CN107375954A - It is injected intravenously lipid microbubble and preparation method thereof - Google Patents
It is injected intravenously lipid microbubble and preparation method thereof Download PDFInfo
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- CN107375954A CN107375954A CN201710743241.9A CN201710743241A CN107375954A CN 107375954 A CN107375954 A CN 107375954A CN 201710743241 A CN201710743241 A CN 201710743241A CN 107375954 A CN107375954 A CN 107375954A
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- lipid microbubble
- intravenous injection
- injection lipid
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- 150000002632 lipids Chemical class 0.000 title claims abstract description 59
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 239000000243 solution Substances 0.000 claims abstract description 44
- 238000010253 intravenous injection Methods 0.000 claims abstract description 28
- 239000011159 matrix material Substances 0.000 claims abstract description 10
- 239000007864 aqueous solution Substances 0.000 claims abstract description 9
- 238000002604 ultrasonography Methods 0.000 claims abstract description 9
- 239000003002 pH adjusting agent Substances 0.000 claims abstract description 7
- 230000007246 mechanism Effects 0.000 claims abstract description 5
- 239000007789 gas Substances 0.000 claims description 19
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 8
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 7
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical class CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 6
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 claims description 5
- KILNVBDSWZSGLL-KXQOOQHDSA-N 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCC KILNVBDSWZSGLL-KXQOOQHDSA-N 0.000 claims description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 239000008103 glucose Substances 0.000 claims description 4
- 235000011187 glycerol Nutrition 0.000 claims description 4
- 229920002674 hyaluronan Polymers 0.000 claims description 4
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims description 4
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 3
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 claims description 3
- 235000010445 lecithin Nutrition 0.000 claims description 3
- 229940067606 lecithin Drugs 0.000 claims description 3
- 239000000787 lecithin Substances 0.000 claims description 3
- 150000008104 phosphatidylethanolamines Chemical class 0.000 claims description 3
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 claims description 2
- PORPENFLTBBHSG-MGBGTMOVSA-N 1,2-dihexadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCC PORPENFLTBBHSG-MGBGTMOVSA-N 0.000 claims description 2
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims description 2
- 229920001661 Chitosan Polymers 0.000 claims description 2
- 235000010469 Glycine max Nutrition 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- 239000003570 air Substances 0.000 claims description 2
- 230000003139 buffering effect Effects 0.000 claims description 2
- 230000003750 conditioning effect Effects 0.000 claims description 2
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical compound FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 claims description 2
- 229960003160 hyaluronic acid Drugs 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- 229910052757 nitrogen Inorganic materials 0.000 claims description 2
- 150000007524 organic acids Chemical group 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 229940083466 soybean lecithin Drugs 0.000 claims description 2
- SFZCNBIFKDRMGX-UHFFFAOYSA-N sulfur hexafluoride Chemical compound FS(F)(F)(F)(F)F SFZCNBIFKDRMGX-UHFFFAOYSA-N 0.000 claims description 2
- 229960000909 sulfur hexafluoride Drugs 0.000 claims description 2
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 claims 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- 229920002385 Sodium hyaluronate Polymers 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 229940045110 chitosan Drugs 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 210000002969 egg yolk Anatomy 0.000 claims 1
- 125000002791 glucosyl group Chemical group C1([C@H](O)[C@@H](O)[C@H](O)[C@H](O1)CO)* 0.000 claims 1
- 229960005150 glycerol Drugs 0.000 claims 1
- 150000007529 inorganic bases Chemical class 0.000 claims 1
- 239000007788 liquid Substances 0.000 claims 1
- 229960003511 macrogol Drugs 0.000 claims 1
- 229940010747 sodium hyaluronate Drugs 0.000 claims 1
- YWIVKILSMZOHHF-QJZPQSOGSA-N sodium;(2s,3s,4s,5r,6r)-6-[(2s,3r,4r,5s,6r)-3-acetamido-2-[(2s,3s,4r,5r,6r)-6-[(2r,3r,4r,5s,6r)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2- Chemical compound [Na+].CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 YWIVKILSMZOHHF-QJZPQSOGSA-N 0.000 claims 1
- 239000002245 particle Substances 0.000 abstract description 24
- 238000000034 method Methods 0.000 abstract description 20
- 238000009826 distribution Methods 0.000 abstract description 12
- 239000003814 drug Substances 0.000 abstract description 5
- 238000005516 engineering process Methods 0.000 abstract description 5
- 229940079593 drug Drugs 0.000 abstract description 4
- 239000003937 drug carrier Substances 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- JGSARLDLIJGVTE-UHFFFAOYSA-N 3,3-dimethyl-7-oxo-6-[(2-phenylacetyl)amino]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-UHFFFAOYSA-N 0.000 description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000004475 Arginine Substances 0.000 description 2
- 244000046052 Phaseolus vulgaris Species 0.000 description 2
- 235000010627 Phaseolus vulgaris Nutrition 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 2
- 235000003704 aspartic acid Nutrition 0.000 description 2
- 150000001510 aspartic acids Chemical class 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical class [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 235000019799 monosodium phosphate Nutrition 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical class [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010019468 Hemiplegia Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 229940068886 polyethylene glycol 300 Drugs 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- 238000002601 radiography Methods 0.000 description 1
- 229910052705 radium Inorganic materials 0.000 description 1
- HCWPIIXVSYCSAN-UHFFFAOYSA-N radium atom Chemical compound [Ra] HCWPIIXVSYCSAN-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/223—Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5015—Organic compounds, e.g. fats, sugars
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5089—Processes
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Radiology & Medical Imaging (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Acoustics & Sound (AREA)
- Dermatology (AREA)
- Physics & Mathematics (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of preparation method for being injected intravenously lipid microbubble, it is rotated by vacuum, and the uniform solution containing matrix material is prepared；Add the aqueous solution containing tackifier, isotonic regulator and pH adjusting agent, ultrasound or 4 DEG C stand overnight well mixed, obtain midbody solution；Free gas is injected, by mechanism, is produced.The preparation technology that the present invention proposes midbody solution is to influence the key factor of microvesicle average grain diameter and particle diameter distribution, midbody solution is prepared using film ultrasound or film aquation method first, improve the stability of preparation, improve the drug safety and validity of intravenous injection lipid microbubble, and it is simple to operate, power consumption it is low, convenient for production, it is easy to promote, is a kind of preparation method for the intravenous injection lipid microbubble that can be used for ultrasonic contrast and/or pharmaceutical carrier.
Description
Technical field
The invention belongs to pharmaceutical technology field, more particularly it relates to a kind of intravenous injection lipid microbubble and its system
Preparation Method.
Background technology
Microvesicle is exactly a kind of trickle bubble, and they are widely present in nature, seem it is ordinary but have it is unusual
Meaning, key are the gas being wherein wrapped in.Gas is a kind of very strong sound scattering body, and with extremely strong compressible
Property, the small iron ball of particle diameter identical are compared with bubble, and the scattering section of bubble is 1,000,000 times of small iron ball.Because ultrasonic wave is connect
The intensity Q of receipts is reflector scattering section S and incident intensity D direct proportion function, and scattering section S is microvesicle intrinsic frequency f
With Scatter radium R function (S=af4R6), when ultrasonic wave runs into gas, caused scattering can be stronger than solid thousands of times.
Microvesicle is artificially added in blood, and original material is entirely different in their acoustic impedance values and blood, ultrasonic wave
Strong scattering will be produced when them are run into, so as to be presented as the enhancing of echo on ultrasonogram, therefore, microvesicle is one
The preferable acoustic contrast agent of kind.
Lipid microbubble is then that one layer of lipid film has been wrapped up on the surface of microvesicle, can not only reduce interfacial tension, is extended micro-
Residence time, and the kernel formed in vivo is steeped, can not only wrap up gas, or medicament-carried good platform,
Especially protide or fat-soluble medicine.Microvesicle occurs as a kind of highly effective cavitation nucleus, easy induced ultrasonic cavitation,
Cavitation occurs that acoustic horn effect can be produced in vivo, causes adjacent cells quilt " ultrasound punching ", causes permeability of cell membrane
Increase, beneficial to insoluble drug release.Therefore, microvesicle is expected in tumour, thrombolysis, inflammation treatment, and improve ventricular function, reduce it is postoperative
Played a role in adverse reaction etc..
For being injected intravenously lipid microbubble, suitable particle diameter is primary.From the point of view of drug safety, microvesicle
Particle diameter if it exceeds 10 μm, after intravenous injection, microvesicle can block capillary and cause local tissue necrosis, even cause
Hemiplegia or death.There are some researches show microvesicle particle diameter is related to its development effect in vivo, diameter is less than 0.5 μm of microvesicle pair
Echo is without obvious contribution.In general, average grain diameter is most suitable in 1.1~3.3 μm of lipid microbubble.It can be seen that average grain
Footpath and particle diameter distribution are to reflect the key index of lipid microbubble quality.
It is vital, system for the average grain diameter and particle diameter distribution of control lipid microbubble to select suitable preparation technology
Standby lipid microbubble mainly has two steps, and first is that homogeneous intermediate is made in the other compositions in prescription by addition to gas
Solution, the step generally use two-phase dripping method, magnetic agitation prepares uniform solution and the aqueous solution containing phosphatide respectively, then passes through
Two-phase is added dropwise to obtain midbody solution, because the phase transition temperature of phosphatide is higher, therefore, it is necessary to higher than 80 DEG C during magnetic agitation
Under the conditions of, phosphatide could be dissolved completely in propane diols, for phosphatide, ester bond is contained in its structure, be easily oxidized,
Harmful substance is generated, and the amount of actual participation formation adipose membrane can be reduced, and cause microvesicle stability to decline；Second is injection gas
Body, activated by certain way, prepare microvesicle, including ultrasonic cavitation, high speed shear, vibration, microfluid and ink-jet marking method etc..
In conventional research, more activation methods for paying close attention to microvesicle.
The content of the invention
Based on this, the defects of in order to overcome above-mentioned prior art, the invention provides a kind of lipid microbubble that is injected intravenously
New preparation method.
In order to realize foregoing invention purpose, this invention takes following technical scheme：
A kind of preparation method for being injected intravenously lipid microbubble, comprises the following steps：
(1), rotated by vacuum, the uniform solution containing matrix material is prepared；
(2), in the above-mentioned uniform solution containing matrix material, 9 times of volumes of addition contain tackifier, isotonic regulator
With the aqueous solution of pH adjusting agent, ultrasound or 4 DEG C stand overnight well mixed, obtain midbody solution；
(3) free gas, is injected in above-mentioned midbody solution, by mechanism, is produced.
In wherein some embodiments, ultrasonic frequency described in step (2) is 25KHz, and the time is 4-6 minutes.
In wherein some embodiments, vacuum described in step (1) revolving temperature be 45-55 DEG C, speed be 400~
500r/min, time 1h-1.5h；It is under conditions of vacuumizing, and the actual transformation temperature of phosphatide is less than theoretical value, so as to
Revolving dissolving phosphatide can be carried out at a lower temperature, avoid phosphatide from being dissolved under high-heat environment, the ester bond in protection structure
It is not hydrolyzed with ehter bond, the generation of blocking oxide reaction, so as to improve the stability of preparation.
In wherein some embodiments, matrix material described in step (1) is egg yolk lecithin, soybean lecithin, hydrogenation
Egg yolk lecithin, hydrogenated soy phosphatidyl choline, phosphatidyl choline, DPPC, phosphatidyl-ethanolamine, two palmityls
One or more in phosphatidyl-ethanolamine, phosphatidic acid, DPPA.
In wherein some embodiments, uniform solution solvent for use described in step (1) is propane diols, ethylene glycol or poly-
Ethylene glycol 300.
In wherein some embodiments, tackifier described in step (2) are glycerine, chitosan, hyaluronic acid or hyalomitome
Sour sodium.
In wherein some embodiments, isotonic regulator described in step (2) is glucose or sodium chloride.
In wherein some embodiments, pH adjusting agent described in step (2) is organic acid, organic base, inorganic acid, inorganic
Alkali or buffering pair.
In wherein some embodiments, free gas described in step (3) is air, nitrogen, sulfur fluoride or fluorocarbon gas
Body.
In wherein some embodiments, mechanism described in step (3) is high speed shear, ultrasonic cavitation or vibration.
In wherein some embodiments, the rotating speed of the high speed shear is 10000-11000rpm/min, time 1-
2min；The frequency of the ultrasonic cavitation is 40KHz-45KHz, time 3-5min；The frequency of the vibration is 4000-
5000rpm/min, time 45-50s.
Present invention also offers the intravenous injection lipid microbubble that above-mentioned preparation method is prepared.
Compared with prior art, the invention has the advantages that：
The preparation technology that the present invention proposes midbody solution be influence microvesicle average grain diameter and particle diameter distribution it is crucial because
Element, midbody solution is prepared using film ultrasound or film aquation method first, both midbody solution preparation methods can be
Phosphatide is completely dissolved less than under conditions of phosphatide phase transition temperature, avoids phosphatide from being dissolved under high-heat environment, in protection structure
Ester bond and ehter bond are not hydrolyzed, the generation of blocking oxide reaction, and so as to improve the stability of preparation, it is micro- to improve intravenous injection lipid
The drug safety and validity of bubble, and it is simple to operate, power consumption it is low, convenient for production, be easy to promote, be that one kind can be used for surpassing
The preparation method of the intravenous injection lipid microbubble of sound radiography and/or pharmaceutical carrier.
Brief description of the drawings
Fig. 1 is C made from Film-ultrasonic technique in the embodiment of the present invention 13F8It is injected intravenously the grain size distribution of lipid microbubble；
Fig. 2 is SF made from Film-ultrasonic technique in the embodiment of the present invention 16It is injected intravenously the grain size distribution of lipid microbubble；
Fig. 3 is film-C made from aquation method in the embodiment of the present invention 33F8It is injected intravenously the grain size distribution of lipid microbubble.
Fig. 4 is film-SF made from aquation method in the embodiment of the present invention 46It is injected intravenously the grain size distribution of lipid microbubble；
Embodiment
The present invention is further discussed below with specific embodiment below in conjunction with the accompanying drawings, the present invention does not address part and is applied to existing skill
Art.It is given below the specific embodiment of the present invention, but embodiment is merely to be described in further detail this explanation, is not intended to limit
The claim of invention.Reagent or raw material used in following examples, unless otherwise specified, derive from commercially available.
The present invention is rotated by vacuum and prepares the uniform solution containing matrix material, is added containing tackifier, isotonic regulation
Agent and the aqueous solution of pH adjusting agent, ultrasound or 4 DEG C stand overnight well mixed, obtain midbody solution, it is filling after injection freely
Gas, the methods of through high speed shear, ultrasonic cavitation or vibration, it can must be injected intravenously lipid microbubble.
Specific method is：
Using film ultrasound, vacuumize revolving to prepare the uniform solution containing matrix material, add containing tackifier, etc.
Conditioning agent and the aqueous solution of pH adjusting agent are oozed, ultrasonic mixing is uniform, obtains midbody solution, injects free gas, passes through at a high speed
The methods of shearing, ultrasonic cavitation or vibration, so as to form lipid microbubble.
Or：Using film aquation method, revolving is vacuumized to prepare the uniform solution containing matrix material, is added containing thickening
The aqueous solution of agent, isotonic regulator and pH adjusting agent, 4 DEG C stand overnight, abundant aquation, obtain midbody solution, injection is freely
Gas, the methods of by high speed shear, ultrasonic cavitation or vibration, so as to form lipid microbubble.
The Film-ultrasonic technique of embodiment 1 prepares C3F8It is injected intravenously lipid microbubble
The Film-ultrasonic technique of the present embodiment prepares C3F8Lipid microbubble is injected intravenously, is comprised the following steps：
(1), vacuumized under 50 DEG C, 400r/min revolving 1 hour with prepare DPPC containing 11mg,
The uniform solution 2.5ml of 7.8mg DPPEs and 1.2mg DPPAs；Prepare uniform solution institute
The solvent used is propane diols；
(2), add and contain 3.15g glycerine, 0.12g sodium chloride, 0.05g sodium dihydrogen phosphates and 0.05g disodium hydrogen phosphates
The aqueous solution, ultrasonic 5min are well mixed, and obtain midbody solution 25ml；
(3) 1.5mL midbody solutions, are taken into 2mL cillin bottles, inject C3F8Gas, it is placed in shaker, in 4550r/
45s is vibrated under min, produces intravenous injection lipid microbubble.
The particle diameter that lipid microbubble is injected intravenously made from the present embodiment is measured, as a result such as Fig. 1, from Fig. 1 results
Understand, the average grain diameter of the obtained intravenous injection lipid microbubble of the present embodiment is 2.237 μm, and particle diameter distribution is more concentrated, and is not deposited
It is less than the lipid microbubble that 0.5 μm and particle diameter be more than 10 μm in particle diameter, meets the security and effectively of intravenous injection lipid microbubble
Property require.
The Film-ultrasonic technique of embodiment 2 prepares SF6It is injected intravenously lipid microbubble
The Film-ultrasonic technique of the present embodiment prepares SF6Lipid microbubble is injected intravenously, is comprised the following steps：
(1) it is big to prepare egg yolk lecithin containing 10mg and 10mg revolving, to be vacuumized under 55 DEG C, 500r/min 1.5 hours
The uniform solution 2.5ml of beans lecithin；Solvent used in preparing uniform solution is propane diols；
(2) water containing 3.15g hyaluronic acids, 0.12g glucose, 0.04g arginine and 0.06g aspartic acids, is added
Solution, ultrasonic 5min are well mixed, and obtain midbody solution 25ml；
(3) 1.5mL midbody solutions, are taken into 2mL cillin bottles, inject SF6Gas, it is placed in shaker, in 4750r/
50s is vibrated under min, produces intravenous injection lipid microbubble.
The particle diameter that lipid microbubble is injected intravenously made from the present embodiment is measured, as a result such as Fig. 2, from Fig. 2 results
Understand, the average grain diameter of the obtained intravenous injection lipid microbubble of the present embodiment is 2.570 μm, and particle diameter distribution is more concentrated, and is not deposited
It is less than the lipid microbubble that 0.5 μm and particle diameter be more than 10 μm in particle diameter, meets the security and effectively of intravenous injection lipid microbubble
Property require.
3 films of embodiment-aquation method prepares C3F8It is injected intravenously lipid microbubble
(1), vacuumized under 50 DEG C, 400r/min revolving 1 hour with prepare DPPC containing 11mg,
The uniform solution 2.5ml of 7.8mg DPPEs and 1.2mg DPPAs；Prepare uniform solution institute
The solvent used is propane diols；
(2), add and contain 3.15g glycerine, 0.12g sodium chloride, 0.05g sodium dihydrogen phosphates and 0.05g disodium hydrogen phosphates
The aqueous solution, 4 DEG C stand overnight, and abundant aquation, obtain midbody solution 25ml；
(3) 1.5mL midbody solutions, are taken into 2mL cillin bottles, inject C3F8Gas, it is placed in shaker, in 4550r/
45s is vibrated under min, produces intravenous injection lipid microbubble.
The particle diameter that lipid microbubble is injected intravenously made from the present embodiment is measured, as a result such as Fig. 3, from Fig. 3 results
Understand, the average grain diameter of the obtained intravenous injection lipid microbubble of the present embodiment is 2.799 μm, and particle diameter distribution is more concentrated, and is not deposited
It is less than the lipid microbubble that 0.5 μm and particle diameter be more than 10 μm in particle diameter, meets the security and effectively of intravenous injection lipid microbubble
Property require.
4 films of embodiment-aquation method prepares SF6It is injected intravenously lipid microbubble
(1) it is big to prepare egg yolk lecithin containing 10mg and 10mg revolving, to be vacuumized under 55 DEG C, 500r/min 1.5 hours
The uniform solution 2.5ml of beans lecithin；Solvent used in preparing uniform solution is propane diols；
(2) water containing 3.15g hyaluronic acids, 0.12g glucose, 0.04g arginine and 0.06g aspartic acids, is added
Solution, 4 DEG C stand overnight, and abundant aquation, obtain midbody solution 25ml；
(3) 1.5mL midbody solutions, are taken into 2mL cillin bottles, inject SF6Gas, it is placed in shaker, in 4750r/
50s is vibrated under min, produces intravenous injection lipid microbubble.
The particle diameter that lipid microbubble is injected intravenously made from the present embodiment is measured, as a result such as Fig. 4, from Fig. 4 results
Understand, the average grain diameter of the obtained intravenous injection lipid microbubble of the present embodiment is 2.820 μm, and particle diameter distribution is more concentrated, and is not deposited
It is less than the lipid microbubble that 0.5 μm and particle diameter be more than 10 μm in particle diameter, meets the security and effectively of intravenous injection lipid microbubble
Property require.
Each technical characteristic of embodiment described above can be combined arbitrarily, to make description succinct, not to above-mentioned reality
Apply all possible combination of each technical characteristic in example to be all described, as long as however, the combination of these technical characteristics is not deposited
In contradiction, the scope that this specification is recorded all is considered to be.
Embodiment described above only expresses the several embodiments of the present invention, and its description is more specific and detailed, but simultaneously
Can not therefore it be construed as limiting the scope of the patent.It should be pointed out that come for one of ordinary skill in the art
Say, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to the protection of the present invention
Scope.Therefore, the protection domain of patent of the present invention should be determined by the appended claims.
Claims (10)
1. a kind of preparation method for being injected intravenously lipid microbubble, it is characterised in that comprise the following steps：
(1), rotated by vacuum, the uniform solution containing matrix material is prepared；
(2), in the above-mentioned uniform solution containing matrix material, 9 times of volumes of addition contain tackifier, isotonic regulator and pH
The aqueous solution of conditioning agent, ultrasound or 4 DEG C stand overnight well mixed, obtain midbody solution；
(3) free gas, is injected in above-mentioned midbody solution, by mechanism, is produced.
2. the preparation method of intravenous injection lipid microbubble according to claim 1, it is characterised in that described in step (1)
The temperature of vacuum revolving is 45~55 DEG C, and speed is 400~500r/min, and the time is 1~1.5h.
3. the preparation method of intravenous injection lipid microbubble according to claim 1, it is characterised in that described in step (2)
The frequency of ultrasound is 25KHz, and the time is 4-6 minutes.
4. the preparation method of the intravenous injection lipid microbubble according to any one of claims 1 to 3, it is characterised in that step
(1) matrix material described in is egg yolk lecithin, soybean lecithin, hydrogenated yolk lecithin, hydrogenated soy phosphatidyl choline, phosphatidyl
Choline, DPPC, phosphatidyl-ethanolamine, DPPE, phosphatidic acid, two palmityl phosphatide
One or more in acid.
5. the preparation method of the intravenous injection lipid microbubble according to any one of claims 1 to 3, it is characterised in that step
(1) uniform solution solvent for use described in is propane diols, ethylene glycol or Liquid Macrogol.
6. the preparation method of the intravenous injection lipid microbubble according to any one of claims 1 to 3, it is characterised in that step
(2) tackifier described in are glycerine, chitosan, hyaluronic acid or Sodium Hyaluronate；The isotonic regulator is glucose or chlorine
Change sodium；The pH adjusting agent is organic acid, organic base, inorganic acid, inorganic base or buffering pair.
7. the preparation method of the intravenous injection lipid microbubble according to any one of claims 1 to 3, it is characterised in that step
(3) free gas described in is air, nitrogen, sulfur fluoride or fluorocarbon gas.
8. the preparation method of the intravenous injection lipid microbubble according to any one of claims 1 to 3, it is characterised in that step
(3) mechanism described in is high speed shear, ultrasonic cavitation or vibration.
9. the preparation method of intravenous injection lipid microbubble according to claim 8, it is characterised in that the high speed shear
Rotating speed is 10000-11000rpm/min, time 1-2min；The frequency of the ultrasonic cavitation is 40KHz-45KHz, and the time is
3-5min；The frequency of the vibration is 4000-5000rpm/min, time 45-50s.
10. the intravenous injection lipid microbubble that the preparation method described in any one of claim 1~9 is prepared.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150343079A1 (en) * | 2012-10-25 | 2015-12-03 | Sogang University Research Foundation | Ultrasound contrast agent with nanoparticles including drug and method for preparing the same |
| CN106821982A (en) * | 2017-01-12 | 2017-06-13 | 东南大学 | A kind of sinapultide microbubble agents and preparation method thereof |
-
2017
- 2017-08-25 CN CN201710743241.9A patent/CN107375954A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150343079A1 (en) * | 2012-10-25 | 2015-12-03 | Sogang University Research Foundation | Ultrasound contrast agent with nanoparticles including drug and method for preparing the same |
| CN106821982A (en) * | 2017-01-12 | 2017-06-13 | 东南大学 | A kind of sinapultide microbubble agents and preparation method thereof |
Non-Patent Citations (2)
| Title |
|---|
| 彭晓艳等: "《C3F8脂质体超声微泡造影剂制备的初步研究》", 《武汉大学学报(医学版)》 * |
| 潘弟仪: "《超声造影剂—全氟丙烷脂质微泡的制备与评价》", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》 * |
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Effective date of registration: 20191021 Address after: 510760 No.71, Dongpeng Avenue, Dongqu, economic and Technological Development Zone, Luogang District, Guangzhou City, Guangdong Province Applicant after: Kangchen Pharmaceutical Co., Ltd., Guangzhou Address before: 510760, Guangdong province Guangzhou Guangzhou economic and Technological Development Zone East Dongpeng Avenue 8, 71, 6, 602 rooms Applicant before: Guangzhou Kangcheng Pharmaceutical Research Co.,Ltd. Applicant before: Kangchen Pharmaceutical Co., Ltd., Guangzhou |
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Application publication date: 20171124 |