CN115674769A - Intelligent preparation control method and equipment for liposome extrusion - Google Patents
Intelligent preparation control method and equipment for liposome extrusion Download PDFInfo
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Abstract
The invention relates to an intelligent preparation control method and equipment for liposome extrusion, wherein a preparation system for liposome extrusion is adopted, the preparation system comprises a preparation unit and a control unit, and the preparation unit comprises a high-pressure pump, an extrusion disc group connected in parallel and a jacket group corresponding to the extrusion disc group; the control unit comprises a temperature control assembly, a monitoring module and a main control module, wherein the temperature control assembly comprises a liquid supply pipeline and a liquid return pipeline which are connected with the jacket set, and a temperature control valve arranged on the pipelines; the control method comprises the following steps: setting preparation parameters in the main control module and starting preparation; the monitoring module monitors parameters and compares the parameters with the preparation parameters; and the main control module controls the temperature control valve to adjust the duty ratio according to the comparison result so as to adjust the preparation temperature, and the preparation is circularly adjusted until the preparation is finished. The invention has the advantages that the processing process of liposome extrusion is intelligentized, the preparation parameters can be timely and accurately adjusted, the product quality is ensured, the batch reproducibility of products is also ensured, and the process requirement of industrial amplification is realized.
Description
Technical Field
The invention relates to an intelligent preparation control method and equipment for liposome extrusion, which are suitable for the technical field of medical biology.
Background
The drug delivery system is a research system for researching carriers for delivering drugs in drug development, and currently researched drug carriers include lipid emulsions, liposomes, microfluids, micro-nano crystals and the like. In the drug carriers, the liposome has good physiological compatibility with a human body, so the liposome has small toxic and side effects when being used as a drug delivery carrier, and can achieve good targeting and sustained release effects after the surface of the liposome is properly modified, so the liposome is the preferred option of the drug carrier in many times.
In the preparation of liposome, in order to ensure good delivery and drug release effects after liposome vesicles are formed, the liposome vesicles are required to be processed and the particle size of the vesicles is controlled. The main technical means at present is to extrude a blank or drug-loaded liposome sample through a certain power source to enable the blank or drug-loaded liposome sample to pass through a Polycarbonate (PC), and the liposome vesicle is subjected to a shearing force generated by high pressure (such as 100 bar) in the process of passing through the PC membrane, so that the originally larger liposome vesicle is broken and fused again to form the liposome vesicle with smaller particle size and better uniformity, thereby meeting the relevant quality index of the liposome vesicle as the DDS drug carrier. And the liposome vesicle is a hollow vesicle formed by phospholipid bilayers through self-assembly. During the phospholipid self-assembly process, it is necessary to ensure that it is always above the phase transition temperature so that good self-assembly can occur to form the desired liposome vesicles.
Most of the existing liposome processing equipment is monomer processing equipment or simple integrated equipment, so that the industrial large-batch processing requirements are difficult to meet, and parameters such as temperature and the like in the processing process cannot be regulated and controlled timely and accurately, so that the product yield is low; and, because the processing mode of liposome raw materials usually adopts two kinds of constant flow processing (namely, the raw materials pass through the extrusion module at a constant flow rate, the pressure of the solution in the process can change constantly) or constant pressure processing (namely, the raw materials pass through the extrusion module at a constant pressure, and the flow rate of the solution in the process can change constantly), the pressure and the flow rate change of the solution in the processing process can cause the preparation temperature to fluctuate, the existing equipment can not adjust the preparation temperature constantly, the difference of products among batches is large, the repeatability among batches is poor, and different process requirements of different raw materials are difficult to meet.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides an intelligent preparation control method and equipment for liposome extrusion. The technical scheme adopted by the invention is as follows: an intelligent preparation control method for liposome extrusion adopts a preparation system for liposome extrusion, the preparation system comprises a preparation unit and a control unit, the preparation unit comprises a high-pressure pump for conveying liposome solution and an extrusion disc group of which at least one input end is communicated with an output end of the high-pressure pump, the extrusion disc group comprises at least one extrusion disc, each extrusion disc is provided with a liquid jacket, each liquid jacket in the same extrusion disc group forms a jacket group, when the number of the extrusion disc groups is more than one, the extrusion disc groups are mutually connected in parallel, and the jacket groups are mutually connected in parallel. When the extrusion disc group is set as one, a plurality of PC films with the specifications arranged from large to small along the flow direction of the solution can be superposed in each extrusion disc in the extrusion disc group, so that the liposome raw material can form liposome vesicles with the required particle size at one time when flowing through the extrusion discs; when a plurality of extrusion disc groups are connected in parallel, except for the arrangement method, PC films with different specifications can be arranged in different extrusion disc groups, so that the liposome raw materials sequentially flow through the corresponding extrusion disc groups from large to small according to the specification, and finally the liposome vesicles with the particle size meeting the requirements are formed.
The control unit comprises a temperature control assembly for controlling the temperature of the liposome solution in the extrusion disc group, a monitoring module for monitoring the temperature of the liposome solution in the extrusion disc group and a main control module for controlling the operation of the preparation system, wherein the temperature control assembly comprises a liquid supply pipeline connected with the input end of the clamping sleeve group, a liquid return pipeline connected with the output end of the clamping sleeve group and temperature control valves respectively arranged on the liquid supply pipeline and the liquid return pipeline and used for controlling the circulation and the interruption of liquid; specifically, the liquid in the temperature control assembly is hot water generally, other heat transfer liquid media in the prior art can be adopted, hot water is introduced into the liquid jacket, the preparation temperature in the extrusion disc is controlled in a hot water bath mode, the heating stability can be ensured, the occurrence of large temperature fluctuation is avoided, the uniformity of heat borne by the liposome solution can be ensured, and the product quality is improved. Furthermore, the preparation temperature is monitored in real time through the monitoring module, the operation of the preparation system is adjusted in real time through the main control module, manual operation in the liposome extrusion process is reduced, intelligent processing of liposome extrusion is achieved, a basis is provided for large-scale industrial processing, timeliness and accuracy of temperature regulation and control are guaranteed, and product quality is guaranteed.
The preparation control method comprises the following steps:
s1, setting preparation parameters in a main control module and starting preparation, wherein the preparation parameters comprise temperature values C1, C2, C3 and C4 which are set in sequence from small to large, setting an on-off period T and setting a duty ratio S; the temperature control valve is opened and closed circularly, the on-off period T is the time for completing one opening and closing of the temperature control valve, and the duty ratio S is the ratio of the time for opening the temperature control valve in a single on-off period T to the whole on-off period T; when preparation is started, the main control module starts the high-pressure pump, controls the liquid in the liquid jacket to flow according to a set on-off period T and a set duty ratio S through a temperature control valve, and executes S2 after the duration time T1 and the time T1 are continued; wherein, the temperature values C1, C2, C3 and C4, the on-off period T and the duty ratio S are set according to the process requirements of the actual liposome sample;
s2, the main control module collects the actual time T 'of the temperature control valve opening in the current on-off period T in real time, calculates the current actual duty ratio S = T'/T, and controls the monitoring module to monitor and collect the real-time temperature c of the liposome solution in the extrusion disc set;
then the main control module compares the real-time temperature c with the set temperature:
if C is more than or equal to C2 and less than or equal to C3, the main control module controls the temperature control valve to keep the set duty ratio S; c2 to C3 represent a normal preparation temperature range, and preparation is carried out according to set preparation parameters in the normal temperature range;
if C1 is more than C and less than C2, the main control module controls the temperature control valve to prolong the actual time T' for opening the temperature control valve in a single on-off period T and increase the actual duty ratio s; when the actual preparation temperature is lower than the normal preparation temperature, the time for supplying hot water in one period in the liquid jacket is prolonged, and a large amount of constant-temperature hot water provides more heat for the liposome solution in the extrusion disc, so that the preparation temperature is increased; the method for controlling the temperature control valve to increase the actual duty ratio s by the main control module comprises the following steps: setting a temperature difference value a > b > d, a = C2-C1, and if a > [ Delta ] C > b, controlling the temperature control valve to increase the actual duty ratio s by s1 by the main control module every time an on-off period T is completed; if b is more than or equal to delta c and more than d, the main control module controls the temperature control valve to improve the actual duty ratio s by s2 every time the on-off period T is completed; if d is more than or equal to Δ c and is more than 0, the main control module controls the temperature control valve to improve the actual duty ratio s by s3 every time the on-off period T is completed; Δ C = C2-C, and s1 > s2 > s3; wherein, the temperature difference values b and d and the duty ratio increasing amounts s1, s2 and s3 are set according to the process requirements of the actual liposome sample;
if C3 is more than C and less than C4, the main control module controls the temperature control valve to shorten the actual time T' for opening the temperature control valve in a single on-off period T, and the actual duty ratio s is reduced; when the actual preparation temperature is higher than the normal preparation temperature, the time for supplying hot water in one period in the liquid jacket is shortened, the heat provided by the hot water for the liposome solution in the extrusion disc is reduced, and the preparation temperature is further reduced; the method for controlling the temperature control valve to reduce the actual duty ratio s by the main control module comprises the following steps: setting a temperature difference value e < f < g, g = C4-C3, if 0 < Δ C' < e, controlling the temperature control valve to reduce the actual duty ratio s by s4 by the main control module every time an on-off period T is completed; if e is less than or equal to deltac' and less than f, the main control module controls the temperature control valve to reduce the actual duty ratio s by s5 every time the on-off period T is completed; if f is less than or equal to deltac' and less than g, the main control module controls the temperature control valve to reduce the actual duty ratio s by s6 every time the on-off period T is completed; Δ C' = C-C3, and s6 > s5 > s4; wherein, the temperature difference values e and f, and the duty ratio improvement amounts s4, s5 and s6 are set according to the process requirements of the actual liposome sample;
if C is less than or equal to C1, the main control module controls the temperature control valve to prolong the actual time T' for opening the temperature control valve in a single on-off period T, and the actual duty ratio s =1; when the actual preparation temperature is lower than the lower limit of the normal regulation temperature, the temperature control valve in a single period is adjusted to be in a fully-opened state, and the preparation temperature of the liposome solution is rapidly raised through continuous hot water supply, so that the preparation temperature can be rapidly adjusted to be in a normal temperature range;
if C is larger than or equal to C4, the main control module controls the temperature control valve to shorten the actual time T' for opening the temperature control valve in a single on-off period T, and the actual duty ratio s =0; when the actual preparation temperature is higher than the upper limit of the normal regulation temperature, the temperature control valve in a single period is regulated to be in a fully closed state, and the subsequent hot water supply to the liquid jacket is cut off, so that the preparation temperature of the liposome solution is quickly reduced, and the preparation temperature is conveniently and quickly regulated to be in a normal temperature range;
and S3, the main control module repeatedly executes the step S2 until the preparation is finished.
In the control method, the actual preparation temperature is monitored in real time through the monitoring module, and when the difference value between the actual temperature and the set temperature is larger, the adjustment range of hot water supply time in each period is correspondingly increased, so that the preparation temperature of the liposome solution is rapidly changed, and the increase of the reject ratio of the product caused by the fact that the liposome solution is in an abnormal preparation temperature for a long time is avoided; and along with the gradual reduction of the difference between the actual temperature and the set temperature, the corresponding reduction is the range of cycle at every turn to hot water supply time adjustment, ensures that the temperature can be adjusted to normal preparation temperature steadily, avoids the temperature fluctuation increase caused by excessive heating or cooling, not only improves the product quality, but also ensures the reproducibility of batch products. Furthermore, parameters such as different adjustment amplitudes, on-off periods and the like can be set for different liposome raw materials, so that the method can be suitable for processing different types of liposomes, and the universality is improved.
Further, in step S1, the preparation parameters further include setting temperature alarm values C5 and C6, where C5 is less than C1 and C6 is greater than C4; in step S2, the main control module compares the real-time temperature c with the set temperature: if C is less than or equal to C5 or C is greater than or equal to C6, the main control module controls the preparation system to stop and gives an alarm; by setting the temperature warning value, the processing can be stopped in time and operators can be reminded when the temperature is abnormally increased or reduced due to the failure of the equipment, so that the production accident is avoided.
Furthermore, the preparation unit also comprises a preparation tank group which is connected with the input end of the high-pressure pump and used for supplying liposome solution, and a collection tank group of which the input end is connected with the output end of the extrusion plate group, wherein the output end of the collection tank group is connected with the input end of the preparation tank group through a circulating valve, the control unit also comprises a weighing sensor used for monitoring the weight of liquid in the preparation tank group, in the preparation process, the liposome solution in the preparation tank group flows into the extrusion plate under the driving of the high-pressure pump, flows into the collection tank group for temporary storage after the extrusion process is completed in the extrusion plate, when the extrusion processing needs to be repeated, the circulating valve is opened, and the liposome solution temporarily stored in the collection tank group is transferred to the preparation tank group so as to be extruded and processed for multiple times, and products can be collected from the collection tank group if the recycling processing is not needed.
Further, in step S1, the preparation parameters further include a set cycle number Q and a solution set remaining amount G, and the circulation valve is in a closed state when the preparation is started.
Still further, the preparation control method further comprises:
1) After preparation is started, the main control module monitors the real-time allowance G of the liposome solution in the preparation tank group through a weighing sensor, the real-time allowance is compared with the set allowance G, if G is larger than G, the circulating valve is kept in a closed state, otherwise, the main control module opens the circulating valve, a count is added in the actual circulating frequency q, and after t2, the main control module closes the circulating valve;
2) And the main control module compares the actual cycle number Q with the set cycle number Q, if Q is less than Q-1, the step 1 is repeatedly executed, and otherwise, the preparation is finished after the time t 3.
Real-time monitoring is carried out on the actual allowance in the preparation tank group through a weighing sensor, when the actual allowance is lower than a set value, the fact that the liposome solution is subjected to one-time extrusion processing is indicated, the processing times are recorded, and if the processing times reach the requirement, the preparation is finished after the processing of the residual solution in the preparation unit is finished; if the processing times do not reach the requirement, the circulating valve is opened through the main control module, the solution temporarily stored in the collection tank set is transferred to the preparation tank set, the extrusion processing is carried out again, the repeated circulating extrusion is convenient, and the liposome vesicles with the particle size meeting the requirement are processed. Specifically, the parameters such as the set margin and the set cycle number can be set according to the actual liposome raw material.
Further, when the number of the extrusion discs in a single extrusion disc group is larger than one, the extrusion discs are connected in parallel, the flux of the single extrusion disc group can be improved, and the processing efficiency is further improved.
Further, the temperature control assembly further comprises a purging module, after preparation is finished, the main control module opens a temperature control valve located on the liquid return pipeline, empties the temperature control assembly and liquid in the liquid jacket, and then controls the purging module to purge the temperature control assembly and the liquid jacket for a duration of t4; liquid in the liquid supply pipeline, the liquid return pipeline and the liquid jacket is dried through the blowing module, and pipeline blockage caused by corrosion is avoided.
The invention also provides intelligent preparation equipment for liposome extrusion, which adopts the intelligent preparation control method for liposome extrusion.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
according to the intelligent preparation control method and the intelligent preparation control equipment for liposome extrusion, the preparation system for liposome extrusion is adopted, so that the processing process of liposome extrusion is accurate and intelligent, and the adverse effect caused by manual operation in the basic process is reduced; the preparation temperature of the liposome solution is regulated and controlled by taking liquid as a medium, the stability of the preparation temperature is ensured, the actual preparation temperature is monitored in real time, and the real-time automatic regulation and control are realized, so that the controllability and the accuracy of the preparation temperature are ensured, the problem of difficult control of process parameters caused by different process requirements required by different liposome raw materials is solved, the quality of products is ensured, the batch reproducibility of the products is also ensured, and the process requirement of industrial amplification is realized.
Drawings
Some specific embodiments of the invention will be described in detail hereinafter, by way of illustration and not limitation, with reference to the accompanying drawings. The same reference numbers in the drawings identify the same or similar elements or components. Those skilled in the art will appreciate that the drawings are not necessarily to scale. In the drawings:
FIG. 1 is a process flow diagram of one embodiment of the present invention;
FIG. 2 is a process flow diagram of the temperature control assembly of the embodiment of FIG. 1;
FIG. 3 is a logic control diagram of the embodiment shown in FIG. 1;
FIG. 4 is a system control diagram of the embodiment shown in FIG. 1;
wherein the reference numerals are as follows:
1. a high pressure pump; 2. a set of extruder disks; 21. an extrusion disc; 3. a clamping sleeve set; 31. a liquid jacket; 4. a monitoring module; 5. a liquid supply line; 6. a return line; 7. a temperature control valve; 8. preparing a tank group; 81. a circulation valve; 82. a weighing sensor; 9. and collecting the tank group.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to the accompanying drawings, and it should be understood that the described embodiments are some, but not all embodiments of the present invention. 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.
In addition, the technical features involved in the different embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
Referring to fig. 1-4, this embodiment provides an intelligent preparation control method for liposome extrusion, which employs a preparation system for liposome extrusion, where the preparation system includes a preparation unit and a control unit, the preparation unit includes a high-pressure pump 1 for delivering liposome solution, at least one extrusion disk set 2 whose input end is communicated with the output end of the high-pressure pump 1, the extrusion disk set 2 includes at least one extrusion disk 21, each extrusion disk 21 has a liquid jacket 31, each liquid jacket 31 in the same extrusion disk set 2 constitutes a jacket set 3, when the number of extrusion disk sets 2 is greater than one, a plurality of extrusion disk sets 2 are connected in parallel, and a plurality of jacket sets 3 are connected in parallel. In the embodiment, the number of the extrusion disc groups 2 is three, when the preparation is performed, a plurality of PC membranes with the specification arranged from large to small along the flow direction of the solution can be superposed in each extrusion disc 21 in the three extrusion disc groups 2, so that liposome raw materials can form liposome vesicles with the particle size meeting the requirement at one time when flowing through the extrusion discs 21, and then the liposome vesicles can be directly output as a product, thereby ensuring the efficiency, further ensuring the product quality by repeated circular extrusion, and the three extrusion disc groups 2 can be connected in parallel for multi-path simultaneous preparation, thereby improving the preparation efficiency; in addition to the above preparation method, in this embodiment, PC membranes with different specifications may be respectively disposed in the three extrusion disc assemblies 2, so that the liposome raw material sequentially flows through the corresponding extrusion disc assemblies 2 from large to small according to the specification, and finally liposome vesicles with a particle size meeting the requirement are formed.
The preparation unit further comprises a preparation tank group 8 connected with the input end of the high-pressure pump 1 and used for supplying liposome solution, and an acquisition tank group 9 with the input end connected with the output end of the extrusion plate group 2, wherein the output end of the acquisition tank group 9 is connected with the input end of the preparation tank group 8 through a circulating valve 81, the control unit further comprises a weighing sensor 82 used for monitoring the weight of liquid in the preparation tank group 8, in the preparation process, the liposome solution in the preparation tank group 8 flows into the extrusion plate 21 under the driving of the high-pressure pump 1, flows into the acquisition tank group 9 for temporary storage after the extrusion process is completed in the extrusion plate 21, when the extrusion processing needs to be repeated, the circulating valve 81 is opened, the liposome solution temporarily stored in the acquisition tank group 9 is transferred to the preparation tank group 8 so as to be subjected to extrusion processing for multiple times, and products can be acquired from the acquisition tank group 9 if the recycling processing is not needed.
The control unit comprises a temperature control assembly for controlling the temperature of the liposome solution in the extrusion disc group 2, a monitoring module 4 for monitoring the temperature of the liposome solution in the extrusion disc group 2 and a main control module for controlling the operation of the preparation system, wherein the temperature control assembly comprises a liquid supply pipeline 5 connected with the input end of the jacket group 3, a liquid return pipeline 6 connected with the output end of the jacket group 3 and a temperature control valve 7 respectively arranged on the liquid supply pipeline 5 and the liquid return pipeline 6 and used for controlling the circulation and the interruption of liquid. In this embodiment, the heat transfer liquid in the temperature control component adopts constant temperature hot water, and the temperature can set up according to the kind of actual liposome raw materials, through letting in hot water in liquid jacket 31, adopts the mode control of hot water bath to extrude the preparation temperature in the dish 21, can ensure the stability of heating, avoids appearing great temperature fluctuation, also can ensure that the heat that the liposome solution received is even, improves the quality of product. Furthermore, the preparation temperature is monitored in real time through the monitoring module 4, the operation of the preparation system is adjusted in real time through the main control module, manual operation in the liposome extrusion process is reduced, intelligent processing of liposome extrusion is realized, a basis is provided for large-scale industrial processing, timeliness and accuracy of temperature regulation and control are guaranteed, and product quality is guaranteed.
The preparation control method comprises the following steps:
s1, setting preparation parameters in a main control module and starting preparation, wherein the preparation parameters comprise temperature values C1, C2, C3 and C4 which are set from small to large in sequence, setting an on-off period T, setting a duty ratio S, setting a cycle number Q and setting a solution allowance G; the temperature control valve 7 is opened and closed circularly, the on-off period T is the time for completing one opening and closing of the temperature control valve 7, and the duty ratio S is the ratio of the opening time of the temperature control valve 7 in a single on-off period T to the whole on-off period T; when preparation is started, the circulating valve 81 is in a closed state, the main control module starts the high-pressure pump 1, controls the liquid in the liquid jacket 31 to flow according to a set on-off period T and a set duty ratio S through the temperature control valve 7, and executes S2 after the time T1 lasts; wherein, the temperature values C1, C2, C3 and C4, the on-off period T and the duty ratio S are set according to the process requirements of the actual liposome sample;
s2, the main control module collects the actual time T 'for opening the temperature control valve 7 in the current on-off period T in real time, calculates the current actual duty ratio S = T'/T, and controls the monitoring module 4 to monitor and collect the real-time temperature c of the liposome solution in the extrusion disc group 2;
then the main control module compares the real-time temperature c with the set temperature:
if C is more than or equal to C2 and less than or equal to C3, the main control module controls the temperature control valve 7 to keep the set duty ratio S; c2 to C3 represent a normal preparation temperature range, and preparation is carried out according to set preparation parameters in the normal temperature range;
if C1 is more than C and less than C2, the main control module controls the temperature control valve 7 to prolong the actual opening time T' of the temperature control valve 7 in a single on-off period T, and the actual duty ratio s is increased; that is, when the actual preparation temperature is lower than the normal preparation temperature, the time for supplying hot water in one period in the liquid jacket 31 is prolonged, and a large amount of constant-temperature hot water provides more heat for the liposome solution in the extrusion disk 21, thereby increasing the preparation temperature; the method for controlling the temperature control valve 7 to increase the actual duty ratio s by the main control module comprises the following steps: setting a temperature difference value a > b > d, a = C2-C1, and if a > [ Delta ] C > b, controlling the temperature control valve 7 by the main control module to increase the actual duty ratio s by s1 every time an on-off period T is completed; if b is more than or equal to delta c and more than d, the main control module controls the temperature control valve 7 to improve the actual duty ratio s by s2 every time the on-off period T is completed; if d is more than or equal to Δ c and is more than 0, the main control module controls the temperature control valve 7 to improve the actual duty ratio s by s3 every time the on-off period T is completed; Δ C = C2-C, and s1 > s2 > s3; wherein, the temperature difference values b and d, and the duty ratio improvement amounts s1, s2 and s3 are set according to the process requirements of the actual liposome sample;
if C3 is more than C and less than C4, the main control module controls the temperature control valve 7 to shorten the actual time T' for opening the temperature control valve 7 in the single on-off period T, and the actual duty ratio s is reduced; that is, when the actual preparation temperature is higher than the normal preparation temperature, the time for supplying hot water in one cycle in the liquid jacket 31 is shortened, the heat supplied by the hot water to the liposome solution in the extrusion plate 21 is reduced, and the preparation temperature is further lowered; the method for controlling the temperature control valve 7 to reduce the actual duty ratio s by the main control module comprises the following steps: setting a temperature difference value e < f < g, g = C4-C3, if 0 < Δ C' < e, controlling the temperature control valve 7 by the main control module to reduce the actual duty ratio s by s4 every time an on-off period T is completed; if e is less than or equal to deltac' and less than f, the main control module controls the temperature control valve 7 to reduce the actual duty ratio s by s5 every time the on-off period T is completed; if f is less than or equal to deltac' and less than g, the main control module controls the temperature control valve 7 to reduce the actual duty ratio s by s6 every time the on-off period T is completed; Δ C' = C-C3, and s6 > s5 > s4; wherein, the temperature difference values e and f, and the duty ratio increasing amounts s4, s5 and s6 are set according to the process requirements of the actual liposome sample;
if C is less than or equal to C1, the main control module controls the temperature control valve 7 to prolong the actual time T' for opening the temperature control valve 7 in the single on-off period T, and the actual duty ratio s =1; when the actual preparation temperature is lower than the lower limit of the normal regulation temperature, the temperature control valve 7 in a single period is adjusted to be in a full-open state, and the preparation temperature of the liposome solution is rapidly raised through continuous hot water supply, so that the preparation temperature can be rapidly adjusted to be in a normal temperature range;
if C is larger than or equal to C4, the main control module controls the temperature control valve 7 to shorten the actual time T' for opening the temperature control valve 7 in a single on-off period T, and the actual duty ratio s =0; when the actual preparation temperature is higher than the upper limit of the normal regulation temperature, the temperature control valve 7 in a single period is regulated to be in a fully closed state, and the subsequent hot water supply to the liquid jacket 31 is cut off, so that the preparation temperature of the liposome solution is quickly reduced, and the preparation temperature is conveniently and quickly regulated to be in a normal temperature range;
s3, the main control module repeatedly executes the step S2 until the preparation is finished; the specific control method for judging the completion of the preparation in this step is described in detail below.
In the control method, the actual preparation temperature is monitored in real time through the monitoring module 4, and when the difference value between the actual temperature and the set temperature is larger, the amplitude of adjusting the hot water supply time in each period is correspondingly increased by controlling the temperature control valve 7, so that the preparation temperature of the liposome solution is changed rapidly, and the increase of the reject ratio of the product caused by the fact that the liposome solution is in the abnormal preparation temperature for a long time is avoided; and along with the difference between the actual temperature and the set temperature is gradually reduced, the amplitude of adjusting the hot water supply time in each period is correspondingly reduced by controlling the temperature control valve 7, the temperature can be stably adjusted to the normal preparation temperature, the problem that the preparation stability is influenced due to the fact that the temperature fluctuation is increased due to excessive heating or cooling is avoided, the product quality is improved, and the repeatability of batch products is also ensured. Furthermore, parameters such as different adjustment amplitudes, on-off periods and the like can be set for different liposome raw materials, so that the method can be suitable for processing different types of liposomes, and the universality is improved.
In a more preferred embodiment, in step S1, the preparation parameters further comprise setting temperature guard values C5, C6, C5 < C1 and C6 > C4; in step S2, the main control module compares the real-time temperature c with the set temperature: if C is less than or equal to C5 or C is greater than or equal to C6, the main control module controls the preparation system to stop and gives an alarm. By setting the temperature warning value, the processing can be stopped in time and operators can be reminded when the temperature is abnormally increased or reduced due to the failure of the equipment, so that the production accident is avoided.
In a more preferred embodiment, the preparation control method further comprises:
1) After preparation is started, the main control module monitors the real-time allowance G of the liposome solution in the preparation tank group 8 through the weighing sensor 82, compares the real-time allowance with the set allowance G, if G is larger than G, the circulating valve 81 keeps a closed state, otherwise, the main control module opens the circulating valve 81, and simultaneously, a count is added in the actual circulating times q, and after t2 time, the main control module closes the circulating valve 81;
2) The main control module compares the actual cycle times Q with the set cycle times Q, if Q is less than Q-1, the step 1 is executed repeatedly, otherwise, the preparation is finished after t3 time;
the actual allowance in the preparation tank group 8 is monitored in real time through the weighing sensor 82, when the actual allowance is lower than a set value, the liposome solution is extruded once, the processing times are recorded, and if the processing times reach the requirement, the preparation is finished after the processing of the residual solution in the preparation unit is finished; if the processing times do not meet the requirements, the circulating valve 81 is opened through the main control module, the solution temporarily stored in the collection tank group 9 is transferred to the preparation tank group 8, extrusion processing is performed again, repeated circulating extrusion is facilitated, and the liposome vesicles with the particle sizes meeting the requirements are processed. Specifically, the parameters such as the set margin and the set cycle number can be set according to the actual liposome raw material. This part of the preparation control method is the specific control method for judging the end of preparation described in the above step S3.
In a more preferred embodiment, when the number of extrusion disks 21 in a single extrusion disk pack 2 is greater than one, multiple extrusion disks 21 are connected in parallel to each other, which can increase the throughput of a single extrusion disk pack 2 and thus the process efficiency.
In a more preferred embodiment, the temperature control assembly further comprises a purging module, after preparation is finished, the main control module opens the temperature control valve 7 on the liquid return pipeline 6, exhausts the liquid in the temperature control assembly and the liquid jacket 31, and then controls the purging module to purge the temperature control assembly and the liquid jacket 31 for a time t4; the liquid in the liquid supply pipeline 5, the liquid return pipeline 6 and the liquid jacket 31 is dried by blowing through the blowing module, so that the pipeline blockage caused by corrosion is avoided.
The invention also provides a biological vaccine intelligent device which adopts the intelligent preparation control method for liposome extrusion.
Due to the application of the technical scheme, compared with the prior art, the invention has the following advantages:
according to the intelligent preparation control method and the intelligent preparation control equipment for liposome extrusion, the preparation system for liposome extrusion is adopted, so that the processing process of liposome extrusion is accurate and intelligent, and the adverse effect caused by manual operation in the basic process is reduced; the preparation temperature of the liposome solution is regulated and controlled by taking liquid as a medium, the stability of the preparation temperature is ensured, the actual preparation temperature is monitored in real time, and the real-time automatic regulation and control are realized, so that the controllability and the accuracy of the preparation temperature are ensured, the problem of difficult control of process parameters caused by different process requirements required by different liposome raw materials is solved, the quality of products is ensured, the batch reproducibility of the products is also ensured, and the process requirement of industrial amplification is realized.
The above embodiments are merely illustrative of the technical concept and features of the present invention, and the purpose thereof is to enable those skilled in the art to understand the content of the present invention and implement the invention, and not to limit the scope of the invention, and all equivalent changes or modifications made according to the spirit of the present invention should be covered by the scope of the present invention.
Claims (8)
1. An intelligent preparation control method for liposome extrusion is characterized in that a preparation system for liposome extrusion is adopted, the preparation system comprises a preparation unit and a control unit, the preparation unit comprises a high-pressure pump (1) for delivering liposome solution, at least one extrusion disc group (2) with an input end communicated with an output end of the high-pressure pump (1), the extrusion disc group (2) comprises at least one extrusion disc (21), each extrusion disc (21) is provided with a liquid jacket (31), each liquid jacket (31) in the same extrusion disc group (2) forms a jacket group (3), when the number of the extrusion disc groups (2) is more than one, a plurality of extrusion disc groups (2) are connected in parallel, and a plurality of jacket groups (3) are connected in parallel;
the control unit comprises a temperature control assembly for controlling the temperature of the liposome solution in the extrusion disc set (2), a monitoring module (4) for monitoring the temperature of the liposome solution in the extrusion disc set (2), and a main control module for controlling the operation of the preparation system, wherein the temperature control assembly comprises a liquid supply pipeline (5) connected with the input end of the clamping set (3), a liquid return pipeline (6) connected with the output end of the clamping set (3), and a temperature control valve (7) which is respectively arranged on the liquid supply pipeline (5) and the liquid return pipeline (6) and is used for controlling the circulation and the interruption of liquid;
the preparation control method comprises the following steps:
s1, setting preparation parameters in the main control module and starting preparation, wherein the preparation parameters comprise temperature values C1, C2, C3 and C4 which are set in sequence from small to large, setting an on-off period T and setting a duty ratio S; the temperature control valve (7) is opened and closed circularly, the on-off period T is the time for completing one opening and closing of the temperature control valve (7), and the duty ratio S is the ratio of the time for opening the temperature control valve (7) in a single on-off period T to the whole on-off period T; when preparation starts, the main control module starts the high-pressure pump (1), controls liquid in the liquid jacket (31) to flow according to a set on-off period T and a set duty ratio S through the temperature control valve (7), and executes S2 after the time lasts for T1 and T1;
s2, the main control module collects the actual opening time T 'of the temperature control valve (7) in the current on-off period T in real time, calculates the current actual duty ratio S = T'/T, and controls the monitoring module (4) to monitor and collect the real-time temperature c of the liposome solution in the extrusion disc set (2) at the same time;
then the main control module compares the real-time temperature c with the set temperature:
if C is more than or equal to C2 and less than or equal to C3, the main control module controls the temperature control valve (7) to keep a set duty ratio S;
if C1 is larger than C and smaller than C2, the main control module controls the temperature control valve (7) to prolong the actual time T' for opening the temperature control valve (7) in a single on-off period T and increase the actual duty ratio s; the method for controlling the temperature control valve (7) to increase the actual duty ratio s by the main control module comprises the following steps: setting a temperature difference value a > b > d, a = C2-C1, and if a >. DELTA.c > b, controlling the temperature control valve (7) by the main control module to increase the actual duty ratio s by s1 every time the on-off period T is completed; if b is more than or equal to Δ c and more than d, the main control module controls the temperature control valve (7) to improve the actual duty ratio s by s2 every time the on-off period T is completed; if d is more than or equal to Δ c and is more than 0, the main control module controls the temperature control valve (7) to improve the actual duty ratio s by s3 every time the on-off period T is completed; Δ C = C2-C, and s1 > s2 > s3;
if C3 is larger than C and smaller than C4, the main control module controls the temperature control valve (7) to shorten the actual time T' for opening the temperature control valve (7) in a single on-off period T, and the actual duty ratio s is reduced; the method for controlling the temperature control valve (7) to reduce the actual duty ratio s by the main control module comprises the following steps: setting a temperature difference value e < f < g, g = C4-C3, if 0 < Δ C' < e, controlling the temperature control valve (7) by the main control module to reduce the actual duty ratio s by s4 every time the on-off period T is completed; if e is less than or equal to deltac' < f, the main control module controls the temperature control valve (7) to reduce the actual duty ratio s by s5 every time the on-off period T is completed; if f is more than or equal to Δ c' < g, the main control module controls the temperature control valve (7) to reduce the actual duty ratio s by s6 every time the on-off period T is completed; Δ C' = C-C3, and s6 > s5 > s4;
if C is less than or equal to C1, the main control module controls the temperature control valve (7) to prolong the actual time T' for opening the temperature control valve (7) in a single on-off period T, and the actual duty ratio s =1;
if C is larger than or equal to C4, the main control module controls the temperature control valve (7) to shorten the actual time T' for opening the temperature control valve (7) in a single on-off period T, and the actual duty ratio s =0;
and S3, the main control module repeatedly executes the step S2 until the preparation is finished.
2. The intelligent preparation control method for liposome extrusion of claim 1, wherein in step S1, the preparation parameters further comprise setting temperature alert values of C5, C6, C5 < C1 and C6 > C4; in step S2, the main control module compares the real-time temperature c with a set temperature:
and if C is less than or equal to C5 or C is greater than or equal to C6, the main control module controls the preparation system to stop and gives an alarm.
3. The intelligent preparation control method for liposome extrusion according to claim 1, wherein the preparation unit further comprises a preparation tank set (8) connected with an input end of the high-pressure pump (1) and used for supplying liposome solution, a collection tank set (9) connected with an input end of the extrusion disk set (2), an output end of the collection tank set (9) is connected with an input end of the preparation tank set (8) through a circulating valve (81), and the control unit further comprises a weighing sensor (82) used for monitoring the weight of liquid in the preparation tank set (8).
4. The intelligent preparation control method for liposome extrusion as claimed in claim 3, wherein in step S1, the preparation parameters further comprise a set circulation number Q and a solution set residual G, and the circulation valve (81) is in a closed state when preparation is started.
5. The intelligent preparation control method for liposome extrusion of claim 4, further comprising:
1) After preparation is started, the main control module monitors the real-time residual amount G of the liposome solution in the preparation tank group (8) through the weighing sensor (82), compares the real-time residual amount with a set residual amount G, if G is larger than G, the circulating valve (81) is kept in a closed state, otherwise, the main control module opens the circulating valve (81), and simultaneously, the counting is increased once in the actual circulating times q, and after t2 time, the main control module closes the circulating valve (81);
2) And the main control module compares the actual cycle number Q with the set cycle number Q, if Q is less than Q-1, the step 1 is repeatedly executed, otherwise, the preparation is finished after t3 time.
6. The intelligent production control method for liposome extrusion according to claim 1, wherein when the number of the extrusion disks (21) in a single extrusion disk group (2) is more than one, a plurality of the extrusion disks (21) are connected in parallel with each other.
7. The intelligent preparation control method for liposome extrusion as claimed in claim 1, wherein the temperature control module further comprises a purging module, after preparation is finished, the main control module opens the temperature control valve (7) on the liquid return pipeline (6), evacuates the liquid in the temperature control module and the liquid jacket (31), and then controls the purging module to purge the temperature control module and the liquid jacket (31) for a time period t4.
8. An intelligent preparation device for liposome extrusion, which is characterized in that the intelligent preparation control method for liposome extrusion of any one of claims 1 to 7 is adopted.
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