CN108078929A - A kind of preparation method of Bupivacaine multivesicular liposome and Bupivacaine multivesicular liposome preparation - Google Patents
A kind of preparation method of Bupivacaine multivesicular liposome and Bupivacaine multivesicular liposome preparation Download PDFInfo
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- CN108078929A CN108078929A CN201711498422.6A CN201711498422A CN108078929A CN 108078929 A CN108078929 A CN 108078929A CN 201711498422 A CN201711498422 A CN 201711498422A CN 108078929 A CN108078929 A CN 108078929A
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- bupivacaine
- preparation
- multivesicular liposome
- colostrum
- emulsion
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
- A61K9/1273—Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1277—Processes for preparing; Proliposomes
Abstract
The invention discloses a kind of preparation method of Bupivacaine multivesicular liposome and Bupivacaine multivesicular liposome preparations, are related to Bupivacaine field of pharmaceutical preparations.The preparation method of the Bupivacaine multivesicular liposome, including:The first solution that neutral fats obtains being formed emulsion is added in into the colostrum mutually formed with the first water containing Bupivacaine by the oil phase containing organic solvent.Compared to the preparation method of existing Bupivacaine multivesicular liposome, the preparation method of the present invention, by mutually forming the step of adding neutral fats after colostrum with the first water containing Bupivacaine by the oil phase containing organic solvent, the Crushing Problem of the multivesicular liposome caused by subsequently removal organic solvent step can be overcome, make the multivesicular liposome form rounding prepared, substantially without phosphatide fragment, the long-acting slow-release effect of raising Bupivacaine drug.
Description
Technical field
The present invention relates to Bupivacaine field of pharmaceutical preparations, in particular to a kind of Bupivacaine multivesicular liposome
Preparation method and Bupivacaine multivesicular liposome preparation.
Background technology
Bupivacaine is 1 class drugs of BCS, good water solubility, but half-life short, for its injection is made to reach long-acting slow-release
Effect is usually developed the dosage form for multivesicular liposome.
The microstructure of multivesicular liposome (MVLs) polymerize globulate for multiple liposomes, each liposome by hydrophobic membrane and
Inner aqueous phase forms, and drug is dissolved in inner aqueous phase.Multivesicular liposome is dispersed in water phase, injection can be formed.Multivesicular liposome
A kind of nonconcentric(al) cellular liposome, inside have the vesicas separated by lipid bilayer of many big sizes, it is this solely
Special structure assigns the stronger rigidity of liposome, and when some capsules rupture therein, drug is simply released from the vesica of rupture
It puts, complete vesica can still maintain the original state, this causes not prominent when the percolation ratio of drug reduces and drug is discharged from liposome
Phenomenon is released, realizes that control drug slowly discharges in one day time range to several weeks.
But observed under the microscope using the multivesicular liposome containing Bupivacaine prepared by existing method, there is rupture
Multivesicular liposome and broken phosphatide fragment, and sample particle diameter has reduction.The long-acting slow-release effect of multivesicular liposome mainly according to
The nonconcentric(al) cellular realizations of Lai Yu, gradual breakdown releases drug from outside to inside during release.Broken multivesicular liposome can make
Drug is unable to reach the long-acting slow-release effect of anticipation or even phenomena such as burst release occurs, influences medication effect.
In consideration of it, special propose the present invention.
The content of the invention
It is an object of the invention to provide a kind of preparation methods of Bupivacaine multivesicular liposome, can greatly reduce cloth
Than the effect of rupture quantity or even realization without broken Bupivacaine multivesicular liposome of cacaine multivesicular liposome.
Another object of the present invention is to provide a kind of Bupivacaine multivesicular liposome preparation.
What the present invention was realized in:
A kind of preparation method of Bupivacaine multivesicular liposome, including:Toward by the oil phase containing organic solvent and containing
Neutral fats obtains being formed emulsion the is added in colostrum (i.e. W/O Water-In-Oils colostrum) that first water of Bupivacaine is mutually formed
One solution.
Further, in some embodiments of the present invention, above-mentioned neutral fats is tricaprylin (TC).
Neutral fats such as TC, only hydrophobic side, no water-wet side is the key that multiple liposomes is made to be combined into multivesicular liposome
Material.
Further, in some embodiments of the present invention, after neutral fats is added in into colostrum, preparation method is also wrapped
Include emulsion forming step:
Emulsion forming step includes:First solution is placed under preset temperature and is stirred, preset temperature is greater than or equal to
41℃。
But inventor flows colostrum it has furthermore been found that if the excessively high organic solvent that can make in oil phase of heating temperature volatilizees
Property reduce and be difficult to shift.
Further, in some embodiments of the present invention, preset temperature is 41-55 DEG C.
Further, in some embodiments of the present invention, the speed of stirring is less than 5000rpm, the time of stirring
1-5min。
Further, in some embodiments of the present invention, the speed of stirring is 2000-5000rpm.
By the speed control of stirring in 2000-5000rpm, mixing time is controlled in 1-5min, on the one hand can making
Property fat be dispersed in oil phase, while keep the structural integrity of colostrum, avoid stirring destruction caused by colostrum structure.
Further, in some embodiments of the present invention, emulsion forming step further includes:
First solution and the second water are mixed, obtain being formed the second solution of emulsion.
Further, in some embodiments of the present invention, the second water mutually contains:30-35mg/mL glucose and 8-
12mM lysines.
Further, in some embodiments of the present invention, emulsion forming step further includes:
Above-mentioned second solution is sheared, forms emulsion (the W/O/W W/O/W emulsions i.e. containing Bupivacaine).
Further, in some embodiments of the present invention, the speed sheared to the second solution is 3500-
4500rpm, time 15-30s.
Further, in some embodiments of the present invention, after emulsion forming step, which also wraps
It includes:Organic solvent removal step;
Organic solvent removal step is:It is mixed with emulsion to remove the organic solvent in emulsion with inert gas.
For example with to remove organic solvent in a manner of inert gas flow and emulsion liquid flow mixed aerosol or will be lazy
Property gas, which is filled in emulsion, removes organic solvent.
Further, in some embodiments of the present invention, inert gas is nitrogen.
Further, in some embodiments of the present invention, Bupivacaine in the addition and colostrum of neutral fats
Mass ratio is 3:(80-120).
The dosage of neutral fats such as TC may influence the slow release effect of drug within the specific limits, and neutral fats dosage increases
Add, may cause:1. multivesicular liposome grain size increases, but because product finally has the step of control grain size, therefore multivesicular liposome can
It can generate broken;2. multivesicular liposome is more rigid, sustained drug release effect is influenced, is affected the treatment.
If extreme excessive or too small of neutral fats dosage, may influence to prepare effect for example can not cause breast, Cheng Dan
Capsule etc..
Further, in some embodiments of the present invention, the solvent of the first water phase be water, the first water mutually also contain with
The combination of one or more of lower solute:Glucuronic acid, hydrochloric acid and phosphoric acid;
The solvent of oil phase is the combination of one or more of organic solvent, the solute that oil phase contains:Two mustard acyl group lecithins
Fat (DEPC), dipalmitoylphosphatidylglycerol (DPPG) and cholesterol.
Wherein, DEPC and DPPG is both sexes fat, i.e. phospholipid molecule, has hydrophilic group and hydrophobic group, is main into membrane material
Material.
Further, in some embodiments of the present invention, in the first water phase containing 50-65mg/mL Bupivacaines,
140-160mM glucuronic acids, 13-17mM hydrochloric acid and 18-22mM phosphoric acid.
Contain in oil phase:16.5-19.5mM DEPC, 3.5-4.8mM DPPG and 28-32mM cholesterol.
Further, in some embodiments of the present invention, before neutral fats is added in toward colostrum, preparation method is also wrapped
Include colostrum forming step;
Colostrum forming step includes:First water phase and oil phase are mixed, is placed in ice bath (0-10 DEG C) and is sheared.
The mixed liquor that first water phase and oil phase mix under condition of ice bath is sheared, the temperature of solution is reduced, avoids
Organic solvent volatilization in oil phase.
Further, in some embodiments of the present invention, the condition of shearing is:Rotating speed 15000-17000rpm, when
Between 7-12min.
Further, in some embodiments of the present invention, the volume ratio of oil phase and the first organic phase is 1:(2-8).
Inventor has found, if the ratio between the first water phase and oil phase are 1:When 1, it is very poor that colostrum forms rear mobility, is unfavorable for
It realizes the follow-up dispersiveness for adding in TC, increases oil phase volume, make TC dispersible uniformly.But oil phase volume addition usage amount is excessive,
Two links can be impacted:
(1) needed before forming emulsion except a greater amount of organic solvents, energy loss, cost increases;
(2) formed before emulsion not except organic solvent, emulsion may be influenced and form effect, it is difficult to form more capsule lipids
Body, and be inclined to and form single capsule liposome or when except organic solvent, a large amount of organic solvents are pulled away, and liposome is caused to rupture, broken
Piece increases.
Further, in some embodiments of the present invention, organic solvent is chloroform or dichloromethane.
A kind of Bupivacaine multivesicular liposome preparation, is prepared by preparation method as described above.The Bupivacaine
Broken multivesicular liposome is not contained even containing less broken multivesicular liposome in multivesicular liposome preparation.
Another object of the present invention is to provide a kind of Bupivacaine multivesicular liposome preparation facilities.
The invention has the advantages that:
Compared to the preparation method of existing Bupivacaine multivesicular liposome, the more capsule lipids of Bupivacaine provided by the invention
The preparation method of body, including into the colostrum mutually formed with the first water containing Bupivacaine by the oil phase containing organic solvent
Add in the step of neutral fats obtains forming the first solution of emulsion;The preparation method is by forming after colostrum again in ancient times
Neutral fats is added in breast can overcome the Crushing Problem of the multivesicular liposome caused by subsequently removal organic solvent step, make preparation
The multivesicular liposome form rounding gone out, substantially without phosphatide fragment, the long-acting slow-release effect of raising Bupivacaine drug.
In addition, Bupivacaine multivesicular liposome preparation facilities provided by the invention can be realized and be initially formed colostrum, add
Neutral fats is mixed to get to form the first solution of emulsion, can be prepared without phosphatide fragment and form rounding by the device
Multivesicular liposome.
Description of the drawings
It in order to illustrate the technical solution of the embodiments of the present invention more clearly, below will be to needed in the embodiment attached
Figure is briefly described, it should be understood that the following drawings illustrates only certain embodiments of the present invention, therefore is not construed as pair
The restriction of scope, for those of ordinary skill in the art, without creative efforts, can also be according to this
A little attached drawings obtain other relevant attached drawings.
Fig. 1 is containing cloth prepared by the preparation method of the Bupivacaine multivesicular liposome provided as the embodiment of the present invention 1
Than cacaine multivesicular liposome emulsion except the morphologic observation figure under the microscope before organic solvent;
The preparation method institute for the Bupivacaine multivesicular liposome that Fig. 2 is provided for the embodiment of the present invention by the embodiment of the present invention 1
The emulsion for the multivesicular liposome containing Bupivacaine prepared is except the morphologic observation figure under the microscope after organic solvent;
Fig. 3 is containing cloth prepared by the preparation method of the Bupivacaine multivesicular liposome provided as comparative example 1 of the present invention
Than cacaine multivesicular liposome emulsion except the morphologic observation figure under the microscope before organic solvent;
Fig. 4 is the ratio containing cloth prepared by the preparation method for the Bupivacaine multivesicular liposome that comparative example 1 of the present invention provides
The emulsion of cacaine multivesicular liposome is except the morphologic observation figure under the microscope after organic solvent;
Fig. 5 is the structure diagram for the Bupivacaine multivesicular liposome preparation facilities that the embodiment of the present invention 2 provides;
Fig. 6 is the internal structure schematic diagram for the three-way device that the embodiment of the present invention 2 provides;
Fig. 7 is the internal structure schematic diagram that the three-way device that the embodiment of the present invention 2 provides is equipped with sieve;
Fig. 8 is the ratio containing cloth prepared by the preparation method for the Bupivacaine multivesicular liposome that the embodiment of the present invention 3 provides
The emulsion of cacaine multivesicular liposome is except the morphologic observation figure under the microscope after organic solvent;
Fig. 9 is the ratio containing cloth prepared by the preparation method for the Bupivacaine multivesicular liposome that the embodiment of the present invention 4 provides
The emulsion of cacaine multivesicular liposome is except the morphologic observation figure under the microscope after organic solvent;
Figure 10 is the ratio containing cloth prepared by the preparation method for the Bupivacaine multivesicular liposome that the embodiment of the present invention 5 provides
The emulsion of cacaine multivesicular liposome is except the morphologic observation figure under the microscope after organic solvent;
Figure 11 is the ratio containing cloth prepared by the preparation method for the Bupivacaine multivesicular liposome that the embodiment of the present invention 6 provides
The emulsion of cacaine multivesicular liposome is except the morphologic observation figure under the microscope after organic solvent;
Figure 12 is the ratio containing cloth prepared by the preparation method for the Bupivacaine multivesicular liposome that the embodiment of the present invention 7 provides
The emulsion of cacaine multivesicular liposome is except the morphologic observation figure under the microscope after organic solvent;
Figure 13 is the ratio containing cloth prepared by the preparation method for the Bupivacaine multivesicular liposome that the embodiment of the present invention 8 provides
The emulsion of cacaine multivesicular liposome is except the morphologic observation figure under the microscope after organic solvent.
Icon:1- the first water phase holding vessels, 2- oil phase holding vessels, 3- neutral fats holding vessels, 4- the first water phase holding vessel controls
Valve processed, 5- oil phase holding vessel control valves, 6- neutral fats holding vessel control valves, 7- temperature controllers, 8- colostrum retort, 9- colostrums
Flow control valve, 10- the second water phase holding vessels, 11- the second water phase holding vessel control valves, 12- emulsion retort, 13- emulsion streams
Fast control valve, 14- three-way devices, 15- nitrogen gas generators, 16- nitrogen gas control valves, the 3rd water phase holding vessels of 17-, the 3rd water of 18-
Phase holding vessel control valve, 19- multivesicular liposome receiving tanks, 121- emulsions enter pipeline;141- outlet ends, 151- nitrogen enter pipe
Road.
Specific embodiment
It, below will be in the embodiment of the present invention to make the purpose, technical scheme and advantage of the embodiment of the present invention clearer
Technical solution be clearly and completely described.The person that is not specified actual conditions in embodiment, builds according to normal condition or manufacturer
The condition of view carries out.Reagents or instruments used without specified manufacturer is the conventional production that can be obtained by commercially available purchase
Product.
The feature and performance of the present invention are described in further detail with reference to embodiments.
Embodiment 1
The preparation method of Bupivacaine multivesicular liposome provided in this embodiment, includes the following steps:
1 forms Water-In-Oil colostrum (W/O)
5mL the first water phases and 25mL oil phases mix to (the first water phase and the volume of oil phase are 1:5), it is placed in ice bath, with
The rotating speed cutting 9min of 16000rpm forms Water-In-Oil colostrum.
Wherein, the composition of the first water phase is as follows:
Solvent is water;
Solute is:60mg/mL Bupivacaines, 150mM glucuronic acids, 15mM hydrochloric acid and 20mM phosphoric acid.
The composition of oil phase is as follows:
Organic solvent is dichloromethane;
Solute is:18.6mM DEPC, 4.2mM DPPG and 30mM cholesterol.
2 add neutral fats (TC)
TC 9mg are added in into the colostrum obtained by above-mentioned steps, and (TC additions and the mass ratio of Bupivacaine in colostrum are
3:100) colostrum, is heated to 41 DEG C, 4min is stirred with the rotating speed of below 4500rpm.
3 form W/O/W emulsion (W/O/W)
3.1 will through step 2, treated that colostrum is transferred in 25mL the second water phases, 4000rpm shearing 20s, formation contains
The emulsion of Bupivacaine multivesicular liposome.
Wherein, the composition of the second water phase is as follows:
Solvent is water;
Solute is:32mg/mL glucose and 10mM lysine solutions.
The grain size and form of sampling detection multivesicular liposome, the results are shown in Table 1 and Fig. 1.
3.2 remove organic solvent
Nitrogen is mixed with above-mentioned emulsion, to remove the organic solvent dichloromethane in emulsion.
The change of size and form of sampling detection multivesicular liposome, the results are shown in Table 1 and Fig. 2.
3.3 centrifugal concentratings (optional step)
It is molten with 0.9% sodium chloride to remove the rotating speed centrifugation 10min with 200 × g, precipitation except the emulsion after organic solvent
Liquid is washed 3 times, obtains the solution of the multivesicular liposome containing Bupivacaine.
Certainly, in some embodiments, it is also possible to directly mix the emulsion after removal organic solvent with the 3rd water, obtain
To the dispersion solvent of Bupivacaine multivesicular liposome.
The composition of 3rd water phase is mutually identical with the second water.
Comparative example 1
The preparation method for the Bupivacaine multivesicular liposome that this comparative example provides is existing preparation method, operating procedure
It is substantially the same manner as Example 1, unlike, in this comparative example, containing 9mg TC in oil phase, that is, it is interpreted as forming colostrum
First add in the process have a TC or colostrum formed before used TC, which does not have the step 2 of embodiment 1.
Using grain of the Bupivacaine multivesicular liposome that the preparation method of this comparative example 1 obtains before and after organic solvent is removed
Footpath size variation is shown in Table 1, removes more capsule lipid morphologic observation results before and after organic solvent as shown in Figure 3 and Figure 4.
Table 1
In table 1, Span is span, Span=(D90-D10)/D50, reflects the width degree of grain size normal distribution,
Span is smaller, and particle diameter distribution is more homogeneous, narrower.
It can be seen that from 1 result of table, the multivesicular liposome of comparative example 1 grain size after organic solvent is removed substantially becomes smaller, and real
Apply the Bupivacaine multivesicular liposome of the example 1 change of size unobvious before and after organic solvent is removed;
And the form that the Bupivacaine multivesicular liposome of Fig. 1 and Fig. 2 display embodiments 1 is observed under the microscope is as a result, can
To find out, the Bupivacaine multivesicular liposome of embodiment 1 is complete before and after organic solvent is removed, without breakage;And comparative example 1
Bupivacaine multivesicular liposome is complete before organic solvent is removed, without damaged (as shown in Figure 3), but has after organic solvent removes
It crushes (as shown by the arrows in figure 4).Embodiment 2
As shown in figure 5, present embodiments provide the preparation side suitable for the Bupivacaine multivesicular liposome described in embodiment 1
The Bupivacaine multivesicular liposome preparation facilities of method, including:
First water phase holding vessel 1, oil phase holding vessel 2, neutral fats holding vessel 3, the first water phase holding vessel control valve 4, oil phase
Holding vessel control valve 5, neutral fats holding vessel control valve 6, temperature controller 7, colostrum retort 8, colostrum flow control valve 9, the
Two water phase holding vessels 10, the second water phase holding vessel control valve 11, emulsion retort 12, emulsion flow control valve 13, three-way device
14, nitrogen gas generator 15, nitrogen gas control valve 16, the 3rd water phase holding vessel 17, the 3rd water phase holding vessel control valve 18 and more capsules
Liposome receiving tank 19.
Wherein, colostrum retort 8, the first mixed solution being mixed to form for reception by the first water phase and oil phase simultaneously should
First mixed solution forms colostrum.
Neutral fats holding vessel 3, for storing neutral fats, the conveyance conduit that neutral fats holding vessel 3 is connected with colostrum retort 8
On be provided with neutral fats holding vessel control valve 6, for controlling the conveying of neutral fats.
Temperature controller 7 is provided with to control liquid in colostrum retort 8 in colostrum retort 8;Temperature controls
Device 7 can be used for temperature (such as 0-10 DEG C) when control is formed colostrum by the first mixed solution and when neutral fats addition colostrum
Afterwards 41 DEG C or more are for example heated to for heating colostrum.
First water phase holding vessel 1 and oil phase holding vessel 2 are respectively used to the first water phase of storage and oil phase.Certainly, the first water phase
The first water phase holding vessel control valve 4 is provided on the conveyance conduit that holding vessel 1 is connected with colostrum retort 8, for controlling first
The conveying of water phase;Oily holding vessel control valve 5 is provided on the conveyance conduit that oil phase holding vessel 2 is connected with colostrum retort 8, is used
In the conveying of control oil phase.
Oily holding vessel control valve, the first water phase holding vessel control valve and neutral fats holding vessel control valve work independently from each other.
Have in the conveyance conduit of the first water phase and the conveyance conduit end of oil phase close to the end of colostrum retort 8 and use
In by the mixing duct of the first water phase and oil phase interflow, what which can collaborate to be formed by the first water phase and oil phase first mixes
Solution is closed to be passed through in colostrum retort 8.The mixing duct is with conveying the conveyance conduit of neutral fats independently of each other or separating or separate
Or it does not disturb.
Certainly, in other examples, the first water phase and oil phase can also be each led into after colostrum retort 8 and mixed again
It closes.
Emulsion retort 12, for receiving by the colostrum from colostrum retort 8 and from the second water phase holding vessel 10
The second mixed solution that second water is mutually formed, and second mixed solution is formed into emulsion.
It is provided with to control the colostrum of colostrum flow velocity on the conveyance conduit that colostrum retort 8 is connected with emulsion retort 12
Flow control valve 9;The second water is provided on the conveyance conduit that second water phase holding vessel 10 is connected with emulsion retort 12 mutually to store
Tank control valve.
Three-way device 14, for the nitrogen from nitrogen gas generator 15 and the emulsion from emulsion retort 12 to be mixed,
To remove the organic solvent in emulsion.
Wherein, the internal structure of three-way device 14 is as shown in fig. 6, there is three-way device 14 nitrogen to enter pipeline 151 and answer
Into pipeline 121, emulsion enters the package nitrogen of pipeline 121 and enters pipeline 151 breast.The nitrogen and answer that nitrogen enters in pipeline 151
The emulsion of breast into pipeline 121 is mixed in the outlet end 141 close to three-way device 14, to form Bupivacaine multivesicular liposome,
Mixed solution flows to multivesicular liposome receiving tank 19 through outlet end 141.
In some other embodiments, the outlet end 141 of three-way device 14 is provided with sieve 142 (as shown in Figure 7),
For controlling and/or uniforming the grain size of Bupivacaine multivesicular liposome.
Wherein, nitrogen gas control valve 16 is provided on the conveyance conduit that nitrogen gas generator 15 is connected with three-way device 14.
It is provided with to control the emulsion of emulsion flow velocity on the conveyance conduit that emulsion retort 12 is connected with three-way device 14
Flow control valve 13.
Multivesicular liposome receiving tank 19, for receiving the emulsion after the removal organic solvent of three-way device 14.
3rd water phase holding vessel 17, for storing the 3rd water phase;On the conveyance conduit of the 3rd water phase holding vessel 17 connection
The 3rd water phase holding vessel control valve 18 is provided with, for controlling the conveying of the 3rd water phase.
3rd water phase can be made with going 151 to be mixed except the emulsion after organic solvent by the 3rd water phase holding vessel control valve 18
It closes, forms the dispersion solvent of Bupivacaine multivesicular liposome.
It should be noted that the 3rd water phase is identical with the second water phase composition in embodiment 1.
Bupivacaine multivesicular liposome preparation facilities provided in this embodiment adds neutral fats, it can be achieved that being initially formed colostrum
The purpose of emulsion is mixed to form, and then is prepared containing the less Bupivacaine for being even free of reduction ratio cacaine multivesicular liposome
The dispersion solvent of multivesicular liposome.
Embodiment 3
The preparation method of Bupivacaine multivesicular liposome provided in this embodiment is substantially the same manner as Example 1, unlike,
In the present embodiment, the organic solvent of oil phase is chloroform.Bupivacaine multivesicular liposome prepared by the present embodiment is in microscope
Under morphologic observation result as shown in Fig. 8.
Fig. 8 is the results show that the multivesicular liposome that the present embodiment is prepared is free of phosphatide fragment and form rounding.
Embodiment 4
The preparation method of Bupivacaine multivesicular liposome provided in this embodiment is substantially the same manner as Example 1, unlike,
In the present embodiment, in step 2, colostrum is heated to 55 DEG C.Bupivacaine multivesicular liposome prepared by the present embodiment exists
The results are shown in Figure 9 for morphologic observation under microscope.
Fig. 9 is the results show that the multivesicular liposome that the present embodiment is prepared is free of phosphatide fragment and form rounding.
Embodiment 5
The preparation method of Bupivacaine multivesicular liposome provided in this embodiment is substantially the same manner as Example 1, unlike,
In the present embodiment, the volume ratio of the first water phase and oil phase is 1:8.
The morphologic observation result such as Figure 10 institutes of Bupivacaine multivesicular liposome under the microscope prepared by the present embodiment
Show.
Figure 10 is the results show that the multivesicular liposome that the present embodiment is prepared is free of phosphatide fragment and form rounding.
Embodiment 6
The preparation method of Bupivacaine multivesicular liposome provided in this embodiment is substantially the same manner as Example 1, unlike,
In the present embodiment, the volume ratio of the first water phase and oil phase is 1:2.
The morphologic observation result such as Figure 11 institutes of Bupivacaine multivesicular liposome under the microscope prepared by the present embodiment
Show.
Figure 11 is the results show that the multivesicular liposome that the present embodiment is prepared is free of phosphatide fragment and form rounding.
Embodiment 7
The preparation method of Bupivacaine multivesicular liposome provided in this embodiment is substantially the same manner as Example 1, unlike,
In the present embodiment, in step 2, (mass ratio of TC additions and Bupivacaine in colostrum is 3:120.
The morphologic observation result such as Figure 12 institutes of Bupivacaine multivesicular liposome under the microscope prepared by the present embodiment
Show.
Figure 12 is the results show that the multivesicular liposome that the present embodiment is prepared is free of phosphatide fragment and form rounding.
Embodiment 8
The preparation method of Bupivacaine multivesicular liposome provided in this embodiment is substantially the same manner as Example 1, unlike,
In the present embodiment, in step 2, (mass ratio of TC additions and Bupivacaine in colostrum is 3:80.
The morphologic observation result such as Figure 13 institutes of Bupivacaine multivesicular liposome under the microscope prepared by the present embodiment
Show.
Figure 13 is the results show that the multivesicular liposome that the present embodiment is prepared is free of phosphatide fragment and form rounding.
To sum up, the preparation method of Bupivacaine multivesicular liposome provided in an embodiment of the present invention is by forming after colostrum
The Crushing Problem of the multivesicular liposome caused by subsequently removal organic solvent step can be overcome by adding in neutral fats into colostrum again,
Make the multivesicular liposome form rounding prepared, substantially without phosphatide fragment, the long-acting slow-release effect of raising Bupivacaine drug.
The foregoing is only a preferred embodiment of the present invention, is not intended to limit the invention, for the skill of this field
For art personnel, the invention may be variously modified and varied.Within the spirit and principles of the invention, that is made any repaiies
Change, equivalent substitution, improvement etc., should all be included in the protection scope of the present invention.
Claims (10)
1. a kind of preparation method of Bupivacaine multivesicular liposome, which is characterized in that it includes:Toward by the oil containing organic solvent
The first solution that neutral fats obtains being formed emulsion is added in the colostrum mutually mutually formed with the first water containing Bupivacaine.
2. the preparation method of Bupivacaine multivesicular liposome according to claim 1, which is characterized in that in the past colostrum
After the middle addition neutral fats, the preparation method further includes emulsion forming step:
The emulsion forming step includes:First solution is placed under preset temperature and is stirred, the preset temperature is big
In or equal to 41 DEG C.
3. the preparation method of Bupivacaine multivesicular liposome according to claim 2, which is characterized in that the preset temperature
For 41-55 DEG C.
4. the preparation method of Bupivacaine multivesicular liposome according to claim 2, which is characterized in that the speed of stirring is low
In 5000rpm, the time of stirring is 1-5min.
5. according to the preparation method of claim 2-4 any one of them Bupivacaine multivesicular liposomes, which is characterized in that described
Emulsion forming step further includes:
First solution after will be agitated is mixed with the second water, obtains being formed the second solution of emulsion.
6. according to the preparation method of claim 1-4 any one of them Bupivacaine multivesicular liposomes, which is characterized in that described
The mass ratio of the addition of neutral fats and the Bupivacaine in the colostrum is 3:(80-120).
7. according to the preparation method of claim 1-4 any one of them Bupivacaine multivesicular liposomes, which is characterized in that described
The solvent of first water phase is water, and first water mutually also contains the combination of one or more of following solute:Glucuronic acid,
Hydrochloric acid and phosphoric acid;
The solvent of the oil phase is organic solvent, and the oil phase contains the combination of one or more of following solute:Two mustard acyls
Base lecithin, dipalmitoylphosphatidylglycerol and cholesterol.
8. according to the preparation method of claim 1-4 any one of them Bupivacaine multivesicular liposomes, which is characterized in that past
The colostrum is added in before the neutral fats, and the preparation method further includes colostrum forming step;
The colostrum forming step includes:The first water phase and the oil phase are mixed, is placed in ice bath and is sheared.
9. the preparation method of Bupivacaine multivesicular liposome according to claim 8, which is characterized in that the first water phase
Volume ratio with the oil phase is 1:(2-8).
10. a kind of Bupivacaine multivesicular liposome preparation, which is characterized in that it is by claim 1-9 any one of them cloth ratio
The preparation method of cacaine multivesicular liposome is made.
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