CN111012917B - Preparation method and device of sustained-release drug-loaded porous membrane based on supercritical fluid technology - Google Patents

Preparation method and device of sustained-release drug-loaded porous membrane based on supercritical fluid technology Download PDF

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CN111012917B
CN111012917B CN201911071330.9A CN201911071330A CN111012917B CN 111012917 B CN111012917 B CN 111012917B CN 201911071330 A CN201911071330 A CN 201911071330A CN 111012917 B CN111012917 B CN 111012917B
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autoclave
scco
separation kettle
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CN111012917A (en
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蒋静智
马莉营
崔海亭
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Hebei University of Science and Technology
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7007—Drug-containing films, membranes or sheets
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D11/00—Solvent extraction
    • B01D11/02—Solvent extraction of solids
    • B01D11/0203—Solvent extraction of solids with a supercritical fluid
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/54—Improvements relating to the production of bulk chemicals using solvents, e.g. supercritical solvents or ionic liquids

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Abstract

The invention relates to a preparation method of a sustained-release drug-loaded porous membrane based on a supercritical fluid technology, which comprises the following steps: (A) weighing a polymer and solid medicine particles, mixing and dissolving the polymer and the solid medicine particles in a solvent to prepare a solution or suspension with the mass concentration of 15-50%; (B) spreading the solution or suspension prepared in step (A) into a thin layer, and mixing the thin layer with ScCO carrying agent 2 Fully contacting; (C) circulating introduction of ScCO 2 Cleaning and drying the porous carrier, and continuously introducing a solvent into the ScCO 2 Is taken out of the system to obtain the porous film. The invention also provides a device for the preparation method. The invention has the advantages of uniform and mild reaction process and high reaction efficiency, and the prepared drug-loaded porous membrane has a more uniform structure.

Description

Preparation method and device of sustained-release drug-loaded porous membrane based on supercritical fluid technology
Technical Field
The invention relates to a preparation method and a device of a sustained-release drug-loaded porous membrane based on a supercritical fluid technology.
Background
Many drugs have strong toxic and side effects on human bodies, have short half-lives and require large doses for frequent administration. This causes great pain to the user and even threatens the life of the patient. Therefore, it has been noticed by more and more scholars how to find a drug carrier to control the effective release of the drug over a long period of time, so that the drug carrier can reach the therapeutic concentration of the drug and can significantly reduce the toxic and side effects of the drug. The internal structure and material properties of the drug carrier play a decisive role in the release rate of the drug.
Nucleic acid, protein and polypeptide biochemical macromolecular substances are regarded more attention because they exhibit strong pharmacological effects, little side effects and few allergic reactions in many processes in which diseases are difficult to cure. However, these biochemical drugs have poor stability, are easily degraded by enzymes in the gastrointestinal tract of a human body if they are administered by conventional oral administration, and in addition, they have a short half-life in vivo, a short duration of therapeutic effect, and generally have low availability in an unprotected state. The porous carrier system can maintain the activity of biochemical substances of the drugs to the maximum extent, and the thickness and the pore size of the porous membrane can be controlled by adjusting the preparation conditions, so that the controlled release or the sustained release of the drugs is realized. Therefore, the development of a carrier with drug slow-release efficacy becomes one of the important development directions in the modern pharmaceutical field.
Biodegradable polymers such as polylactic acid, polycaprolactone, and the like have received much attention from researchers because of their good biocompatibility, their non-toxicity as well as their degradation products, their suitable physical and mechanical properties and formability, and their satisfactory degradation rate.
The preparation method of the polymer porous drug carrier has various methods, such as a casting/particle leaching method, a solvent evaporation phase inversion method, a temperature induced phase inversion method, an immersion precipitation phase inversion method and the like. However, some of the methods need to use a large amount of organic solvent, the residual solvent is difficult to remove, the environment is polluted, the performance of the material is influenced, and even certain toxicity is brought to patients in the drug loading and administration process. Some prepared porous drug carriers have low porosity, and the pore structure is difficult to meet the requirement of sustained release drug delivery. Some preparation processes are complex, and the longest period of the preparation process needs 1 week.
ScCO 2 The induced phase separation for preparing the drug-loaded porous polymer carrier is a new technology proposed in recent years. Studies have shown that ScCO is used 2 The induced phase separation process for preparing the porous polymer drug carrier has the advantages that the traditional preparation method does not have: the preparation process is simple and easy to implement, and no additive is required to be added; ScCO 2 No gas-liquid interface is generated in the drying process of the polymer carrier, so that the collapse of a pore structure cannot occur in the drying process, and no post-treatment is needed; ScCO 2 ScCO in the preparation of drug-loaded porous Polymer Carrier 2 Enter the polymer matrix to strengthen the movement of polymer molecular chains, increase gaps and reduce the glass transition temperature, thereby being more beneficial to the diffusion and adsorption of drug molecules in the polymer matrix. However, the research finds that in the process of preparing the drug-loaded porous membrane, the small changes of pressure and temperature can cause great influence on the membrane structure, so that the structural performance of the prepared drug-loaded membrane is unstable.
The applicant finds that small changes of pressure and temperature cause ScCO 2 The dissolution and diffusion capacities of the components have important influences, and further the stability of the preparation process is influenced, so that the preparation process is difficult to control.
Disclosure of Invention
In order to solve the problems, the invention provides a preparation method and a device of a sustained-release drug-carrying porous membrane based on a supercritical fluid technology, which has the advantages of uniform and mild reaction process, high reaction efficiency and more uniform structure of the prepared drug-carrying porous membrane.
The invention adopts the following technical scheme:
a preparation method of a sustained-release drug-loaded porous membrane based on a supercritical fluid technology comprises the following steps:
(A) weighing a polymer and solid medicine particles, mixing and dissolving the polymer and the solid medicine particles in a solvent to prepare a solution or suspension with the mass percentage concentration of 15-50%;
(B) spreading the solution or suspension prepared in the step (A) into a thin layer, and mixing the thin layer with ScCO with a carrying agent 2 Fully contacting;
(C) circulating introduction of ScCO 2 Cleaning and drying the porous carrier, and continuously introducing a solvent into the ScCO 2 Is taken out of the system to obtain the porous film.
Further, the polymer comprises polymethyl methacrylate, polylactic acid, polycaprolactone or a mixture of polylactic acid and polycaprolactone.
Further, the solid medicine particles comprise antibiotic particles or nucleic acid, protein and polypeptide biochemical macromolecular medicine particles.
Further, the solvent is acetone, ethanol or dichloromethane.
Further, the carrying agent is absolute ethyl alcohol.
The device for preparing the medicine-carrying porous film by the preparation method comprises CO sequentially connected through a main pipeline 2 Gas cylinder, cooling water tank, plunger pump, mixer, purifier, preheater, autoclave, primary separation kettle and secondary separation kettleSeparating from the kettle; a return pipe is arranged between the secondary separation kettle and the mixer, and a return valve, a flowmeter and a one-way valve are sequentially arranged on the return pipe; a branch pipeline is arranged on the high-pressure kettle, and a constant flow pump is arranged at the end part of the branch pipeline; and a film injector is arranged in the high-pressure kettle.
In the medicine-carrying porous film preparation device, a high-pressure kettle water bath is arranged outside the preheater and the high-pressure kettle; a primary separation kettle water bath is arranged outside the primary separation kettle; a secondary separation kettle water bath is arranged outside the secondary separation kettle; and an anti-blocking water bath device is arranged outside the reflux valve.
In the medicine-carrying porous film preparation device, the branch pipeline is connected with the high-pressure kettle through the atomizing nozzle, the aperture of the spray hole of the atomizing nozzle is 0.20mm, and the spray angle is 100 degrees.
In the medicine-carrying porous film preparation device, the film injector is an aluminum mold with a groove with the depth of 0.1-0.5 mm.
In the medicine-carrying porous film preparation device, a fine-adjustment pressure-stabilizing back pressure valve is arranged between the high-pressure kettle and the first-stage separation kettle.
The invention has the beneficial effects that: the method for adding the carrying agent in the preparation process can ensure that the phase inversion process becomes uniform and mild, and the solvent can be quickly separated from the system in the subsequent drying process, thereby shortening the drying time and obtaining a medicine-carrying porous membrane with a more uniform structure.
1) The invention can prepare the drug-loaded porous membrane material with the sustained and controlled release function. The toxic and side effects of the medicine are greatly reduced or the biochemical properties of the medicine are effectively protected while the effective treatment concentration is achieved.
2）ScCO 2 High mass transfer coefficient, CO 2 Are linear small molecules and diffuse into the polymer more readily than other small molecule gases. Can reach the equilibrium concentration in a short time, thereby shortening the preparation time of the drug-carrying carrier.
3）ScCO 2 Near the critical point, the property of the product is very sensitive to the change of the operating parameters, and the operating parameters can be effectively adjusted by adding the carrying agentSeveral effects on pore structure and preparation time. And CO 2 No toxicity and environmental protection, and the advantages are matched with the safety requirement of medical supplies.
4) Set up a fine setting steady voltage backpressure valve between autoclave and one-level separation cauldron, it can play the steady voltage effect to the high pressure, guarantees to have certain pressure differential between two kettles, can guarantee again to circulate the even running of dry and pressure release process, easily realizes the regulation to the aperture.
5) In the preparation device, ethanol is atomized and sprayed into the autoclave and is separated from CO 2 The mouth is close, which is beneficial to the rapid dissolution of ethanol in ScCO 2 Then quickly diffused with the airflow, and simultaneously, the carrier is added to ensure that the solvent in the porous carrier can be more quickly dissolved in ScCO in the drying process 2 Both of these reasons contribute to the enhancement of the effect of ethanol as a carrier.
6) The porous films with three-dimensional structures of different volumes and shapes can be obtained by utilizing casting containers of different shapes and volumes, and the requirements of different focuses are met.
7) The preparation process can synthesize dendritic or star-shaped polymer through modifying polymer molecules, and the dendritic or star-shaped polymer is used for fixing enzyme, antibody, medicine or other biological reagents.
8) The invention can make the drug carrier into nanometer micropores, which is beneficial to the drug carrier to permeate the endothelial tissue without being absorbed.
9) A two-component separation kettle is arranged behind the high-pressure kettle for separating ScCO 2 Dissolved organic solvent, ScCO separated twice 2 The drug-loaded porous film is basically free of organic solvent, so that the drug-loaded porous film which is almost completely dry and free of solvent residue can be obtained while the organic solvent is recycled.
Drawings
Fig. 1 is a schematic structural diagram of a drug-loaded porous film preparation device of the present invention.
Fig. 2 is a schematic structural diagram of the film injector of the present invention.
Fig. 3 is a schematic sectional view of the atomizing nozzle of the present invention.
Fig. 4 is an electron microscope image of the cross section of the drug-loaded porous film prepared in example 3 of the present invention.
Fig. 5 is an electron microscope image of the cross section of the drug-loaded porous film prepared in example 4 of the present invention.
FIG. 6 is an electron microscope image of the cross section of the drug-loaded porous membrane prepared in example 5 of the present invention.
Wherein 1, CO 2 A gas cylinder, 2, a cooling water tank, 3, a plunger pump, 4, a mixer, 5, a purifier, 6, a preheater, 7, an autoclave water bath, 8, an autoclave, 8-1, an autoclave gas inlet, 8-2, a pressure relief valve, 8-3, an autoclave gas outlet, 8-4, an atomizing nozzle, 9, a membrane casting device, 10, a primary separation kettle water bath, 11, a primary separation kettle, 11-1, a primary separation kettle gas inlet, 11-2, a primary separation kettle solvent outlet, 11-3, a primary separation kettle gas outlet, 12, a secondary separation kettle water bath 13, a secondary separation kettle, 13-1, a secondary separation kettle gas inlet, 13-2, a secondary separation kettle solvent outlet, 13-3, a secondary separation kettle gas outlet, 14, a advection pump, 15, a reflux valve, 16, a flowmeter, 17, a reflux pump, a reflux condenser, a reflux, The device comprises a check valve 18, a return pipe 19, a branch pipeline 20, a fine-tuning pressure-stabilizing back pressure valve 21 and an anti-blocking water bath device.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail below with reference to the following embodiments and the accompanying drawings. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
As shown in figures 1-3, a drug-loaded porous film preparation device for the preparation method comprises CO sequentially connected through a main pipeline 2 The device comprises a gas cylinder 1, a cooling water tank 2, a plunger pump 3, a mixer 4, a purifier 5, a preheater 6, an autoclave 8, a first-stage separation kettle 11 and a second-stage separation kettle 13.
A return pipe 18 is arranged between the secondary separation kettle 13 and the mixer 4, and a return valve 15, a flowmeter 16 and a one-way valve 17 are sequentially arranged on the return pipe 18; a branch pipeline 19 is arranged on the high-pressure kettle 8, and a constant flow pump 14 is arranged at the end part of the branch pipeline 19.
The return valve 15 is arranged in the anti-clogging water bath device 21. The anti-blocking water bath device can be a simple device, namely the backflow valve is arranged in a water bath pool with the temperature of 50-60 ℃, the blocking rate of the backflow valve can be greatly reduced, the performance of the backflow valve cannot be influenced by the temperature due to proper temperature, after the experiment is finished, the backflow valve is moved out of the water bath pool, the surrounding surface of the backflow valve is blown dry, and the backflow valve is prevented from rusting.
And a film injector 9 is arranged in the autoclave 8. The film injection device 9 is an aluminum die and is a cylinder with the diameter of 4cm and the height of 1.5cm, and a rectangular groove with the depth of 0.1-0.5mm is formed in the upper surface of the cylinder.
An autoclave water bath 7 is arranged outside the preheater 6 and the autoclave 8; a primary separation kettle water bath 10 is arranged outside the primary separation kettle 11; and a secondary separation kettle water bath 12 is arranged outside the secondary separation kettle 13.
The branch pipeline 19 is connected with the high-pressure kettle 8 through an atomizing nozzle 8-4, the aperture of an orifice of the atomizing nozzle 8-4 is 0.20mm, and the spraying angle is 100 degrees. A fine-tuning pressure-stabilizing back pressure valve 20 is arranged between the high-pressure kettle 8 and the first-stage separation kettle 11. The aperture of the atomizing nozzle is much smaller than the diameter of the branch pipeline, and the whole branch pipeline is filled with ethanol, so that the ethanol can not flow out of the branch pipeline after the advection pump is closed, in the device, an ethanol inlet is arranged beside an air inlet of the high-pressure kettle (an outlet of the atomizing nozzle 8-4 for spraying the ethanol is arranged beside an air inlet 8-1 of the high-pressure kettle and is about 2cm away from the air inlet), and the ethanol is dissolved in the ScCO 2 Then the ethanol can be quickly diffused along with the airflow of the air inlet, and the ethanol liquid column is always in a vertical state, thereby being beneficial to the ethanol to ScCO 2 The medium diffusion is beneficial to improving the function of the absolute ethyl alcohol as the carrying agent for two reasons.
Primary routing of CO 2 The gas cylinder is led out, passes through a cooling water tank, a plunger pump, a mixer, a purifier and a preheater and is communicated with the high-pressure kettle through a gas inlet 8-1 of the high-pressure kettle. The gas inlet 8-1 of the high-pressure kettle is adjacent to the atomizing nozzle 8-4, the gas outlet 8-3 of the high-pressure kettle is communicated with the gas inlet 11-1 of the first-stage separation kettle through a fine-adjustment pressure-stabilizing back pressure valve 20, and the high-pressure kettle is also provided with pressure reliefValve 8-2.
The gas outlet 11-3 of the first-stage separation kettle is connected with the gas inlet 13-1 of the second-stage separation kettle, the solvent outlet 11-2 of the first-stage separation kettle is arranged on the first-stage separation kettle 11, and the solvent outlet 13-2 of the second-stage separation kettle is arranged on the second-stage separation kettle. The gas outlet 13-3 of the second-stage separation kettle is connected with a return pipe 18, and then is connected with a flowmeter 16 and a one-way valve 17 through a return valve 15 and then is connected with the mixer 4.
Before the preparation is started, the advection pump 14 is started to fill the branch pipeline with absolute ethyl alcohol, then the film casting device 9 containing the polymer organic solution is quickly placed into the high-pressure kettle 8, and CO is started 2 Gas cylinder 1, CO 2 Cooled by a cooler 2, pressurized by a plunger pump 3 and discharged ScCO from a separation kettle 13 2 Mixing in mixer 4, filtering to remove impurities with purifier 5, introducing into preheater 6 for preheating, blowing into autoclave 8 via autoclave gas inlet 8-1, and introducing into autoclave 8 when CO is introduced 2 And (3) after the supercritical state is reached, closing the gas inlet 8-1 and the gas outlet 8-3 of the high-pressure kettle, closing the constant-flow pump, and maintaining the pressure. The high-pressure kettle 8 is positioned in the high-pressure kettle water bath 7, the high-pressure kettle 8 is sequentially connected with the first separation kettle and the second separation kettle, the two separation kettles are respectively positioned in the corresponding separation kettle water baths, after the preset pressure maintaining time is reached, the high-pressure kettle gas inlet 8-1 and the high-pressure kettle gas outlet 8-3 are opened, the plunger pump 3 is started, and ScCO is continuously and circularly introduced into the high-pressure kettle 8 and the separation kettles 2 To dry the porous material formed in the film casting machine 9. Continuously introducing ScCO 2 Can also remove ScCO dissolved in 2 And (3) discharging and recovering the organic solvent through a solvent outlet of the separation kettle, closing the plunger pump 3, closing the autoclave gas inlet 8-1 and the autoclave gas outlet 8-3, slowly releasing the pressure of the autoclave 8 (about 60 min) until the pressure is zero, taking out the film casting device 9, and taking out the porous film.
Example 2
A preparation method of a medicine-carrying porous film with a slow release effect based on a supercritical fluid technology by adopting the device in example 1 comprises the following steps:
A. weighing a certain mass of dry polymer or a mixture of a plurality of polymers with different mechanical properties and a certain mass of solid medicine, then simultaneously dissolving the polymer and the medicine into a solvent to prepare a solution or suspension with the mass percentage concentration of 15-50%, standing for 5-30min after the solution or suspension is prepared, and removing air bubbles in the solution or suspension.
Wherein, the polymer can be but not limited to polymethyl methacrylate, polylactic acid, polycaprolactone or a mixture of polylactic acid and polycaprolactone. The solid medicine can be, but not limited to, erythromycin, griseofulvin and other antibiotic particles with toxicity or nucleic acid, protein and polypeptide biochemical macromolecular drug particles. The solvent may be acetone, ethanol, dichloromethane, and the like. The mass ratio of the polymer to the solid medicine can be selected according to the treatment proportion.
B. Slowly pouring the solution or suspension which is kept still and has air bubbles discharged into an aluminum film casting device, spreading the solution or suspension into a uniform thin layer with a certain thickness by using a scraper, then putting the film casting device containing the solution or suspension into an autoclave which is heated to 30-50 ℃, and sealing the autoclave.
C. The preparation process uses absolute ethyl alcohol as a carrying agent and adopts an advection pump to pump. Before the preparation is started, the advection pump is started to fill up a pipeline connecting the advection pump and the high-pressure kettle with absolute ethyl alcohol, the pipeline is provided with an atomizing nozzle in the high-pressure kettle, the diameter of the nozzle of the atomizing nozzle is much smaller than that of the pipeline, and the whole pipeline is filled with the ethyl alcohol, so that the ethyl alcohol cannot flow out of the pipeline after the advection pump is closed. An absolute ethyl alcohol inlet on the high-pressure kettle is positioned beside an air inlet of the high-pressure kettle, and the ethyl alcohol is dissolved in the ScCO 2 Then the ethanol can be quickly diffused along with the airflow of the air inlet, and the ethanol liquid column is always in a vertical state, thereby being beneficial to the ethanol to ScCO 2 The medium diffusion is beneficial to improving the effect of the absolute ethyl alcohol as a carrying agent for two reasons.
D. The absolute ethanol constant-current pump is started in advance, and then CO is started 2 Gas cylinder and plunger pump, blowing CO into autoclave 2 The absolute ethyl alcohol in the nozzle of the atomizing nozzle is dissolved in ScCO 2 Then the gas flow pumped into the gas port along with the high pressure is rapidly diffused until the CO in the high pressure kettle 2 The pressure reaches 6-25MPa, and CO is 2 When the supercritical state is reached, the advection pump is closed, the gas inlet and the gas outlet of the high-pressure kettle are closedAnd (3) maintaining the pressure of the gas outlet valve for 30-120min, wherein in the process, the polymer rich phase in the solution or suspension in the film casting device is continuously subjected to glass transition and is solidified to form a porous material, and the polymer poor phase forms crystal nuclei and gradually grows up to fill gaps in the porous material.
E. After the preset pressure maintaining time is reached, the gas inlet and outlet valves of the autoclave are opened, and the plunger pump is started to enable the ScCO to be in the open state 2 Flowing at a circulating flow rate of 2-40kg/h through the autoclave, the first-stage separation kettle, the second-stage separation kettle, the mass flow meter and the one-way valve until the CO is mixed with the gas 2 ScCO discharged from steel cylinder 2 After mixing in the mixer, the mixture was introduced into an autoclave to dry the porous material formed in the film casting machine. The circulation drying time is 30-120min, and the porous film is completely dried.
F. And closing the plunger pump, closing the inlet and outlet valves of the high-pressure kettle, slowly releasing pressure of the high-pressure kettle until the pressure is zero, taking out the film casting device, and taking out the porous film.
G. And characterizing the pore diameter, porosity, crystal form and the like of the carrier by SEM, XRD and Fourier infrared spectrum.
Example 3
Firstly, 5g of polylactic acid polymer and 2g of 5-fluorouracil drug are weighed, the two solutes are simultaneously added into acetone with the volume of 34ml, and suspension with the polylactic acid mass percent concentration of about 15 percent is prepared by stirring. The solution was then poured into an aluminum film casting vessel having a height of 1.5cm and a diameter of 4cm, and having a rectangular groove of 0.1-0.5mm in thickness on the upper surface. Spread to a uniform thin layer with a certain thickness using a doctor blade, and then quickly put the film casting machine into an autoclave at 35 ℃. CO is turned on 2 Gas cylinder and plunger pump, blowing CO into autoclave 2 Simultaneously starting a constant-flow pump, spraying absolute ethyl alcohol serving as a carrying agent into the high-pressure kettle through a nozzle, closing the constant-flow pump after the pressure of the high-pressure kettle reaches 15MPa, closing an inlet and outlet valve of the high-pressure kettle, maintaining the pressure, opening the inlet and outlet valve of the high-pressure kettle after the pressure is maintained for 60min, and starting a plunger pump to enable ScCO to 2 Flowing through the high-pressure kettle, the first-stage separation kettle, the second-stage separation kettle, the mass flow meter and the one-way valve at a circulating flow rate of 2-40kg/h, and circularly introducing ScCO 2 After 90min, CO was turned off 2 And (3) closing an inlet valve and an outlet valve of the high-pressure kettle, slowly releasing the pressure of the high-pressure kettle (about 60 min) until the pressure is zero, taking out the film casting device, and thus obtaining the dried polymethyl methacrylate drug-loaded porous film, wherein the cross-sectional electron microscope image of the drug-loaded porous film is shown in fig. 4.
The cross-sectional electron microscope image of the polylactic acid porous carrier obtained from fig. 4 shows that the porous carrier has uniform pore size distribution, high porosity, good connectivity among pores, less collapse of pore structure and good mechanical properties.
Example 4
Firstly weighing 5g of polymethyl methacrylate and 2g of amoxicillin, simultaneously adding the two solutes into acetone with the volume of 20ml, and stirring to prepare a suspension with the mass percent concentration of the polymethyl methacrylate of about 20%. The solution was then poured into an aluminum film casting vessel having a height of 1.5cm and a diameter of 4cm, and having a rectangular groove of 0.1-0.5mm in thickness on the upper surface. Spread into a uniform thin layer with a certain thickness using a doctor blade, and then rapidly put the film casting machine into an autoclave at 40 ℃. Turn on CO 2 A gas cylinder and a plunger pump for blowing CO into the autoclave 2 Simultaneously starting a constant-flow pump, spraying absolute ethyl alcohol serving as a carrying agent into the high-pressure kettle through a nozzle, closing the constant-flow pump after the pressure of the high-pressure kettle reaches 6MPa, closing an inlet and outlet valve of the high-pressure kettle, maintaining the pressure, opening the inlet and outlet valve of the high-pressure kettle after the pressure is maintained for 60min, and starting a plunger pump to enable ScCO to 2 The ScCO flows through the high-pressure kettle, the primary separation kettle, the secondary separation kettle, the mass flow meter and the one-way valve at a circulating flow rate of 10kg/h, and is circularly introduced 2 After 30min, CO is turned off 2 And (3) closing an inlet valve and an outlet valve of the high-pressure kettle by using a gas cylinder and a plunger pump, slowly releasing pressure of the high-pressure kettle (about 60 min) until the pressure is zero, and taking out the film casting device to obtain the dry polymethyl methacrylate drug-loaded porous film.
FIG. 5 is a sectional electron microscope image of the obtained porous PMMA-methacrylate film, which shows that the porous PMMA-methacrylate film has uniform pore structure and good connectivity.
Example 5
First weighing5g of polycaprolactone polymer and 2g of griseofulvin medicine, and the two solutes are simultaneously added into acetone with the volume of 8ml, and are stirred to prepare suspension with the mass percent concentration of polycaprolactone of about 50%. The solution was then poured into an aluminum film casting machine having a height of 1.5cm and a diameter of 4cm and having rectangular grooves of 0.1 to 0.5mm in thickness on the upper surface. Spreading with a scraper to form a uniform thin layer with a certain thickness, and rapidly placing the film casting device into an autoclave at 50 deg.C to start CO 2 A gas cylinder and a plunger pump for blowing CO into the autoclave 2 Simultaneously starting a constant-flow pump, spraying absolute ethyl alcohol serving as a carrying agent into the high-pressure kettle through a nozzle, closing the constant-flow pump after the pressure of the high-pressure kettle reaches 15MPa, closing an inlet and outlet valve of the high-pressure kettle, maintaining the pressure, opening the inlet and outlet valve of the high-pressure kettle after the pressure is maintained for 60min, and starting a plunger pump to enable ScCO to 2 The ScCO flows through the high-pressure kettle, the primary separation kettle, the secondary separation kettle, the mass flow meter and the one-way valve at a circulating flow rate of 20kg/h, and is circularly introduced 2 After 120min, CO was turned off 2 And (3) closing an inlet valve and an outlet valve of the high-pressure kettle by using a gas cylinder and a plunger pump, slowly releasing pressure of the high-pressure kettle (about 60 min) until the pressure is zero, and taking out the film casting device to obtain the dry polymethyl methacrylate drug-loaded porous film.
FIG. 6 is a sectional electron microscope image of the prepared polycaprolactone porous film, and it can be seen from the image that the obtained porous film has uniform pore diameter and high porosity, and compared with polylactic acid and methyl methacrylate porous films, the porous film has smaller pore diameter, high porosity and better mechanical strength.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents or improvements made within the spirit and principle of the present invention should be included in the scope of the present invention.

Claims (9)

1. A preparation method of a sustained-release drug-loaded porous membrane based on a supercritical fluid technology is characterized in that a device for preparing the sustained-release drug-loaded porous membrane based on the supercritical fluid technology is utilized, and comprises the following steps:
(A) weighing a polymer and solid medicine particles, mixing and dissolving in a solvent to prepare a solution or suspension with the mass percent concentration of 15-50%;
(B) spreading the solution or suspension prepared in step (A) into a thin layer, and mixing the thin layer with ScCO carrying agent 2 Fully contacting;
(C) circulating introduction of ScCO 2 Cleaning and drying the porous carrier, and continuously introducing a solvent into the ScCO 2 The medium quilt is taken out of the system to obtain a porous film;
the device for preparing the sustained-release drug-loaded porous membrane based on the supercritical fluid technology comprises CO sequentially connected through a main pipeline 2 The device comprises a gas cylinder (1), a cooling water tank (2), a plunger pump (3), a mixer (4), a purifier (5), a preheater (6), an autoclave (8), a primary separation kettle (11) and a secondary separation kettle (13); a return pipe (18) is arranged between the secondary separation kettle (13) and the mixer (4), and a return valve (15), a flowmeter (16) and a one-way valve (17) are sequentially arranged on the return pipe (18); a branch pipeline (19) is arranged on the high-pressure kettle (8), and a constant flow pump (14) is arranged at the end part of the branch pipeline (19); and a film injector (9) is arranged in the autoclave (8).
2. The method of claim 1, wherein the polymer comprises polymethyl methacrylate, polylactic acid, polycaprolactone, or a mixture of polylactic acid and polycaprolactone.
3. The method of claim 1, wherein the solid drug particles comprise antibiotic particles or nucleic acid, protein and polypeptide biochemical macromolecular drug particles.
4. The method according to claim 1, wherein the solvent is acetone, ethanol or dichloromethane.
5. The method of claim 1, wherein the carrier is absolute ethanol.
6. The production method according to any one of claims 1 to 5, wherein an autoclave water bath (7) is provided outside the preheater (6) and the autoclave (8); a primary separation kettle water bath (10) is arranged outside the primary separation kettle (11); a secondary separation kettle water bath (12) is arranged outside the secondary separation kettle (13); and an anti-blocking water bath device (21) is arranged outside the return valve.
7. The production method according to any one of claims 1 to 5, wherein the branch pipe (19) is connected to the autoclave (8) through an atomizing nozzle (8-4), the atomizing nozzle (8-4) has an orifice diameter of 0.20mm and a spray angle of 100 °.
8. The method for preparing a coating according to any one of claims 1 to 5, wherein the film injector (9) is an aluminum mold with a groove having a depth of 0.1 to 0.5 mm.
9. The preparation method according to any one of claims 1 to 5, characterized in that a fine-tuning pressure-stabilizing back pressure valve (20) is arranged between the autoclave (8) and the primary separation kettle (11).
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Citations (2)

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Publication number Priority date Publication date Assignee Title
CN103315980A (en) * 2013-06-09 2013-09-25 浙江大学 Mucous membrane adhesive polymer drug-loaded pasting film preparation method base on supercutical fluid technology
CN211634419U (en) * 2019-11-05 2020-10-09 河北科技大学 Device for preparing sustained-release drug-loaded porous membrane based on supercritical fluid technology

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103315980A (en) * 2013-06-09 2013-09-25 浙江大学 Mucous membrane adhesive polymer drug-loaded pasting film preparation method base on supercutical fluid technology
CN211634419U (en) * 2019-11-05 2020-10-09 河北科技大学 Device for preparing sustained-release drug-loaded porous membrane based on supercritical fluid technology

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