CN109718205B - Preparation method and system of drug liposome - Google Patents
Preparation method and system of drug liposome Download PDFInfo
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- CN109718205B CN109718205B CN201910181051.1A CN201910181051A CN109718205B CN 109718205 B CN109718205 B CN 109718205B CN 201910181051 A CN201910181051 A CN 201910181051A CN 109718205 B CN109718205 B CN 109718205B
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Abstract
The application relates to the field of pharmaceutical preparations, in particular to a preparation method of a pharmaceutical liposome, which comprises the following steps: adjusting the liquid carbon dioxide to a supercritical state; dissolving the supercritical carbon dioxide in one pipeline with the core material medicament, dissolving the supercritical carbon dioxide in the other pipeline with the wall material solution, and enabling the temperature of the supercritical carbon dioxide dissolved with the wall material solution to be higher than that of the supercritical carbon dioxide dissolved with the core material medicament; introducing the temperature-adjusted supercritical carbon dioxide dissolved with the core material medicine into a granulation kettle from the upper part, and introducing the temperature-adjusted supercritical carbon dioxide dissolved with the wall material solution into the granulation kettle from the lower part to perform liposome granulation; the pressure of the supercritical carbon dioxide dissolved with the core material medicine and the pressure of the supercritical carbon dioxide dissolved with the wall material solution are larger than the pressure in the granulating kettle; the embedded liposomes were collected. The method reduces the agglomeration of core material particles and the probability of multiple embedding of liposome, and improves the encapsulation efficiency of the liposome.
Description
Technical Field
The application relates to the field of pharmaceutical preparations, in particular to a preparation method and a system of a pharmaceutical liposome.
Background
Liposomes are artificial membranes, which are closed vesicles with a bilayer structure formed by amphiphilic molecules (e.g., phospholipids and sphingolipids) dispersed in an aqueous phase, the hydrophobic tails of the molecules tend to aggregate together to avoid the aqueous phase, and the hydrophilic heads of the molecules are exposed to the aqueous phase. Liposomes can be used for transgenes or drugs, and liposomal drugs for drugs refer to microvesicles formed by encapsulating drugs in lipid bilayers. Specifically, the liposome drug utilizes the characteristic that liposome can be fused with cell membrane to deliver the drug into the cell.
In the prior art, the liposome is produced by feeding the prepared emulsion or the prepared emulsion according to a certain proportion into a supercritical kettle, starting the supercritical state, and then adding a hydrophilic solution to form an oil-in-water phospholipid bimolecular structure. However, in the prior art, agglomeration of core particles and multiple embedding of liposome are easily caused in the process of liposome production, and the embedding effect and the embedding rate of the liposome are influenced.
Therefore, how to avoid the agglomeration of core particles and the multiple embedding of the liposome and improve the embedding effect of the liposome is a technical problem which needs to be solved urgently by technical personnel in the field.
Disclosure of Invention
The application provides a preparation method and a system of a drug liposome, which are used for reducing agglomeration of core material particles and multiple embedding of the liposome and improving the embedding effect of the liposome.
In order to solve the technical problem, the application provides the following technical scheme:
a preparation method of a drug liposome comprises the following steps: adjusting the liquid carbon dioxide to a supercritical state; mixing and dissolving the supercritical carbon dioxide and the core material medicament in one pipeline, mixing and dissolving the supercritical carbon dioxide and the wall material solution in the other pipeline, and adjusting the temperature to ensure that the temperature of the supercritical carbon dioxide dissolved with the wall material solution is higher than that of the supercritical carbon dioxide dissolved with the core material medicament; introducing the temperature-adjusted supercritical carbon dioxide dissolved with the core material medicine into a granulation kettle from the upper part, and introducing the temperature-adjusted supercritical carbon dioxide dissolved with the wall material solution into the granulation kettle from the lower part to perform liposome granulation; wherein, the pressure of the supercritical carbon dioxide dissolved with the core material medicament and the pressure of the supercritical carbon dioxide dissolved with the wall material solution are both larger than the pressure in the granulating kettle; the embedded liposomes were collected from the carbon dioxide.
In the method for preparing a pharmaceutical liposome as described above, the core material solution is preferably a mixture of menthol + acetone and a drug, and the ratio of menthol + acetone is preferably (4 to 2): 1.
In the method for preparing a pharmaceutical liposome, the wall material solution is preferably a mixture of lecithin and hyaluronic acid, and the ratio of lecithin to hyaluronic acid is (0.1-1): 1.
in the method for preparing a pharmaceutical liposome as described above, it is preferable that the temperature of the supercritical carbon dioxide in which the wall material solution is dissolved is adjusted to 30 to 70 ℃, and the temperature of the supercritical carbon dioxide in which the core material solution is dissolved is adjusted to 50 to 80 ℃.
In the method for preparing a pharmaceutical liposome as described above, preferably, the pressure of the supercritical carbon dioxide solution in which the core drug is dissolved is 26Mpa, the pressure of the supercritical carbon dioxide solution in which the wall material solution is dissolved is 22Mpa, and the pressure in the granulation tank is 7 Mpa.
In the method for preparing pharmaceutical liposomes as described above, it is preferable to maintain the control of the liposome granulation in the granulation tank.
The method for preparing pharmaceutical liposome as described above, wherein, preferably, the temperature of liposome granulation is controlled to 65 ℃.
In the method for preparing a pharmaceutical liposome as described above, it is preferable that supercritical carbon dioxide in which the core drug is dissolved is introduced into the granulation tank through the nozzle, and the supercritical carbon dioxide in which the core drug is dissolved is kept warm inside the nozzle.
In the method for preparing a liposome of a drug as described above, it is preferable that the supercritical carbon dioxide dissolved with the core drug to be introduced into the granulation vessel is gasified, and the direction of movement of the core particles is changed to move the core particles in order after the core particles are precipitated.
A system for preparing a pharmaceutical liposome, comprising: granulating kettle; the lower part of the granulating kettle is connected with a pipeline system for conveying the supercritical carbon dioxide dissolved with the wall material solution, and the temperature of the supercritical carbon dioxide dissolved with the wall material solution is adjusted; the upper part of the granulating kettle is connected with a pipeline system for conveying the supercritical carbon dioxide dissolved with the core material medicine, and the temperature of the supercritical carbon dioxide dissolved with the core material medicine is adjusted; the temperature of the supercritical carbon dioxide dissolved with the wall material solution after the temperature is adjusted is higher than the temperature of the supercritical carbon dioxide dissolved with the core material medicament after the temperature is adjusted; wherein, the pressure of the supercritical carbon dioxide dissolved with the core material medicament and the pressure of the supercritical carbon dioxide dissolved with the wall material solution are both larger than the pressure in the granulating kettle.
In contrast to the above background art, the method for preparing the liposome provided by the present invention comprises: adjusting the liquid carbon dioxide to a supercritical state; mixing and dissolving the supercritical carbon dioxide and the core material medicament in one pipeline, mixing and dissolving the supercritical carbon dioxide and the wall material solution in the other pipeline, and adjusting the temperature to ensure that the temperature of the supercritical carbon dioxide dissolved with the wall material solution is higher than that of the supercritical carbon dioxide dissolved with the core material medicament; introducing the temperature-adjusted supercritical carbon dioxide dissolved with the core material medicine into a granulation kettle from the upper part, and introducing the temperature-adjusted supercritical carbon dioxide dissolved with the wall material solution into the granulation kettle from the lower part to perform liposome granulation; wherein, the pressure of the supercritical carbon dioxide dissolved with the core material medicament and the pressure of the supercritical carbon dioxide dissolved with the wall material solution are both larger than the pressure in the granulating kettle; the embedded liposomes were collected from the carbon dioxide. Specifically, the core particles move from top to bottom, the wall material moves from bottom to top, and the wall material and the core particles meet to form a stable embedded liposome bimolecular structure. Because the temperature of the supercritical carbon dioxide dissolved with the wall material solution is higher than that of the supercritical carbon dioxide dissolved with the core material medicament, the convection velocity of the wall material and the core material particles can be increased, so that the wall material and the core material suspension particles are fully mixed, the embedding effect and the encapsulation rate are improved, the rapid upward movement of the wall material also reduces the probability of repeated contact between the core material suspension particles and the wall material, and the core material suspension particles are prevented from being embedded for many times.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only some embodiments described in the present invention, and other drawings can be obtained by those skilled in the art according to the drawings.
FIG. 1 is a schematic diagram of a system for preparing liposomes of drugs provided in the examples herein;
FIG. 2 is a flow chart of a method for preparing a pharmaceutical liposome provided in the examples herein;
fig. 3 is a schematic structural diagram of a granulation kettle provided in an embodiment of the present application.
Wherein, 1-liquid carbon dioxide storage tank, 2-first high pressure valve, 3-second high pressure valve, 4-first heat exchanger, 5-second heat exchanger, 6-first high pressure pump, 7-second high pressure pump, 8-first high pressure stirring kettle, 9-second high pressure stirring kettle, 10-third high pressure pump, 11-fourth high pressure pump, 12-third heat exchanger, 13-fourth heat exchanger, 14-first pressure regulating valve, 15-second pressure regulating valve, 16-wall material supercritical buffer kettle, 17-third high pressure valve, 18-fourth high pressure valve, 19-granulation kettle, 191-nozzle, 192-collection cavity, 193-reaction cavity, 194-tube pass heat exchanger, 195-prestoring cavity, 196-heat preservation jacket, 197-micron-sized filter screen structural unit, 198-liposome outlet control valve, 199-supercritical carbon dioxide circulation outlet control valve, and 20-hot water storage tank.
Detailed Description
Reference will now be made in detail to embodiments of the present invention, examples of which are illustrated in the accompanying drawings, wherein like or similar reference numerals refer to the same or similar elements or elements having the same or similar function throughout. The embodiments described below with reference to the drawings are illustrative only and should not be construed as limiting the invention.
As shown in fig. 1, the present application provides a system for preparing a pharmaceutical liposome, comprising: the lower part of the granulating kettle 19 is connected with a pipeline system for conveying the supercritical carbon dioxide dissolved with the wall material solution, and the upper part of the granulating kettle 19 is connected with a pipeline system for conveying the supercritical carbon dioxide dissolved with the core material medicine.
Specifically, the piping system for transporting the supercritical carbon dioxide in which the wall material mixed solution is dissolved is as follows: the liquid carbon dioxide storage tank 1, the first high-pressure valve 2, the first heat exchanger 4 and the first high-pressure pump 6 are sequentially connected, so that the temperature and the pressure of the liquid carbon dioxide stored in the liquid carbon dioxide storage tank 1 are adjusted to be in a supercritical state through the first high-pressure valve 2, the first heat exchanger 4 and the first high-pressure pump 6. The first high-pressure stirred tank 8 and the third high-pressure pump 10 are connected so that the wall material solution stored in the first high-pressure stirred tank 8 is pressurized by the third high-pressure pump 10. The first high-pressure pump 6 and the third high-pressure pump 10 are both connected to the third heat exchanger 12 to dissolve the wall material liquid in the supercritical carbon dioxide, and further to adjust the temperature of the supercritical carbon dioxide in which the wall material liquid is dissolved. The third heat exchanger 12 is sequentially connected with the first pressure regulating valve 14 and the wall material supercritical buffer kettle 16, so that the supercritical carbon dioxide dissolved with the wall material solution after further temperature adjustment is stored in the wall material supercritical buffer kettle 16 for later use. The wall material supercritical buffer kettle 16 is connected with a third high pressure valve 17, so that the supercritical carbon dioxide dissolved with the wall material solution and stored in the wall material supercritical buffer kettle 16 enters the lower part of the granulation kettle 19 after passing through the third high pressure valve 17.
Specifically, the piping system for transporting the supercritical carbon dioxide dissolved with the core drug is as follows: the liquid carbon dioxide storage tank 1, the second high-pressure valve 3, the second heat exchanger 5 and the second high-pressure pump 7 are sequentially connected, so that the liquid carbon dioxide stored in the liquid carbon dioxide storage tank 1 is adjusted in temperature and pressure to a supercritical state through the second high-pressure valve 3, the second heat exchanger 5 and the second high-pressure pump 7. The second high-pressure agitation tank 9 and the fourth high-pressure pump 11 are connected so that the core material medicine stored in the second high-pressure agitation tank 9 is pressurized by the fourth high-pressure pump 11. The second high-pressure pump 7 and the fourth high-pressure pump 11 are both connected to the fourth heat exchanger 13, so that the core material drug is dissolved in the supercritical carbon dioxide to form an inclusion compound, the temperature of the supercritical carbon dioxide in which the core material drug is dissolved is further adjusted, and the temperature of the supercritical carbon dioxide in which the wall material solution is dissolved after the temperature adjustment is higher than the temperature of the supercritical carbon dioxide in which the core material drug is dissolved after the temperature adjustment. The fourth high-pressure pump 11 is sequentially connected with the second pressure regulating valve 15 and the fourth high-pressure valve 18, so that the supercritical carbon dioxide dissolved with the core drug enters the upper part of the granulating kettle 19 after passing through the second pressure regulating valve 15 and the fourth high-pressure valve 18.
The upper part of the granulation kettle 19 is connected with a supercritical carbon dioxide circulation outlet control valve and a liposome outlet control valve from top to bottom so as to discharge carbon dioxide and embedded liposome.
In addition, the preparation system of the drug liposome also comprises: the hot water storage tank 20 connected to the first heat exchanger 4 and the second heat exchanger 5 provides a heat source for the first heat exchanger 4 and the second heat exchanger 5, and of course, the hot water storage tank 20 may also provide a heat source for the third heat exchanger 12 and the fourth heat exchanger 13.
As shown in fig. 2, the present application provides a method for preparing a pharmaceutical liposome, comprising the following steps:
step S210, adjusting the liquid carbon dioxide to a supercritical state;
specifically, liquid carbon dioxide in the liquid carbon dioxide storage tank 1 enters the first heat exchanger 4 through the first high-pressure valve 2, and simultaneously enters the second heat exchanger 5 through the second high-pressure valve 3, and the liquid carbon dioxide in the two pipelines is heated through the first heat exchanger 4 and the second heat exchanger 5 in the two pipelines.
Then, the carbon dioxide heated by the first heat exchanger 4 passes through the first high-pressure pump 6, and the carbon dioxide heated by the second heat exchanger 5 passes through the second high-pressure pump 7, and after being pressurized by the first high-pressure pump 6 and the second high-pressure pump 7, the carbon dioxide in the two pipelines is in a supercritical state.
Step S220, mixing and dissolving the supercritical carbon dioxide in one pipeline and the core material medicament, mixing and dissolving the supercritical carbon dioxide in the other pipeline and the wall material solution, and adjusting the temperature to ensure that the temperature of the supercritical carbon dioxide dissolved with the wall material solution is higher than that of the supercritical carbon dioxide dissolved with the core material medicament;
wherein, the core material medicine is a mixed solution of menthol, acetone and medicine. The menthol and the acetone are prepared according to the proportion (4-2): 1, and the preferable menthol and the acetone are prepared according to the proportion (3: 1).
Specifically, the core material drugs are prepared in the above-mentioned ratio, and mixed in the second high-pressure stirring tank 9. The mixed core material medicament is pressurized by the fourth high-pressure pump 11 and then mixed and dissolved with the supercritical carbon dioxide in one pipeline pressurized by the second high-pressure pump 7, namely, the pressurized core material medicament is dissolved into the pressurized supercritical carbon dioxide to form an inclusion compound. Then, the temperature of the supercritical carbon dioxide dissolved with the core material medicine is adjusted by a fourth heat exchanger 13, and the temperature of the supercritical carbon dioxide dissolved with the core material medicine is kept between 30 ℃ and 70 ℃ after the temperature is adjusted; preferably, the temperature thereof is maintained between 40 ℃ and 60 ℃; it is further preferred that the temperature is maintained between 45 ℃ and 50 ℃. Then, the supercritical carbon dioxide dissolved with the core drug is subjected to temperature adjustment and then to pressure adjustment through the second pressure adjustment valve 15.
The wall material solution is a mixture of lecithin and hyaluronic acid. Wherein the lecithin is lecithin (1-palmitoyl-2-oleoyl phosphatidyl serine choline) derived from egg yolk, and the content of lecithin is above 90%. Hyaluronic acid (D-glucuronic acid and N-acetylglucosamine) can achieve target delivery due to its binding site for drugs. Specifically, the ratio of lecithin to hyaluronic acid is (0.1-1): 1, the preferable ratio of lecithin to hyaluronic acid is (0.5-0.8): 1, the proportion of lecithin and hyaluronic acid is preferably (0.6-0.7): 1.
specifically, the wall material solution is prepared in the above-mentioned ratio, and is mixed in the first high-pressure stirring tank 8. The mixed wall material solution is pressurized by the third high-pressure pump 10 and then mixed and dissolved with the supercritical carbon dioxide in one pipeline pressurized by the first pressurizing pump 6, namely, the pressurized wall material solution is dissolved in the pressurized supercritical carbon dioxide. Then, the temperature of the supercritical carbon dioxide dissolved with the wall material solution is adjusted by the third heat exchanger 12, and the temperature of the supercritical carbon dioxide dissolved with the wall material solution is kept between 50 ℃ and 80 ℃ after the temperature is adjusted, and the preferable temperature is kept between 60 ℃ and 70 ℃; it is further preferred that the temperature is maintained between 65 ℃ and 68 ℃. Then, the supercritical carbon dioxide dissolved with the wall material solution is adjusted in temperature and then adjusted in pressure by the first pressure adjusting valve 14, and reaches the wall material supercritical buffer tank 16 for standby.
For example: preparing a core material medicament: accurately weighing 100 g of medicine, 1730 g of menthol and 270 g of acetone, heating to 40 ℃, dissolving and stirring uniformly, pressurizing to 20Mpa, homogenizing for later use, dissolving the medicine for later use in supercritical carbon dioxide to form supercritical carbon dioxide with the core medicine dissolved therein, heating to 45 ℃ by a heat exchanger, and pressurizing to 26Mpa by a high-pressure pump;
preparing a wall material solution: 780 g of lecithin and 1300 g of hyaluronic acid with 94% of yolk source are weighed and dissolved in supercritical carbon dioxide to form supercritical carbon dioxide dissolved with wall material solution, and the temperature is heated to 65 ℃ and the pressure is 22 Mpa.
Step S230, introducing the temperature-adjusted supercritical carbon dioxide dissolved with the core material medicine into a granulation kettle from the upper part, introducing the temperature-adjusted supercritical carbon dioxide dissolved with the wall material solution into the granulation kettle from the lower part, and performing liposome granulation, wherein the pressure of the supercritical carbon dioxide dissolved with the core material medicine and the pressure of the supercritical carbon dioxide dissolved with the wall material solution are both greater than the pressure in the granulation kettle;
after the pressure adjustment is performed by the second pressure adjusting valve 15, the supercritical carbon dioxide dissolved with the core material drug is sprayed into the granulation kettle 19 from the upper part of the granulation kettle 19 through the fourth high pressure valve 18 through the nozzle, and the supercritical carbon dioxide dissolved with the core material drug entering the granulation kettle 19 rapidly expands and gasifies because the pressure of the supercritical carbon dioxide dissolved with the core material drug is higher than the pressure in the granulation kettle 19, and the dissolved core material is precipitated in the form of fine particles because the solubility of the core material in the supercritical carbon dioxide is low, so that suspended particle particles are formed. The supercritical carbon dioxide dissolved with the wall material solution stored in the wall material supercritical buffer kettle 16 enters the granulation kettle 19 from the lower part of the granulation kettle 19 through the third high pressure valve 17. The core particles move from top to bottom, the wall material moves from bottom to top, and the wall material and the core particles meet to form a stable embedded liposome bimolecular structure. Because the temperature of the supercritical carbon dioxide dissolved with the wall material solution is higher than that of the supercritical carbon dioxide dissolved with the core material medicine, the convection velocity of the wall material and the core material particles can be enhanced, so that the wall material and the core material suspension particles are fully mixed, the embedding effect and the encapsulation rate are improved, the rapid upward movement of the wall material also reduces the chance of repeated contact of the core material suspension particles and the wall material, the probability of repeated embedding of the core material suspension particles is further avoided, and the large use of solvents in the traditional liposome preparation process is also avoided.
Specifically, as shown in fig. 3, the granulating kettle 19 is divided into three chambers from bottom to top. After temperature adjustment, the supercritical carbon dioxide dissolved with the core drug passes through the upper collection chamber 192 through the nozzle 191, and extends into the middle reaction chamber 193, preferably into the middle upper portion of the reaction chamber 193. Since the carbon dioxide is gasified to take away heat, the temperature in the reaction chamber 193 is rapidly lowered, and the core material drug, the wall material solution and the carbon dioxide mixed in the reaction chamber 193 can be kept warm in order to avoid clogging of the nozzle 191 due to the temperature lowering. Specifically, a tube-pass heat exchanger 194 is arranged in the reaction chamber 193, and a medium with a certain temperature is introduced into the tube-pass heat exchanger 194, so that the core material, the wall material and the carbon dioxide in the reaction chamber 193 are insulated. Preferably, the nozzle 191 extends into the middle of the tube-side heat exchanger 194 in the reaction chamber 193, so as to ensure that the supercritical carbon dioxide dissolved with the core material solution is sprayed out from the nozzle without causing agglomeration of the core material particles due to temperature reduction.
In addition, in order to prevent the nozzle 191 from being clogged, the supercritical carbon dioxide in which the core drug is dissolved, which flows through the nozzle 191, may be kept warm. Specifically, a heating cavity can be arranged in the nozzle 191, heating oil with a certain temperature is introduced into the heating cavity, and the heating oil is used for heating, so that the fluid flowing through the nozzle 191 can be prevented from being gasified and cooled in advance to block the nozzle 191.
On the basis, the supercritical carbon dioxide dissolved with the core medicament and circulating in the nozzle 191 is subjected to heat preservation, and the fluid introduced into the granulating kettle 19 is also subjected to heat preservation, so that the blockage of the nozzle 191 caused by the gasification and cooling of the carbon dioxide is avoided, and the ejection speed of the supercritical carbon dioxide dissolved with the core medicament can be further controlled. Specifically, since the supercritical carbon dioxide dissolved with the core material drug has a certain pressure, the opening size of the nozzle 191 is reduced to increase the ejection speed, that is, the expansion strength is increased, thereby ensuring that the core material particles are distributed in the granulation kettle without a "dead zone", and further improving the embedding effect and the encapsulation efficiency. And also, since the opening size of the nozzle 191 is reduced, the particle size of the core material particles is ensured to be small, so that the average particle size of the produced liposome fine particles is small, for example: the particle size of the nano-particles is between 40nm and 80nm, so that the nano-particles achieve the nano-granulation effect and are far smaller than the production particle size of the common liposome.
In order to further ensure that the wall material in the supercritical carbon dioxide dissolved with the wall material solution can rise rapidly, that is, to ensure that a predetermined temperature difference exists between the carbon dioxide dissolved with the wall material solution and the supercritical carbon dioxide dissolved with the core material drug, the temperature of the supercritical carbon dioxide dissolved with the wall material solution is a predetermined temperature, so that the pre-storage cavity 195 in which the supercritical carbon dioxide dissolved with the wall material solution is pre-stored at the lower part is insulated, for example, an insulation jacket 196 is arranged outside the pre-storage cavity 195, and a medium with a predetermined temperature is introduced into the insulation jacket 196, thereby adjusting the temperature of the supercritical carbon dioxide dissolved with the wall material solution.
On the basis, the supercritical carbon dioxide dissolved with the core material medicine to be introduced into the granulating kettle 19 is gasified, and after the core material is separated out by fine particles, the core material particles which move disorderly are changed and move orderly, so that the collision among the core material particles is reduced, the agglomeration among the core material particles is reduced, and the embedding of the liposome is more stable. Specifically, the baffle plate, such as an arch baffle plate, is arranged in the reaction cavity in the middle of the granulating kettle 19, so that the movement of the core material particles is orderly, the agglomeration phenomenon of the core material particles is reduced, and the embedding stability is improved.
For example: spraying supercritical carbon dioxide dissolved with core material medicine into the granulating kettle from top to bottom through a nozzle, controlling the pressure of the granulating kettle at 7Mpa, opening a wall material high-pressure valve (a third high-pressure kettle), performing heat exchange adjustment again (by introducing a medium with a preset temperature into a heat-insulating jacket), then allowing the supercritical carbon dioxide dissolved with wall material solution to reach 65 ℃ to enter the granulating kettle for granulating, and controlling the pressure of the supercritical carbon dioxide dissolved with wall material solution at 22 Mpa. Step S204, collecting the embedded liposome from the carbon dioxide.
Because the preparation method can ensure stable liposome embedding effect and encapsulation efficiency, the liposome is prepared in the reaction cavity 193, and carbon dioxide has stable temperature change before and after reaction, so that whether the liposome is embedded or not can be determined by measuring the temperature change of the carbon dioxide, namely whether the embedding rate of the liposome achieves the preset embedding effect and encapsulation efficiency or not can be determined.
After the liposome in the reaction kettle 193 is embedded completely through temperature measurement, the liposome outlet control valve 198 and the supercritical carbon dioxide circulation outlet control valve 199 are opened, the liposome and the carbon dioxide flow upwards to the collection cavity 192, the carbon dioxide continuously flows upwards from the micron-sized filter screen structure unit 197 arranged in the collection cavity 192 and flows out through a pipeline controlled by the carbon dioxide circulation outlet control valve 199, and the liposome is intercepted and collected from the pipeline controlled by the liposome outlet control valve 198.
For example: after granulating in the granulating kettle for 20 minutes, by measuring the temperature of the carbon dioxide to reach a preset temperature, opening a supercritical carbon dioxide circulation outlet control valve, reducing the pressure to 6.5Mpa, circularly discharging the carbon dioxide, and simultaneously opening a liposome outlet control valve. Preparing a liposome: 3940 g, drug loading rate of 2.5%, encapsulation rate of 94%, average particle size of 75 +/-15 nm, polymerization index of 0.55, potential: -25.9 ± 0.5/mV.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Any reference sign in a claim should not be construed as limiting the claim concerned.
Furthermore, it should be understood that although the present description refers to embodiments, not every embodiment may contain only a single embodiment, and such description is for clarity only, and those skilled in the art should integrate the description, and the embodiments may be combined as appropriate to form other embodiments understood by those skilled in the art.
Claims (5)
1. The preparation method of the medicinal liposome is characterized by comprising the following steps:
adjusting the liquid carbon dioxide to a supercritical state;
mixing and dissolving supercritical carbon dioxide and a core material medicament in one pipeline, mixing and dissolving supercritical carbon dioxide and a wall material solution in the other pipeline, adjusting the temperature of the supercritical carbon dioxide dissolved with the core material solution to 50-80 ℃, adjusting the temperature of the supercritical carbon dioxide dissolved with the wall material solution to 30-70 ℃, and adjusting the temperature to ensure that the temperature of the supercritical carbon dioxide dissolved with the wall material solution is higher than that of the supercritical carbon dioxide dissolved with the core material medicament;
introducing the temperature-adjusted supercritical carbon dioxide dissolved with the core drug into a granulation kettle from the upper part through a nozzle, preserving the heat of the supercritical carbon dioxide dissolved with the core drug in the nozzle, introducing the temperature-adjusted supercritical carbon dioxide dissolved with the wall material solution into the granulation kettle from the lower part, gasifying the supercritical carbon dioxide dissolved with the core drug introduced into the granulation kettle, separating out core particles, changing the movement direction of the core particles to move the core particles in order, thus carrying out liposome granulation, and controlling the heat preservation of the liposome granulation in the granulation kettle;
wherein the pressure of the supercritical carbon dioxide dissolved with the core material medicament is 26Mpa, the pressure of the supercritical carbon dioxide dissolved with the wall material solution is 22Mpa, the pressure of the supercritical carbon dioxide dissolved with the core material medicament and the pressure of the supercritical carbon dioxide dissolved with the wall material solution are both greater than the pressure in the granulation kettle, and the pressure in the granulation kettle is 7 Mpa;
the embedded liposomes were collected from the carbon dioxide.
2. The method for preparing a pharmaceutical liposome according to claim 1, wherein the core material solution is a mixture of menthol + acetone and a drug, and the ratio of menthol + acetone is (4-2): 1.
3. The method for preparing a pharmaceutical liposome according to claim 2, wherein the wall material solution is a mixed solution of lecithin and hyaluronic acid, and the ratio of lecithin to hyaluronic acid is (0.1-1): 1.
4. a process for the preparation of pharmaceutical liposomes according to any one of claims 1 to 3 wherein the temperature of liposome granulation is controlled to 65 ℃.
5. A system for preparing a pharmaceutical liposome, comprising: granulating kettle; the lower part of the granulating kettle is connected with a pipeline system for conveying the supercritical carbon dioxide dissolved with the wall material solution, the temperature of the supercritical carbon dioxide dissolved with the wall material solution is adjusted, and the temperature of the supercritical carbon dioxide dissolved with the wall material solution is adjusted to be between 30 and 70 ℃; the upper part of the granulating kettle is connected with a pipeline system for conveying the supercritical carbon dioxide dissolved with the core material medicine, the temperature of the supercritical carbon dioxide dissolved with the core material medicine is adjusted, and the temperature of the supercritical carbon dioxide dissolved with the core material solution is adjusted to be between 50 and 80 ℃; the temperature of the supercritical carbon dioxide dissolved with the wall material solution after the temperature is adjusted is higher than the temperature of the supercritical carbon dioxide dissolved with the core material medicament after the temperature is adjusted; introducing the temperature-adjusted supercritical carbon dioxide dissolved with the core drug into a granulation kettle through a nozzle, preserving the heat of the supercritical carbon dioxide dissolved with the core drug inside the nozzle, changing the movement direction of core particles to enable the core particles to move orderly after the supercritical carbon dioxide dissolved with the core drug introduced into the granulation kettle is gasified and the core particles are separated out, thereby carrying out liposome granulation and controlling the heat preservation of the liposome granulation in the granulation kettle;
wherein the pressure of the supercritical carbon dioxide dissolved with the core material drug is 26Mpa, the pressure of the supercritical carbon dioxide dissolved with the wall material solution is 22Mpa, the pressure of the supercritical carbon dioxide dissolved with the core material drug and the pressure of the supercritical carbon dioxide dissolved with the wall material solution are both greater than the pressure in the granulation kettle, and the pressure in the granulation kettle is 7 Mpa.
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| CN111012671B (en) * | 2019-11-25 | 2022-07-05 | 上海强德食品科技有限公司 | Physical preparation method of microcapsule |
| CN113143885A (en) * | 2021-04-13 | 2021-07-23 | 广东普萃特医生物工程有限公司 | Supercritical emulsification granulation process of lutein |
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