to
About 15 DEG C, add 3mg Alprostadil, be stirred to dissolve and mix, obtain mixing oil phase；
Weigh 50g glucose, add in 700ml water, be stirred to dissolve, temperature control about 15 DEG C, obtain water
Phase；Under agitation, aqueous phase is mixed with mixing oil phase, temperature control about 15 DEG C；Measuring pH is 6.9,
Benefit adds water to full dose (1L)；By high pressure homogenizer homogeneous 4 times under the pressure of 300bar, control
Temperature about 25 DEG C；Through aseptic filtration, filling in cillin bottle, freeze-drying, gland, packaging, i.e.
?.
Embodiment 9: the preparation of composition of the present invention
Weigh 50g Solutol HS15,0.5g phosphatidyl glycerol, 10g medium chain triglyceride
Three esters, are stirred to dissolve at about 40 DEG C and mix, and temperature is reduced to about 25 DEG C, add
5mg Alprostadil, is stirred to dissolve and mixes, and obtains mixing oil phase；Weigh 30g glucose,
Add in 700ml water, be stirred to dissolve, temperature control about 15 DEG C, obtain aqueous phase；Under agitation, will
Aqueous phase mixes with mixing oil phase, temperature control about 15 DEG C；With 0.5M vinegar acid for adjusting pH to 3.5, add
Water is to full dose (1L)；By high pressure homogenizer homogeneous 10 times under the pressure of 50bar, temperature control 20 DEG C
Left and right；Through aseptic filtration, filling in cillin bottle, freeze-drying, gland, packaging, to obtain final product.
Embodiment 10: the preparation of composition of the present invention
Weigh 20g Solutol HS15,5g phosphatidyl glycerol, 5g medium chain triglyceride three
Ester, is stirred to dissolve at about 60 DEG C and mixes, and temperature is reduced to about 25 DEG C, adds 5mg
Alprostadil, is stirred to dissolve and mixes, and obtains mixing oil phase；Weigh 70g glucose, add
Enter in 700ml water, be stirred to dissolve, temperature control about 25 DEG C, obtain aqueous phase；Under agitation, by water
Mix with mixing oil phase, temperature control about 25 DEG C；PH to 5.5 is regulated in right amount with 0.5M citric acid,
Benefit adds water to full dose (1L)；By high pressure homogenizer homogeneous 2 times under the pressure of 500bar, control
Temperature about 8 DEG C；Through aseptic filtration, filling in cillin bottle, freeze-drying, gland, packaging, i.e.
?.
Embodiment 11: the preparation of composition of the present invention
Weigh 30g Solutol HS15,10g phosphatidyl glycerol, 10g medium chain triglyceride
Three esters, are stirred to dissolve at about 60 DEG C and mix, and temperature is reduced to about 22 DEG C, add
5mg Alprostadil, is stirred to dissolve and mixes, and obtains mixing oil phase；Weigh 75g glucose,
Add in 700ml water, be stirred to dissolve, temperature control about 22 DEG C, obtain aqueous phase；Under agitation, will
Aqueous phase mixes with mixing oil phase, temperature control about 22 DEG C；With 0.5M citron acid for adjusting pH to 6.5, mend
Add water to full dose (1L)；By high pressure homogenizer homogeneous 2 times under the pressure of 400bar, temperature control 5 DEG C
Left and right；Through aseptic filtration, filling in cillin bottle, freeze-drying, gland, packaging, to obtain final product.
Embodiment 12: the preparation of composition of the present invention
Weigh 10g Solutol HS15,1g phosphatidyl glycerol, 4g medium chain triglyceride three
Ester, is stirred to dissolve at about 60 DEG C and mixes, and temperature is reduced to about 27 DEG C, adds 5mg
Alprostadil, is stirred to dissolve and mixes, and obtains mixing oil phase；Weigh 75g glucose, add
Enter in 700ml water, be stirred to dissolve, temperature control about 27 DEG C, obtain aqueous phase；Under agitation, by water
Mix with mixing oil phase, temperature control about 27 DEG C；Regulate with 0.5M hydrochloric acid and 0.5M NaOH
PH to 5.0, mends and adds water to full dose (1L)；By high pressure homogenizer homogeneous under the pressure of 400bar
2 times, temperature control about 9 DEG C；Through aseptic filtration, filling in cillin bottle, freeze-drying, gland,
Packaging, to obtain final product.
Embodiment 13: the preparation of composition of the present invention
Weigh 25g Solutol HS15,1g DOPS, 10g
Medium chain triglyceride, 5g phosphatid ylcholine, be stirred to dissolve at about 60 DEG C and mix, temperature
Degree is reduced to about 20 DEG C, adds 5mg Alprostadil, is stirred to dissolve and mixes, obtain
Mixing oil phase；Weigh 75g glucose, add in 700ml water, be stirred to dissolve, 20 DEG C of left sides of temperature control
The right side, obtains aqueous phase；Under agitation, aqueous phase is mixed with mixing oil phase, temperature control about 20 DEG C；With
0.5M hydrochloric acid and 0.5M NaOH regulation pH to 5.0, mend and add water to full dose (1L)；By height
Pressure homogenizer homogeneous 2 times under the pressure of 400bar, temperature control about 9 DEG C；Through aseptic filtration, filling
In cillin bottle, freeze-drying, gland, packaging, to obtain final product.
Embodiment 14: the preparation of composition of the present invention
Weigh in 25g Solutol HS15,1g DOPG, 10g
Chain triglyceride, 5g phosphatid ylcholine, be stirred to dissolve at about 60 DEG C and mix, temperature
It is reduced to about 28 DEG C, adds 5mg Alprostadil, be stirred to dissolve and mix, mixed
Close oil phase；Weigh 75g glucose, add in 700ml water, be stirred to dissolve, temperature control about 28 DEG C,
Obtain aqueous phase；Under agitation, aqueous phase is mixed with mixing oil phase, temperature control about 28 DEG C；Use 0.5M
Hydrochloric acid and 0.5M NaOH regulation pH to 5.0, mend and add water to full dose (1L)；Equal by high pressure
Matter machine is homogeneous 2 times under the pressure of 400bar, temperature control about 7 DEG C；Through aseptic filtration, filling in west
In woods bottle, freeze-drying, gland, packaging, to obtain final product.
Embodiment 15: the preparation of composition of the present invention
Weigh 25g Solutol HS15,1g 1-palmityl-2-oleoyl-phosphatidyl glycerol,
5g isopropyl myristate, 5g phosphatid ylcholine, be stirred to dissolve at about 60 DEG C and mix,
Temperature is reduced to about 24 DEG C, adds 5mg Alprostadil, is stirred to dissolve and mixes,
To mixing oil phase；Weigh 75g maltose, add in 700ml water, be stirred to dissolve, temperature control 24 DEG C
Left and right, obtains aqueous phase；Under agitation, aqueous phase is mixed with mixing oil phase, temperature control about 24 DEG C；With
0.5M hydrochloric acid and 0.5M NaOH regulation pH to 5.0, mend and add water to full dose (1L)；By height
Pressure homogenizer homogeneous 2 times under the pressure of 400bar, temperature control about 8 DEG C；Through aseptic filtration, filling
In cillin bottle, freeze-drying, gland, packaging, to obtain final product.
Embodiment 16: the preparation of composition of the present invention
Weigh 25g Solutol HS15,1g DPPG, 5g oil
Acetoacetic ester, 5g phosphatid ylcholine, be stirred to dissolve at about 60 DEG C and mix, and temperature reduces
To about 23 DEG C, add 5mg Alprostadil, be stirred to dissolve and mix, obtain miscella
Phase；Weigh 75g fructose, add in 700ml water, be stirred to dissolve, temperature control about 23 DEG C, obtain
Aqueous phase；Under agitation, aqueous phase is mixed with mixing oil phase, temperature control about 23 DEG C；Use 0.5M hydrochloric acid
Regulate pH to 5.0 with 0.5M NaOH, mend and add water to full dose (1L)；Pass through high pressure homogenizer
Homogeneous 2 times under the pressure of 400bar, temperature control about 4 DEG C；Through aseptic filtration, filling in cillin bottle
In, freeze-drying, gland, packaging, to obtain final product.
Embodiment 17: the preparation of composition of the present invention
Weigh 25g poloxamer, 1g DSPG, 5g glycerol decanoate, 5g phosphorus
Phosphatidylcholine, is stirred to dissolve at about 60 DEG C and mixes, and temperature is reduced to about 18 DEG C,
Add Alprostadil 5mg, be stirred to dissolve and mix, obtain mixing oil phase；Weigh 75g mountain
Pears alcohol, adds in 700ml water, is stirred to dissolve, temperature control about 18 DEG C, obtains aqueous phase；In stirring
Under, aqueous phase is mixed with mixing oil phase, temperature control about 18 DEG C；With 0.5M hydrochloric acid and 0.5M hydrogen-oxygen
Change sodium regulation pH to 5.0, mend and add water to full dose (1L)；By high pressure homogenizer 400bar's
Homogeneous 2 times under pressure, temperature control about 12 DEG C；Through aseptic filtration, filling in cillin bottle, freezing dry
Dry, gland, packaging, to obtain final product.
Embodiment 18: the preparation of composition of the present invention
Weigh 25g PEG-8-caprylic/capric glyceride, 1g GLYCEROL,DIMYRISTOYL PHOSPHATIDYL,
5g glycerol caprylate, 5g phosphatid ylcholine, be stirred to dissolve at about 60 DEG C and mix, temperature
Degree is reduced to about 25 DEG C, adds 5mg Alprostadil, is stirred to dissolve and mixes, obtain
Mixing oil phase；Weigh 75g trehalose, add in 700ml water, be stirred to dissolve, 25 DEG C of left sides of temperature control
The right side, obtains aqueous phase；Under agitation, aqueous phase is mixed with mixing oil phase, temperature control about 25 DEG C；With
0.5M hydrochloric acid and 0.5M NaOH regulation pH to 5.0, mend and add water to full dose (1L)；By height
Pressure homogenizer homogeneous 2 times under the pressure of 400bar, temperature control about 15 DEG C；Through aseptic filtration, fill
It is loaded in cillin bottle, freeze-drying, gland, packaging, to obtain final product.
Embodiment 19: the preparation of composition of the present invention
Weigh 25g Emulsifier EL-60,1g DPPA, 5g glyceryl linoleate,
5g phosphatid ylcholine, is stirred to dissolve at about 60 DEG C and mixes, and temperature is reduced to 26 DEG C of left sides
The right side, adds 5mg Alprostadil, is stirred to dissolve and mixes, and obtains mixing oil phase；Weigh breast
Sugar 75g, adds in 700ml water, is stirred to dissolve, temperature control about 26 DEG C, obtains aqueous phase；Stirring
Mix down, aqueous phase is mixed with mixing oil phase, temperature control about 26 DEG C；With 0.5M hydrochloric acid and 0.5M hydrogen
Sodium oxide molybdena regulation pH to 5.0, mends and adds water to full dose (1L)；By high pressure homogenizer at 400bar
Pressure under homogeneous 2 times, temperature control about 6 DEG C；Through aseptic filtration, filling in cillin bottle, freezing
It is dried, gland, packaging, to obtain final product.
Comparative example 1
Weigh 0.9g Solutol HS 15,0.3g lecithin E80,1.5g median chain triglyceride oil, mix
Closing uniformly, heating stirs, and adds 0.5mg Alprostadil, and stirring is to dissolving, as miscella
Phase；Weigh 5g mannitol, be dissolved in 80ml water for injection, as aqueous phase；Under agitation by aqueous phase
It is slowly added to mix in oil phase, adds 0.1mol/L hydrochloric acid about 2mL, regulate pH to 5, supplement
Water for injection is to 100mL, through 0.22 μm membrane filtration, props up packing according to 1mL/, freeze-drying,
Gland, packaging, to obtain final product.
Comparative example 2
By 6g midchain oil, 5mg Alprostadil, 3g lecithin, 9g glycerine, 1.5g oleic acid and 12g
Solutol HS 15 mixes, and heating makes it all dissolve, as mixing oil phase；By 100g lactose,
50g trehalose is added to the water, and stirring is to dissolving, as aqueous phase；At 30-50 DEG C, while stirring will
Aqueous phase is slowly added to mix in oil phase, becomes micro emulsion, is then stirred for 0.5h, forms the micro-of stable uniform
Breast；Hydro-oxidation sodium regulation pH to 6-7, is settled to 1000mL, then by gained micro emulsion by 0.22 μm
Membrane filtration, freeze-drying, add a cover aluminium lid, obtain (every μ g Han Alprostadil 5), above mistake
Cheng Jun is carried out under the conditions of nitrogen charging.
Embodiment 20: stability test
(1) pH, average grain diameter and potential measurement
Take the sample of each previous embodiment 1-19 and comparative example 1-2, redissolve also with 5% glucose solution
Dilute 10 times, measure pH, with Malvern Nano-ZS90 particle size analyzer determination average grain diameter and Zeta
Current potential, result such as table 1 below:
Table 1: average grain diameter and potential measurement result
| Sample | pH | Average grain diameter (nm) | Zeta potential (mv) |
| Embodiment 1 | 5.2 | 45 | -7.8 |
| Embodiment 2 | 4.0 | 40 | -7.9 |
| Embodiment 3 | 5.1 | 51 | -7.1 |
| Embodiment 4 | 3.5 | 60 | -7.4 |
| Embodiment 5 | 7.0 | 46 | -4.7 |
| Embodiment 6 | 6.5 | 88 | -8.4 |
| Embodiment 7 | 6.8 | 91 | -9.2 |
| Embodiment 8 | 6.9 | 61 | -5.7 |
| Embodiment 9 | 3.5 | 46 | -7.3 |
| Embodiment 10 | 5.5 | 51 | -6.8 |
| Embodiment 11 | 6.5 | 42 | -8.2 |
| Embodiment 12 | 5.1 | 67 | -7.6 |
| Embodiment 13 | 5.0 | 71 | -7.8 |
| Embodiment 14 | 5.0 | 66 | -7.1 |
| Embodiment 15 | 5.0 | 81 | -6.8 |
| Embodiment 16 | 5.0 | 54 | -6.9 |
| Embodiment 17 | 5.0 | 89 | -6.7 |
| Embodiment 18 | 5.0 | 88 | -7.5 |
| Embodiment 19 | 3.0 | 91 | -7.5 |
| Comparative example 1 | 5.1 | 57 | -1.8 |
| Comparative example 2 | 6.6 | 55 | -2.0 |
Result shows, composition of the present invention is after redissolving and diluting, and pH change is little, average particle
Footpath is less than 100nm, and its Zeta potential absolute value is significantly higher than comparative example 1 and 2, illustrates between its emulsion droplet
Repulsive force bigger, be conducive to it stable.
(2) relevant substance-measuring
Take the sample of each previous embodiment 1-19 and comparative example 1-2, be placed in 25 DEG C, relative humidity 60%
Under the conditions of, carry out stability test, after standing 0 and 18 month, sampling and measuring has related substance.
Assay method is as follows:
Flowing phase: 0.0067mol/l phosphate buffer-ACN (3: 1)
Flow velocity: 1ml/min
Detection wavelength: 278nm
Column temperature: 25 DEG C
Sample cell temperature: 5 DEG C
Sampling volume: 50 μ l
Post-column derivation instrument past column reaction liquid: 1mol/l KOH；Flow velocity: 0.5ml/min；Column temperature: 60 DEG C.
Sample pure water shakes up after redissolving, and precision pipettes in right amount, is placed in 10ml measuring bottle, with 80%
Methanol solution constant volume, shakes up, and obtains need testing solution, and precision measures need testing solution 50 μ l and injects liquid
Chromatography, records chromatogram, and calculating by areas of peak normalization method total has related substance amount, is shown in Table 2.
Table 2: relevant content of material
Result shows, composition of the present invention is in preparation process, after adding Alprostadil, controls
Temperature below 30 DEG C then Alprostadil seldom degrade, have related substance to be substantially less than comparative example 1 and 2.
After study on the stability 18 months, the relevant content of material of composition of the present invention is substantially less than contrast
Example 1 and 2.It is not limited by theory, thus it is speculated that the reason lower about content of material is, institute of the present invention
Stating more Alprostadil in composition to be wrapped in emulsion droplet, therefore stability is higher.
Embodiment 21: entrapment efficiency determination
Take the sample of each previous embodiment 1-19 and comparative example 1-2, shake up after redissolving with pure water, accurate
Pipetting 2.0ml, be placed in 15ml ultra-filtration centrifuge tube, 4000rpm/min is centrifuged 20min, takes off layer
Liquid, according to the condition direct injected of embodiment 20 (two), measures free drug concentration；According to embodiment
The test sample preparation method of 20, prepares test sample；Precision weighs Alprostadil in right amount simultaneously, with anhydrous
Ethanol dissolves and is diluted to the concentration suitable with test sample as reference substance solution, according to embodiment 20
(2) method sample introduction, measures the content that after redissolving, medicine is total, computational envelope rate, the results are shown in Table 3.
Table 3: entrapment efficiency determination result
Result shows, the envelop rate of composition of the present invention is significantly higher than comparative example 1 and 2.It is not subject to
Theory is limited, thus it is speculated that rich in anionic phospholipid in the emulsion droplet of composition of the present invention, and anion phosphorus
Fat is higher to Alprostadil affinity.Therefore, composition of the present invention has significantly higher encapsulating
Rate, advantageously reduces free drug concentration, decreases the blood vessel irritation of preparation.
Specific description of embodiments of the present invention above is not limiting as the present invention, and those skilled in the art can
To be variously modified according to the present invention or to deform, without departing from the spirit of the present invention, all should be belonged to this
Invention scope of the following claims.
Claims (11)
1. an Alprostadil freeze-dried micro emulsion composition, described composition comprises Alprostadil, nonionic
Type emulsifying agent, oil phase, anionic phospholipid, freeze drying protectant；
Wherein, by mass percentage, each raw material of described composition with the amount of composition is: Alprostadil
0.001-0.04%, nonionic emulsifier 1-55%, anionic phospholipid 0.1-20%, oil phase
0.6-28%, freeze drying protectant 5-98%.
Composition the most according to claim 1, it is characterised in that by mass percentage, institute
The amount stating each raw material of composition and composition is: Alprostadil 0.002-0.02%, nonionic emulsifier
5-40%, anionic phospholipid 0.5-10%, oil phase 5-25%, freeze drying protectant 5-85%；
Preferably, by mass percentage, each raw material of described composition with the amount of composition is: Alprostadil
0.002-0.02%, nonionic emulsifier 10-30%, anionic phospholipid 0.5-5%, oil phase 10-25%,
Freeze drying protectant 30-70%；
Preferably, during described composition also comprises phosphatid ylcholine, phosphatidyl-ethanolamine or pH adjusting agent
One or more；Preferably, by mass percentage, described phosphatid ylcholine 0-16%, phosphatide
Acyl monoethanolamine 0-16%, pH adjusting agent 0-1%.
Composition the most according to claim 1 and 2, it is characterised in that described nonionic breast
Agent is selected from polysorbate, Emulsifier EL-60, PEG-8-caprylic/capric glyceride, pool
In Luo Shamu or Solutol HS15 (Macrogol 15 Hydroxystearate)
One or more；
Preferably, described nonionic emulsifier be polyoxyethylene sorbitan monoleate and/or polyethylene glycol 15-hydroxyl hard
Resin acid ester；More preferably Solutol HS15.
Composition the most according to any one of claim 1 to 3, it is characterised in that described the moon
Ionic phosphatide is selected from phosphatidyl glycerol, phosphatidylserine, phosphatidylinositols, phosphatidic acid, two oil
Acyl phosphatidylserine, DOPG, 1-palmityl-2-oleoyl-phosphatidyl glycerol, two palm fibres
Palmitic acid acyl phosphatidyl glycerol, DSPG, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL or two palms
One or more in acyl phosphatidic acid；
Preferably, described anionic phospholipid is selected from phosphatidyl glycerol, phosphatidylserine, phosphatidyl
One or more in inositol or phosphatidic acid；More preferably phosphatidyl glycerol.
Composition the most according to any one of claim 1 to 4, it is characterised in that described oil
Mutually selected from medium chain triglyceride, glyceryl linoleate, glycerol caprylate, glycerol decanoate, oleic acid second
One or more in ester or isopropyl myristate；
Preferably, described oil phase is in medium chain triglyceride, glycerol caprylate or glycerol decanoate
One or more；More preferably medium chain triglyceride.
Composition the most according to any one of claim 1 to 5, it is characterised in that described in freeze
Dry protective agent is selected from mannitol, lactose, sorbierite, trehalose, sucrose, glucose, fructose or wheat
One or more in bud sugar；
Preferably, described freeze drying protectant one in mannitol, lactose, sucrose or glucose
Or it is multiple；More preferably glucose.
7. according to the composition according to any one of claim 2 to 6, it is characterised in that described pH
Conditioning agent is selected from hydrochloric acid, NaOH, potassium hydroxide, acetic acid or its salt, phosphoric acid or its salt, citron
One or more in acid or its salt.
Composition the most according to any one of claim 1 to 7, it is characterised in that described group
Compound redissolves through glucose injection, water for injection or normal saline solution before use；Multiple
Molten rear pH is 3.0-7.0, preferably 4.5-7.0, further preferred 5.0-6.5.
9. a preparation method for composition according to any one of claim 1 to 8, described
Preparation method comprises the steps:
(1) by nonionic emulsifier, anionic phospholipid, oil phase and optional phosphatid ylcholine
With optional phosphatidyl-ethanolamine mixing, stirring, to dissolving, is lowered the temperature, and adds Alprostadil, and stirring is extremely
Dissolve, obtain mixing oil phase；
(2) being added to the water by freeze drying protectant, stirring, to dissolving, obtains aqueous phase；
(3) the aqueous phase mixing that mixing oil phase step (1) obtained and step (2) obtain, appoints
Selection of land adds pH adjusting agent to pH 3.0-7.0；
Preferably, described preparation method is further comprising the steps of:
(4) adding water in the mixture that step (3) obtains, homogeneous processes, and filters, freezing dry
Dry.
The preparation method of composition the most according to claim 9, described preparation method includes as follows
Step:
(1) by nonionic emulsifier, anionic phospholipid, oil phase and optional phosphatid ylcholine
With optional phosphatidyl-ethanolamine mixing, at 20-80 DEG C, stirring is to dissolving, and is cooled to 2-29 DEG C,
Preferably 20-29 DEG C；Rear addition Alprostadil, stirring, to dissolving, obtains mixing oil phase；
(2) freeze drying protectant is added to the water, stirring to dissolving, temperature control 2-29 DEG C, preferably 20-29 DEG C,
Obtain aqueous phase；
(3) the aqueous phase mixing that mixing oil phase step (1) obtained and step (2) obtain, control
Temperature 2-29 DEG C, preferably 20-29 DEG C；Add pH adjusting agent to pH3.0-7.0；
(4) in the mixture that step (3) obtains, add water to prescription full dose, under 50-1000bar all
Matter processes, the most homogeneous process 1-10 time, preferably 2 times, and temperature control 2-29 DEG C, preferably 2-10 DEG C；
Aseptic filtration, freeze-drying.
Described in composition according to any one of 11. claims 1 to 8 and claim 9 or 10
The composition that preparation method obtains has, in preparation, the four limbs ulcer, micro-that treatment CAO disease causes
Four limbs tranquillization pain that thin vessels dyshaemia causes, cardiovascular and cerebrovascular microcirculation disorder, transplant after Ink vessel transfusing
Thrombosis, Ductal dependence congenital heart disease, the food of chronic hepatitis effect, medicine or
Purposes in health products；
Preferably, CAO disease includes Buerger's disease or Arteriosclerosis obliterans.
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