CN114469734A - Preparation device and preparation method of anthracycline liposome - Google Patents
Preparation device and preparation method of anthracycline liposome Download PDFInfo
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- CN114469734A CN114469734A CN202111352147.3A CN202111352147A CN114469734A CN 114469734 A CN114469734 A CN 114469734A CN 202111352147 A CN202111352147 A CN 202111352147A CN 114469734 A CN114469734 A CN 114469734A
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- A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
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Abstract
The invention provides a preparation device and a preparation method of an anthracycline liposome, and aims to solve the technical problem of low encapsulation efficiency in preparation of the anthracycline liposome in the prior art. The adopted technical scheme is as follows: an anthracycline liposome preparation device, comprising: an inner water phase pipe and an oil phase channel parallel to the inner water phase pipe; the outlet end of the inner water phase pipe penetrates through the outlet end of the oil phase channel, and a space for forming a confluence channel is formed between the outer wall of the inner water phase pipe and the inner wall of the oil phase channel; the outlet end of the oil phase channel is positioned in the compound chamber; the compound chamber is provided with an external water phase inlet and a discharge port, and an external water phase flow channel pointing to the discharge port from the external water phase inlet covers the outlet end of the oil phase channel. In addition, the invention also provides a method for preparing the anthracycline 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 preparation device and a preparation method of anthracycline liposome.
Background
Anthracyclines, including doxorubicin, epirubicin, daunorubicin, aclarubicin, and the like. Can be widely used for treating malignant tumor and solid tumor of blood system, such as acute leukemia, lymphoma, breast cancer, gastric cancer, soft tissue sarcoma, ovarian cancer, etc.
Anthracyclines cause cardiotoxicity, which limits their clinical use. In order to reduce toxicity, liposomes have been tried as carriers for anthracycline drugs. Clinical results show that the anthracycline liposome can obviously reduce toxic and side effects on the premise of not reducing the drug effect. In the prior art, when preparing the anthracycline liposome, most anthracycline drugs are dissolved in water for injection to prepare a water phase, lipids are 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 anthracycline liposome solution. The technology has the defect of low entrapment rate, and the prepared anthracycline liposome solution often contains a large amount of free anthracycline medicines which are not wrapped in the liposome.
Disclosure of Invention
The invention aims to provide a preparation device of anthracycline liposome, which can improve the encapsulation efficiency.
Based on the same inventive concept, another object of the present invention is to provide a method for preparing anthracycline liposomes using the above device.
In particular, the amount of the solvent to be used,
an anthracycline liposome preparation device, comprising: an inner water phase pipe and an oil phase channel parallel to the inner water phase pipe; the outlet end of the inner water phase pipe penetrates through the outlet end of the oil phase channel, and a space for forming a confluence channel is formed between the outer wall of the inner water phase pipe and the inner wall of the oil phase channel; the outlet end of the oil phase channel is positioned in the compound chamber; the compound chamber is provided with an external water phase inlet and a discharge port, and an external water phase flow channel pointing to the discharge port from the external water phase inlet covers the outlet end of the oil phase channel.
The working principle of the preparation device of the anthracycline liposome is as follows: continuously injecting the inner water phase dissolved with the anthracycline into the inner water phase tube; dissolving lipid in polar organic solvent to obtain oil phase, and continuously injecting the oil phase into the oil phase channel; the external water phase is injected into the recombination chamber through the external water phase inlet. Adjusting the relative flow rate of the internal water phase and the oil phase to ensure that the internal water phase is extruded and wrapped by the oil phase coming from the oil phase channel when overflowing from the outlet end of the internal water phase pipe, so as to be dispersed in the oil phase; meanwhile, in the dispersion process, the polar organic solvent in the oil phase can diffuse to the boundary internal water phase, so that the concentration of the polar organic solvent at the boundary is reduced, the lipid is separated out, the internal water phase dispersed in the oil phase can be surrounded by the lipid, and discontinuous and dispersed water bubbles are formed in the oil phase. Adjusting the relative flow rate of the oil phase and the external water phase, so that the oil phase wrapped with the water bubbles is wrapped by the external water phase flowing from the external water phase inlet to the discharge port and is dispersed in the external water phase when overflowing from the outlet end of the oil phase channel; in the dispersion process, the polar organic solvent in the oil phase can diffuse to the outer water phase of the boundary, so that the concentration of the polar organic solvent at the boundary is reduced, the lipid is separated out, and oil bubbles wrapping the water bubbles, namely the anthracycline liposome, are formed in the outer water phase.
Compared with the prior art, the preparation device provided by the application has the beneficial effects that: firstly forming dispersed tiny water bubbles in an oil phase by an internal water phase dissolved with the anthracycline, and then separating the oil phase wrapped with the water bubbles in an external water phase to form anthracycline liposome; thus, the anthracycline medicine can be fully wrapped, and the encapsulation efficiency is improved.
Optionally, the external water phase inlet and the discharge outlet are oppositely arranged at two sides of the compound chamber; the oil phase channel is vertical to the outer water phase flow channel; the confluence channel is positioned on one side of the inner water phase pipe corresponding to the inlet of the outer water phase.
Optionally, the cross sections of the inner water phase pipe and the oil phase channel are fan-shaped, and the corresponding central angle is less than or equal to 180 °; the inner water phase pipe comprises a plane pipe wall and an arc pipe wall, and the oil phase channel comprises a plane inner wall and an arc inner wall; the plane pipe wall is attached to the plane inner wall, and an interval for forming a confluence channel is arranged between the arc-surface pipe wall and the arc-surface inner wall.
Optionally, the inner water phase tubes and the oil phase channels are arranged in multiple rows along the outer water phase flow channel, and the inner water phase tubes correspond to the oil phase channels one to one; the plurality of inner water phase pipes of each column are arranged in a staggered mode with the plurality of inner water phase pipes of the adjacent columns.
Optionally, an oil phase chamber is arranged at the top of the composite chamber, and the oil phase channel is communicated with the oil phase chamber and the composite chamber from top to bottom; an inner water phase chamber is arranged at the bottom of the composite chamber, and an oil phase channel and the inner water phase chamber are communicated with each other up and down through an inner water phase pipe; the oil phase chamber is provided with an oil phase inlet, and the inner water phase chamber is provided with an inner water phase inlet.
Optionally, the compound chamber comprises a dish part and a top cover; the dish part, the inner water phase pipe and the inner water phase chamber are of an integrated structure, and the bottom of the dish part forms the top of the inner water phase chamber; the top cover, the oil phase channel and the oil phase chamber are of an integrated structure, and the top cover forms the bottom of the oil phase chamber.
The application also provides a preparation method of the anthracycline liposome, which adopts the preparation device and comprises the following steps:
s1 preparation of oil phase: dissolving phospholipid and cholesterol in absolute ethyl alcohol to prepare an oil phase with the phospholipid concentration of 30-50 g/L and the cholesterol concentration of 10-20 g/L;
s2 preparation of the internal aqueous phase: dissolving hydrochloric acid and an anthracycline medicament into water for injection to prepare an internal water phase with the pH value of 4 and the concentration of the anthracycline medicament of 6-12 g/L;
s3 preparation of external water phase: dissolving hydrochloric acid and monosaccharide in water for injection to prepare an external water phase with the pH of 4 and the sugar concentration of 600-1200 mmol/L;
s4 preparation of liposomes: injecting the inner water phase into the inner water phase pipe, injecting the oil phase into the oil phase channel, and injecting the outer water phase into the composite chamber through the outer water phase inlet; the relative flow rates of the inner water phase, the oil phase and the outer water phase are adjusted by controlling the injection speed; when the internal water phase overflows from the outlet end of the internal water phase pipe, the internal water phase is extruded and wrapped by the oil phase coming from the oil phase channel, so that the oil phase wrapped with the water bubbles is formed in the confluence channel; and when the oil phase wrapped with the water bubbles overflows from the outlet end of the oil phase channel, the oil phase is wrapped by the outer water phase flowing from the outer water phase inlet to the discharge port, so that the oil phase is dispersed in the outer water phase to form the oil bubbles wrapped with the water bubbles, namely the anthracycline liposome.
Optionally, the monosaccharide is glucose or fructose.
Optionally, when the internal aqueous phase, the oil phase and the external aqueous phase are injected, the ratio of the unit flow rates of the internal aqueous phase, the oil phase and the external aqueous phase is 1: 2-3: 16.
Optionally, the height and width of the external water phase flow channel are correspondingly adapted to the height and width of the external water phase inlet; the interval between the bottom of the oil phase channel and the bottom of the compound chamber is not more than the height of the outer water phase channel and less than two times of the interval between the bottom of the oil phase channel and the bottom of the compound chamber; the ratio of the sum of the inner diameter sectional areas of the inner water phase pipes, the sum of the inner diameter sectional areas of the oil phase channels and the inner diameter sectional area of the outer water phase inlet is 2:3: 3.
The working principle of the preparation method of the anthracycline liposome is as follows: the relative flow rates of the internal water phase and the oil phase are adjusted by controlling the injection speed; when the inner water phase dissolved with the anthracycline overflows from the outlet end of the inner water phase pipe, the inner water phase is extruded and wrapped by the oncoming oil phase and is dispersed into the oil phase to form tiny water bubbles. The relative flow rates of the oil phase and the external water phase are adjusted by controlling the injection speed; when the oil phase overflows from the outlet end of the oil phase channel, the oil phase is extruded and wrapped by the external water phase and is dispersed into the external water phase to form oil bubbles wrapping water bubbles, namely the anthracycline liposome.
Compared with the prior art, the preparation method provided by the application has the beneficial effects that: firstly forming dispersed tiny water bubbles in an oil phase by an internal water phase dissolved with the anthracycline, and then separating the oil phase wrapped with the water bubbles in an external water phase to form anthracycline liposome; thus, the anthracycline medicine can be fully wrapped, and the encapsulation efficiency is improved.
Drawings
In order to more clearly illustrate the embodiments of the present application 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 of the present application, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.
FIG. 1 is a schematic view of a manufacturing apparatus;
FIG. 2 is a schematic sectional view of a manufacturing apparatus;
FIG. 3 is an enlarged view of portion A of FIG. 2;
FIG. 4 is a schematic view of an assembly of the manufacturing apparatus;
FIG. 5 is a schematic structural diagram of the oil phase chamber, the oil phase channel and the top cover;
FIG. 6 is a schematic view of another angle of FIG. 5;
reference numerals: 1. an inner aqueous phase pipe; 2. an oil phase channel; 3. a compounding chamber; 4. an external water phase inlet; 5. a discharge outlet; 6. an external water phase flow channel; 7. a confluence passage; 8. an oil phase chamber; 9. an internal aqueous phase chamber; 10. a dish portion; 11. and a top cover.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the drawings in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
As shown in figures 1-6, the invention provides a preparation device of anthracycline liposome. The preparation device comprises: an inner water phase pipe 1 and an oil phase channel 2 parallel to the inner water phase pipe 1; the outlet end of the inner water phase pipe 1 penetrates from the outlet end of the oil phase channel 2, and a space for forming a confluence channel 7 is formed between the outer wall of the inner water phase pipe 1 and the inner wall of the oil phase channel 2; the outlet end of the oil phase channel 2 is positioned in the compound chamber 3; the compound chamber 3 is provided with an external water phase inlet 4 and a discharge port 5, and an external water phase flow channel 6 which is directed from the external water phase inlet 4 to the discharge port 5 covers the outlet end of the oil phase channel 2. It will be appreciated that the external water phase will pass through the outlet end of the oil phase channel 2 as it flows from the external water phase inlet 4 to the discharge opening 5, thereby entraining and squeezing the oil phase overflowing from the oil phase channel 2. The inner diameter of the inner water phase pipe 1 is usually 0.2mm or less, and the inner diameter of the oil phase passage 2 is usually 0.3mm or less. In addition, the indoor height of the compound chamber 3 can be compressed, so that the whole chamber of the compound chamber 3 forms an external water phase flow passage 6; the height of the external water phase flow channel 6 is basically the same as that of the external water phase inlet 4, and the width of the external water phase flow channel 6 is basically the same as that of the external water phase inlet 4; generally, the interval between the bottom of the oil phase channel 2 and the bottom of the composite chamber 3 is 1mm or less.
The following describes specific embodiments of the production apparatus: continuously injecting the inner water phase dissolved with the anthracycline into the inner water phase tube 1; dissolving lipid in polar organic solvent to obtain oil phase, and continuously injecting the oil phase into oil phase channel 2; the external aqueous phase is injected into the recombination chamber 3 through the external aqueous phase inlet 4. Adjusting the relative flow rate of the internal water phase and the oil phase to ensure that the internal water phase is extruded and wrapped by the oil phase coming from the oil phase channel 2 when overflowing from the outlet end of the internal water phase pipe 1, so as to be dispersed in the oil phase; meanwhile, in the dispersion process, the polar organic solvent in the oil phase can diffuse to the boundary internal water phase, so that the concentration of the polar organic solvent at the boundary is reduced, the lipid is separated out, the internal water phase dispersed in the oil phase can be surrounded by the lipid, and discontinuous and dispersed water bubbles are formed in the oil phase. Adjusting the relative flow rate of the oil phase and the external water phase, so that the oil phase wrapped with the water bubbles is wrapped by the external water phase flowing from the external water phase inlet 4 to the discharge port 5 and is dispersed in the external water phase when overflowing from the outlet end of the oil phase channel 2; in the dispersion process, the polar organic solvent in the oil phase can diffuse to the outer water phase of the boundary, so that the concentration of the polar organic solvent at the boundary is reduced, the lipid is separated out, and oil bubbles wrapping the water bubbles, namely the anthracycline liposome, are formed in the outer water phase.
Preparing the anthracycline liposome by the preparation device, forming dispersed tiny water bubbles in an oil phase of an internal water phase dissolved with the anthracycline, and separating the oil phase wrapped with the water bubbles in an external water phase to form the anthracycline liposome; thus, the anthracycline medicine can be fully wrapped, and the encapsulation efficiency is improved. In addition, the injection speed is controlled to adjust the relative flow rates of the inner water phase, the oil phase and the outer water phase, and the size of the prepared adriamycin liposome can be adjusted within a certain range. In addition, the preparation device disclosed by the application is also suitable for continuous production and is beneficial to realizing industrial application.
Further, the external water phase inlet 4 and the discharge outlet 5 are arranged on two sides of the compound chamber 3 opposite to each other; the oil phase channel 2 is vertical to the outer water phase flow channel 6; the confluence passage 7 is located at one side of the inner water phase pipe 1 corresponding to the outer water phase inlet 4.
Further, the cross sections of the inner water phase pipe 1 and the oil phase channel 2 are fan-shaped, and the corresponding central angles are less than or equal to 180 degrees; the inner water phase pipe 1 comprises a plane pipe wall and a cambered surface pipe wall, and the oil phase channel 2 comprises a plane inner wall and a cambered surface inner wall; the plane pipe wall is attached to the plane inner wall, and an interval for forming a confluence channel 7 is arranged between the arc-shaped pipe wall and the arc-shaped inner wall. It will be appreciated that the converging channel 7 is located on the side of the inner water phase tube 1 facing the outer water phase inlet 4. The outer water phase flowing from the outer water phase inlet 4 to the discharge outlet 5 can be matched with the cambered wall of the inner water phase pipe 1 to extrude the oil phase overflowing from the confluence channel 7; meanwhile, the outer water phase can also wrap the oil phase and separate from the edge of the cambered surface pipe wall, so that oil bubbles are formed in the outer water phase. The structure can enable the external water phase to fully act on the oil phase overflowing from the confluence channel 7, and fully extrude the oil phase, so that the oil phase is uniformly and discontinuously dispersed in the external water phase, and tiny oil bubbles, namely the anthracycline liposome, are formed in the external water phase.
Furthermore, the inner water phase tubes 1 and the oil phase channels 2 are arranged in a plurality of rows along the outer water phase flow channel 6, and the inner water phase tubes 1 correspond to the oil phase channels 2 one by one; the plurality of inner water phase pipes 1 of each column are arranged in a staggered manner with the plurality of inner water phase pipes 1 of the adjacent column. It should be understood that the inner water phase tubes 1 of adjacent rows are arranged in a staggered manner, so that the outer water phase can sufficiently act on the oil phase overflowing from the confluence channel 7 to sufficiently and effectively extrude the oil phase, thereby obtaining tiny and uniform oil bubbles, namely the anthracycline liposome.
Further, an oil phase chamber 8 is arranged at the top of the compound chamber 3, and the oil phase channel 2 is communicated with the oil phase chamber 8 and the compound chamber 3 from top to bottom; an inner water phase chamber 9 is arranged at the bottom of the compound chamber 3, and the inner water phase pipe 1 is vertically communicated with the oil phase channel 2 and the inner water phase chamber 9; the oil phase chamber 8 is provided with an oil phase inlet, and the inner water phase chamber 9 is provided with an inner water phase inlet. It will be appreciated that the oil phase inlet communicates with a hose carrying the oil phase and is fitted with a peristaltic pump; the inner water phase inlet is communicated with a hose for conveying the inner water phase and is matched with a peristaltic pump; the external water phase inlet 4 is communicated with a hose for conveying the external water phase and is matched with a peristaltic pump. In order to better control the hydraulic pressure difference of the preparation device during operation, the discharge opening 5 can also be communicated with a discharge hose and adapted with a peristaltic pump. The device is provided with a plurality of inner water phase pipes 1 and oil phase channels 2, and is provided with confluent inner water phase chambers 9 and oil phase chambers 8, so that the device is favorable for industrial production. The peristaltic pump of each phase controls the unit flow rate of the upstream confluence, so that the relative flow rates of the inner water phase, the oil phase and the outer water phase can be controlled.
Further, the compound chamber 3 includes a dish portion 10 and a top cover 11; the dish part 10, the inner water phase pipe 1 and the inner water phase chamber 9 are of an integrated structure, and the bottom of the dish part 10 forms the top of the inner water phase chamber 9; the top cover 11, the oil phase channel 2 and the oil phase chamber 8 are of an integrated structure, and the top cover 11 forms the bottom of the oil phase chamber 8. It should be understood that the dish portion 10, the inner aqueous phase tube 1, and the inner aqueous phase chamber 9 may be directly formed by etching, photolithography, or the like; the top cover 11, the oil phase channel 2 and the oil phase chamber 8 can be directly processed and formed by means of etching, photoetching and the like. And finally, the dish part 10 and the top cover 11 are glued to finish the assembly of the preparation device, and the preparation device has the advantages of simple structure and convenience in assembly.
The application also provides a preparation method of the anthracycline liposome, which comprises the following steps:
example 1
S1: dissolving phospholipid and cholesterol in anhydrous ethanol to obtain oil phase with phospholipid concentration of 50g/L and cholesterol concentration of 20 g/L.
S2: dissolving hydrochloric acid and adriamycin in water for injection to obtain an inner water phase with pH of 4 and adriamycin 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: injecting the inner water phase into the inner water phase pipe 1; injecting the oil phase into the oil phase channel 2; injecting an external water phase into the compound chamber 3 through an external water phase inlet 4; the ratio of the unit flow rates of the internal aqueous phase, the oil phase and the external aqueous phase was maintained at 1:3: 16. And collecting the solution discharged from the discharge port 5, wherein the solution is the adriamycin liposome solution.
Example 2
S1: dissolving phospholipid and cholesterol in anhydrous ethanol to obtain oil phase with phospholipid concentration of 50g/L and cholesterol concentration of 20 g/L.
S2: dissolving hydrochloric acid and epirubicin in water for injection to obtain an internal water phase with pH of 4 and epirubicin 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: injecting the inner water phase into the inner water phase pipe 1; injecting the oil phase into the oil phase channel 2; injecting an external water phase into the compound chamber 3 through an external water phase inlet 4; the ratio of the unit flow rates of the internal aqueous phase, the oil phase and the external aqueous phase was maintained at 1:3: 16. And collecting the solution discharged from the discharge port 5, wherein the solution is the epirubicin liposome solution.
Example 3
S1: dissolving phospholipid and cholesterol in anhydrous ethanol to obtain oil phase with phospholipid concentration of 30g/L and cholesterol concentration of 10 g/L.
S2: dissolving hydrochloric acid and daunorubicin in water for injection to obtain an internal water phase with pH of 4 and daunorubicin concentration of 6 g/L.
S3: dissolving hydrochloric acid and fructose in water for injection to obtain external water phase with pH of 4 and sugar concentration of 600 mmol/L.
S4: injecting the inner water phase into the inner water phase pipe 1; injecting the oil phase into the oil phase channel 2; injecting an external water phase into the compound chamber 3 through an external water phase inlet 4; the ratio of the unit flow rates of the internal aqueous phase, the oil phase and the external aqueous phase was maintained at 1:2: 16. And collecting the solution discharged from the discharge port 5, namely the daunorubicin liposome solution.
Example 4
S1: dissolving phospholipid and cholesterol in anhydrous ethanol to obtain oil phase with phospholipid concentration of 35g/L and cholesterol concentration of 16 g/L.
S2: hydrochloric acid and aclacinomycin are dissolved in water for injection to prepare an inner water phase with pH of 4 and aclacinomycin concentration of 7 g/L.
S3: dissolving hydrochloric acid and fructose in water for injection to obtain external water phase with pH of 4 and sugar concentration of 800 mmol/L.
S4: injecting the inner water phase into the inner water phase pipe 1; injecting the oil phase into the oil phase channel 2; injecting an external water phase into the compound chamber 3 through an external water phase inlet 4; the ratio of the unit flow rates of the internal aqueous phase, the oil phase and the external aqueous phase was maintained at 1:2.4: 16. And collecting the solution discharged from the discharge port 5, wherein the solution is the aclacinomycin liposome solution.
Comparative example 1
S1: dissolving phospholipid and cholesterol in anhydrous ethanol to obtain oil phase with phospholipid concentration of 50g/L and cholesterol concentration of 20 g/L.
S2: hydrochloric acid, adriamycin and glucose are dissolved in water for injection to prepare a water phase with the pH value of 4, the adriamycin concentration of 0.59g/L and the sugar concentration of 1129 mmol/L.
And (3) putting the oil phase and the water phase into a homogenizer according to the volume ratio of 3:17 for homogenizing and mixing to obtain the adriamycin liposome solution.
Comparative example 2
S1: dissolving phospholipid and cholesterol in anhydrous ethanol to obtain oil phase with phospholipid concentration of 50g/L and cholesterol concentration of 20 g/L.
S2: dissolving hydrochloric acid, epirubicin, and glucose in water for injection to obtain water phase with pH of 4, epirubicin concentration of 0.59g/L, and sugar concentration of 1129 mmol/L.
And (3) putting the oil phase and the water phase into a homogenizer according to the volume ratio of 3:17 for homogenizing and mixing to obtain the epirubicin liposome solution.
Comparative example 3
S1: dissolving phospholipid and cholesterol in anhydrous ethanol to obtain oil phase with phospholipid concentration of 30g/L and cholesterol concentration of 10 g/L.
S2: dissolving hydrochloric acid, daunorubicin, and fructose in water for injection to obtain water phase with pH of 4, daunorubicin concentration of 0.35g/L, and sugar concentration of 565 mmol/L.
And (3) putting the oil phase and the water phase into a homogenizer according to the volume ratio of 2:17 for homogenizing and mixing to obtain the daunorubicin liposome solution.
Comparative example 4
S1: dissolving phospholipid and cholesterol in anhydrous ethanol to obtain oil phase with phospholipid concentration of 35g/L and cholesterol concentration of 16 g/L.
S2: dissolving hydrochloric acid, aclacinomycin and fructose in water for injection to obtain water phase with pH of 4, aclacinomycin concentration of 0.41g/L and sugar concentration of 753 mmol/L.
And (3) putting the oil phase and the water phase into a homogenizer for homogenizing and mixing according to the volume ratio of 2.4:17 to prepare the aclacinomycin liposome solution.
Note 1: the anthracycline liposome solution prepared in the examples 1 to 4 is separated and purified, and impurities such as ethanol and the like are removed, so that the anthracycline liposome injection can be obtained.
Note 2: in the devices for preparing anthracycline liposomes used in examples 1 to 4, the height and width of the external aqueous phase channel 6 are the same as those of the external aqueous phase inlet 4; the interval between the bottom of the oil phase channel 2 and the bottom of the compound chamber 3 is less than or equal to the height of the outer water phase channel 6, which is less than two times the interval between the bottom of the oil phase channel 2 and the bottom of the compound chamber 3 and is less than or equal to 2 mm; and the ratio of the sum of the inner diameter sectional areas of the inner water phase pipes 1, the sum of the inner diameter sectional areas of the oil phase channels 2 and the inner diameter sectional area of the outer water phase inlet 4 is 2:3: 3.
Samples were obtained from the anthracycline liposome solutions prepared in examples 1 to 4 and comparative examples 1 to 4, and the anthracycline liposome and the free anthracycline in each sample were separated by dialysis. The content of the separated free anthracycline is measured by a high performance liquid chromatography, and the total amount of the free anthracycline in each sample is calculated. And calculating the total amount of the anthracycline drugs contained in each sample according to the ingredients of the examples 1-4 and the comparative examples 1-4. And finally, calculating the encapsulation rate according to the ratio of the total amount of free anthracyclines to the total amount of anthracyclines in each sample.
Table 1: encapsulation efficiency of examples 1 to 4 and comparative examples 1 to 4
| Encapsulation efficiency | |
| Example 1 | 84.34% |
| Example 2 | 83.91% |
| Example 3 | 81.94% |
| Example 4 | 82.57% |
| Comparative example 1 | 52.18% |
| Comparative example 2 | 51.97% |
| Comparative example 3 | 48.32% |
| Comparative example 4 | 49.73% |
From table 1, it can be seen. The encapsulation efficiency of examples 1 to 4 is significantly higher than that of comparative examples 1 to 4. This means that the internal aqueous phase, in which the anthracycline drug is dissolved, is first dispersed in the oil phase to form tiny blisters; and dispersing the oil phase in the external water phase to form oil bubbles wrapping the water bubbles. Can fully wrap the anthracycline medicine, thereby improving the encapsulation efficiency.
Although specific embodiments of the present invention have been described above, it will be appreciated by those skilled in the art that changes or modifications may be made to these embodiments without departing from the principles and spirit of the invention, and that such changes and modifications are within the scope of the invention.
Claims (10)
1. An anthracycline liposome preparation device, comprising:
an inner aqueous phase pipe (1); and
an oil phase channel (2) parallel to the inner water phase pipe (1);
wherein,
the outlet end of the inner water phase pipe (1) penetrates through the outlet end of the oil phase channel (2), and a space for forming a confluence channel (7) is formed between the outer wall of the inner water phase pipe (1) and the inner wall of the oil phase channel (2);
the outlet end of the oil phase channel (2) is positioned in the compound chamber (3);
the compound chamber (3) is provided with an external water phase inlet (4) and a discharge outlet (5), and an external water phase flow channel (6) pointing to the discharge outlet (5) from the external water phase inlet (4) covers the outlet end of the oil phase channel (2).
2. The device for preparing anthracycline liposomes according to claim 1, wherein:
the outer water phase inlet (4) and the discharge port (5) are oppositely arranged on two sides of the compound chamber (3); the oil phase channel (2) is vertical to the outer water phase flow channel (6); the confluence channel (7) is positioned on one side of the inner water phase pipe (1) corresponding to the outer water phase inlet (4).
3. The device for preparing anthracycline liposomes according to claim 2, wherein:
the cross sections of the inner water phase pipe (1) and the oil phase channel (2) are in a fan shape, and the corresponding central angle is less than or equal to 180 degrees;
the inner water phase pipe (1) comprises a plane pipe wall and an arc pipe wall, and the oil phase channel (2) comprises a plane inner wall and an arc inner wall;
the plane pipe wall is attached to the plane inner wall, and an interval for forming a confluence channel (7) is arranged between the arc-shaped pipe wall and the arc-shaped inner wall.
4. The device for preparing anthracycline liposomes according to any one of claims 1 to 3, wherein:
the inner water phase pipes (1) and the oil phase channels (2) are arranged in a plurality of rows along the outer water phase flow channel (6), and the inner water phase pipes (1) correspond to the oil phase channels (2) one by one;
the plurality of inner water phase pipes (1) in each row are arranged in a staggered mode with the plurality of inner water phase pipes (1) in the adjacent row.
5. The device for preparing anthracycline liposomes according to claim 4, wherein:
the top of the compound chamber (3) is provided with an oil phase chamber (8), and the oil phase channel (2) is communicated with the oil phase chamber (8) and the compound chamber (3) up and down;
an inner water phase chamber (9) is arranged at the bottom of the composite chamber (3), and the inner water phase pipe (1) is communicated with the oil phase channel (2) and the inner water phase chamber (9) up and down;
the oil phase chamber (8) is provided with an oil phase inlet, and the inner water phase chamber (9) is provided with an inner water phase inlet.
6. The device for preparing anthracycline liposomes according to claim 5, wherein:
the compound chamber (3) comprises a dish part (10) and a top cover (11);
the dish part (10), the inner water phase pipe (1) and the inner water phase chamber (9) are of an integrated structure, and the bottom of the dish part (10) forms the top of the inner water phase chamber (9);
top cap (11), oil phase passageway (2), oil phase room (8) formula structure as an organic whole, top cap (11) constitute the bottom of oil phase room (8).
7. A preparation method of anthracycline liposome is characterized in that:
a device for preparing the anthracycline liposome of any one of claims 4 to 6, comprising the following steps:
s1 preparation of oil phase: dissolving phospholipid and cholesterol in absolute ethyl alcohol to prepare an oil phase with the phospholipid concentration of 30-50 g/L and the cholesterol concentration of 10-20 g/L;
s2 preparation of the internal aqueous phase: dissolving hydrochloric acid and an anthracycline medicament into water for injection to prepare an internal water phase with the pH value of 4 and the concentration of the anthracycline medicament of 6-12 g/L;
s3 preparation of external aqueous phase: dissolving hydrochloric acid and monosaccharide in water for injection to prepare an external water phase with the pH of 4 and the sugar concentration of 600-1200 mmol/L;
s4 preparation of liposomes: injecting the inner water phase into the inner water phase pipe (1), injecting the oil phase into the oil phase channel (2), and injecting the outer water phase into the composite chamber (3) through the outer water phase inlet (4); the relative flow rates of the inner water phase, the oil phase and the outer water phase are adjusted by controlling the injection speed; when the internal water phase overflows from the outlet end of the internal water phase pipe (1), the internal water phase is extruded and wrapped by the oil phase coming from the oil phase channel (2), so that the oil phase wrapped with the bubbles is formed in the confluence channel (7); and when the oil phase wrapped with the water bubbles overflows from the outlet end of the oil phase channel (2), the oil phase wrapped with the water bubbles is wrapped with the external water phase flowing from the external water phase inlet (4) to the discharge port (5) so as to be dispersed in the external water phase, and the oil bubbles wrapped with the water bubbles, namely the anthracycline liposome, are formed.
8. The method for preparing anthracycline liposomes according to claim 7, wherein: the monosaccharide is glucose or fructose.
9. The method for preparing anthracycline liposomes according to claim 7, wherein:
when the water is injected into the internal water phase, the oil phase and the external water phase, the unit flow ratio of the internal water phase, the oil phase and the external water phase is 1: 2-3: 16.
10. The method for preparing anthracycline liposomes according to claim 7, wherein:
the height and the width of the outer water phase flow channel (6) are correspondingly matched with the height and the width of the outer water phase inlet (4);
the interval between the bottom of the oil phase channel (2) and the bottom of the compound chamber (3) is not more than the height of the outer water phase channel (6) and less than twice of the interval between the bottom of the oil phase channel (2) and the bottom of the compound chamber (3);
the ratio of the sum of the inner diameter sectional areas of the inner water phase pipes (1), the sum of the inner diameter sectional areas of the oil phase channels (2) and the inner diameter sectional area of the outer water phase inlet (4) is 2:3: 3.
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