CN114469733B - Preparation device and preparation method of doxorubicin liposome - Google Patents
Preparation device and preparation method of doxorubicin liposome Download PDFInfo
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- CN114469733B CN114469733B CN202111352135.0A CN202111352135A CN114469733B CN 114469733 B CN114469733 B CN 114469733B CN 202111352135 A CN202111352135 A CN 202111352135A CN 114469733 B CN114469733 B CN 114469733B
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- 229940042317 doxorubicin liposome Drugs 0.000 title claims abstract description 53
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
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- 238000000034 method Methods 0.000 claims abstract description 6
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 110
- 229960004679 doxorubicin Drugs 0.000 claims description 55
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 48
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 40
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- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 16
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- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 12
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- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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Abstract
The invention provides a preparation device and a preparation method of doxorubicin liposome. Aims at solving the technical problem of low encapsulation efficiency in the prior art for preparing the doxorubicin liposome. The adopted technical scheme is as follows: a device for preparing doxorubicin liposome, comprising: an inner water phase pipe, an oil phase pipe and an outer water phase channel which are coaxial; the outlet end of the inner water phase pipe is positioned in the oil phase pipe, and the outlet end of the oil phase pipe is positioned in the outer water phase channel; the outer diameter of the inner water phase pipe is smaller than the inner diameter of the oil phase pipe, and the outer diameter of the oil phase pipe is smaller than the inner diameter of the outer water phase channel; the flow direction of the inner water phase in the inner water phase pipe is the same as the flow direction of the outer water phase in the outer water phase channel, and is opposite to the flow direction of the oil phase in the oil phase pipe. In addition, the invention also provides a method for preparing the doxorubicin liposome by adopting the preparation device. The preparation device and the preparation method provided by the invention have the advantage of high encapsulation efficiency.
Description
Technical Field
The invention relates to the technical field of liposome preparation, in particular to a device and a method for preparing doxorubicin liposome.
Background
Doxorubicin is an antitumor antibiotic, can inhibit synthesis of RNA and DNA, has the strongest inhibitory effect on RNA, has a broad antitumor spectrum, has an effect on various tumors, belongs to a periodic nonspecific drug, and has a killing effect on tumor cells in various growth periods.
Clinically, doxorubicin has large toxic and side effects. Mainly comprises the following steps: affecting bone marrow hematopoietic function, manifested by thrombocytopenia and leukopenia; cardiotoxicity, severe heart failure; nausea, vomiting, stomatitis, alopecia, hyperpyrexia, phlebitis, skin pigmentation, etc. can be seen; few patients have fever, hemorrhagic erythema and impaired liver function. These toxic side effects severely limit the clinical application of doxorubicin.
With the development of medical technology, attempts have been made to use liposomes as carriers of doxorubicin. Clinical results show that the toxic and side effects of the doxorubicin liposome are obviously reduced, the half life of the drug is obviously prolonged, and the drug effect is also improved. In the prior art, when preparing the doxorubicin liposome, most of the doxorubicin is dissolved in water for injection to prepare a water phase, the lipid is dissolved in an organic solvent to prepare an oil phase, and then the water phase and the oil phase are mixed by a homogenizer to prepare the doxorubicin liposome solution. The technology has the defect of low encapsulation efficiency, and the prepared doxorubicin liposome solution often contains a large amount of free doxorubicin which is not encapsulated in the liposome.
Disclosure of Invention
The invention aims to provide a preparation device of doxorubicin liposome, which can improve encapsulation efficiency and greatly reduce the content of free doxorubicin in the prepared doxorubicin liposome solution.
Based on the same inventive concept, another object of the present invention is to provide a method for preparing doxorubicin liposome using the aforementioned device.
In particular, the method comprises the steps of,
a device for preparing doxorubicin liposome, comprising: an inner water phase pipe, an oil phase pipe and an outer water phase channel which are coaxial; the outlet end of the inner water phase pipe is positioned in the oil phase pipe, and the outlet end of the oil phase pipe is positioned in the outer water phase channel; the outer diameter of the inner water phase pipe is smaller than the inner diameter of the oil phase pipe, and the outer diameter of the oil phase pipe is smaller than the inner diameter of the outer water phase channel; the flow direction of the inner water phase in the inner water phase pipe is the same as the flow direction of the outer water phase in the outer water phase channel, and is opposite to the flow direction of the oil phase in the oil phase pipe.
The working principle of the preparation device of the doxorubicin liposome disclosed above is as follows: continuously injecting the internal water phase dissolved with the doxorubicin into an internal water phase pipe; dissolving lipid in organic solvent to obtain oil phase, and continuously injecting the oil phase into the oil phase pipe; the outer aqueous phase was continuously injected into the outer aqueous phase channel. And adjusting the relative flow rates of the inner water phase, the oil phase and the outer water phase. The inner water phase overflowed from the outlet end of the inner water phase pipe is squeezed and wrapped by the oil phase which is forthcoming in the oil phase pipe, and intermittent and dispersed water bubbles are formed in the oil phase; the oil phase overflowed from the outlet end of the oil phase pipe is squeezed and wrapped by the external water phase which is forthcoming in the external water phase channel, and discontinuous and dispersed oil bubbles are formed in the external water phase; these vesicles, which encapsulate the vesicles, are the doxorubicin liposomes.
Compared with the prior art, the preparation device that this application provided's beneficial effect is: the inner water phase overflowed from the inner water phase pipe is squeezed and wrapped by the countercurrent oil, so that discontinuous and dispersed water bubbles are formed in the oil phase by the inner water phase dissolved with the doxorubicin. And then the countercurrent outer water phase is utilized to squeeze and pinch the overflowed oil phase of the oil phase pipe, so that discontinuous and dispersed oil bubbles are formed in the outer water phase. Therefore, the doxorubicin can be fully encapsulated, so that the encapsulation rate is improved, and the content of free doxorubicin in the prepared doxorubicin liposome solution is greatly reduced. In addition, the relative flow rates of the inner water phase, the oil phase and the outer water phase can be changed by adjusting the injection speed, and the size of the prepared doxorubicin liposome can be flexibly adjusted.
Optionally, the inner water phase pipe, the oil phase pipe and the outer water phase channel are arranged in parallel and correspond to each other one by one; the inlet ends of the plurality of inner water phase pipes are communicated with the same inner water phase chamber, the inlet ends of the plurality of oil phase pipes are communicated with the same oil phase chamber, and the inlet ends of the plurality of outer water phase channels are communicated with the same outer water phase chamber; the inner water phase chamber, the oil phase chamber and the outer water phase chamber are respectively provided with a feed inlet and are matched with peristaltic pumps.
Optionally, the outer water phase chamber is located above the inner water phase chamber, a composite chamber is arranged in the outer water phase chamber, and the oil phase chamber is arranged in the composite chamber; the outer water phase channel penetrates through the bottom of the composite chamber and is communicated with the outer water phase chamber; the top end of the oil phase pipe is communicated with the oil phase chamber, and the bottom end of the oil phase pipe is arranged in the outer water phase channel in a penetrating way; the bottom end of the inner water phase pipe is communicated with the inner water phase chamber, and the top end of the inner water phase pipe is penetrated in the oil phase pipe; the inner cavity of the outer water phase chamber and the outline of the composite chamber are gradually converged from top to bottom and are in a circular truncated cone shape; the feed inlet of outer aqueous phase room sets up in upper portion, the complex room has the bin outlet.
Optionally, the inner water phase chamber and the outer water phase chamber are of an integrated structure and are funnel-shaped; a partition piece is arranged at the junction of the inner water phase chamber and the outer water phase chamber, and the inner wall of the inner water phase chamber is provided with an annular step for supporting and limiting the partition piece; the upper surface of the partition piece is recessed downwards and is a concave cambered surface; the outer bottom surface of the composite chamber is a concave cambered surface which is concave upwards; the partition has a first through hole penetrating the upper and lower surfaces thereof for mounting the inner water phase pipe.
Optionally, the inlet ends of the inner water phase pipes are connected to the same inner water phase substrate, the inner water phase pipes and the inner water phase substrate are of an integrated structure, and the inner water phase substrate is limited between the partition piece and the annular step.
Optionally, the tops of the outer water phase chamber and the composite chamber are opened and are closed by the same top cover; the discharge port is arranged on the top cover; the top cover is provided with an opening for the oil phase chamber to penetrate, and the outer peripheral surface of the oil phase chamber is provided with an annular edge which is closed by the opening.
Optionally, the outer bottom surface of the oil phase chamber is a convex cambered surface; the bottom of the oil phase chamber is provided with a second through hole penetrating through the inner surface and the outer surface of the oil phase chamber and used for penetrating through the oil phase pipe; the inlet ends of the oil phase pipes are connected to the same oil phase substrate, and the oil phase pipes and the oil phase substrate are of an integrated structure.
The application also provides a preparation method of the doxorubicin liposome, which adopts the preparation device and comprises the following steps:
s1, preparing an oil phase: dissolving phospholipid and cholesterol in absolute ethyl alcohol to prepare an oil phase with the phospholipid concentration of 40-50 g/L and the cholesterol concentration of 15-20 g/L;
s2, preparing an inner water phase: dissolving hydrochloric acid and doxorubicin in water for injection to prepare an inner water phase with pH of 4 and doxorubicin concentration of 8-10 g/L;
s3, preparing an outer water phase: dissolving hydrochloric acid and glucose in water for injection to prepare an external water phase with pH of 4 and sugar concentration of 1000-1200 mmol/L;
s4, preparing liposome: injecting the inner water phase into the inner water phase pipe, the oil phase into the oil phase pipe, and the outer water phase into the outer water phase channel; regulating and controlling the unit flow of the inner water phase, the oil phase and the outer water phase by peristaltic pumps of each phase; when the inner water phase overflows from the outlet end of the inner water phase pipe, the inner water phase is squeezed and wrapped by the oil phase coming from the oil phase pipe, and dispersed water bubbles are formed in the oil phase; when the oil phase overflows from the outlet end of the oil phase pipe, the oil phase is squeezed and wrapped by an external water phase coming from the external water phase channel, and oil bubbles wrapping the water bubbles are formed in the external water phase; the doxorubicin liposome can be prepared.
Optionally, the ratio of the unit flow rates of the inner water phase, the oil phase and the outer water phase is 1:2-3:21.
Optionally, the ratio of the inner diameter sectional area of the inner water phase pipe, the outer diameter sectional area of the inner water phase pipe, the inner diameter sectional area of the oil phase pipe, the outer diameter sectional area of the oil phase pipe and the inner diameter sectional area of the outer water phase channel is 1:1.1:1.5:1.6:3.
For the preparation method of the doxorubicin liposome disclosed above. When the inner water phase dissolved with the doxorubicin overflows from the outlet end of the inner water phase pipe; at the junction of the inner water phase and the oil phase, ethanol in the oil phase diffuses into the inner water phase, so that the concentration of ethanol is reduced, and phospholipid is separated out; the internal water phase with dissolved doxorubicin can form discontinuous and dispersed blisters in the oil phase by extrusion wrapping of the oil phase and the internal water phase with countercurrent. When the oil phase overflows from the outlet end of the oil phase pipe; at the junction of the oil phase and the outer water phase, ethanol in the oil phase diffuses to the outer water phase, so that the concentration of ethanol is reduced, and phospholipid is separated out; the outer water phase accompanied with countercurrent is squeezed and wrapped by the oil phase, so that discontinuous and dispersed oil bubbles can be formed in the outer water phase; i.e. doxorubicin liposomes. The preparation method comprises the steps of dispersing an internal water phase dissolved with doxorubicin in an oil phase to form tiny water bubbles; and dispersing the oil phase in the outer water phase to form oil bubbles wrapping the water bubbles. The doxorubicin can be fully encapsulated, so that the encapsulation rate is improved, and the content of the doxorubicin which is free in an external water phase is greatly reduced. In addition, the relative flow rates of the inner water phase, the oil phase and the outer water phase can be adjusted by controlling peristaltic pumps of all phases, and the size of the prepared doxorubicin liposome can be regulated. In addition, the preparation method is convenient for continuous production of the doxorubicin liposome, and industrial application is realized by utilization.
Drawings
In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings that are required in the embodiments or the description of the prior art will be briefly described below, it being obvious that the drawings in the following description are only some embodiments of the present application, and that other drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a schematic structural view of a manufacturing apparatus;
FIG. 2 is a schematic cross-sectional view of a manufacturing apparatus;
fig. 3 is an enlarged view of a portion a in fig. 2;
FIG. 4 is an assembly schematic of a manufacturing apparatus;
FIG. 5 is a schematic view of the assembly of the inner water phase chamber and the inner water phase pipe;
FIG. 6 is a schematic diagram of the assembly of an oil phase chamber and an oil phase tube;
FIG. 7 is a schematic structural view of a composite chamber;
reference numerals: 1. an inner water phase pipe; 2. an oil phase pipe; 3. an outer aqueous phase channel; 4. an inner aqueous phase chamber; 5. an oil phase chamber; 6. an outer aqueous phase chamber; 7. a compound chamber; 8. a discharge port; 9. a partition; 10. an annular step; 11. an inner aqueous phase substrate; 12. a top cover; 13. annular ribs; 14. an oil phase substrate.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
As shown in figures 1-7, the invention provides a preparation device of doxorubicin liposome. The preparation device comprises: an inner water phase pipe 1, an oil phase pipe 2 and an outer water phase channel 3 which are coaxial; it should be understood that the inner water phase tube 1, the oil phase tube 2, and the outer water phase channel 3 are generally circular in cross section. The outlet end of the inner water phase pipe 1 is positioned in the oil phase pipe 2, and the outlet end of the oil phase pipe 2 is positioned in the outer water phase channel 3; the outer diameter of the inner water phase pipe 1 is smaller than the inner diameter of the oil phase pipe 2, and the outer diameter of the oil phase pipe 2 is smaller than the inner diameter of the outer water phase channel 3; the flow direction of the inner water phase in the inner water phase pipe 1 is the same as the flow direction of the outer water phase in the outer water phase channel 3, and is opposite to the flow direction of the oil phase in the oil phase pipe 2. It should be understood that the inner diameter of the outer water phase channel 3 is generally equal to or less than 0.4mm, the inner diameter of the oil phase pipe 2 is generally equal to or less than 0.3mm, and the inner diameter of the inner water phase pipe 1 is generally equal to or less than 0.2mm.
Specific embodiments of the preparation apparatus are described below: continuously injecting the internal water phase dissolved with the doxorubicin into an internal water phase pipe 1; dissolving lipid in organic solvent to obtain oil phase, and continuously injecting the oil phase into the oil phase pipe 2; the outer aqueous phase is continuously injected into the outer aqueous phase channel 3. And adjusting the relative flow rates of the inner water phase, the oil phase and the outer water phase. The inner water phase overflowed from the outlet end of the inner water phase pipe 1 is squeezed and wrapped by the oil phase which is forthcoming in the oil phase pipe 2, and intermittent and dispersed water bubbles are formed in the oil phase; the oil phase overflowed from the outlet end of the oil phase pipe 2 is squeezed and wrapped by the outer water phase from the head-on in the outer water phase channel 3, and discontinuous and dispersed oil bubbles are formed in the outer water phase; these vesicles, which encapsulate the vesicles, are the doxorubicin liposomes.
Compared with the prior art, the preparation device that this application provided's beneficial effect is: the inner water phase overflowed from the inner water phase pipe 1 is extruded and wrapped by the countercurrent oil, so that discontinuous and dispersed water bubbles are formed in the oil phase by the inner water phase dissolved with the doxorubicin. And then the oil phase overflowed from the oil phase pipe 2 is squeezed and wrapped by the countercurrent outer water phase, so that discontinuous and dispersed oil bubbles are formed in the outer water phase. Therefore, the doxorubicin can be fully encapsulated, so that the encapsulation rate is improved, and the content of free doxorubicin in the prepared doxorubicin liposome solution is greatly reduced. In addition, the relative flow rates of the inner water phase, the oil phase and the outer water phase can be changed by adjusting the injection speed, and the size of the prepared doxorubicin liposome can be flexibly adjusted.
Further, the inner water phase pipe 1, the oil phase pipe 2 and the outer water phase channel 3 are arranged in parallel and correspond to each other one by one; the inlet ends of a plurality of inner water phase pipes 1 are communicated with the same inner water phase chamber 4, the inlet ends of a plurality of oil phase pipes 2 are communicated with the same oil phase chamber 5, and the inlet ends of a plurality of outer water phase channels 3 are communicated with the same outer water phase chamber 6; the inner water phase chamber 4, the oil phase chamber 5 and the outer water phase chamber 6 are respectively provided with a feed inlet and are matched with peristaltic pumps. It should be understood that the feed inlet of the internal aqueous phase chamber 4 is an internal aqueous phase inlet which communicates with a hose carrying the internal aqueous phase and fitted with a peristaltic pump; the feeding port of the oil phase chamber 5 is an oil phase inlet which is communicated with a hose for conveying the oil phase and is provided with a peristaltic pump; the feed inlet of the outer water phase chamber 6 is an outer water phase inlet which is communicated with a hose for conveying the outer water phase and is adapted to a peristaltic pump. When the inner diameter and the outer diameter of the inner water phase pipe 1, the inner diameter and the outer diameter of the oil phase pipe 2 and the inner diameter of the outer water phase channel 3 are fixed, the relative flow rates of the inner water phase, the oil phase and the outer water phase can be regulated and controlled by regulating the unit flow rate of the peristaltic pump for conveying the inner water phase, the unit flow rate of the peristaltic pump for conveying the oil phase and the unit flow rate of the peristaltic pump for conveying the outer water phase.
Further, the outer water phase chamber 6 is positioned above the inner water phase chamber 4, a composite chamber 7 is arranged in the outer water phase chamber 6, and the oil phase chamber 5 is arranged in the composite chamber 7; the outer water phase channel 3 penetrates through the bottom of the composite chamber 7, and is communicated with the composite chamber 7 and the outer water phase chamber 6; the top end of the oil phase pipe 2 is communicated with the oil phase chamber 5, and the bottom end of the oil phase pipe is arranged in the outer water phase channel 3 in a penetrating way; the bottom end of the inner water phase pipe 1 is communicated with the inner water phase chamber 4, and the top end of the inner water phase pipe is penetrated in the oil phase pipe 2; the inner cavity of the outer water phase chamber 6 and the outline of the composite chamber 7 are gradually convergent from top to bottom and are in a truncated cone shape; the feed inlet of the outer water phase chamber 6 is arranged at the upper part, and the compound chamber 7 is provided with a discharge outlet 8. It will be appreciated that the outer aqueous phase will flow helically downwards along the inner wall of the outer aqueous phase chamber 6 and after flowing to the bottom of the outer aqueous phase chamber 6, again upwards along the middle of the outer aqueous phase chamber 6 and into the outer aqueous phase channel 3. The outer water phase of the rotational flow is faced to the oil phase overflowed from the oil phase pipe 2, so that the size of the prepared liposome is smaller. The bottom end of the outer water phase channel 3 is an inlet end, and the top end is an outlet end. The top end of the oil phase pipe 2 is an inlet end, and the bottom end is an outlet end. The bottom end of the inner water phase channel is an inlet end, and the top end is an outlet end.
Further, the inner water phase chamber 4 and the outer water phase chamber 6 are of an integrated structure and are funnel-shaped; a partition piece 9 is arranged at the junction of the inner water phase chamber 4 and the outer water phase chamber 6, and the inner wall of the inner water phase chamber 4 is provided with an annular step 10 for supporting and limiting the partition piece 9; the upper surface of the partition piece 9 is recessed downwards and is a concave cambered surface; the outer bottom surface of the composite chamber 7 is a concave cambered surface which is concave upwards; the partition 9 has a first through hole penetrating the upper and lower surfaces thereof for mounting the inner water phase pipe 1. It will be appreciated that the outer aqueous phase, before entering the outer aqueous phase channel 3, after leaving the outer aqueous phase channel 3, is all close to the peripheral side of the outer aqueous phase chamber 6 and away from the middle of the outer aqueous phase chamber 6; the upper surface of the partition 9 is set to be a concave arc surface which is concave downwards, and the outer bottom surface of the composite chamber 7 is set to be a concave arc surface which is concave upwards, so that the outer water phase is led to the middle part of the outer water phase chamber 6, and the outer water phase is more uniformly distributed to the outer water phase channel 3 in the middle part and the outer water phase channel 3 at the periphery.
Further, the inlet ends of the inner water phase pipes 1 are connected to the same inner water phase substrate 11, the inner water phase pipes 1 and the inner water phase substrate 11 are in an integrated structure, and the inner water phase substrate 11 is limited between the partition piece 9 and the annular step 10. It should be understood that the inner aqueous phase base plate 11 has an inner aqueous phase through hole corresponding to the inner aqueous phase pipe 1. The inner water phase pipe 1 and the inner water phase substrate 11 can be integrally processed and formed by means of etching, photoetching and the like, so that the precision is improved, and the assembly is convenient. And the inner water phase pipe 1 and the partition piece 9 with the concave cambered surface are arranged into a split structure, so that the processing is convenient. The inner water phase pipe 1 passes through the partition 9 from bottom to top, and the inner water phase base plate 11 is glued with the partition 9 and the annular step 10, so that the installation of the partition 9 and the inner water phase pipe 1 is completed.
Further, the tops of the outer water phase chamber 6 and the composite chamber 7 are opened and are closed by the same top cover 12; the discharge opening 8 is arranged on the top cover 12; the top cover 12 has an opening through which the oil phase chamber 5 penetrates, and the outer peripheral surface of the oil phase chamber 5 has an annular ridge 13 which closes the opening. It should be understood that the oil phase substrate 14 has oil phase through holes corresponding to the oil phase pipes 2.
Further, the outer bottom surface of the oil phase chamber 5 is a convex cambered surface; the bottom of the oil phase chamber 5 is provided with a second through hole penetrating through the inner surface and the outer surface of the oil phase chamber and used for penetrating through the oil phase pipe 2; the inlet ends of the oil phase pipes 2 are connected to the same oil phase substrate 14, and the oil phase pipes 2 and the oil phase substrate 14 are of an integrated structure. It should be understood that the oil phase pipe 2 is led to pass through the oil phase chamber 5 from top to bottom, and the oil phase pipe 2 is led to pass through the corresponding outer water phase channel 3; the oil phase substrate 14 and the oil phase chamber 5 are glued to complete the installation of the oil phase tube 2. The compound chamber 7 is glued with the top cover 12, the top cover 12 is glued with the outer water phase chamber 6, the oil phase chamber 5 passes through the top cover 12 from top to bottom, the oil phase pipe 2 is sleeved on the periphery of the corresponding inner water phase pipe 1, and finally the annular edge 13 of the oil phase chamber 5 is glued with the top cover 12, so that the installation of the oil phase chamber 5 can be completed.
The application also provides a preparation method of the doxorubicin liposome, which comprises the following examples:
example 1
S1: dissolving phospholipid and cholesterol in absolute ethanol to obtain oil phase with phospholipid concentration of 40g/L and cholesterol concentration of 15 g/L.
S2: hydrochloric acid and doxorubicin were dissolved in water for injection to prepare an inner aqueous phase having a pH of 4 and a doxorubicin concentration of 8 g/L.
S3: hydrochloric acid and glucose are dissolved in water for injection to prepare an external water phase with pH of 4 and sugar concentration of 1000 mmol/L.
S4: and respectively injecting the inner water phase, the oil phase and the outer water phase into the inner water phase pipe 1, the oil phase pipe 2 and the outer water phase channel 3 through peristaltic pumps of all phases. And peristaltic pumps of all phases are regulated and controlled to ensure that the ratio of unit flow rates of the inner water phase, the oil phase and the outer water phase is kept at 1:2:21. The solution discharged from the outer water phase channel 3 is collected and is the doxorubicin liposome solution.
Example 2
S1: dissolving phospholipid and cholesterol in absolute ethanol to obtain oil phase with phospholipid concentration of 45g/L and cholesterol concentration of 17.5 g/L.
S2: hydrochloric acid and doxorubicin were dissolved in water for injection to prepare an inner aqueous phase having a pH of 4 and a doxorubicin concentration of 9 g/L.
S3: hydrochloric acid and glucose are dissolved in water for injection to prepare an external water phase with pH of 4 and sugar concentration of 1100 mmol/L.
S4: and respectively injecting the inner water phase, the oil phase and the outer water phase into the inner water phase pipe 1, the oil phase pipe 2 and the outer water phase channel 3 through peristaltic pumps of all phases. And peristaltic pumps of all phases are regulated and controlled to ensure that the ratio of unit flow rates of the inner water phase, the oil phase and the outer water phase is kept at 1:2:21. The solution discharged from the outer water phase channel 3 is collected and is the doxorubicin liposome solution.
Example 3
S1: dissolving phospholipid and cholesterol in absolute ethanol to obtain oil phase with phospholipid concentration of 50g/L and cholesterol concentration of 20 g/L.
S2: hydrochloric acid and doxorubicin were dissolved in water for injection to prepare an inner aqueous phase having a pH of 4 and a doxorubicin concentration of 10 g/L.
S3: hydrochloric acid and glucose are dissolved in water for injection to prepare an external water phase with pH of 4 and sugar concentration of 1200 mmol/L.
S4: and respectively injecting the inner water phase, the oil phase and the outer water phase into the inner water phase pipe 1, the oil phase pipe 2 and the outer water phase channel 3 through peristaltic pumps of all phases. And peristaltic pumps of all phases are regulated and controlled to ensure that the ratio of unit flow rates of the inner water phase, the oil phase and the outer water phase is kept at 1:2:21. The solution discharged from the outer water phase channel 3 is collected and is the doxorubicin liposome solution.
Example 4
S1: dissolving phospholipid and cholesterol in absolute ethanol to obtain oil phase with phospholipid concentration of 40g/L and cholesterol concentration of 15 g/L.
S2: hydrochloric acid and doxorubicin were dissolved in water for injection to prepare an inner aqueous phase having a pH of 4 and a doxorubicin concentration of 8 g/L.
S3: hydrochloric acid and glucose are dissolved in water for injection to prepare an external water phase with pH of 4 and sugar concentration of 1000 mmol/L.
S4: and respectively injecting the inner water phase, the oil phase and the outer water phase into the inner water phase pipe 1, the oil phase pipe 2 and the outer water phase channel 3 through peristaltic pumps of all phases. And peristaltic pumps of all phases are regulated and controlled to ensure that the ratio of unit flow rates of the inner water phase, the oil phase and the outer water phase is kept at 1:3:21. The solution discharged from the outer water phase channel 3 is collected and is the doxorubicin liposome solution.
Example 5
S1: dissolving phospholipid and cholesterol in absolute ethanol to obtain oil phase with phospholipid concentration of 45g/L and cholesterol concentration of 17.5 g/L.
S2: hydrochloric acid and doxorubicin were dissolved in water for injection to prepare an inner aqueous phase having a pH of 4 and a doxorubicin concentration of 9 g/L.
S3: hydrochloric acid and glucose are dissolved in water for injection to prepare an external water phase with pH of 4 and sugar concentration of 1100 mmol/L.
S4: and respectively injecting the inner water phase, the oil phase and the outer water phase into the inner water phase pipe 1, the oil phase pipe 2 and the outer water phase channel 3 through peristaltic pumps of all phases. And peristaltic pumps of all phases are regulated and controlled to ensure that the ratio of unit flow rates of the inner water phase, the oil phase and the outer water phase is kept at 1:3:21. The solution discharged from the outer water phase channel 3 is collected and is the doxorubicin liposome solution.
Example 6
S1: dissolving phospholipid and cholesterol in absolute ethanol to obtain oil phase with phospholipid concentration of 50g/L and cholesterol concentration of 20 g/L.
S2: hydrochloric acid and doxorubicin were dissolved in water for injection to prepare an inner aqueous phase having a pH of 4 and a doxorubicin concentration of 10 g/L.
S3: hydrochloric acid and glucose are dissolved in water for injection to prepare an external water phase with pH of 4 and sugar concentration of 1200 mmol/L.
S4: and respectively injecting the inner water phase, the oil phase and the outer water phase into the inner water phase pipe 1, the oil phase pipe 2 and the outer water phase channel 3 through peristaltic pumps of all phases. And peristaltic pumps of all phases are regulated and controlled to ensure that the ratio of unit flow rates of the inner water phase, the oil phase and the outer water phase is kept at 1:3:21. The solution discharged from the outer water phase channel 3 is collected and is the doxorubicin liposome solution.
Comparative example 1
Dissolving phospholipid and cholesterol in absolute ethanol to obtain oil phase with phospholipid concentration of 40g/L and cholesterol concentration of 15 g/L;
dissolving hydrochloric acid, doxorubicin and glucose in water for injection to obtain water phase with pH of 4, doxorubicin concentration of 0.36g/L and glucose concentration of 955 mmol/L;
and (3) putting the oil phase and the water phase into a homogenizer according to the volume ratio of 1:11 for homogenizing and mixing to obtain the doxorubicin liposome solution.
Comparative example 2
Dissolving phospholipid and cholesterol in absolute ethanol to obtain oil phase with phospholipid concentration of 50g/L and cholesterol concentration of 20 g/L;
dissolving hydrochloric acid, doxorubicin and glucose in water for injection to obtain water phase with pH of 4, doxorubicin concentration of 0.45g/L and glucose concentration of 1145 mmol/L;
and (3) putting the oil phase and the water phase into a homogenizer according to the volume ratio of 1:11 for homogenizing and mixing to obtain the doxorubicin liposome solution.
Comparative example 3
Dissolving phospholipid and cholesterol in absolute ethanol to obtain oil phase with phospholipid concentration of 40g/L and cholesterol concentration of 15 g/L;
dissolving hydrochloric acid, doxorubicin and glucose in water for injection to obtain water phase with pH of 4, doxorubicin concentration of 0.36g/L and glucose concentration of 955 mmol/L;
and (3) putting the oil phase and the water phase into a homogenizer according to the volume ratio of 3:22 for homogenizing and mixing to obtain the doxorubicin liposome solution.
Comparative example 4
Dissolving phospholipid and cholesterol in absolute ethanol to obtain oil phase with phospholipid concentration of 50g/L and cholesterol concentration of 20 g/L;
dissolving hydrochloric acid, doxorubicin and glucose in water for injection to obtain water phase with pH of 4, doxorubicin concentration of 0.45g/L and glucose concentration of 1145 mmol/L;
and (3) putting the oil phase and the water phase into a homogenizer according to the volume ratio of 3:22 for homogenizing and mixing to obtain the doxorubicin liposome solution.
Note 1: the doxorubicin liposome solutions prepared in examples 1 to 6 were subjected to separation and purification to remove impurities such as ethanol, thereby obtaining doxorubicin liposome injection.
And (2) injection: the doxorubicin liposome preparation apparatus used in examples 1 to 6 had a ratio of the inner diameter sectional area of the inner aqueous phase tube 1, the outer diameter sectional area of the inner aqueous phase tube 1, the inner diameter sectional area of the oil phase tube 2, the outer diameter sectional area of the oil phase tube 2, and the inner diameter sectional area of the outer aqueous phase channel 3 of 1:1.1:1.5:1.6:3.
Samples were obtained from the doxorubicin liposome solutions prepared in examples 1 to 6 and comparative examples 1 to 4, and the doxorubicin liposome and free doxorubicin in each sample were separated by dialysis. The content of free doxorubicin isolated was determined by high performance liquid chromatography and the total amount of free doxorubicin in each sample was calculated. The total amount of doxorubicin contained in each sample was calculated from the ingredients of examples 1 to 6 and comparative examples 1 to 4. Finally, the encapsulation efficiency can be calculated according to the ratio of the total free doxorubicin to the total doxorubicin in each sample.
Table 1: encapsulation efficiency of examples 1 to 6 and comparative examples 1 to 4
| Encapsulation efficiency | |
| Example 1 | 84.33% |
| Example 2 | 85.91% |
| Example 3 | 87.19% |
| Example 4 | 82.82% |
| Example 5 | 83.26% |
| Example 6 | 84.71% |
| Comparative example 1 | 46.84% |
| Comparative example 2 | 47.17% |
| Comparative example 3 | 50.39% |
| Comparative example 4 | 51.32% |
From Table 1, it can be seen. The encapsulation efficiency of examples 1-6 is significantly higher than that of comparative examples 1-4. This means that the doxorubicin-dissolved internal aqueous phase is dispersed in the oil phase to form fine blisters; and dispersing the oil phase in the outer water phase to form oil bubbles wrapping the water bubbles. The doxorubicin can be fully encapsulated, so that the encapsulation rate is improved, and the content of the doxorubicin which is free in an external water phase is greatly reduced.
While particular embodiments of the present invention have been described above, it will be understood by those skilled in the art that various changes and modifications may be made to these embodiments without departing from the spirit and scope of the invention.
Claims (10)
1. The preparation device of the doxorubicin liposome is characterized in that:
comprising the following steps: an inner water phase pipe (1), an oil phase pipe (2) and an outer water phase channel (3) which are coaxial;
wherein,,
the outlet end of the inner water phase pipe (1) is positioned in the oil phase pipe (2), and the outlet end of the oil phase pipe (2) is positioned in the outer water phase channel (3);
the outer diameter of the inner water phase pipe (1) is smaller than the inner diameter of the oil phase pipe (2), and the outer diameter of the oil phase pipe (2) is smaller than the inner diameter of the outer water phase channel (3);
the flow direction of the inner water phase in the inner water phase pipe (1) is the same as the flow direction of the outer water phase in the outer water phase channel (3), and is opposite to the flow direction of the oil phase in the oil phase pipe (2).
2. The apparatus for preparing doxorubicin liposome according to claim 1, wherein:
the inner water phase pipe (1), the oil phase pipe (2) and the outer water phase channel (3) are arranged in parallel and correspond to each other one by one;
the inlet ends of a plurality of inner water phase pipes (1) are communicated with the same inner water phase chamber (4), the inlet ends of a plurality of oil phase pipes (2) are communicated with the same oil phase chamber (5), and the inlet ends of a plurality of outer water phase channels (3) are communicated with the same outer water phase chamber (6);
the inner water phase chamber (4), the oil phase chamber (5) and the outer water phase chamber (6) are respectively provided with a feed inlet and are matched with peristaltic pumps.
3. The apparatus for preparing doxorubicin liposome according to claim 2, wherein:
the outer water phase chamber (6) is positioned above the inner water phase chamber (4), a composite chamber (7) is arranged in the outer water phase chamber (6), and the oil phase chamber (5) is arranged in the composite chamber (7);
the outer water phase channel (3) penetrates through the bottom of the composite chamber (7) and is communicated with the composite chamber (7) and the outer water phase chamber (6);
the top end of the oil phase pipe (2) is communicated with the oil phase chamber (5), and the bottom end of the oil phase pipe is penetrated in the outer water phase channel (3);
the bottom end of the inner water phase pipe (1) is communicated with the inner water phase chamber (4), and the top end of the inner water phase pipe is penetrated in the oil phase pipe (2);
the inner cavity of the outer water phase chamber (6) and the outline of the composite chamber (7) are gradually convergent from top to bottom and are in a truncated cone shape;
the feed inlet of the outer water phase chamber (6) is arranged at the upper part, and the composite chamber (7) is provided with a discharge outlet (8).
4. The apparatus for preparing doxorubicin liposome according to claim 3, wherein:
the inner water phase chamber (4) and the outer water phase chamber (6) are of an integrated structure and are funnel-shaped;
a partition piece (9) is arranged at the junction of the inner water phase chamber (4) and the outer water phase chamber (6), and an annular step (10) for supporting and limiting the partition piece (9) is arranged on the inner wall of the inner water phase chamber (4);
the upper surface of the partition piece (9) is recessed downwards and is a concave cambered surface; the outer bottom surface of the composite chamber (7) is a concave cambered surface which is concave upwards;
the partition (9) has a first through hole penetrating the upper and lower surfaces thereof for mounting the inner water phase pipe (1).
5. The apparatus for preparing doxorubicin liposome according to claim 4, wherein:
the inlet ends of a plurality of inner water phase pipes (1) are connected to the same inner water phase base plate (11), the inner water phase pipes (1) and the inner water phase base plate (11) are of an integrated structure, and the inner water phase base plate (11) is limited between the partition piece (9) and the annular step (10).
6. The apparatus for preparing doxorubicin liposome according to any one of claims 3 to 5, characterized in that:
the tops of the outer water phase chamber (6) and the composite chamber (7) are open and are closed by the same top cover (12); the discharge opening (8) is arranged on the top cover (12);
the top cover (12) is provided with an opening for the oil phase chamber (5) to penetrate, and the outer peripheral surface of the oil phase chamber (5) is provided with an annular rib (13) which is closed to the opening.
7. The apparatus for preparing doxorubicin liposome according to claim 6, wherein:
the outer bottom surface of the oil phase chamber (5) is a convex cambered surface;
the bottom of the oil phase chamber (5) is provided with a second through hole penetrating through the inner surface and the outer surface of the oil phase chamber and used for penetrating through the oil phase pipe (2);
inlet ends of the oil phase pipes (2) are connected to the same oil phase substrate (14), and the oil phase pipes (2) and the oil phase substrate (14) are of an integrated structure.
8. A preparation method of doxorubicin liposome is characterized by comprising the following steps:
a production apparatus using the doxorubicin liposome according to any one of claims 2 to 7, comprising the steps of:
s1, preparing an oil phase: dissolving phospholipid and cholesterol in absolute ethyl alcohol to prepare an oil phase with the phospholipid concentration of 40-50 g/L and the cholesterol concentration of 15-20 g/L;
s2, preparing an inner water phase: dissolving hydrochloric acid and doxorubicin in water for injection to prepare an inner water phase with pH of 4 and doxorubicin concentration of 8-10 g/L;
s3, preparing an outer water phase: dissolving hydrochloric acid and glucose in water for injection to prepare an external water phase with pH of 4 and sugar concentration of 1000-1200 mmol/L;
s4, preparing liposome: injecting the inner water phase into the inner water phase pipe (1), the oil phase into the oil phase pipe (2) and the outer water phase into the outer water phase channel (3); regulating and controlling the unit flow of the inner water phase, the oil phase and the outer water phase by peristaltic pumps of each phase; when the inner water phase overflows from the outlet end of the inner water phase pipe (1), the inner water phase is squeezed and wrapped by the oil phase coming from the oil phase pipe (2), and dispersed water bubbles are formed in the oil phase; when the oil phase overflows from the outlet end of the oil phase pipe (2), the oil phase is squeezed and wrapped by an external water phase from the head-on in the external water phase channel (3), and oil bubbles wrapping the water bubbles are formed in the external water phase; the doxorubicin liposome can be prepared.
9. The method for preparing doxorubicin liposome according to claim 8, wherein: the ratio of the unit flow rates of the inner water phase, the oil phase and the outer water phase is 1:2-3:21.
10. The method for preparing doxorubicin liposome according to claim 8, wherein:
the ratio of the inner diameter sectional area of the inner water phase pipe (1), the outer diameter sectional area of the inner water phase pipe (1), the inner diameter sectional area of the oil phase pipe (2), the outer diameter sectional area of the oil phase pipe (2) and the inner diameter sectional area of the outer water phase channel (3) is 1:1.1:1.5:1.6:3.
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