CN110101878A - A kind of stable and uniform gas micro freeze-drying acoustic contrast agent and preparation method thereof - Google Patents
A kind of stable and uniform gas micro freeze-drying acoustic contrast agent and preparation method thereof Download PDFInfo
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- CN110101878A CN110101878A CN201910507578.9A CN201910507578A CN110101878A CN 110101878 A CN110101878 A CN 110101878A CN 201910507578 A CN201910507578 A CN 201910507578A CN 110101878 A CN110101878 A CN 110101878A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 60
- 238000004108 freeze drying Methods 0.000 title claims abstract description 51
- 239000002872 contrast media Substances 0.000 title claims abstract description 46
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- 239000007924 injection Substances 0.000 claims description 62
- 229940090044 injection Drugs 0.000 claims description 62
- 238000002347 injection Methods 0.000 claims description 62
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- 238000003760 magnetic stirring Methods 0.000 claims description 10
- 230000001105 regulatory effect Effects 0.000 claims description 10
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- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims description 8
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical class CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 claims description 6
- WMIYKQLTONQJES-UHFFFAOYSA-N hexafluoroethane Chemical compound FC(F)(F)C(F)(F)F WMIYKQLTONQJES-UHFFFAOYSA-N 0.000 claims description 3
- QYSGYZVSCZSLHT-UHFFFAOYSA-N octafluoropropane Chemical compound FC(F)(F)C(F)(F)C(F)(F)F QYSGYZVSCZSLHT-UHFFFAOYSA-N 0.000 claims description 3
- 229960004065 perflutren Drugs 0.000 claims description 3
- TXEYQDLBPFQVAA-UHFFFAOYSA-N tetrafluoromethane Chemical compound FC(F)(F)F TXEYQDLBPFQVAA-UHFFFAOYSA-N 0.000 claims description 3
- PSSHQAXMSKKIBE-UHFFFAOYSA-N 1,1-difluoropentane Chemical compound CCCCC(F)F PSSHQAXMSKKIBE-UHFFFAOYSA-N 0.000 claims 1
- 238000007689 inspection Methods 0.000 claims 1
- 230000008569 process Effects 0.000 abstract description 17
- 239000000047 product Substances 0.000 abstract description 15
- 239000007788 liquid Substances 0.000 abstract description 14
- 238000009826 distribution Methods 0.000 abstract description 9
- 239000002245 particle Substances 0.000 abstract description 8
- 238000010924 continuous production Methods 0.000 abstract description 6
- 238000001514 detection method Methods 0.000 abstract description 5
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- 238000012216 screening Methods 0.000 abstract description 5
- 239000011265 semifinished product Substances 0.000 abstract description 5
- 238000012545 processing Methods 0.000 abstract description 3
- 239000012752 auxiliary agent Substances 0.000 abstract description 2
- 238000010954 commercial manufacturing process Methods 0.000 abstract description 2
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
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- 238000005516 engineering process Methods 0.000 description 4
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- 239000003795 chemical substances by application Substances 0.000 description 3
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
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- 206010002329 Aneurysm Diseases 0.000 description 1
- XRPKRSLLVXAECN-UHFFFAOYSA-N CCCC.[F] Chemical compound CCCC.[F] XRPKRSLLVXAECN-UHFFFAOYSA-N 0.000 description 1
- 206010008479 Chest Pain Diseases 0.000 description 1
- 208000035965 Postoperative Complications Diseases 0.000 description 1
- XGCDHPDIERKJPT-UHFFFAOYSA-N [F].[S] Chemical compound [F].[S] XGCDHPDIERKJPT-UHFFFAOYSA-N 0.000 description 1
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- 238000009098 adjuvant therapy Methods 0.000 description 1
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- 230000008081 blood perfusion Effects 0.000 description 1
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- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
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- 238000002474 experimental method Methods 0.000 description 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical compound FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 1
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- 238000001727 in vivo Methods 0.000 description 1
- 238000003475 lamination Methods 0.000 description 1
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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
Landscapes
- Health & Medical Sciences (AREA)
- Physics & Mathematics (AREA)
- Acoustics & Sound (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Radiology & Medical Imaging (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The present invention relates to medical auxiliary agent technical fields, and in particular to a kind of stable and uniform gas micro freeze-drying acoustic contrast agent and preparation method thereof.Stable and uniform gas micro provided by the invention freeze-drying acoustic contrast agent and preparation method thereof solves the problems, such as in current commercial manufacturing processes can not industrialization amplify, by the gas and liquid velocity ratio that control microballoon preparatory phase, it is reasonably distributed the microspherulite diameter of preparation, 2-7 μm of microballoon percentage can reach 77% or more, it does not need additional increase and prepares microballoon semi-finished product, separation, screening, the processing steps such as detection and adjustment, greatly reduce process costs, product yield is improved, it is made to be more suitable for industrialized production.The present invention uses microballoon processed and the continual technique of filling continuous production simultaneously, it is short from microballoon processed to filling interval time, it is filling rapidly to ensure that the microballoon of preparation obtains before particle diameter distribution changes, so that the microballoon in final products is maintained the particle diameter distribution before freeze-drying, it is ensured that product quality.
Description
Technical field
The present invention relates to medical auxiliary agent technical fields, and in particular to a kind of stable and uniform gas micro freeze-drying acoustic contrast agent
And preparation method thereof.
Background technique
Contrast-enhanced ultrasound technique accurate, rapidly, clearly can reflect body major organs lesion, and adjuvant treatment is played
Key effect, when that clearly can not determine lesion using conventional developing technique, contrast-enhanced ultrasound technique is without side-effects, intuitive, price
It is cheap, real-time visualization and the advantages such as can use in bedside.
Ultrasonic contrast principle are as follows: ultrasonic wave propagates to scatterer, and dimension can occur when being less than the interface of incident acoustic wave wavelength
Scattering, power and the size of scatterer, the shape and related with the acoustic impedance difference of perienchyma of scattering.Although containing in blood
There are the tangible substance such as red blood cell, leucocyte, blood platelet, but its acoustic impedance difference very little, scattering is very faint, so in ordinary ultrasonic instrument
On can not show.If acoustic impedance and the completely different medium of blood, such as microbubble are artificially added in blood, then blood
, there is nebulous echo, here it is the basic principles of ultrasonic contrast in interior scattering enhancing.
Tissue acoustic contrast exactly utilizes this principle, is injected intravenously acoustic contrast agent, for example the solution containing microbubble is made
For contrast agent with blood perfusion enter organ, tissue, make organ, tissue development enhancing, thus for clinical diagnosis provide it is important according to
According to.Currently, using ultrasonic contrast enhancing technology to the clinical heart on the basis of conventional Ultrasound cardiogram and vascular ultrasound
The Precise Diagnosis of vascular diseases and treatment produce tremendous influence, including: clearly show that chambers of the heart intima boundary significantly improves
The accuracy of left ventricular ejection fraction measurement can aid in correct identification cardiac anatomy, improve coronary artery disease
And the diagnostic accuracy of acute coronary syndrome, quickly identify acute chest pain, more effectively diagnose aneurysm type and
Evaluate postoperative complications etc..
Acoustic contrast agent needed for above-mentioned contrast-enhanced ultrasound technique is a kind of diagnosis examination that can significantly increase ultrasonic scattering signal
Agent.General its is made of the ball wall material of insoluble gas microbubbles and package microvesicle.Usual microbubble gas can be air, nitrogen,
Carbon dioxide, fluorocarbon gas, fluorine sulphur gas etc., and common ball wall material then has albumin, surfactant, lipid and high score
Sub- material etc..The main function of ball wall material is gas in protection microvesicle, makes it not to external diffusion, while being prevented between adjacent microvesicle
Fusion.
Ideal acoustic contrast agent should have uniform and stable feature.On the one hand, human capillary vessel's mean inside diameter is small
In 8 μm, excessive contrast agent microsphere can not flow freely in capillary and interfere blood flow, and too small microballoon then surpasses
Sound reflecting ability is poor, causes ultrasonic image unintelligible, therefore microsphere diameter should control in a certain range.On the other hand, it makes
Shadow agent microballoon need to have certain stability, can smoothly commercially produce, transport and save.Meanwhile it should also protect
Card after being injected in human body, be resistant in longer circulation time in vivo human body artery pressure (about 250mmHg) without
It is destroyed, to complete various clinical ultrasound diagnosis.
For microballoon class contrast products, the control of microspherulite diameter proportional region is current process difficult point.It is prepared by microballoon
After can be layered rapidly, such as take no action to be unable to get uniform and stable product.Currently used method is by various separation
Mode that is excessive or crossing minimicrosphere, such as a kind of method for preparing microsphere disclosed in Chinese patent application CN1194161A, are exactly logical
It crosses stratification to defoam and excessive microballoon, obtains semi-finished product microballoon product, detection control is carried out to semi-finished product and adjust
Packing is mixed to after meeting the requirements.Preparation method microspherulite diameter distribution is too wide, needs to increase process and carries out microballoon screening, and
Due to can not achieve continuous production, and different batches of technique is difficult to control to be consistent, therefore the differences between batches of finished product are big.
In conclusion at present microballoon technical process processed the problem of are as follows: 1) microspherulite diameter distribution it is too wide, need to increase
Process carries out microballoon screening, and temperature decline influences the mobility of medical fluid, and subsequent packing loading amount is difficult to control.2) due to preparation
Thus obtained microsphere is the state of gas-in-liquid, and Character instability, if separated the microballoon of different-grain diameter by physical means, microballoon holds
Easily destroyed to some extent.3) part medical fluid can be lost when defoaming and excessive microballoon, influences recovery rate, is unfavorable for
Industrialized production.4) due to can not achieve continuous production, and different batches of technique is difficult to control to be consistent, therefore batch of finished product
Between difference it is big, the quality requirement of injection drug can not be met.
Summary of the invention
In order to solve above-mentioned problem in the prior art, the present invention provides a kind of stable and uniform gas micro freeze-drying ultrasounds
Contrast agent and preparation method thereof, stable and uniform gas micro freeze-drying acoustic contrast agent provided by the invention and preparation method thereof solve
At present in commercial manufacturing processes can not industrialization amplification the problem of, pass through control microballoon preparatory phase gas and flow rate of liquid
Than being reasonably distributed the microspherulite diameter of preparation, 2-7 μm of microballoon percentage can reach 77% or more, not need additionally to increase system
Standby microballoon semi-finished product, separate, screening, and the processing steps such as detection and adjustment greatly reduce process costs, improve product receipts
Rate makes it be more suitable for industrialized production.The present invention uses microballoon processed and the continual technique of filling continuous production, Cong Zhiwei simultaneously
Ball is short to filling interval time, it is ensured that the microballoon of preparation obtained before particle diameter distribution changes rapidly it is filling, make finally to produce
Microballoon in product maintains the particle diameter distribution before freeze-drying, it is ensured that product quality.
Technical scheme is as follows:
A kind of preparation method of stable and uniform gas micro freeze-drying acoustic contrast agent, includes the following steps:
S1, injection solution is mixed according to prescription ratio, is mixed with magnetic stirring apparatus with the speed of 500 turns/min
Uniformly, working solution is made；
The working solution flow of S2, regulating step S1 preparation, makes it flow into sound and vibration room with appropriate speed, while adjusting carbon fluorine class
The flow of insoluble gas is added in sound and vibration room, starts to prepare microballoon, obtain work microballoon stoste；
S3, after in the microballoon stoste that works made from step S2 work microspheres quality stablize after, by work microballoon obtained
Stoste is continuously conveyed through piping to surge tank, directly uses bottle placer to carry out filling, by freeze-drying, lid, lamp are rolled in tamponade
Examine entire technical process to get.
Further, in the step S1 injection solution include following weight percent component:
The carbohydrate injection 20- that human serum albumin 25-45% that concentration is 50-90mg/mL, concentration are 100-135mg/mL
27%, concentration is the 0.9% sodium chloride injection 28-55% of 2.5-4.9mg/L.
Further, in the step S1 injection solution include following weight percent component:
Carbohydrate injection 23% that human serum albumin 30% that concentration is 60mg/mL, concentration are 110mg/mL, concentration are
The sodium chloride injection 47% of 4.2mg/mL.
Further, the carbohydrate injection is one of glucose injection, fructose injection, inverted sugar injection
Or it is several.
Further, in the step S2 carbon fluorine class insoluble gas be perfluoromethane, it is hexafluoroethane, perfluoropropane, complete
One or more of fluorine butane, Freon C318, R-4112.
Further, the flow of working solution is 15-180mL/min, the carbon fluorine class insoluble gas in the step S2
Flow be in 20-120mL/min.
Further, the flow of working solution is 35-90mL/min in the step S2, the carbon fluorine class insoluble gas
Flow is in 40-60mL/min.
Compared with prior art, technical advantage of the invention is as follows:
(1) preparation method of stable and uniform gas micro freeze-drying acoustic contrast agent provided by the invention, by controlling microballoon
The gas and liquid velocity ratio of preparatory phase are reasonably distributed the microspherulite diameter of preparation, and 2-7 μm of microballoon percentage can reach
77% or more, moreover, the preparation method of stable and uniform gas micro freeze-drying acoustic contrast agent provided by the invention does not need
Additional increase prepares microballoon semi-finished product, separates, screening, and the processing steps such as detection and adjustment greatly reduce process costs, improve
Product yield makes it be more suitable for industrialized production, while the present invention uses microballoon processed and the continual work of filling continuous production
Skill, it is short from microballoon processed to filling interval time, it is ensured that the microballoon of preparation obtained before particle diameter distribution changes rapidly it is filling,
The microballoon in final products is set to maintain the particle diameter distribution before freeze-drying, it is thus also avoided that pilot process discontinuously caused medicament microbiological contamination
The generation of phenomenon, it is ensured that product quality.
(2) acoustic contrast agent is lyophilized in stable and uniform gas micro provided by the invention, adjusts the ratio of each component, makes to make
The medicament particle diameter distribution obtained is uniform, and 2-7 μm of microballoon percentage is enable to reach 77% or more.
(3) stable and uniform gas micro freeze-drying acoustic contrast agent provided by the invention changes by adjusting the ratio of each component
Into preparation process, medicament pollution is reduced, while also ing save production cost, it is easy to accomplish industrialization.
Specific embodiment
The specific embodiment of form by the following examples makees further specifically above content of the invention
It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to following embodiment.
The preparation method of embodiment 1, a kind of stable and uniform gas micro freeze-drying acoustic contrast agent
The preparation method of the stable and uniform gas micro freeze-drying acoustic contrast agent, includes the following steps:
S1, injection solution is mixed according to prescription ratio, is mixed with magnetic stirring apparatus with the speed of 500 turns/min
Uniformly, working solution is made；
The working solution flow of S2, regulating step S1 preparation, makes it flow into sound and vibration room with 15mL/min speed, while adjusting carbon
The flow of fluorine class insoluble gas is 20mL/min, is added in sound and vibration room, starts to prepare microballoon, obtain work microballoon stoste；
S3, after in the microballoon stoste that works made from step S2 work microspheres quality stablize after, by work microballoon obtained
Stoste is continuously conveyed through piping to surge tank, directly uses bottle placer to carry out filling, by freeze-drying, lid, lamp are rolled in tamponade
Examine entire technical process to get.
Injection solution includes the component of following weight percent in the step S1:
Carbohydrate injection 20% that human serum albumin 25% that concentration is 50mg/mL, concentration are 100mg/mL, sodium chloride note
Penetrate liquid 55%.
The carbohydrate injection is made of glucose injection, fructose injection by weight 5:1.
Carbon fluorine class insoluble gas is made of perfluoromethane, hexafluoroethane by weight 2:3 in the step S2.
The preparation method of embodiment 2, a kind of stable and uniform gas micro freeze-drying acoustic contrast agent
The preparation method of the stable and uniform gas micro freeze-drying acoustic contrast agent, includes the following steps:
S1, injection solution is mixed according to prescription ratio, is mixed with magnetic stirring apparatus with the speed of 500 turns/min
Uniformly, working solution is made；
The working solution flow of S2, regulating step S1 preparation, makes it flow into sound and vibration room with 110mL/min speed, then adjusts
The flow of carbon fluorine class insoluble gas is 75mL/min, is added in sound and vibration room, starts to prepare microballoon, obtain work microballoon stoste；
S3, after in the microballoon stoste that works made from step S2 work microspheres quality stablize after, by work microballoon obtained
Stoste is continuously conveyed through piping to surge tank, directly uses bottle placer to carry out filling, by freeze-drying, lid, lamp are rolled in tamponade
Examine entire technical process to get.
Injection solution includes the component of following weight percent in the step S1:
Carbohydrate injection 26% that human serum albumin 45% that concentration is 90mg/mL, concentration are 130mg/mL, concentration are
0.9% sodium chloride injection 2 9% of 2.6mg/mL.
The carbohydrate injection is glucose injection.
Carbon fluorine class insoluble gas is perfluoropropane in the step S2.
The preparation method of embodiment 3, a kind of stable and uniform gas micro freeze-drying acoustic contrast agent
The preparation method of the stable and uniform gas micro freeze-drying acoustic contrast agent, includes the following steps:
S1, injection solution is mixed according to prescription ratio, is mixed with magnetic stirring apparatus with the speed of 500 turns/min
Uniformly, working solution is made；
The working solution flow of S2, regulating step S1 preparation, makes it flow into sound and vibration room with 80mL/min speed, then adjusts carbon
The flow of fluorine class insoluble gas is 55mL/min, is added in sound and vibration room, starts to prepare microballoon, obtain work microballoon stoste；
S3, after in the microballoon stoste that works made from step S2 work microspheres quality stablize after, by work microballoon obtained
Stoste is continuously conveyed through piping to surge tank, directly uses bottle placer to carry out filling, by freeze-drying, lid, lamp are rolled in tamponade
Examine entire technical process to get.
Injection solution includes the component of following weight percent in the step S1:
Concentration is 60mg/mL human serum albumin 30%, concentration is 110mg/mL carbohydrate injection 23%, concentration are
0.9% sodium chloride injection 47% of 4.2mg/mL.
The carbohydrate injection is made of glucose injection, fructose injection, inverted sugar injection by weight 2:3:1.
In the step S2 carbon fluorine class insoluble gas by perfluorinated butane, Freon C318, R-4112 by volume
6:2:5 composition.
The preparation method of embodiment 4, a kind of stable and uniform gas micro freeze-drying acoustic contrast agent
The preparation method of the stable and uniform gas micro freeze-drying acoustic contrast agent, includes the following steps:
S1, injection solution is mixed according to prescription ratio, is mixed with magnetic stirring apparatus with the speed of 500 turns/min
Uniformly, working solution is made；
The working solution flow of S2, regulating step S1 preparation, makes it flow into sound and vibration room with 180mL/min speed, then adjusts
The flow of carbon fluorine class insoluble gas is 120mL/min, is added in sound and vibration room, starts to prepare microballoon, obtain work microballoon stoste；
S3, after in the microballoon stoste that works made from step S2 work microspheres quality stablize after, by work microballoon obtained
Stoste is continuously conveyed through piping to surge tank, directly uses bottle placer to carry out filling, by freeze-drying, lid, lamp are rolled in tamponade
Examine entire technical process to get.
Injection solution includes the component of following weight percent in the step S1:
Carbohydrate injection 27% that human serum albumin 45% that concentration is 90mg/mL, concentration are 135mg/mL, concentration are
0.9% sodium chloride injection 28% of 2.5mg/L.
The carbohydrate injection can be inverted sugar injection.
Carbon fluorine class insoluble gas is Freon C318 in the step S2.
Comparative example 1, a kind of preparation method that acoustic contrast agent is lyophilized
The preparation method of the freeze-drying acoustic contrast agent, includes the following steps:
S1, injection solution is mixed according to prescription ratio, is mixed with magnetic stirring apparatus with the speed of 500 turns/min
Uniformly, working solution is made；
The working solution flow of S2, regulating step S1 preparation, makes it flow into sound and vibration room with 200mL/min speed, then adjusts
The flow of carbon fluorine class insoluble gas is 55mL/min, is added in sound and vibration room, starts to prepare microballoon, obtain work microballoon stoste；
S3, after in the microballoon stoste that works made from step S2 work microspheres quality stablize after, by work microballoon obtained
Stoste is continuously conveyed through piping to surge tank, directly uses bottle placer to carry out filling, by freeze-drying, lid, lamp are rolled in tamponade
Examine entire technical process to get.
Injection solution includes the component of following weight percent in the step S1:
Concentration is 60mg/mL human serum albumin 30%, concentration is 110mg/mL carbohydrate injection 23%, concentration are
0.9% sodium chloride injection 47% of 4.2mg/mL.
The carbohydrate injection is made of glucose injection, fructose injection, inverted sugar injection by weight 2:3:1.
In the step S2 carbon fluorine class insoluble gas by perfluorinated butane, Freon C318, R-4112 by volume
6:2:5 composition.
Comparative example 1 is substantially the same manner as Example 3, and difference is, treatment fluid flow enters the speed of sound and vibration room in 1 step S2 of comparative example
Degree improves.
Comparative example 2, a kind of preparation method that acoustic contrast agent is lyophilized
The preparation method of the freeze-drying acoustic contrast agent, includes the following steps:
S1, injection solution is mixed according to prescription ratio, is mixed with magnetic stirring apparatus with the speed of 500 turns/min
Uniformly, working solution is made；
The working solution flow of S2, regulating step S1 preparation, makes it flow into sound and vibration room with 80mL/min speed, then adjusts carbon
The flow of fluorine class insoluble gas is 150mL/min, is added in sound and vibration room, starts to prepare microballoon, obtain work microballoon stoste；
S3, after in the microballoon stoste that works made from step S2 work microspheres quality stablize after, by work microballoon obtained
Stoste is continuously conveyed through piping to surge tank, directly uses bottle placer to carry out filling, by freeze-drying, lid, lamp are rolled in tamponade
Examine entire technical process to get.
Injection solution includes the component of following weight percent in the step S1:
Concentration is 60mg/mL human serum albumin 30%, concentration is 110mg/mL carbohydrate injection 23%, concentration are
0.9% sodium chloride injection 47% of 4.2mg/mL.
The carbohydrate injection is made of glucose injection, fructose injection, inverted sugar injection by weight 2:3:1.
In the step S2 carbon fluorine class insoluble gas by perfluorinated butane, Freon C318, R-4112 by volume
6:2:5 composition.
Comparative example 2 is substantially the same manner as Example 3, and difference is, the stream of carbon fluorine class insoluble gas in 2 step S2 of comparative example
The flow for entering sound and vibration room improves.
Comparative example 3, a kind of preparation method that acoustic contrast agent is lyophilized
The preparation method of the freeze-drying acoustic contrast agent, includes the following steps:
S1, injection solution is mixed according to prescription ratio, is mixed with magnetic stirring apparatus with the speed of 500 turns/min
Uniformly, working solution is made；
The working solution flow of S2, regulating step S1 preparation, makes it flow into sound and vibration room with 80mL/min speed, then adjusts carbon
The flow of fluorine class insoluble gas is 55mL/min, is added in sound and vibration room, starts to prepare microballoon, obtain work microballoon stoste；
S3, after in the microballoon stoste that works made from step S2 work microspheres quality stablize after, by work microballoon obtained
Stoste is continuously conveyed through piping to surge tank, directly uses bottle placer to carry out filling, by freeze-drying, lid, lamp are rolled in tamponade
Examine entire technical process to get.
Injection solution includes the component of following weight percent in the step S1:
Concentration is 40mg/mL human serum albumin 20%, concentration is 135mg/mL carbohydrate injection 27%, concentration are
0.9% sodium chloride injection 53% of 4.7mg/L.
The carbohydrate injection is made of glucose injection, fructose injection, inverted sugar injection by weight 2:3:1.
In the step S2 carbon fluorine class insoluble gas by perfluorinated butane, Freon C318, R-4112 by volume
6:2:5 composition.
Comparative example 3 is substantially the same manner as Example 3, and difference is, the weight percent drop of human serum albumin in comparative example 3
Low, the weight percent of sodium chloride injection increases.
Comparative example 4, a kind of preparation method that acoustic contrast agent is lyophilized
The preparation method of the freeze-drying acoustic contrast agent, includes the following steps:
S1, injection solution is mixed according to prescription ratio, is mixed with magnetic stirring apparatus with the speed of 500 turns/min
Uniformly, working solution is made；
The working solution flow of S2, regulating step S1 preparation, makes it flow into sound and vibration room with 80mL/min speed, then adjusts carbon
The flow of fluorine class insoluble gas is 55mL/min, is added in sound and vibration room, starts to prepare microballoon, obtain work microballoon stoste；
S3, after in the microballoon stoste that works made from step S2 work microspheres quality stablize after, by work microballoon obtained
Stoste is continuously conveyed through piping to surge tank, directly uses bottle placer to carry out filling, by freeze-drying, lid, lamp are rolled in tamponade
Examine entire technical process to get.
Injection solution includes the component of following weight percent in the step S1:
Concentration is 90mg/mL human serum albumin 45%, concentration is 75mg/mL carbohydrate injection 15%, concentration are
0.9% sodium chloride injection 40% of 3.6mg/L.
The carbohydrate injection is made of glucose injection, fructose injection, inverted sugar injection by weight 2:3:1.
In the step S2 carbon fluorine class insoluble gas by perfluorinated butane, Freon C318, R-4112 by volume
6:2:5 composition.
Comparative example 4 is substantially the same manner as Example 3, and difference is, the weight percent drop of carbohydrate injection in comparative example 4
Low, the weight percent of sodium chloride injection increases.
Test example one, microspherulite diameter testing experiment
1. test material: the canned freeze-drying of freeze-drying acoustic contrast agent of embodiment 1-4 and the preparation of comparative example 1-4 preparation method
Preceding work microballoon stoste.
2. test method: the canned freeze-drying of freeze-drying acoustic contrast agent of example 1-4 to be performed and the preparation of comparative example 1-4 preparation method
After work microballoon stoste before is stablized, microballoon stoste is sampled, with the grain of Kurt particle size analyzer MS3 detection microballoon
Diameter.
3. test result: microballoon testing result is as shown in table 1:
1 microspherulite diameter of table and distributed data
It can be with the freeze-drying Ultrasound Contrast Agent microspheres partial size of embodiment 1-4 preparation method preparation is between 2-7 μm by table 1
Percentage reaches 77%, and microballoon concentration is all larger than 1.4 × 109A/mL, wherein 3 effect of embodiment is best, is of the invention best
Embodiment, in contrast, comparative example 1-4 microspherulite diameter homogeneity is poor, microballoon concentration decreases, and can be with by experimental data
Find out, gas liquid ratio appropriate can prevent the generation of larger microballoon and the present invention from realizing that the key technology of continuous production is wanted
Point.
Test example two, contrast agent stability test
1. test material: the freeze-drying acoustic contrast agent prepared according to embodiment 1-4 and comparative example 1-4 preparation method.
2. test method: respectively by test material at 2-10 DEG C of temperature, placed 3 months and 18 months under conditions of dry,
Test the quality of medicament.
3. test result: pharmacy quality stability data is shown in Table 2:
2 agent stability experimental test data of table
As can be seen from Table 2, the freeze-drying acoustic contrast agent that 1-4 of the embodiment of the present invention is provided places 3-18 months, stability
Well, microballoon concentration and 2-7 μm of microballoon accounting are basically unchanged.Therefore, it follows that freeze-drying acoustic contrast agent provided by the invention
Long-term to place, stabilization is never degenerated, and has long-time stability.
The influence of test example three, time of repose to microspheres quality
Test method: work microballoon stoste prepared by 3 preparation method of embodiment is received with 7 transparent ground conical flasks
Collect each 50mL of sound and vibration liquid, respectively sealing and standing 5min, 10min, 20min, 30min, 60min, 120min, 180min, observes molten
Liquid status, it is separately sampled to the sound and vibration liquid upper and lower part after each standing, detect microsphere average grain diameter, testing result and standing
Preceding comparison.The result shows that apparent lamination occurs in the sound and vibration liquid for standing 60min, 120min and 180min, stand 30min's
Sound and vibration liquid does not observe apparent layering, and the sound and vibration liquid top average grain diameter for standing 30min increases to 3.136 by 2.990, lower part
Average grain diameter is decreased to 2.814 by 2.990, illustrates that standing 30min or more causes major diameter microballoon top to be assembled, and affects microballoon
Homogeneity, the microsphere average grain diameter of the sound and vibration liquid upper and lower part within 10min is substantially unchanged, stands 20min upper flat
Equal partial size is 2.964, and lower part average grain diameter is slightly 2.941.Therefore, the time of repose of sound and vibration liquid controls within 10min not
It will affect product quality, the time of repose the short more can guarantee that the homogeneity of microballoon is unaffected.Therefore, when design technology of the present invention
It is required that carrying out directly filling, continuous operation while prepared by microballoon, it is ensured that be filled into bottle before the variation of microballoon homogeneity.
The above-described embodiments merely illustrate the principles and effects of the present invention, and is not intended to limit the present invention.It is any ripe
The personage for knowing this technology all without departing from the spirit and scope of the present invention, carries out modifications and changes to above-described embodiment.Cause
This, institute is complete without departing from the spirit and technical ideas disclosed in the present invention by those of ordinary skill in the art such as
At all equivalent modifications or change, should be covered by the claims of the present invention.
Claims (7)
1. a kind of preparation method of stable and uniform gas micro freeze-drying acoustic contrast agent, which comprises the steps of:
S1, injection solution is mixed according to prescription ratio, is mixed with magnetic stirring apparatus with the speed of 500 turns/min
It is even, working solution is made；
The working solution flow of S2, regulating step S1 preparation, makes it flow into sound and vibration room with appropriate speed, while it is insoluble to adjust carbon fluorine class
Property gas flow be added sound and vibration room in, start to prepare microballoon, obtain work microballoon stoste；
S3, after in the microballoon stoste that works made from step S2 microspheres quality stablize after, by work microballoon obtained through piping
It is continuously conveyed to surge tank, directly uses bottle placer to carry out filling, by freeze-drying, lid, the entire technique mistake of lamp inspection are rolled in tamponade
Journey to get.
2. the preparation method of stable and uniform gas micro freeze-drying acoustic contrast agent as described in claim 1, which is characterized in that institute
State the component that injection solution in step S1 includes following weight percent:
The carbohydrate injection 20- that human serum albumin 25-45% that concentration is 50-90mg/mL, concentration are 100-135mg/mL
27%, concentration is the 0.9% sodium chloride injection 28-55% of 2.5-4.9mg/L.
3. the preparation method of stable and uniform gas micro freeze-drying acoustic contrast agent as claimed in claim 1 or 2, feature exist
In injection solution includes the component of following weight percent in the step S1:
Carbohydrate injection 23% that human serum albumin 30% that concentration is 60mg/mL, concentration are 110mg/mL, concentration 4.2mg/
The sodium chloride injection 47% of mL.
4. the preparation method of stable and uniform gas micro freeze-drying acoustic contrast agent as claimed in claim 2 or claim 3, feature exist
In the carbohydrate injection is one or more of glucose injection, fructose injection, inverted sugar injection.
5. the preparation method of stable and uniform gas micro freeze-drying acoustic contrast agent as described in claim 1, which is characterized in that institute
Stating carbon fluorine class insoluble gas in step S2 is perfluoromethane, hexafluoroethane, perfluoropropane, perfluorinated butane, Freon C318, ten
One or more of difluoropentane.
6. the preparation method of stable and uniform gas micro freeze-drying acoustic contrast agent as described in claim 1, which is characterized in that institute
The flow for stating working solution in step S2 is 15-180mL/min, and the flow of the carbon fluorine class insoluble gas is in 20-120mL/
min。
7. the preparation method of stable and uniform gas micro freeze-drying acoustic contrast agent as claimed in claim 6, which is characterized in that institute
The flow for stating working solution in step S2 is 35-90mL/min, and the flow of the carbon fluorine class insoluble gas is in 40-60mL/
min。
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| CN114010805A (en) * | 2021-10-13 | 2022-02-08 | 力品药业(厦门)股份有限公司 | Stabilizer-containing microsphere, preparation method and application thereof |
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Address after: 361027 building 6, 2010 wengjiao West Road, Haicang District, Xiamen City, Fujian Province Applicant after: Lipin Pharmaceutical (Xiamen) Co.,Ltd. Applicant after: LP PHARMACEUTICAL (XIAMEN) Co.,Ltd. Address before: 361027 building 6, 2010 wengjiao West Road, Haicang District, Xiamen City, Fujian Province Applicant before: Lipin Pharmaceutical (Xiamen) Co.,Ltd. Applicant before: LP PHARMACEUTICAL (XIAMEN) Co.,Ltd. |
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Application publication date: 20190809 |