CN112618734A - Liposome microbubble preparation for injection and preparation process thereof - Google Patents
Liposome microbubble preparation for injection and preparation process thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 238000002347 injection Methods 0.000 title claims abstract description 18
- 239000007924 injection Substances 0.000 title claims abstract description 18
- 239000002502 liposome Substances 0.000 title claims abstract description 18
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims abstract description 57
- 229910018503 SF6 Inorganic materials 0.000 claims abstract description 28
- SFZCNBIFKDRMGX-UHFFFAOYSA-N sulfur hexafluoride Chemical compound FS(F)(F)(F)(F)F SFZCNBIFKDRMGX-UHFFFAOYSA-N 0.000 claims abstract description 28
- 229960000909 sulfur hexafluoride Drugs 0.000 claims abstract description 27
- 238000004108 freeze drying Methods 0.000 claims abstract description 21
- 239000000243 solution Substances 0.000 claims abstract description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000001914 filtration Methods 0.000 claims abstract description 13
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 12
- 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 claims abstract description 10
- 239000012528 membrane Substances 0.000 claims abstract description 10
- 238000011049 filling Methods 0.000 claims abstract description 8
- 239000007864 aqueous solution Substances 0.000 claims abstract description 7
- 239000000463 material Substances 0.000 claims abstract description 7
- 230000001954 sterilising effect Effects 0.000 claims abstract 2
- 150000003904 phospholipids Chemical class 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 14
- 239000000203 mixture Substances 0.000 claims description 10
- 238000004806 packaging method and process Methods 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 6
- 238000003825 pressing Methods 0.000 claims description 6
- 239000008215 water for injection Substances 0.000 claims description 6
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 5
- 229930195725 Mannitol Natural products 0.000 claims description 5
- 239000000594 mannitol Substances 0.000 claims description 5
- 235000010355 mannitol Nutrition 0.000 claims description 5
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 4
- 229930006000 Sucrose Natural products 0.000 claims description 4
- 239000005720 sucrose Substances 0.000 claims description 4
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims description 2
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims description 2
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims 1
- 239000004471 Glycine Substances 0.000 claims 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims 1
- 238000009472 formulation Methods 0.000 claims 1
- 239000008101 lactose Substances 0.000 claims 1
- 239000012982 microporous membrane Substances 0.000 claims 1
- 238000004659 sterilization and disinfection Methods 0.000 claims 1
- 238000001514 detection method Methods 0.000 abstract description 10
- 238000003384 imaging method Methods 0.000 abstract description 6
- 210000004204 blood vessel Anatomy 0.000 abstract description 4
- 239000003814 drug Substances 0.000 abstract description 4
- 230000000694 effects Effects 0.000 abstract description 3
- 230000002708 enhancing effect Effects 0.000 abstract description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 abstract description 2
- 239000000032 diagnostic agent Substances 0.000 abstract description 2
- 229940039227 diagnostic agent Drugs 0.000 abstract description 2
- 150000002500 ions Chemical class 0.000 abstract description 2
- 230000010412 perfusion Effects 0.000 abstract description 2
- 230000005855 radiation Effects 0.000 abstract description 2
- 239000007789 gas Substances 0.000 description 16
- 238000010438 heat treatment Methods 0.000 description 15
- 238000005187 foaming Methods 0.000 description 14
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 10
- 230000000052 comparative effect Effects 0.000 description 7
- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 235000021314 Palmitic acid Nutrition 0.000 description 5
- 238000007710 freezing Methods 0.000 description 5
- 230000008014 freezing Effects 0.000 description 5
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 5
- 230000010355 oscillation Effects 0.000 description 5
- 229940057838 polyethylene glycol 4000 Drugs 0.000 description 4
- 210000004185 liver Anatomy 0.000 description 3
- YNQYZBDRJZVSJE-QTOMIGAPSA-M sodium;2,3-dihydroxypropyl [(2r)-2,3-di(octadecanoyloxy)propyl] phosphate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCCCCCC YNQYZBDRJZVSJE-QTOMIGAPSA-M 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- BIABMEZBCHDPBV-MPQUPPDSSA-N 1,2-palmitoyl-sn-glycero-3-phospho-(1'-sn-glycerol) Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@@H](O)CO)OC(=O)CCCCCCCCCCCCCCC BIABMEZBCHDPBV-MPQUPPDSSA-N 0.000 description 1
- 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 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000005388 borosilicate glass Substances 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000009965 odorless effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000002601 radiography Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
Images
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
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Acoustics & Sound (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Radiology & Medical Imaging (AREA)
- Epidemiology (AREA)
- Physics & Mathematics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The company develops a liposome microbubble preparation for injection, which is a diagnostic agent capable of obviously enhancing medical ultrasonic detection signals. In the aspect of perfusion detection and imaging of human body micro blood vessels and tissues, the ultrasonic detection has the advantages of good imaging effect, real-time performance, simple and convenient operation, no ion radiation, no damage, wide application range and the like. The preparation method comprises the steps of dissolving liposome membrane materials DPPA and DPPE-PEG5000 by using a tert-butyl alcohol aqueous solution, dissolving at 50-60 ℃, adding water to 80% of the total amount, adding a prescription amount of excipient, performing constant volume, sterilizing, filtering to obtain a solution with the pH value of 6-8, performing freeze-drying by using a freeze-dryer, and filling sulfur hexafluoride gas into a medicine bottle after freeze-drying. The product is activated by shaking with normal saline before application.
Description
Technical Field
The invention belongs to the technical field of medicines, relates to a liposome microbubble preparation for injection and a preparation process thereof, and particularly relates to a preparation method of a phospholipid microbubble contrast agent with longer liver parenchyma imaging time.
Background
The liposome microbubble for injection in the market at present is sulfur hexafluoride microbubble for injection, sulfur hexafluoride, chemical formula is SF6, the liposome microbubble is colorless, odorless, nontoxic and noncombustible stable gas, molecular weight is 146.07, density is 6.1kg/m3 at 20 ℃ and 0.1MPa, and the density is about 5 times of air density. The sulfur hexafluoride is gaseous at normal temperature and normal pressure, the critical temperature is 45.6 ℃, the triple point temperature is-50.8 ℃, and the sublimation point temperature is-63.8 ℃ at normal pressure. The sulfur hexafluoride molecular structure is arranged in an octahedron shape, the bonding distance is small, the bonding energy is high, the stability is high, and the sulfur hexafluoride molecular structure is similar to the nitrogen in the compatibility of the electrical structure material when the temperature is not more than 180 ℃. Due to the characteristics of high density and low solubility in blood of the sulfur hexafluoride gas, the sulfur hexafluoride gas is not easy to penetrate through the wall of the microsphere and diffuse after being applied in the blood vessel, can resist arterial pressure, and can meet clinical requirements after staying in the blood vessel for a long time. The gas is inert and nontoxic, has no metabolism in vivo, is almost completely discharged from lung in an expiration mode in a short time after being injected into a human body, and has high safety. Thus the prior art is primarily sulfur hexafluoride microbubbles. Sulfur hexafluoride microbubbles are also a current focus of research.
However, the conventional liposome microbubbles for injection mainly contain sulfur hexafluoride gas, polyethylene glycol 4000, distearoyl phosphatidylcholine (DSPC), and Dipalmitoylphosphatidylglycerol Sodium (DSPG). The foaming rate is relatively small, and the liver imaging time is relatively short.
Therefore, a new liposome microbubble preparation for injection is urgently needed, the foaming rate is improved, and the liver radiography time is prolonged.
Disclosure of Invention
Aiming at the problems, the invention provides a diagnostic medicament capable of obviously enhancing medical ultrasonic detection signals, in particular to a liposome microbubble preparation for injection and a preparation process thereof.
In order to achieve the purpose, the invention discloses a liposome microbubble preparation for injection, which is freeze-dried powder, is filled with sulfur hexafluoride gas, and is oscillated and activated into milky liquid medicine for use after being injected with normal saline. The method specifically comprises the following steps:
the liposome microbubble preparation for injection comprises freeze-dried powder and sulfur hexafluoride gas, wherein the freeze-dried powder comprises liposome membrane materials of DPPA, DPPE-PEG5000, an excipient and tert-butyl alcohol, and the weight ratio of the DPPA to the DPPE-PEG5000 to the excipient to the tert-butyl alcohol is as follows: 1-9: 1-9: 2-16: 10 to 50.
According to a further technical scheme, the excipient is one or more of mannitol, sucrose and trehalose.
According to a further technical scheme, the pH value is 6.0-8.0.
The invention also discloses a preparation process of the liposome microbubble for injection, which comprises the following steps:
(1) preparing a phospholipid solution: adding a prescribed amount of tert-butyl alcohol into an equal amount of water to prepare a 50% tert-butyl alcohol aqueous solution, adding a prescribed amount of DPPA and DPPE-PEG5000, and stirring and dissolving at 50-60 ℃;
(2) primary volume fixing: adding water for injection into the phospholipid solution until the amount of the phospholipid solution reaches 80% of the prescription amount, and uniformly stirring;
(3) dissolving an excipient: adding excipient into the solution, stirring and dissolving;
(4) and (3) secondary constant volume: adding water to a constant volume to full volume;
(5) and (3) degerming and filtering: passing the medicinal liquid through a 0.45 μm and 2 0.22 μm microporous filter membranes;
(6) filling the mixture into bottles with the volume of 1g per bottle, and freeze-drying the bottles in a freeze dryer.
The lyophilization conditions were as follows:
putting the product into a box, freezing to below-40 +/-2 ℃, preserving the heat for 3 hours, starting a vacuum pump to vacuumize the front box to 20 +/-5 Pa, and heating and sublimating according to the following conditions:
setting the heat conducting oil for 4 hours, heating to-15 +/-2 ℃, and keeping for 20-26 hours;
setting the heat conducting oil for 4.5 hours, heating to 25 +/-2 ℃, and keeping for 10-15 hours;
and refilling sulfur hexafluoride gas into the freeze-drying front box, pressing the plug after the sulfur hexafluoride gas reaches 1 atmosphere, and binding and packaging the plug after the sulfur hexafluoride gas is taken out of the box.
The oscillation is activated before use.
Has the advantages that: the invention is characterized in that liposome membrane materials such as DSPG, DPPE-PEG5000 and DSPC are dissolved by organic solvent, then a certain amount of excipient is added to prepare freeze-dried powder, and sulfur hexafluoride is encapsulated in a 2ml borosilicate glass tube injection bottle after freeze-drying. The company develops a liposome microbubble preparation for injection, and the microbubble preparation is a diagnostic agent capable of obviously enhancing medical ultrasonic detection signals. In the aspect of perfusion detection and imaging of human body micro blood vessels and tissues, the ultrasonic detection has the advantages of good imaging effect, real-time performance, simple and convenient operation, no ion radiation, no damage, wide application range and the like.
Description of the drawings:
FIG. 1: example 1 foaming Rate detection Profile
FIG. 2: example 2 foaming ratio detection Pattern
FIG. 3: comparative example 1 foaming ratio test Pattern
FIG. 4: comparative example 2 foaming ratio detection Pattern
The specific implementation mode is as follows:
the following examples are intended to further illustrate the invention and are not to be construed as limiting the invention in any way.
Example 1
The prescription composition is as follows:
| raw and auxiliary materials | Single dose (mg) |
| Sulfur hexafluoride | 49 |
| DPPA | 40 |
| DPPE-PEG5000 | 60 |
| Mannitol | 100 |
| Tert-butyl alcohol | 200 |
| Adding water to | 1000 |
The preparation method comprises the following steps:
(1) preparing a phospholipid solution: adding water with the same amount into tert-butyl alcohol according to the prescription amount to prepare a 50% tert-butyl alcohol aqueous solution, adding DPPA and DPPE-PEG5000 according to the prescription amount, and stirring and dissolving at 50-60 ℃.
(2) Primary volume fixing: adding water for injection into the phospholipid solution to reach the prescription amount of 80%, and uniformly stirring.
(3) Dissolving mannitol: the prescription amount of mannitol is added into the solution, and stirred to dissolve.
(4) And (3) secondary constant volume: adding water to fix the volume to the full volume.
(5) And (3) degerming and filtering: filtering the medicinal liquid with 0.45 μm and 2 0.22 μm microporous filter membranes;
(6) filling the mixture into bottles with the volume of 1g per bottle, and freeze-drying the bottles in a freeze dryer.
The lyophilization conditions were as follows:
putting the product into a box, freezing to below-40 +/-2 ℃, preserving the heat for 3 hours, starting a vacuum pump to vacuumize the front box to 20 +/-5 Pa, and heating and sublimating according to the following conditions:
setting the heat conducting oil for 4 hours, heating to-15 +/-2 ℃, and keeping for 20-26 hours;
setting the heat conducting oil for 4.5 hours, heating to 25 +/-2 ℃, and keeping for 10-15 hours;
and refilling sulfur hexafluoride gas into the freeze-drying front box, pressing the plug after the sulfur hexafluoride gas reaches 1 atmosphere, and binding and packaging the plug after the sulfur hexafluoride gas is taken out of the box.
The oscillation is activated before use. The foaming ratio was measured using a coulter apparatus, and is shown in fig. 1.
Example 2
The prescription composition is as follows:
the preparation method comprises the following steps:
(1) preparing a phospholipid solution: adding water with the same amount into tert-butyl alcohol according to the prescription amount to prepare a 50% tert-butyl alcohol aqueous solution, adding DPPA and DPPE-PEG5000 according to the prescription amount, and stirring and dissolving at 50-60 ℃.
(2) Primary volume fixing: adding water for injection into the phospholipid solution to reach the prescription amount of 80%, and uniformly stirring.
(3) Dissolving sucrose: the prescribed amount of sucrose is added to the solution and stirred to dissolve.
(4) And (3) secondary constant volume: adding water to fix the volume to the full volume.
(5) And (3) degerming and filtering: filtering the medicinal liquid with 0.45 μm and 2 0.22 μm microporous filter membranes;
(6) filling the mixture into bottles with the volume of 1g per bottle, and freeze-drying the bottles in a freeze dryer.
The lyophilization conditions were as follows:
putting the product into a box, freezing to below-40 +/-2 ℃, preserving the heat for 3 hours, starting a vacuum pump to vacuumize the front box to 20 +/-5 Pa, and heating and sublimating according to the following conditions:
setting the heat conducting oil for 4 hours, heating to-15 +/-2 ℃, and keeping for 20-26 hours;
setting the heat conducting oil for 4.5 hours, heating to 25 +/-2 ℃, and keeping for 10-15 hours;
and refilling sulfur hexafluoride gas into the freeze-drying front box to achieve 1 atmosphere, and then pressing the plug. And (5) binding the cover after the box is taken out. And (6) packaging.
The oscillation is activated before use. The foaming ratio was measured using a coulter apparatus, as shown in fig. 2.
Comparative example 1:
the prescription composition is as follows:
the preparation method comprises the following steps:
(1) preparing a phospholipid solution: adding equal amount of water into the tert-butyl alcohol according to the prescription amount to prepare a 50% tert-butyl alcohol aqueous solution, adding polyethylene glycol 4000, DSPG-Na and DSPC according to the prescription amount, and stirring and dissolving at 50-60 ℃.
(2) Primary volume fixing: adding water for injection into the phospholipid solution to reach the prescription amount of 80%, and uniformly stirring.
(3) Dissolving palmitic acid: the prescription amount of palmitic acid is added in the above steps, and stirred to dissolve.
(4) And (3) secondary constant volume: adding water to fix the volume to the full volume.
(5) And (3) degerming and filtering: filtering the medicinal liquid with 0.45 μm and 2 0.22 μm microporous filter membranes;
(6) filling the mixture into bottles with the volume of 1g per bottle, and freeze-drying the bottles in a freeze dryer.
The lyophilization conditions were as follows:
putting the product into a box, freezing to below-40 +/-2 ℃, preserving the heat for 3 hours, starting a vacuum pump to vacuumize the front box to 20 +/-5 Pa, and heating and sublimating according to the following conditions:
setting the heat conducting oil for 4 hours, heating to-15 +/-2 ℃, and keeping for 20-26 hours;
setting the heat conducting oil for 4.5 hours, heating to 25 +/-2 ℃, and keeping for 10-15 hours;
and refilling sulfur hexafluoride gas into the freeze-drying front box to achieve 1 atmosphere, and then pressing the plug. And (5) binding the cover after the box is taken out. And (6) packaging.
The oscillation is activated before use. The foaming ratio was measured using a coulter apparatus, and is shown in fig. 3.
Comparative example 2:
the prescription composition is as follows:
| raw and auxiliary materials | Single dose (mg) |
| Sulfur hexafluoride | 59 |
| Polyethylene glycol 4000 | 10 |
| DSPG- |
5 |
| |
8 |
| |
2 |
| Tert-butyl alcohol | 200 |
| Adding water to | 1000 |
The preparation method comprises the following steps:
(1) preparing a phospholipid solution: adding equal amount of water into the tert-butyl alcohol according to the prescription amount to prepare a 50% tert-butyl alcohol aqueous solution, adding polyethylene glycol 4000, DSPG-Na and DSPC according to the prescription amount, and stirring and dissolving at 50-60 ℃.
(2) Primary volume fixing: adding water for injection into the phospholipid solution to reach the prescription amount of 80%, and uniformly stirring.
(3) Dissolving palmitic acid: the prescription amount of palmitic acid is added in the above steps, and stirred to dissolve.
(4) And (3) secondary constant volume: adding water to fix the volume to the full volume.
(5) And (3) degerming and filtering: filtering the medicinal liquid with 0.45 μm and 2 0.22 μm microporous filter membranes;
(6) filling the mixture into bottles with the volume of 1g per bottle, and freeze-drying the bottles in a freeze dryer.
The lyophilization conditions were as follows:
putting the product into a box, freezing to below-40 +/-2 ℃, preserving the heat for 3 hours, starting a vacuum pump to vacuumize the front box to 20 +/-5 Pa, and heating and sublimating according to the following conditions:
setting the heat conducting oil for 4 hours, heating to-15 +/-2 ℃, and keeping for 20-26 hours;
setting the heat conducting oil for 4.5 hours, heating to 25 +/-2 ℃, and keeping for 10-15 hours;
and refilling sulfur hexafluoride gas into the freeze-drying front box to achieve 1 atmosphere, and then pressing the plug. And (5) binding the cover after the box is taken out. And (6) packaging.
The oscillation is activated before use. The foaming ratio was measured using a coulter apparatus, and is shown in fig. 4.
Verification examples
Measurement of foaming ratio
The samples obtained in examples 1-2 of the present invention and comparative examples 1-2 were subjected to vibration activation, and then the foaming rate of the samples was measured using a particle size analyzer, and the volume concentration and the number concentration of the foaming rate are shown in the following table.
As can be seen from the above results, the experimental solutions of examples 1-2 have higher foaming number concentration and volume concentration than those of comparative examples 1-2, and the number of bubbles of 2-4 μm is relatively large, which is presumed to be higher in contrast effect than those of comparative examples 1-2.
The above description is only a preferred embodiment of the present invention, and should not be taken as limiting the invention in any way, and those skilled in the art can easily make modifications, equivalents and improvements on the above embodiment without departing from the technical scope of the present invention.
Claims (4)
1. The liposome microbubble preparation for injection is characterized by comprising freeze-dried powder and sulfur hexafluoride gas, wherein the freeze-dried powder comprises liposome membrane materials of DPPA, DPPE-PEG5000, an excipient and tert-butyl alcohol, and the weight ratio of DPPA to DPPE-PEG5000 to the excipient to the tert-butyl alcohol is as follows: 1-9: 1-9: 2-16: 10 to 50.
2. The liposomal microbubble formulation for injection according to claim 1, wherein the excipient comprises one or more of mannitol, sucrose, glycine, lactose, and trehalose.
3. The liposomal microbubble preparation for injection according to claim 1, wherein the pH is between 6.0 and 8.0.
4. The liposomal microbubble preparation for injection according to claim 1, wherein the preparation process comprises the following steps:
(1) preparation of phospholipid solution: preparing 50% tert-butyl alcohol aqueous solution from tert-butyl alcohol, adding DPPA and DPPE-PEG5000, and stirring and dissolving at 50-60 ℃ to obtain phospholipid solution;
(2) primary volume fixing: adding water for injection into the phospholipid solution to 80% of the total amount, and stirring uniformly;
(3) dissolving an excipient: adding excipient into the solution, stirring and dissolving;
(4) and (3) secondary constant volume: adding water to a constant volume of 1 g/branch;
(5) and (3) degerming and filtering: filtering with a 0.45 μm microporous membrane, and filtering with 2 0.22 μm microporous membranes for sterilization; determining the filling amount according to the content to be filled;
(6) filling the semi-added rubber plug into a freeze-drying box, and refilling sulfur hexafluoride gas into the freeze-drying front box after freeze-drying is finished, and then pressing the plug after 1 atmosphere is reached; after the box is taken out, the cover is bound; and (6) packaging.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011549224.XA CN112618734A (en) | 2020-12-24 | 2020-12-24 | Liposome microbubble preparation for injection and preparation process thereof |
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| CN113144224A (en) * | 2021-04-27 | 2021-07-23 | 南京恒远科技开发有限公司 | Freeze-dried phospholipid microvesicle with long liver parenchyma imaging time and preparation process thereof |
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| CN109529033A (en) * | 2018-07-09 | 2019-03-29 | 彭盛 | A kind of stable oxygen carrier microvesicle and its preparation method and application |
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| CN1160357A (en) * | 1994-05-23 | 1997-09-24 | ImaRx药物公司 | Gas filled microspheres as computed tomography contrast agents |
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| CN113144224A (en) * | 2021-04-27 | 2021-07-23 | 南京恒远科技开发有限公司 | Freeze-dried phospholipid microvesicle with long liver parenchyma imaging time and preparation process thereof |
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