CN1468596A - Liposome producing process and apparatus - Google Patents
Liposome producing process and apparatus Download PDFInfo
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- CN1468596A CN1468596A CNA021326509A CN02132650A CN1468596A CN 1468596 A CN1468596 A CN 1468596A CN A021326509 A CNA021326509 A CN A021326509A CN 02132650 A CN02132650 A CN 02132650A CN 1468596 A CN1468596 A CN 1468596A
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Abstract
The liposome producing apparatus is one preparing tank with sealed cover, injecting port and valve, inside rotary material holder with driving magnet, and magnetic diver outside the tank to drive the magnet. After the compounded material is painted to the magnetically material holder and CO2 is injected into the tank to reach critical, subcritical or supercritical state, the material holder is rotated, CO2 is released to lower the pressure inside the tank and dispersant liquid is injected into the tank to form medicinal liposome. The said liposome producing process is fast, high in efficiency and suitable for industrial production.
Description
Technical field: the present invention relates to a kind of production method and equipment of producing fat-soluble active ingredient liposome, particularly utilize method and the special equipment of subcritical critical or postcritical carbon dioxide, as the preparation method and the specialized apparatus of medicine or lipid of cosmetics as solvent production liposome.
Background technology: the biphase dispersion method production technology of existing medicinal liposome, all be to adopt organic solvent that phospholipid, sterin (as cholesterol) and fat-soluble active matter are dissolved, reclaim organic solvent with boulton process then, and form the liposome that is enclosed with fat-soluble active ingredient.This method production process, organic solvent is inflammable and explosive, safety inadequately, and easily residual in the medicine organic solvent arranged.Main is that the liposome mixture of producing like this has not by liposomal encapsulated free active ingredient.Bibliographical information is arranged in recent years.The liposome rate (envelop rate) that these methods obtain is only 35～65%.As replacing organic solvent with critical or postcritical carbon dioxide, with phospholipid, sterin, the allotment of fat-soluble active ingredient, and mix with supercritical carbon dioxide, utilize CO 2 fluid high density and similar gas like lower viscosity, feature with very big diffusion coefficient (diffusion velocity of similar gas) is dissolved the raw material that forms liposome medicament.After the dissolving pressure and temperature is returned to the normal temperature and pressure process, dissolved composition just separates with carbon dioxide, and carbon dioxide is released recovery.Employed production equipment all is highly compressed preparation jar, and the preparation jar has openable seal cover.The raw material of configuration is put into the preparation jar, or is applied in tank skin.The experiment proved that as just adding arbitrarily and release of carbon dioxide, the active ingredient that then has part not to be wrapped equally can not form good liposome.In actual production process, only keep half an hour to one hour as the critical state of carbon dioxide or subcritical state, liposome encapsulation can only reach about 80%.Main is so simple dissolving, and a little raw materials can not be dissolved in supercritical carbon dioxide fully, and the liposome of formation causes envelop rate to reduce greatly with inhomogeneous sometimes.And, if the raw material that forms liposome in preparation jar with CO
2Static relatively, seal the deadline and will extend greatly, both made raw material only be coated with very thin (1 millimeters thick), the time just can be dissolved into liposome after reaching one hour, will need several hrs if raw material layer is thick again.Volume of production can only be seldom like this, and unfavorable formation large-scale production is unfavorable for reducing production costs; It is also long that liposome is dispersed in time of dispersion liquid.
Summary of the invention:
Purpose of the present invention is exactly the problem that the indissoluble that will solve raw material is separated, the production process time is long, in order to improve the quality that liposome forms, improve and seal, reduce production costs, a kind of liposome production technology and the special equipment that can seal active ingredient well is provided.
Liposome production technology of the present invention is: the raw material of liposome is mixed, as joining after the mixing such as phospholipid, sterin, fat-soluble active ingredient in closed jar, add CO again in jar
2, and make and reach subcritical or critical in the jar or surpass CO
2Critical temperature and pressure.Be characterized in working as raw material at subcritical critical or postcritical CO
2After the following dissolving, the CO in the toilet-cleaning jar
2, make that pressure is reduced to about normal pressure in the jar, preferably a little more than normal pressure, as reaching 0.2～0.4Mpa.Add dispersion liquid in jar, immersion or stirring form the liposome that is enclosed with fat-soluble active ingredient.The present invention is applied in magnetic force gig bin with raw materials mixed, and this magnetic force gig bin of smearing raw material is put in the preparation jar, injects CO then in the preparation jar
2, make in the preparation jar to reach CO
2Critical or subcritical or supercriticality is rotated magnetic force gig bin, makes raw material dissolve the formation liposome fast, discharges CO again
2Blood pressure lowering preferably slowly evenly discharges CO
2CO in the preparation jar
2Pressure injects dispersion liquid near behind normal pressure or the normal pressure in jar, rotation magnetic force gig bin soaks the formation liposome.Preferably deployed raw material is applied in magnetic force gig bin, also can spreads upon preparation jar inwall simultaneously, rotate magnetic force gig bin and also make the raw material of jar inwall dissolve the formation liposome fast.
Also can carry out pretreatment to raw material, the raw material of indissoluble is mixed with other raw materials earlier with behind the organic solvent dissolution again, just the raw material of indissoluble mixes with other raw material after pretreatment again and is applied in magnetic force gig bin and puts into jar, adds subcritical critical or postcritical CO
2Dissolving.The consumption of organic solvent is generally by 6～14% of molten thing weight.The sterin (as cholesterol) of indissoluble should be ground with ether earlier and mix with phospholipid, fat-soluble active ingredient again after molten, spread upon magnetic force gig bin and put into jar and critical or supercritical CO
2Dissolving.The ether consumption is 8～12% of a sterin quality.Preferably, will grind molten cholesterol with ether again and grind mixed with it earlier with phospholipid and critical or fat-soluble active ingredient ground and mixed.Ether slowly discharges CO in early stage
2The time, just can all separate earlier, guarantee not residual ether in liposome, and a spot of ether can't bring unsafe factor.In order to increase the dissolution velocity of mixed material, increase the uniformity that forms liposome, be provided with magnetic force gig bin in jar.Evenly be applied in magnetic force gig bin in the deployed raw material of above-mentioned composition ratio.Because the rotation of material frame has increased CO in the preparation jar
2Moving, quicken CO
2To the dissolving of raw material and dissolve each other, favourable quick formation fat has shortened preparation time to plastid.Magnetic force gig bin has been arranged, increased the area that raw material is smeared greatly.So magnetic force gig bin can be multiple version, mainly be that the material frame of smearing raw material is arranged, the material frame preferably adopts multiple-plate version, so that the smearing and placing of raw material.Subcritical critical or postcritical CO
2Temperature be 15～60 ℃, pressure is 6～35MPa.Temperature is lower than 15 ℃, then also will specially lower the temperature, and increases the cooling control device, and generally is unfavorable for the dissolving of raw material phospholipid, fat-soluble active ingredient and cholesterol.It is favourable to the dissolving of raw material that temperature increases, but be unsuitable for too high, the one, need to increase heating facility, increase energy consumption, the 2nd, general temperature is higher than 60 ℃ can make active ingredient transform the rotten effect of losing activity, the 3rd, the high more CO of temperature
2Density low more, be unfavorable for dissolving raw material more.Corresponding pressure is lower than 6MPa under the condition of room temperature, can not form critical or supercritical even precritical CO
2Hypertonia is just high more to the requirement of equipment, and increases the expense that realizes high pressure, is higher than 35MPa so pressure generally is unsuitable for.Owing to can stir carbon dioxide and raw material at the carbon dioxide liquid state, so the present invention can smear deployed raw material thicker, coating layer thickness is preferably in 2-6mm, and it is big that the thickness of increase coating helps volume of production, enhance productivity, help suitability for industrialized production.
The equipment of production liposome of the present invention, the preparation jar that with closure is arranged, the preparation jar has inlet and valve, it is characterized in that: have the gig bin in the preparation jar, the rotating part of gig bin has drive magnet, preparation jar outer corresponding magnetic driver, the formation magnetic force gig bin of having.The gig bin can be existing various gig bin, can be various ways and structure.Preparation jar is put into and be arranged on to magnetic force gig bin, can be that the axle of gig bin inserts the bearing in the preparation jar and is provided with; Also can be that the gig bin itself is divided into support section and rotating part, support section is rotationally connected with rotating part, and (revolute pair is connected, be connected as axle and bearing) support section be arranged on the preparation jar, with the preparation jar in contact, rotating part can relatively rotate.Rotating part is mainly used in smears raw material, so rotating part can be various ways and structure.In order more to help smearing raw material, the rotating part of gig bin has the multilayer dose plate equally, or perhaps the gig bin of multi-layer sheet form.For the ease of discharging the product of preparation, the bottom of preparation jar is preferably with discharge line and valve.
Compared with the prior art the present invention has increased magnetic force gig bin in the preparation jar, also can rotate at high pressure conditions, owing to increased the stirring of carbon dioxide course of dissolution, the dissolving of having quickened raw material forms liposome, has reduced the operating time, has reduced production cost; Increased magnetic force gig bin, also increased the application area and the thickness of raw material, improved and produced the amount of preparation raw material and liposome, and improved production efficiency.Increase the liposome raw material particularly the utilization rate of active ingredient except stablizing, reduced the loss of raw material in preparation process, in the liposome forming process, the envelop rate of active ingredient can reach 100%, makes the in use effective absorbance of active ingredient improve greatly; Owing to do not have free active ingredient, more reduced the zest of irritant active ingredient to human body; Can grind miscible separating earlier with micro-organic solvent for more insoluble material in addition, thereby increase dissolubility, also more effectively guarantee to form even high-quality liposome, and the assurance organic solvent is all separated; The liposome stability of making reached more than 1 year.An obvious characteristic of the present invention is that preparation time shortens greatly.Secondly, be higher than normal pressure if the pressure in will prepare jar is discharged into, after adding dispersant, the pressure in the preparation jar just is higher than normal pressure.Like this, when the discharging dispersion liquid, needn't rely on deadweight, also can not form negative pressure, help reducing the equipment setting height(from bottom), also can not infiltrate objectionable impurities in the preparation jar because of negative pressure.
Description of drawings: accompanying drawing has represented that a kind of the present invention prepares the employed special equipment structural representation of liposome technology with carbon dioxide as solvent.Example below in conjunction with accompanying drawing further specifies the present invention.
The specific embodiment:
The preparation technology of embodiment one, a kind of elemene medicinal liposome and preparation equipment
The equipment of this production liposome of the present invention has the preparation jar 2 of with closure, the preparation jar cylindrical reaction still for the band end socket.Preparation jar top has inlet 1 and by-pass valve control.Have gig bin 3 in the preparation jar, have drive magnet 7 below the rotating part of gig bin, have corresponding magnetic driver 5 below preparation is jar outer, constitute magnetic force gig bin.It is put into and is arranged on preparation jar, and the lower end axle of gig bin 6 inserts the interior base bearing in the preparation jar and forms setting.Also can be that the gig bin itself is divided into support section and rotating part, the upper support part be connected with following rotation section split axle and bearing, and upper support partly is arranged on the supporting seat of preparation jar, and rotating part can relatively rotate.Rotating part is mainly used in smears raw material, and the rotating part of gig bin has the multilayer dose plate, has formed the gig bin of multi-layer sheet form.Preparation pot bottom side direction has discharge line 4 and valve.
Get former lecithin 3Kg, cholesterol 1Kg, elemene 1Kg.Be applied in after the mixing on the magnetic force gig bin, put in the preparation jar, the loam cake sealing of tube wall preparation jar slowly adds CO in jar
2, and make CO in the jar
2Remain on subcritical or supercriticality.After the preparation jar seals, after magnetic force gig bin at the uniform velocity slowly rotates 30min always, slowly evenly discharge the CO for preparing in the jar
2, when reaching 0.2MPa, in jar, add 100 liters of dispersion liquids.Can rotate magnetic force gig bin, dispersion liquid soaked after 2 hours, and elemene lipidosome forms, and adopts gas chromatography, measures no free elemene lipidosome, and envelop rate is 100%.
Embodiment two,
Raw material: get former lecithin 4Kg, cholesterol 1.2Kg, elemene 1.1Kg.
Pretreatment: the lecithin of recipe quantity mixed making lecithin softening with elemene, form mixture (1); The cholesterol of recipe quantity is added micro-ether grind, form mixture (2) to dissolving; Mixed with grinding in (2) addings (1), form mixture (3).
Mixture (3) evenly is applied to each demixing plate face of magnetic force gig bin, and thickness remains on 5 ± 1mm, and puts into the preparation jar together, after sealing, is heated to temperature required 55 ℃ (constant temperature), adds carbon dioxide with pump in the preparation jar.Through the overanxious CO of 0.22un microporous filter membrane
2Gas reaches required pressure 100kg/cm in jar
2, start magnetic driver and rotate multilayer dose frame constant voltage after 20 minutes, bleed off CO
2To 0.1Mpa, add dispersion medium (through the 0.22um filtering with microporous membrane) to required 100 liters, soaking and stirring was disperseed 1-2 hour, with CO
2Gas pressurization, filtration (1um microporous filter membrane) are scattered in the 20ml peace bottle, feed CO
2After seal, make the elemene lipidosome medicine.Adopt gas chromatograph to carry out gas chromatography (internal standard method) and measure, do not measure free elemene, the liposome encapsulation that records elemene is 100%.
Embodiment three, get lecithin 300g, Cera Flava 100g, pyrrolidone carboxylic acid sodium 100g.Pretreatment:
Lecithin is mixed with the pyrrolidone carboxylic acid sodium, form mixture (1), Cera Flava is added micro-ether grind to dissolving formation mixture (2), mixed with grinding in (2) addings (1), form mixture (3).
Raw mix (3) evenly is applied on the space of a whole page of material frame of magnetic force rotation, thickness remains on 3 ± 1mm.Material is placed in the preparation jar the slowly logical people CO in sealing back
2, making it to reach supercriticality, the material frame that passes through simultaneously in the preparation jar outer magnetic driver driving jar rotates.Constant voltage and stir 40min after, slowly discharge CO
2Make that pressure reaches 0.3MPa in the jar, in jar, add dispersion liquid and continued dispersed with stirring 2 hours for 10 liters.Preparation pot bottom side direction has discharge line 4 and valve, discharges the liposome cosmetics liquid after opening valve, and with CO
2After the gas pressure filtration, be scattered in the peace bottle logical people CO
2After seal, measure with gas chromatography (internal standard method), do not measure free pyrrolidone carboxylic acid sodium, envelop rate is 100%.
Embodiment four, get soybean phospholipid 200g, cholesterol 60g, linoleic acid 100g.
Pretreatment: make soybean phospholipid softening soybean phospholipid and linoleic acid ground and mixed, form mixture (1), cholesterol is added 8% ether grind to dissolving and form mixture (2), will (2) add grind in (1) mixed, formation mixture (3).
Raw mix (3) evenly is applied on the space of a whole page of material frame of magnetic force rotation, thickness remains on 3 ± 1mm.Material is placed in the preparation jar the slowly logical people CO in sealing back
2, making it to reach supercriticality, the material frame that passes through simultaneously in the preparation jar outer magnetic driver driving jar rotates.Constant voltage and stir 40min after, slowly discharge CO
2Make that pressure reaches 0.2MPa in the jar, in jar, add dispersion liquid and continued dispersed with stirring 2 hours for 10 liters.Preparation pot bottom side direction has discharge line 4 and valve, opens to be higher than non-pressurized pressure in utilizing behind the valve jar and successfully to discharge the liposome cosmetics liquid, and with CO
2After the gas pressure filtration, be scattered in the peace bottle logical people CO
2After seal, measure with gas chromatography (internal standard method), do not measure free linoleic acid, envelop rate is 100%.
Claims (10)
1, a kind of production technology of liposome is to make the raw material mixed configuration of liposome, it is characterized in that: raw materials mixed is applied in magnetic force gig bin, the magnetic force gig bin of smearing raw material is put in the preparation jar, inject CO then in the preparation jar
2, make in the jar of purchasing to reach CO
2Critical or supercritical or subcritical state rotate magnetic force gig bin and raw material, discharge CO
2Dispersion liquid is injected in blood pressure lowering in jar, rotation magnetic force gig bin forms medicinal liposome.
2, as the production technology of the said liposome of claim 1, it is characterized in that: with even velocity rotation magnetic force gig bin.
3, as the production technology of the said liposome of claim 1, it is characterized in that: deployed raw material evenly is applied in magnetic force gig bin and preparation jar inwall, coating layer thickness 2-6mm.
4, as the production technology of the said liposome of claim 1, it is characterized in that: CO in the preparation jar
2Pressure be 6～35Mpa, CO
2Temperature be 15～60 ℃, CO
2Critical or the subcritical state retention time is 30～60 minutes.
5, as the production technology of the said liposome of claim 1, it is characterized in that: slowly at the uniform velocity discharge the pressure in the preparation jar, pressure in the preparation jar is reduced to a little more than normal pressure, the jar internal pressure reaches 0.2～0.4Mpa, add dispersion liquid then in the preparation jar, soaking and stirring forms the liposome that is enclosed with fat-soluble active substance.
6, as the production technology of claim 3 or 4 or 5 said liposomees, it is characterized in that: preparation and the operating process of soaking, magnetic force gig bin are always with at the uniform velocity rotation.
7, as the production technology of the said liposome of claim 1, it is characterized in that: the material place of smearing of magnetic force gig bin is the multilayer dose plate.
8, a kind of equipment of producing liposome, the preparation jar that with closure is arranged, the preparation jar has inlet and valve, it is characterized in that: have the gig bin in the preparation jar, the rotating part of gig bin has drive magnet, preparation jar outer corresponding magnetic driver, the formation magnetic force gig bin of having.
9, as the equipment of the said production liposome of claim 1, it is characterized in that: the rotating part of gig bin has the multilayer dose plate.
10, as the equipment of the said production liposome of claim 1, it is characterized in that: the preparation pot bottom has discharge line and valve.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA021326509A CN1468596A (en) | 2002-07-21 | 2002-07-21 | Liposome producing process and apparatus |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA021326509A CN1468596A (en) | 2002-07-21 | 2002-07-21 | Liposome producing process and apparatus |
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|---|---|
| CN1468596A true CN1468596A (en) | 2004-01-21 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA021326509A Pending CN1468596A (en) | 2002-07-21 | 2002-07-21 | Liposome producing process and apparatus |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102008518A (en) * | 2010-11-16 | 2011-04-13 | 中国科学院西北高原生物研究所 | Seabuckthorn seed oil liposome preparation process |
| CN102379847A (en) * | 2010-08-31 | 2012-03-21 | 华东理工大学 | Controlled synthesis method of nanometer polyenic taxusol liposome |
| CN109432008A (en) * | 2018-12-07 | 2019-03-08 | 河南工业大学 | A kind of preparation method of nano liposomes |
| CN109852473A (en) * | 2018-12-07 | 2019-06-07 | 河南工业大学 | A kind of preparation method of composite antioxidant liposome |
-
2002
- 2002-07-21 CN CNA021326509A patent/CN1468596A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102379847A (en) * | 2010-08-31 | 2012-03-21 | 华东理工大学 | Controlled synthesis method of nanometer polyenic taxusol liposome |
| CN102379847B (en) * | 2010-08-31 | 2013-03-13 | 华东理工大学 | Controlled synthesis method of nanometer polyenic taxusol liposome |
| CN102008518A (en) * | 2010-11-16 | 2011-04-13 | 中国科学院西北高原生物研究所 | Seabuckthorn seed oil liposome preparation process |
| CN109432008A (en) * | 2018-12-07 | 2019-03-08 | 河南工业大学 | A kind of preparation method of nano liposomes |
| CN109852473A (en) * | 2018-12-07 | 2019-06-07 | 河南工业大学 | A kind of preparation method of composite antioxidant liposome |
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