CN115501781A - Liquid preparation device and method of isavuconazole sulfate for injection - Google Patents

Liquid preparation device and method of isavuconazole sulfate for injection Download PDF

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Publication number
CN115501781A
CN115501781A CN202211136193.4A CN202211136193A CN115501781A CN 115501781 A CN115501781 A CN 115501781A CN 202211136193 A CN202211136193 A CN 202211136193A CN 115501781 A CN115501781 A CN 115501781A
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CN
China
Prior art keywords
piston
reducing section
sulfate
isavuconazole
shaft
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Granted
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CN202211136193.4A
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Chinese (zh)
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CN115501781B (en
Inventor
龙光林
刘凌瑞
梁琦琳
胡彦霞
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Chengdu Jingfu Pharmaceutical Technology Co ltd
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Chengdu Jingfu Pharmaceutical Technology Co ltd
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Priority to CN202211136193.4A priority Critical patent/CN115501781B/en
Priority claimed from CN202211136193.4A external-priority patent/CN115501781B/en
Publication of CN115501781A publication Critical patent/CN115501781A/en
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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F27/00—Mixers with rotary stirring devices in fixed receptacles; Kneaders
    • B01F27/80—Mixers with rotary stirring devices in fixed receptacles; Kneaders with stirrers rotating about a substantially vertical axis
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F21/00—Dissolving
    • B01F21/02—Methods
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F21/00—Dissolving
    • B01F21/10—Dissolving using driven stirrers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
    • B01F23/80—After-treatment of the mixture
    • B01F23/808—Filtering the mixture
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F27/00—Mixers with rotary stirring devices in fixed receptacles; Kneaders
    • B01F27/80—Mixers with rotary stirring devices in fixed receptacles; Kneaders with stirrers rotating about a substantially vertical axis
    • B01F27/90—Mixers with rotary stirring devices in fixed receptacles; Kneaders with stirrers rotating about a substantially vertical axis with paddles or arms 
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/75—Discharge mechanisms
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/90—Heating or cooling systems
    • B01F35/92—Heating or cooling systems for heating the outside of the receptacle, e.g. heated jackets or burners
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
    • B01F35/90—Heating or cooling systems
    • B01F2035/98—Cooling
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F2101/00—Mixing characterised by the nature of the mixed materials or by the application field
    • B01F2101/22—Mixing of ingredients for pharmaceutical or medical compositions
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
    • B01F2101/00—Mixing characterised by the nature of the mixed materials or by the application field
    • B01F2101/2202—Mixing compositions or mixers in the medical or veterinary field

Abstract

The invention discloses a liquid preparation device and a method of isavuconazole sulfate for injection, which comprises a jacket mixing tank; the bottom outlet of the jacket mixing tank is connected with the sterile collection tank through a filter; the jacket mixing tank comprises an outer shell and an inner shell, and a cooling coil is arranged between the outer shell and the inner shell; a stirring cavity is arranged in the inner shell, and a reducing section is arranged at the lower part of the stirring cavity; a stirring shaft is vertically arranged in the stirring cavity, a piston is connected onto the stirring shaft in a sliding manner, and the piston can slide along the length direction of the stirring shaft; the stirring shaft penetrates through the piston and extends into the reducing section, and the radial size of the piston is matched with that of the reducing section; an inlet pipe is arranged on the upper sealing cover at the top of the inner shell and is communicated with the reducing section; this scheme of adoption to the piston pushes down for the filtration and the collection efficiency of solution, very big increase the solution preparation efficiency that isavuconazole sulfate joined in marriage.

Description

Liquid preparation device and method of isavuconazole sulfate for injection
Technical Field
The invention relates to the technical field of pharmaceutical equipment, in particular to a liquid preparation device and method of isavuconazole sulfate for injection.
Background
The isavuconazole sulfate for injection is an azole antifungal agent, is suitable for treating invasive aspergillosis and invasive mucormycosis, is also a sterile powder injection, and is developed and developed by Basilea pharmaceutical company of Switzerland; at present, only 1 isavuconazole sulfate raw material manufacturer exists in China, and no isavuconazole sulfate for injection is approved in China.
In the prior art, the original grinding of isavuconazole sulfate is a preparation freeze-drying process, and a finished product is prepared by liquid preparation, filtration, filling and freeze-drying in turn in the research and development process; in the specific liquid preparation and filtration process, firstly, adding about 70 percent of water for injection in the volume of the total batch into a jacket mixing tank with a weight removed, then adding mannitol into the water for injection, and dissolving the mannitol by stirring; the drug substance is then added, and the mannitol solution is cooled to 0-5 ℃ before the drug substance is added. Adding the isavuconazole sulfate bulk drug into the mannitol solution, stirring and dissolving, and adding 0.5N sulfuric acid solution to adjust the pH value; after the adjustment is completed, pressurizing the preparation tank by using nitrogen, and filtering the solution into a sterile collection tank by using a filter; the filter sterilized solution is stored in a sterile collection tank at a temperature of 0-5 ℃.
In the liquid preparation and filtration process, as the inner space of the mixing tank is larger, the nitrogen is increased in the process of flushing nitrogen and pressurizing, the filling time is increased, the pressurizing pressure is slowly increased, the efficiency of the solution entering the sterile collection tank through the filter is reduced, and finally the efficiency of the preparation freeze-drying process of the isaconazole sulfate is reduced.
Disclosure of Invention
The invention does not solve the defects of the prior art, and aims to provide a liquid preparation device and a liquid preparation method of isavuconazole sulfate for injection.
The invention is realized by the following technical scheme:
a liquid preparation device of isavuconazole sulfate for injection comprises a jacket mixing tank;
the bottom outlet of the jacket mixing tank is connected with a sterile collection tank through a filter;
the jacket mixing tank comprises an outer shell and an inner shell, and a cooling coil is arranged between the outer shell and the inner shell;
a stirring cavity is arranged in the inner shell, and a reducing section is arranged at the lower part of the stirring cavity;
a stirring shaft is vertically arranged in the stirring cavity, a piston is connected on the stirring shaft in a sliding manner, and the piston can slide along the length direction of the stirring shaft; the stirring shaft penetrates through the piston and extends into the reducing section, and the radial size of the piston is matched with that of the reducing section;
an inlet pipe is arranged on the upper sealing cover at the top of the inner shell, and the inlet pipe is communicated with the reducing section.
Compared with the prior art, the injection liquid preparation device has the advantages that in the process of injecting nitrogen to pressurize, the use amount of nitrogen is increased, the filling time is increased, the pressurizing pressure is increased slowly, the efficiency of a solution entering an aseptic collection tank through a filter is reduced, and the efficiency of a preparation freeze-drying process of isaconazole sulfate preparation is reduced finally; a stirring shaft is arranged in the stirring cavity, the upper end of the stirring shaft is connected with the upper sealing cover, the lower end of the stirring shaft extends into the diameter-reduced section, and a stirring blade is arranged at the lower end of the stirring shaft, so that the solution in the diameter-reduced section is mixed and stirred; a piston is connected with the stirring shaft in a sliding way, and a through hole for the stirring shaft to pass through is formed in the middle of the piston to realize sliding; the diameter of the piston is the same as the inner diameter of the reducing section, so that the piston can enter the reducing section; during the specific operation process, various materials are added into the diameter-reducing section through the inlet pipe, the materials are fully and uniformly mixed through the stirring shaft, after the stirring is finished, nitrogen can be injected into the diameter-reducing section through the inlet pipe, after the nitrogen is injected for a certain time, the piston is gradually pressed down in the diameter-reducing section, and the pressure on the mixed solution can be increased through excessive nitrogen while the mixed solution is not contacted, so that the mixed solution quickly enters the sterile collection tank through the filter for storage; through the steps, the nitrogen consumption can be reduced, and the filtering and collecting efficiency of the solution is improved by pressing down the piston; in addition, various materials in the scheme such as the inlet pipe and the like are made of corrosion-resistant materials; the filter uses a 0.22 micron filter that allows redundant filtration of the solution into a sterile collection tank.
Preferably, the stirring shaft comprises an outer shaft and an inner shaft, the upper end of the outer shaft is fixedly connected with the inner shell, and the lower end of the outer shaft extends into the reducing section; the upper end of the inner shaft is connected with an output shaft of a rotating motor outside the inner shell, and the lower end of the inner shaft penetrates out of the lower end of the outer shaft; the piston and the outer shaft are slidably connected; the piston is used for preventing the piston from rotating and damaging the inner shell.
Preferably, a connecting plate is arranged at the top of the piston, the piston is connected with an outer shaft in a sliding mode through the connecting plate, the connecting plate is connected with the outer shaft in a sliding mode in a sealing mode, and a gap is reserved between the middle of the piston and the outer shaft; for avoiding excessive friction.
The piston is further optimized, the piston further comprises a fixed plate, the fixed plate is fixedly connected with the outer shaft and is positioned above the piston, a linear driving motor is arranged on the fixed plate, and the linear driving motor is connected with the piston through a screw rod; for driving the piston.
Preferably, the piston is provided with an inlet channel, the lower end of the inlet pipe is connected with the upper end of the inlet channel, and the inlet pipe is communicated with the reducing section through the inlet channel; the inlet pipe is fixed on the fixed plate, and a telescopic pipe is arranged on the inlet pipe between the fixed plate and the piston; the cooling coil pipe is used for avoiding bending of the inlet pipe and avoiding damage to the arrangement position of the cooling coil pipe.
Further preferably, an exhaust pipe is further arranged on the upper sealing cover at the top of the inner shell, and the exhaust pipe is connected with the middle part of the inlet pipe through an electromagnetic control valve; is used for facilitating the cyclic utilization of nitrogen.
The thermometer sequentially penetrates through the first through hole from the upper sealing cover on the top of the inner shell and extends into the reducing section, and the thermometer is connected with the first through hole in a sliding manner; a sleeve which is connected in a sliding manner is arranged in the second through hole, the upper end of the sleeve is connected with the top of the inner shell, the lower end of the sleeve extends into the reducing section, the PH tester is arranged on an upper sealing cover at the top of the inner shell, and a probe of the PH tester is arranged at the lower end of the sleeve; the temperature and the pH value of the mixed solution are measured in real time.
Further preferably, the cooling coil is arranged on the outer side of the reducing section, and a heat-insulating layer is filled between the outer shell and the inner shell; for improving the cooling effect.
Further preferably, an electromagnetic one-way valve is arranged between the outlet at the bottom of the jacket mixing tank and the filter, and a placing cavity of the electromagnetic one-way valve is arranged between the outer shell and the inner shell; to avoid nitrogen reflux.
Further optimized, the preparation method of the isavuconazole sulfate solution for injection comprises the following steps:
s1: controlling the lower end of the piston to enter the upper end of the reducing section;
s2: sequentially adding water for injection and mannitol into the diameter-reduced section through an inlet pipe, and controlling the stirring shaft to stir to obtain a mannitol solution;
s3: after stirring is finished, controlling the cooling coil to cool the mannitol solution to 0-5 ℃;
s4: adding the isavuconazole sulfate bulk drug into a mannitol solution through the inlet pipe, and controlling the stirring shaft to stir again;
s5: after stirring and dissolving, adding a sulfuric acid solution into the reducing section through the inlet pipe to adjust the pH value to be 1.3-1.6;
s6: after the PH value is adjusted, filling nitrogen into the diameter-reducing section through the inlet pipe, opening the electromagnetic one-way valve at the bottom outlet of the jacket mixing tank, and then gradually controlling the piston to move downwards until all the solution enters the sterile collection tank;
s7: the nitrogen in the reduced diameter section is then extracted through an extraction tube connected to the middle of the inlet tube, which is then opened and the piston is reset.
Compared with the prior art, the invention has the following advantages and beneficial effects:
the invention provides a liquid preparation device and method of isavuconazole sulfate for injection, and by adopting the scheme, nitrogen can be directly filled into a mixing tank, a solution is pressed into a sterile collection tank, the nitrogen consumption is reduced by reducing the inner space, and then the nitrogen is pressed down by a piston, so that the filtering and collecting efficiency of the solution is accelerated, and the liquid preparation efficiency of isavuconazole sulfate is greatly improved.
Drawings
In order to more clearly illustrate the technical solutions of the exemplary embodiments of the present invention, the drawings that are required in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and that those skilled in the art may also derive other related drawings based on these drawings without inventive effort. In the drawings:
FIG. 1 is a schematic structural diagram of an embodiment of the present invention;
FIG. 2 is a partial schematic view A of an embodiment of the present invention;
FIG. 3 is a partial schematic view B of an embodiment of the present invention;
FIG. 4 is a top view of a retaining plate according to one embodiment of the present invention;
fig. 5 is a top view of a connection plate according to an embodiment of the present invention.
Reference numbers and corresponding part names in the drawings:
1-jacket mixing tank, 101-outer shell, 102-inner shell, 103-cooling coil, 104-stirring shaft, 1041-outer shaft, 1042-inner shaft, 105-stirring cavity, 106-reducing section, 107-piston, 1071-inlet channel, 1072-first through hole, 1073-second through hole, 108-inlet pipe, 109-connecting plate, 110-fixing plate, 111-linear driving motor, 112-telescopic pipe, 113-exhaust pipe, 114-electromagnetic control valve, 115-heat preservation layer, 116-electromagnetic one-way valve, 117-sleeve, 118-screw rod, 2-filter, 3-sterile collection tank, 4-rotating motor, 5-thermometer, 6-PH tester.
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 examples and accompanying drawings, and the exemplary embodiments and descriptions thereof are only used for explaining the present invention and are not meant to limit the present invention.
Example 1
The embodiment 1 provides a solution preparation device of isavuconazole sulfate for injection, which is shown in fig. 1 to 5 and comprises a jacket mixing tank 1;
the bottom outlet of the jacket mixing tank 1 is connected with a sterile collection tank 3 through a filter 2;
the jacket mixing tank 1 comprises an outer shell 101 and an inner shell 102, and a cooling coil 103 is arranged between the outer shell 101 and the inner shell 102;
a stirring cavity 105 is arranged in the inner shell 102, and a reducing section 106 is arranged at the lower part of the stirring cavity 105;
a stirring shaft 104 is vertically arranged in the stirring cavity 105, a piston 107 is connected on the stirring shaft 104 in a sliding manner, and the piston 107 can slide along the length direction of the stirring shaft 104; the stirring shaft 104 penetrates through the piston 107 and extends into the reduced diameter section 106, and the radial size of the piston 107 is matched with that of the reduced diameter section 106;
the top of the inner shell 102 is capped with an inlet tube 108, and the inlet tube 108 communicates with the reduced diameter section 106.
Compared with the prior art, the method has the advantages that in the process of injecting nitrogen and pressurizing, the consumption of nitrogen is increased, the filling time is increased, the pressurizing pressure is increased slowly, the efficiency of a solution entering the sterile collection tank 3 through the filter 2 is reduced, and the efficiency of a preparation freeze-drying process of the isaconazole sulfate preparation is reduced finally; a stirring shaft 104 is arranged in the stirring cavity 105, the upper end of the stirring shaft 104 is connected with the upper sealing cover, the lower end of the stirring shaft extends into the diameter-reduced section 106, and a stirring blade is arranged at the lower end of the stirring shaft 104, so that the solution in the diameter-reduced section 106 is mixed and stirred; a piston 107 is also connected on the stirring shaft 104 in a sliding way, and the middle part of the piston 107 is provided with a through hole for the stirring shaft 104 to pass through so as to realize sliding; the diameter of the piston 107 is the same as the inner diameter of the reduced diameter section 106, so that the piston 107 can enter the reduced diameter section 106; in the specific operation process, various materials are added into the diameter-reducing section 106 through the inlet pipe 108 and are fully and uniformly mixed through the stirring shaft 104, after stirring is completed, nitrogen can be injected into the diameter-reducing section 106 through the inlet pipe 108, after a certain time of injection, the piston 107 is gradually pressed down in the diameter-reducing section 106, and through excessive nitrogen, the pressure on the mixed solution can be increased while the mixed solution is not contacted, so that the mixed solution quickly enters the sterile collection tank 3 through the filter 2 to be stored; through the steps, the nitrogen consumption can be reduced, and the filtering and collecting efficiency of the solution is accelerated by pressing down the piston 107; in addition, various materials in the scheme, such as the inlet pipe 108 and the like, are made of corrosion-resistant materials; the filter 2 uses a 0.22 micron filter and can filter the solution into the sterile collection tank 3 by means of redundant filtration.
Referring to fig. 1 and 2, as an embodiment for preventing the piston 107 from rotating and damaging the inner shell 102, the following are provided: the stirring shaft 104 comprises an outer shaft 1041 and an inner shaft 1042, the upper end of the outer shaft 1041 is fixedly connected with the inner shell 102, and the lower end of the outer shaft 1041 extends into the reduced diameter section 106; the upper end of the inner shaft 1042 is connected with an output shaft of the rotating motor 4 outside the inner shell 102, and the lower end of the inner shaft 1042 penetrates out of the lower end of the outer shaft 1041; piston 107 and outer shaft 1041 are slidably connected;
it can be understood that the stirring shaft 104 includes an outer shaft 1041 and an inner shaft 1042, the outer shaft 1041 is fixed, the inner shaft 1042 rotates around its own axis under the driving of the rotating motor 4, the lower end of the inner shaft 1042 penetrating through the outer shaft 1041 is provided with a stirring blade, so as to realize stirring; at this time, the piston 107 is slidably sleeved on the outer shaft 1041, and thus vertical sliding can be realized.
Referring to fig. 1, fig. 2 and fig. 5, as an embodiment for avoiding excessive friction force, the embodiments are configured as follows: the top of the piston 107 is provided with a connecting plate 109, the piston 107 is connected with the outer shaft 1041 in a sliding manner through the connecting plate 109, the connecting plate 109 is connected with the outer shaft 1041 in a sealing and sliding manner, and a gap is reserved between the middle part of the piston 107 and the outer shaft 1041;
it can be understood that the connecting plate 109 is arranged at the top of the piston 107, the connecting plate 109 is connected with the outer shaft 1041 in a sliding and sealing manner, and the piston 107 is not in contact with the outer shaft 1041, and a gap is left between the piston 107 and the outer shaft 1041, so that the situation that the sliding effect is influenced by an overlarge contact surface and the outer shaft 1041 is damaged is avoided; in addition, although various sliding seal connection methods are known in the art, the exposed gap does not affect the pressure output of the entire lower end of the piston 107 even if the completely sealed state is not reached.
Referring to fig. 2 and 4, as an embodiment of the driving piston 107, it is configured as follows: the piston type hydraulic cylinder is characterized by further comprising a fixing plate 110, the fixing plate 110 is fixedly connected with the outer shaft 1041 and is positioned above the piston 107, a linear driving motor 111 is arranged on the fixing plate 110, and the linear driving motor 111 is connected with the piston 107 through a screw rod 118; in the scheme, a fixing plate 110 is arranged above the piston 107, the fixing plate 110 is fixed on an outer shaft 1041, a linear driving motor 111 is arranged on the fixing plate 110, a screw rod 118 is arranged on an output shaft of the linear driving motor 111, and the lower end of the screw rod 118 is connected with a connecting plate 109, so that the piston 107 is driven to slide up and down; wherein the number of the linear driving motors 111 may be plural.
Referring to fig. 1 and 2, as an embodiment for avoiding the bending of the inlet pipe 108 and the damage to the arrangement position of the cooling coil 103, the following are provided: an inlet channel 1071 is arranged on the piston 107, the lower end of an inlet pipe 108 is connected with the upper end of the inlet channel 1071, and the inlet pipe 108 is communicated with the reducing section 106 through the inlet channel 1071; the inlet pipe 108 is fixed on the fixed plate 110, and a telescopic pipe 112 is arranged on the inlet pipe 108 between the fixed plate 110 and the piston 107;
it can be understood that the inlet pipe 108 is vertically arranged on the upper cover of the inner shell 102, the outer end of the inlet pipe 108 is provided with an end cover to realize closing and opening, the lower end of the inlet pipe 108 is detachably connected with the upper end of the inlet channel 1071 on the piston 107 to realize mutual communication, and the middle part of the inlet pipe 108 can be fixed on the fixing plate 110 to facilitate the stability of the inlet pipe 108; an inlet pipe 108 between the fixed plate 110 and the connecting plate 109 is provided with a telescopic pipe 112 which can adapt to the up-and-down sliding of the piston 107 by the length expansion and contraction; in addition, the telescopic tube 112 may be a corrosion-resistant telescopic hose.
Referring to fig. 1 and 2, as an embodiment for facilitating the recycling of nitrogen, the following are provided: the upper sealing cover at the top of the inner shell 102 is also provided with an air exhaust pipe 113, and the air exhaust pipe 113 is connected with the middle part of the inlet pipe 108 through an electromagnetic control valve 114;
it can be understood that the upper end of the exhaust pipe 113 penetrates through the upper sealing cover, the end part of the exhaust pipe is provided with an end cover, the upper end can be closed and opened, the lower end of the exhaust pipe is communicated with the middle part of the inlet pipe 108, the electromagnetic control valve 114 is used for realizing intelligent control, the electromagnetic control valve 114 is opened, and an exhaust device is connected to the upper end of the exhaust pipe 113, so that the recovery of nitrogen can be realized.
Referring to fig. 1, as an embodiment of real-time testing the temperature and PH of the mixed solution, the temperature and PH are set as follows: the temperature gauge 5 sequentially penetrates through the first through hole 1072 from a top cover of the inner shell 102 and extends into the reducing section 106, and the temperature gauge 5 is in sliding connection with the first through hole 1072; a sleeve 117 in sliding connection is arranged in the second through hole 1073, the upper end of the sleeve 117 is connected with the top of the inner shell, the lower end of the sleeve 117 extends into the reducing section 106, the PH tester 6 is arranged on a sealing cover on the top of the inner shell 102, and a probe of the PH tester 6 is arranged at the lower end of the sleeve 117;
it can be understood that the piston 107 is provided with a first through hole 1072 and a second through hole 1073 which are vertically through, the head of the thermometer 5 is positioned outside the upper cover for easy observation, and the lower end thereof slides through the first through hole 1072 and extends into the reducing section 106 to detect the temperature of the solution; a sleeve 117 is arranged in the second through hole 1073 in a sliding manner, the PH tester 6 is fixedly arranged at the outer side of the upper end enclosure, a probe of the PH tester is fixedly arranged at the lower end of the sleeve 117, and a lead between the sleeve 117 and the PH tester is positioned in the sleeve 117 so as to facilitate the real-time detection of the PH value of the solution; in addition, the thermometer 5 and the sleeve 117 can be fixedly coupled to the fixing plate 110 for stability.
Referring to fig. 1, as an embodiment of improving the cooling effect, the following are set: the cooling coil 103 is arranged outside the reducing section 106, and an insulating layer 115 is filled between the outer shell 101 and the inner shell 102; in this scheme, cooling coil 103 is all concentrated and is set up in reducing section 106, is convenient for make the inside solution of reducing section 106 cool off fast, and all the other positions are filled heat preservation 115 for isolated ambient temperature.
Referring to fig. 3, as an embodiment for avoiding the nitrogen backflow, the following are provided: an electromagnetic one-way valve 116 is arranged between the outlet at the bottom of the jacket mixing tank 1 and the filter 2, and a placing cavity of the electromagnetic one-way valve 116 is arranged between the outer shell 101 and the inner shell 102; in the scheme, an electromagnetic one-way valve 116 is arranged at the outlet at the bottom of the jacket mixing tank 1, part of nitrogen can be pressed into the sterile collection tank 3 and used for storing the solution in the sterile collection tank 3, and the electromagnetic one-way valve 116 can avoid nitrogen backflow during air extraction; the electromagnetic check valve 116 is arranged in the placing cavity, so that the electromagnetic check valve 116 can be prevented from being influenced by the cooling coil 103.
Example 2
The embodiment 1 is further optimized on the basis of the embodiment 2, and provides a preparation method of isavuconazole sulfate for injection, which comprises the following steps:
s1: the lower end of the control piston 107 enters the upper end of the reducing section 106;
s2: sequentially adding water for injection and mannitol into the diameter-reduced section 106 through an inlet pipe 108, and controlling the stirring shaft 104 to stir to obtain a mannitol solution;
s3: after stirring is finished, controlling a cooling coil 103 to cool the mannitol solution to 0-5 ℃;
s4: adding the isavuconazole sulfate bulk drug into the mannitol solution through an inlet pipe 108, and controlling the stirring shaft 104 to stir again;
s5: after stirring and dissolving, adding a sulfuric acid solution into the reducing section 106 through an inlet pipe 108 to adjust the pH value to be between 1.3 and 1.6;
s6: after the pH value is adjusted, nitrogen is filled into the diameter-reducing section 106 through the inlet pipe 108, the electromagnetic one-way valve 116 at the bottom outlet of the jacket mixing tank 1 is opened, and then the piston 107 is gradually controlled to move downwards until the solution completely enters the sterile collection tank 3;
s7: the nitrogen in the reduced diameter section 106 is then extracted through an extraction tube 113 connected to the middle of the inlet tube 108, and the inlet tube 108 is then opened and the piston 107 is reset.
The specific working principle is as follows: in the initial stage, the lower end of the piston 107 is controlled to enter the upper end of the reducing section 106, so that the inner part of the reducing section 106 is called as a stirring space, and the entering liquid can be prevented from being splashed to the position outside the reducing section 106; then adding water for injection accounting for 70% of the total batch volume at an inlet pipe 108, then adding mannitol with a specified amount into the water for injection, starting a rotating motor 4 to rotate an inner shaft 1042, fully stirring the solution to dissolve, controlling a cooling coil 103 to cool the mannitol solution to 0-5 ℃ after stirring and dissolving, and observing the temperature in real time through a thermometer 5; after the temperature is adjusted, the isavuconazole sulfate bulk drug is added into the mannitol solution, then the inner shaft 1042 is controlled to rotate again to be stirred and dissolved, after the stirring and dissolving is completed, 0.5N sulfuric acid solution is added through the inlet pipe 108 to adjust the PH value to be within the range of 1.3-1.6, the pH tester 6 is used for real-time observation, after the adjustment is completed, the solution enters the filtering process through the solution preparation process, in the filtering process, the electromagnetic one-way valve 116 is opened, nitrogen is injected into the diameter reduction section 106 through the inlet pipe 108, after the nitrogen is injected for a certain time, the linear driving motor 111 is started, the piston 107 is controlled to move downwards, pressure is generated on the solution through a large amount of nitrogen in the solution, the solution quickly enters the sterile collection tank 3 through the filter 2, after the solution completely enters the sterile collection tank 3, the air extraction device is connected to the air extraction pipe 113, the electromagnetic control valve 114 is opened, the nitrogen in the interior is extracted, then the inlet pipe 108 is opened to balance the internal pressure, and the linear driving motor 111 drives the piston 107 to reset, thereby completing the filtering process.
The above-mentioned embodiments are intended to illustrate the objects, technical solutions and advantages of the present invention in further detail, and it should be understood that the above-mentioned embodiments are merely exemplary embodiments of the present invention, and are not intended to limit the scope of the present invention, and any modifications, equivalent substitutions, improvements and the like made within the spirit and principle of the present invention should be included in the scope of the present invention.

Claims (10)

1. The preparation device of the isavuconazole sulfate for injection is characterized by comprising a jacket mixing tank (1);
the bottom outlet of the jacket mixing tank (1) is connected with a sterile collection tank (3) through a filter (2);
the jacket mixing tank (1) comprises an outer shell (101) and an inner shell (102), and a cooling coil (103) is arranged between the outer shell (101) and the inner shell (102);
a stirring cavity (105) is arranged in the inner shell (102), and a reducing section (106) is arranged at the lower part of the stirring cavity (105);
a stirring shaft (104) is vertically arranged in the stirring cavity (105), a piston (107) is connected to the stirring shaft (104) in a sliding manner, and the piston (107) can slide along the length direction of the stirring shaft (104); the stirring shaft (104) penetrates through the piston (107) and extends into the reducing section (106), and the radial size of the piston (107) is matched with that of the reducing section (106);
an inlet pipe (108) is arranged on the top of the inner shell (102) in a sealing mode, and the inlet pipe (108) is communicated with the reducing section (106).
2. The liquid preparation device of isavuconazole sulfate for injection according to claim 1, wherein the stirring shaft (104) comprises an outer shaft (1041) and an inner shaft (1042), the upper end of the outer shaft (1041) is fixedly connected with the inner shell (102), and the lower end of the outer shaft (1041) extends into the reducing section (106); the upper end of the inner shaft (1042) is connected with an output shaft of a rotating motor (4) outside the inner shell (102), and the lower end of the inner shaft (1042) penetrates out of the lower end of the outer shaft (1041); the piston (107) and the outer shaft (1041) are slidably connected.
3. The device for preparing isaconazole sulfate injection according to claim 2, characterized in that the top of the piston (107) is provided with an attachment plate (109), the piston (107) is slidably connected with an outer shaft (1041) through the attachment plate (109), the attachment plate (109) is slidably connected with the outer shaft (1041) in a sealing manner, and a gap is left between the middle part of the piston (107) and the outer shaft (1041).
4. The liquid preparation device of isavuconazole sulfate for injection according to claim 2, further comprising a fixing plate (110), wherein the fixing plate (110) is fixedly connected with the outer shaft (1041) and is located above the piston (107), the fixing plate (110) is provided with a linear driving motor (111), and the linear driving motor (111) is connected with the piston (107) through a screw rod (118).
5. The liquid preparation device of isavuconazole sulfate for injection according to claim 4, wherein the piston (107) is provided with an inlet channel (1071), the lower end of the inlet pipe (108) is connected with the upper end of the inlet channel (1071), and the inlet pipe (108) is communicated with the reducing section (106) through the inlet channel (1071); the inlet pipe (108) is fixed on the fixing plate (110), and a telescopic pipe (112) is arranged on the inlet pipe (108) between the fixing plate (110) and the piston (107).
6. The liquid preparation device of isavuconazole sulfate for injection according to claim 2, characterized in that the upper cover on the top of the inner shell (102) is further provided with an air suction pipe (113), and the air suction pipe (113) is connected with the middle part of the inlet pipe (108) through an electromagnetic control valve (114).
7. The liquid preparation device of isavuconazole sulfate for injection according to claim 1, further comprising a thermometer (5) and a PH tester (6), wherein the piston (107) is further provided with a first through hole (1072) and a second through hole (1073), the thermometer (5) sequentially passes through the first through hole (1072) from a cover on the top of the inner shell (102) and extends into the reducing section (106), and the thermometer (5) is slidably connected with the first through hole (1072); be equipped with sliding connection's sleeve pipe (117) in second through-hole (1073), sleeve pipe (117) upper end with inboard casing (102) top is connected, sleeve pipe (117) lower extreme stretches into in reducing section (106), PH tester (6) are located on the closing cap on inlayer casing (102) top, the probe of PH tester (6) is located sleeve pipe (117) lower extreme.
8. The liquid preparation device of isavuconazole sulfate for injection according to claim 1, wherein the cooling coil (103) is arranged outside the reducing section (106), and an insulating layer (115) is filled between the outer shell (101) and the inner shell (102).
9. The liquid preparation device of isavuconazole sulfate for injection according to claim 1, wherein an electromagnetic check valve (116) is arranged between the bottom outlet of the jacketed mixing tank (1) and the filter (2), and a placing cavity of the electromagnetic check valve (116) is arranged between the outer shell (101) and the inner shell (102).
10. The method for preparing the isavuconazole sulfate solution for injection according to any one of claims 1 to 9, which comprises the following steps:
s1: controlling the lower end of the piston (107) to enter the upper end of the reducing section (106);
s2: sequentially adding water for injection and mannitol into the diameter-reduced section (106) through an inlet pipe (108), and controlling the stirring shaft (104) to stir to obtain a mannitol solution;
s3: after stirring is finished, controlling the cooling coil (103) to cool the mannitol solution to 0-5 ℃;
s4: adding the isavuconazole sulfate bulk drug into a mannitol solution through the inlet pipe (108), and controlling the stirring shaft (104) to stir again;
s5: after stirring and dissolving, adding a sulfuric acid solution into the reducing section (106) through the inlet pipe (108) to adjust the pH value to be between 1.3 and 1.6;
s6: after the PH value is adjusted, nitrogen is filled into the diameter-reducing section (106) through an inlet pipe (108), an electromagnetic one-way valve (116) at the bottom outlet of the jacket mixing tank (1) is opened, and then the piston (107) is gradually controlled to move downwards until the solution completely enters the sterile collection tank (3);
s7: the nitrogen in the reduced diameter section (106) is then extracted through an extraction tube (113) connected to the middle of the inlet tube (108), the inlet tube (108) is then opened and the piston (107) is reset.
CN202211136193.4A 2022-09-19 Liquid preparation device and method of isaconazole sulfate for injection Active CN115501781B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202211136193.4A CN115501781B (en) 2022-09-19 Liquid preparation device and method of isaconazole sulfate for injection

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202211136193.4A CN115501781B (en) 2022-09-19 Liquid preparation device and method of isaconazole sulfate for injection

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Publication Number Publication Date
CN115501781A true CN115501781A (en) 2022-12-23
CN115501781B CN115501781B (en) 2024-04-30

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4587793A (en) * 1985-01-16 1986-05-13 Home Health Care Of America, Inc. Pharmaceutical infusion products and the process and apparatus for the making thereof
CN107982221A (en) * 2016-10-27 2018-05-04 江苏正大丰海制药有限公司 Injection sulfuric acid Chinese mugwort Saperconazole freeze drying powder injection and preparation method
CN212017640U (en) * 2020-02-26 2020-11-27 辽宁恒泰实业有限责任公司 High-efficient mixing arrangement of production pipeline cleaner
CN112426917A (en) * 2020-11-05 2021-03-02 徐国购 Adjustable speed agitator tank with cooling and temperature sensing function
CN213160236U (en) * 2020-07-21 2021-05-11 永州金蕊生物科技股份有限公司 Membrane concentration device for honeysuckle extraction

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4587793A (en) * 1985-01-16 1986-05-13 Home Health Care Of America, Inc. Pharmaceutical infusion products and the process and apparatus for the making thereof
CN107982221A (en) * 2016-10-27 2018-05-04 江苏正大丰海制药有限公司 Injection sulfuric acid Chinese mugwort Saperconazole freeze drying powder injection and preparation method
CN212017640U (en) * 2020-02-26 2020-11-27 辽宁恒泰实业有限责任公司 High-efficient mixing arrangement of production pipeline cleaner
CN213160236U (en) * 2020-07-21 2021-05-11 永州金蕊生物科技股份有限公司 Membrane concentration device for honeysuckle extraction
CN112426917A (en) * 2020-11-05 2021-03-02 徐国购 Adjustable speed agitator tank with cooling and temperature sensing function

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