A preparation process of leuprorelin acetate microspheres for injection

Abstract

The invention discloses a preparation process of leuprorelin acetate microspheres for injection, and relates to the pharmaceutical field. The preparation process comprises preparing an external water phase W1, preparing an oil phase O, preparing an internal water phase W2, preparing colostrum, preparing a multiple emulsion, solidifying, collecting microspheres, and freeze drying. The equipment used in the preparation process comprises a preparation tank, wherein a stirring and volatilizing mechanism is arranged in the preparation tank, the preparation tank is connected to a circulation cylinder through a connecting conduit, a condensation and liquefaction mechanism and a recycling mechanism are arranged in the circulation cylinder, a vacuum machine is arranged between the condensation and liquefaction mechanism and the preparation tank through the circulation cylinder, and a switching component is arranged between the connecting conduit and the condensation and liquefaction mechanism and the recycling mechanism. The preparation tank, the stirring and volatilizing mechanism and the condensation and liquefaction mechanism are used to realize repeated collection of dichloromethane, and the recycling mechanism is combined to circulate and reuse the dichloromethane, thereby avoiding waste of dichloromethane and simultaneously avoiding dichloromethane escaping into the environment to cause poisoning of personnel.

Description

Technical Field

[0001] The invention relates to the pharmaceutical field, in particular to a preparation process of leuprorelin acetate microspheres for injection. Background Art

[0002] Leuprorelin acetate microspheres for injection are a common drug. They are often used in the treatment of endometriosis, uterine fibroids, central precocious puberty, and prostate cancer. In the preparation process of leuprorelin acetate microspheres for injection, dichloromethane is used as a solvent to prepare the oil phase. During the solidification process, the dichloromethane needs to be separated again to initially obtain porous microspheres. The role of dichloromethane is similar to that of a catalyst. Since dichloromethane is harmful to the human body, inhalation of high concentrations of dichloromethane can cause symptoms such as dizziness, headache, nausea, and vomiting. In severe cases, it may affect the central nervous system, cause anesthesia, and even endanger life. Long-term exposure to low concentrations of dichloromethane may cause damage to organs such as the liver and kidneys.

[0003] In the existing preparation process of leuprorelin acetate microspheres for injection, during the solidification step, the separation of dichloromethane easily causes dichloromethane to escape into the air and be inhaled by the human body, which poses a certain risk. Summary of the invention

[0004] The object of the present invention is to provide a preparation process of leuprorelin acetate microspheres for injection to solve the problems raised in the above background technology.

[0005] To achieve the above object, the present invention provides the following technical solutions: A preparation process of leuprorelin acetate microspheres for injection, comprising the following steps: S1. Calculate by weight: 5-30 parts of leuprorelin acetate, 45-270 parts of lactide-glycolide copolymer, 10-50 parts of mannitol, and 4-8 parts of polyvinyl alcohol; S2. Prepare the external aqueous phase W1: Place leuprolide acetate in a preparation tank, add water for injection to dissolve, and shake until completely dissolved; S3, preparing oil phase O: adding lactide-co-glycolide copolymer into dichloromethane to dissolve, and stirring until mixed evenly; S4, preparing the internal aqueous phase W2: dissolving polyvinyl alcohol in water for injection, stirring until completely dissolved, to prepare a polyvinyl alcohol aqueous solution; S5, preparing colostrum: mixing the oil phase O and the external water phase W1, and high-speed shear emulsification to obtain W1 / O colostrum; S6, preparing a double emulsion: injecting the obtained W1 / O colostrum into the internal water phase W2, and obtaining a W1 / O / W2 type double emulsion by high-speed shear emulsification; S7, solidification: volatilize the dichloromethane in the emulsion by stirring and vacuuming to form porous microspheres; S8, collecting microspheres: removing large particles by sieving, and collecting precipitated microspheres by centrifugation; S9. Preparation of lyophilized protective agent: dissolve mannitol in water for injection and stir until mixed evenly; S10, freeze drying: adding the prepared mannitol solution to the collected microspheres, mixing evenly and freeze drying to obtain leuprolide acetate microspheres for injection; The equipment used in the above-mentioned preparation process includes a preparation tank, in which a stirring and volatilization mechanism is arranged, and the preparation tank is connected to a circulation cylinder via a connecting conduit, and a condensation and liquefaction mechanism and a recycling mechanism are arranged in the circulation cylinder, and a vacuum machine is arranged between the condensation and liquefaction mechanism and the preparation tank via the circulation cylinder, and a switching component is arranged between the connecting conduit and the condensation and liquefaction mechanism and the recycling mechanism.

[0006] As a further solution of the present invention: the stirring and volatilization mechanism includes a stirring motor arranged on the top of the preparation tank, the stirring motor is connected to a stirring shaft, the outer side of the stirring shaft is evenly provided with matching grooves, a matching sleeve is slidably installed on the stirring shaft, a stirring blade is connected to the bottom of the matching sleeve, an annular clamping groove is arranged on the outer side of the matching sleeve, a clamping ring is rotatably installed on the outer side of the annular clamping groove, an annular frame is arranged on the outer side of the clamping ring, air blowing pipes are evenly arranged on the annular frame, the air blowing pipes are interconnected, a connecting disc is arranged at the center of the annular frame, a heating air pump is arranged on the connecting disc, the connecting disc is rotatably installed between the stirring shaft, the heating air pump is connected to an air guide pipe, and the air guide pipe is connected to the air blowing pipe.

[0007] As a further solution of the present invention: a suspension cable is connected to the connecting disc, a winding drum is rotatably mounted on the lower side of the top of the preparation tank, the suspension cable is connected to the winding drum, and the winding drum is connected to a winding motor.

[0008] As a further solution of the present invention: heating scrapers are evenly arranged on the bottom of the stirring shaft, and the heating scrapers are in contact with the bottom inner wall of the preparation tank.

[0009] As a further scheme of the present invention: the condensation and liquefaction mechanism includes a liquefaction tank arranged in the circulation cylinder, a top cover is arranged on the top of the liquefaction tank, an air inlet pipe is arranged between the liquefaction tank and the top cover, the air inlet pipe is connected to the connecting duct through a switching component, one end of the air inlet pipe located in the liquefaction tank is connected to a branch pipe, diversion pipes are evenly arranged on the branch pipes, vertical liquefaction pipes are evenly arranged on the diversion pipes, the liquefaction pipes and the diversion pipes are connected, the upper and lower ends of the liquefaction pipes are open, a U-shaped condenser is inserted in the liquefaction pipe, a condenser is arranged on the top cover, a cold water pipe and a return water pipe are connected to the condenser, a section of the U-shaped condenser located in the liquefaction pipe is connected to the cold water pipe, a section of the U-shaped condenser located outside the liquefaction pipe is connected to the return water pipe, and the upper end of the liquefaction pipe is sealed and installed with the U-shaped condenser.

[0010] As a further solution of the present invention: the vacuum machine is connected to an exhaust pipe, the exhaust pipe is connected to a connecting pipe 1 in the circulation cylinder, and the end of the connecting pipe 1 extends into the liquefaction tank.

[0011] As a further solution of the present invention: the recycling mechanism includes a circulation tank adjacent to the liquefaction tank, a suction pump is arranged at the bottom of the liquefaction tank, the suction pump is connected to an extraction pipe, the end of the extraction pipe is arranged in the circulation tank, a receiving tank is arranged in the circulation tank below the end of the extraction pipe, the top of the circulation tank is connected to a delivery pipe, a suction pump is installed at the bottom of the delivery pipe, and the delivery pipe is connected to a switching component.

[0012] As a further solution of the present invention: a rack is provided on the edge of the circulation groove, and clamping grooves are provided on both sides of the rack, a U-shaped frame is slidably clamped in the clamping groove, a matching gear is rotatably installed in the U-shaped frame, the matching gear and the rack are meshed with each other, the matching gear is connected to drive motor 1, a vertical frame is provided on the top of the U-shaped frame, a drive motor 2 is provided on the vertical frame, the drive motor 2 is connected to a rotating shaft, a swing frame is provided on the rotating shaft, and a heating roller is horizontally installed on the end of the swing frame.

[0013] As a further solution of the present invention: the switching assembly includes a telescopic tube 1 connected to the end of the connecting duct, a mounting column is provided on the inner wall of the circulation cylinder, a rotating motor is horizontally installed on the mounting column, the rotating motor is connected to a mounting ring, a connecting tube 2 is fixedly installed in the mounting ring, one end of the connecting tube 2 is connected to the telescopic tube 1, the other end of the connecting tube 2 is provided with a telescopic tube 2, the telescopic tube 2 is connected to a docking joint, a mounting plate is provided on the mounting ring, a telescopic motor is provided on the mounting plate, the telescopic motor is connected to a clamping frame, the clamping frame is clamped with the docking joint, and the docking joint is respectively docked with the ends of the intake pipe and the delivery pipe.

[0014] Compared with the prior art, the present invention has the following beneficial effects: (1) The oil phase O is prepared in the preparation tank. When in use, dichloromethane liquid is introduced into the preparation tank through the connecting conduit and stirred to mix evenly. During the fixation process, the dichloromethane in the emulsion is separated from the gaseous state by the stirring volatilization mechanism, and the dichloromethane is transformed into a liquid state by combining with the condensation and liquefaction mechanism and stored in the condensation and liquefaction mechanism. When dichloromethane is reused for the preparation of the oil phase O, the liquid dichloromethane in the condensation and liquefaction mechanism is extracted by the recycling mechanism and sent to the preparation tank by combining with the switching component.

[0015] (2) During the curing stage, the stirring shaft is rotated by the stirring motor, and the winding motor is used to drive the suspension cable to be retracted and extended, thereby controlling the connection disk and the annular frame, the air blowing pipe, and the stirring blades to rise and fall, thereby stirring and introducing hot air in combination with the height of the liquid level in the preparation tank to accelerate the volatilization of dichloromethane.

[0016] (3) After the dichloromethane is transformed into gas in the preparation tank by the stirring volatilization mechanism, it is sent to the condensation and liquefaction mechanism through the connecting pipe and the switching component. The condenser sends low-temperature water along the cold water pipe into the U-shaped condenser tube, and then discharges it from the other end of the U-shaped condenser tube, and is sent back to the condenser through the return pipe for reuse. The gaseous dichloromethane goes along the air inlet pipe to the branch pipe and the shunt pipe, and then disperses into the vertically arranged liquefaction pipe. When the condensed water enters the U-shaped condenser tube, it encounters the gaseous dichloromethane in the liquefaction pipe, and the dichloromethane liquefies and adheres to the outer wall of the U-shaped condenser tube, and finally drips into the liquefaction tank along the outer wall of the U-shaped condenser tube. The vacuum machine is connected with the liquefaction tank in combination with the liquefaction pipe, the air inlet pipe, the switching assembly and the connecting conduit, so that a vacuum environment is also formed in the preparation tank, thereby accelerating the volatilization rate of the dichloromethane in the preparation tank, and at the same time sending the volatilized gaseous dichloromethane into the condensation and liquefaction mechanism for re-condensation, liquefaction and collection, so as to facilitate subsequent reuse. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 It is a schematic diagram of the preparation process of the present invention.

[0018] Figure 2 It is a schematic diagram of the overall structure of the present invention.

[0019] Figure 3 It is a schematic diagram of the internal structure of the preparation tank and the circulation cylinder in the present invention.

[0020] Figure 4 It is a schematic diagram of the installation of the stirring and volatilizing mechanism in the preparation tank of the present invention.

[0021] Figure 5 It is a schematic structural diagram of the stirring and volatilizing mechanism in the present invention.

[0022] Figure 6 It is a schematic diagram of the installation of the stirring blade in the present invention.

[0023] Figure 7 It is a schematic diagram of the installation of the circulation drum in the present invention.

[0024] Figure 8 It is a schematic diagram of the internal structure of the circulation drum in the present invention.

[0025] Fig. 9 It is a structural schematic diagram of the condensation and liquefaction mechanism in the present invention.

[0026] Fig.10 It is a schematic diagram of the connection between the liquefaction tube and the U-shaped condenser tube in the present invention.

[0027] Fig.11 It is a structural schematic diagram of the recycling mechanism in the present invention.

[0028] Fig.12 for Fig.11 Enlarged structural diagram at B in the middle.

[0029] Fig.13 It is a schematic diagram of the installation structure of the heating roller in the receiving tank of the present invention.

[0030] Fig.14 for Figure 7 Enlarged structural diagram at A in the middle.

[0031] In the figure: 1, preparation tank; 10, connecting conduit; 2, circulation cylinder; 3, vacuum machine; 30, exhaust pipe; 31, connecting pipe 1; 4, stirring and volatilizing mechanism; 40, stirring motor; 41, stirring shaft; 42, heating scraper; 43, matching groove; 44, stirring blade; 45, matching sleeve; 46, annular clamping groove; 48, clamping ring; 49, annular frame; 410, blowing pipe; 411, connecting disc; 412, air guide pipe; 413, heating air pump; 414, suspension cable; 415, winding drum; 416, winding motor; 5, condensation and liquefaction mechanism; 50, liquefaction tank; 52, top cover; 53, air inlet pipe; 54, branch pipe; 55, shunt pipe; 56, liquefaction pipe; 57 , U-shaped condenser; 58, condenser; 59, cold water pipe; 510, return pipe; 6, recycling mechanism; 60, circulation tank; 61, extraction pipe; 62, suction pump; 63, receiving tank; 64, delivery pipe; 65, rack; 650, snap-in groove; 66, U-shaped frame; 67, drive motor one; 68, matching gear; 69, vertical frame; 610, drive motor two; 611, rotating shaft; 612, swing frame; 613, heating roller; 7, switching assembly; 70, telescopic tube one; 71, mounting column; 72, rotating motor; 73, mounting ring; 74, connecting tube two; 75, mounting plate; 76, telescopic motor; 77, docking head; 78, snap-in frame; 79, telescopic tube two. DETAILED DESCRIPTION

[0032] In the description of the present invention, it is necessary to understand that the orientations or positional relationships indicated by terms such as “longitudinal”, “lateral”, “upper”, “lower”, “top”, “bottom”, “inside” and “outside” are based on the orientations or positional relationships shown in the accompanying drawings and are only for the convenience of describing the present invention and simplifying the description. They do not indicate or imply that the device or element referred to must have a specific orientation, be constructed and operated in a specific orientation, and therefore cannot be understood as a limitation on the present invention.

[0033] In addition, the terms "one" and "two" are used for descriptive purposes only and should not be understood as indicating or implying relative importance or implicitly indicating the number of the indicated technical features. Therefore, a feature defined as "one" or "two" may explicitly or implicitly include one or more of the feature. In the description of the present invention, the meaning of "multiple" is two or more, unless otherwise clearly and specifically defined.

[0034] In the present invention, unless otherwise clearly specified and limited, the terms "installed", "connected", "connected", "fixed" and the like should be understood in a broad sense, for example, it can be a fixed connection, a detachable connection, or an integral connection; it can be a mechanical connection or an electrical connection; it can be a direct connection or an indirect connection through an intermediate medium, it can be the internal connection of two elements or the interaction relationship between two elements. For ordinary technicians in this field, the specific meanings of the above terms in the present invention can be understood according to specific circumstances.

[0035] The technical solution of the present invention is further described in detail below in conjunction with specific implementation methods.

[0036] like Figure 1 As shown, a preparation process of leuprorelin acetate microspheres for injection comprises the following steps: S1. Calculate by weight: 10 parts of leuprorelin acetate, 105 parts of lactide-co-glycolide copolymer, 18 parts of mannitol, and 6 parts of polyvinyl alcohol; S2. Prepare the external aqueous phase W1: Place leuprolide acetate in a preparation tank, add water for injection to dissolve, and shake until completely dissolved; S3, preparing oil phase O: adding lactide-co-glycolide copolymer into dichloromethane to dissolve, and stirring until mixed evenly; S4, preparing the internal aqueous phase W2: dissolving polyvinyl alcohol in water for injection, stirring until completely dissolved, to prepare a polyvinyl alcohol aqueous solution; S5, preparing colostrum: mixing the oil phase O and the external water phase W1, and high-speed shear emulsification to obtain W1 / O colostrum; S6, preparing a double emulsion: injecting the obtained W1 / O colostrum into the internal water phase W2, and obtaining a W1 / O / W2 type double emulsion by high-speed shear emulsification; S7, solidification: volatilize the dichloromethane in the emulsion by stirring and vacuuming to form porous microspheres; S8, collecting microspheres: removing large particles by sieving, and collecting precipitated microspheres by centrifugation; S9. Preparation of lyophilized protective agent: dissolve mannitol in water for injection and stir until mixed evenly; S10, freeze drying: adding the prepared mannitol solution to the collected microspheres, mixing evenly and freeze drying to obtain leuprolide acetate microspheres for injection; like Figure 2 , Figure 3As shown, the equipment used in the above-mentioned preparation process includes a preparation tank 1, in which a stirring and volatilization mechanism 4 is arranged, and the preparation tank 1 is connected to a circulation cylinder 2 through a connecting conduit 10, and a condensation and liquefaction mechanism 5 and a recycling mechanism 6 are arranged in the circulation cylinder 2, and a vacuum machine 3 is arranged between the condensation and liquefaction mechanism 5 and the preparation tank 1 through the circulation cylinder 2, and a switching component 7 is arranged between the connecting conduit 10 and the condensation and liquefaction mechanism 5 and the recycling mechanism 6.

[0037] Specifically, the oil phase O is configured in the preparation tank 1. When in use, dichloromethane liquid is introduced into the preparation tank 1 through the connecting conduit 10, and stirred and mixed evenly. During the fixation process, the dichloromethane in the emulsion is separated from the gaseous state by the stirring volatilization mechanism 4, and the dichloromethane is transformed into a liquid state again in combination with the condensation and liquefaction mechanism 5, and stored in the condensation and liquefaction mechanism 5. When the dichloromethane is reused for the preparation of the oil phase O, the liquid dichloromethane in the condensation and liquefaction mechanism 5 is extracted by the recycling mechanism 6 and sent to the preparation tank 1 in combination with the switching component 7.

[0038] Further, such as Figure 4 , Figure 5 , Figure 6 As shown, the stirring and volatilizing mechanism 4 includes a stirring motor 40 arranged on the top of the preparation tank 1, the stirring motor 40 is connected to a stirring shaft 41, the outer side of the stirring shaft 41 is evenly provided with matching grooves 43, a matching sleeve 45 is slidably installed on the stirring shaft 41, and a stirring blade 44 is connected to the bottom of the matching sleeve 45, an annular clamping groove 46 is arranged on the outer side of the matching sleeve 45, a clamping ring 48 is rotatably installed on the outer side of the annular clamping groove 46, an annular frame 49 is arranged on the outer side of the clamping ring 48, and air blowing pipes 410 are evenly arranged on the annular frame 49, and the air blowing pipes 410 are mutually connected, and a connecting disc 411 is arranged at the center of the annular frame 49, and a heating air pump 413 is arranged on the connecting disc 411, and the connecting disc 411 is rotatably installed between the stirring shaft 41, and the heating air pump 413 is connected to an air guide pipe 412, and the air guide pipe 412 is connected to the air blowing pipe 410.

[0039] The connecting disc 411 is connected with a suspension cable 414 , a winding drum 415 is rotatably mounted on the lower side of the top of the preparation tank 1 , the suspension cable 414 is connected to the winding drum 415 , and the winding drum 415 is connected with a winding motor 416 .

[0040] The bottom of the stirring shaft 41 is evenly provided with heating scrapers 42 , and the heating scrapers 42 are in contact with the bottom inner wall of the preparation tank 1 .

[0041] Specifically, during the curing stage, the stirring shaft 41 is driven to rotate by the stirring motor 40, and the winding motor 416 is combined to drive the suspension cable 414 to be retracted and released, thereby controlling the connection disk 411 and the annular frame 49, the blowing pipe 410, and the stirring blade 44 to rise and fall, thereby combining the height of the liquid level in the preparation tank 1 to stir and introduce hot air to accelerate the volatilization of dichloromethane.

[0042] More specifically, when the stirring shaft 41 rotates, it synchronously drives the matching sleeve 45 to rotate, and then drives the stirring blade 44 to rotate. At the same time, the clamping ring 48 is rotatably installed between the annular clamping groove 46 on the outside of the matching sleeve 45. When the stirring shaft 41 rotates, it will not drive the clamping ring 48 and the annular frame 49 to rotate synchronously. At the same time, the top connecting plate is rotatably installed between the stirring shaft 41. When the suspension cable 414 is retracted or released, the blowing pipe 410 will be adjusted to rise and fall, and at the same time, the rotation of the bottom stirring blade 44 will not be interfered with.

[0043] Further, such as Figure 7 , Figure 8 , Fig. 9 , Fig.10 As shown, the condensation liquefaction mechanism 5 includes a liquefaction tank 50 arranged in the circulation cylinder 2, a top cover 52 is arranged on the top of the liquefaction tank 50, an air intake pipe 53 is arranged between the liquefaction tank 50 and the top cover 52, the air intake pipe 53 is connected to the connecting conduit 10 through the switching component 7, and one end of the air intake pipe 53 located in the liquefaction tank 50 is connected to a branch pipe 54, and the branch pipe 54 is evenly provided with a shunt pipe 55, and the shunt pipe 55 is evenly provided with a vertical liquefaction pipe 56, and the liquefaction pipe 56 is connected to the liquefaction tank 50. The shunt pipes 55 are connected, and the upper and lower ends of the liquefaction pipe 56 are open. A U-shaped condenser 57 is inserted in the liquefaction pipe 56. A condenser 58 is provided on the top cover 52. The condenser 58 is connected to a cold water pipe 59 and a return water pipe 510. A section of the U-shaped condenser 57 located inside the liquefaction pipe 56 is connected to the cold water pipe 59, and a section of the U-shaped condenser 57 located outside the liquefaction pipe 56 is connected to the return water pipe 510. The upper end of the liquefaction pipe 56 and the U-shaped condenser 57 are sealed.

[0044] Specifically, after the dichloromethane is formed into gas in the preparation tank 1 in combination with the stirring volatilization mechanism 4, it is sent to the condensation and liquefaction mechanism 5 through the connecting conduit 10 and the switching component 7. The condenser 58 sends low-temperature water along the cold water pipe 59 into the U-shaped condenser 57, and then discharges it from the other end of the U-shaped condenser 57, and is sent back to the condenser 58 by the return pipe 510 for reuse. The gaseous dichloromethane reaches the branch pipe 54 and the shunt pipe 55 along the air inlet pipe 53, and then disperses into the vertically arranged liquefaction pipe 56. When the condensed water enters the U-shaped condenser 57, it encounters the gaseous dichloromethane in the liquefaction pipe 56, and the dichloromethane is liquefied and attached to the outer wall of the U-shaped condenser 57, and finally drips into the liquefaction tank 50 along the outer wall of the U-shaped condenser 57.

[0045] Further, such as Figure 8 As shown, the vacuum machine 3 is connected to an exhaust pipe 30 , and the exhaust pipe 30 is connected to a connecting pipe 31 in the circulation cylinder 2 , and an end of the connecting pipe 31 extends into the liquefaction tank 50 .

[0046] Specifically, the vacuum machine 3 is connected with the liquefaction tank 50 in combination with the exhaust pipe 30, and cooperates with the liquefaction pipe 56, the air inlet pipe 53, the switching component 7, and the connecting conduit 10, so that a vacuum environment is also formed in the preparation tank 1, thereby accelerating the volatilization rate of the dichloromethane in the preparation tank 1, and at the same time sending the volatilized gaseous dichloromethane into the condensation and liquefaction mechanism 5 for re-condensation, liquefaction and collection, so as to facilitate subsequent reuse.

[0047] Further, such as Figure 8 , Fig.11 As shown, the recycling mechanism 6 includes a circulation tank 60 arranged adjacent to the liquefaction tank 50, a suction pump 62 is arranged at the bottom of the liquefaction tank 50, the suction pump 62 is connected to the extraction pipe 61, the end of the extraction pipe 61 is arranged in the circulation tank 60, and a receiving tank 63 is arranged in the circulation tank 60 below the end of the extraction pipe 61, the top of the circulation tank 60 is connected to the delivery pipe 64, the bottom of the delivery pipe 64 is lifted and installed with a suction pump, and the delivery pipe 64 is connected to the switching component 7.

[0048] Specifically, when dichloromethane is used to prepare the oil phase O, the liquid dichloromethane in the liquefaction tank 50 is extracted through the suction pump 62 and the extraction pipe 61, sent to the receiving tank 63, and then sent to the preparation tank 1 in combination with the suction pump, the delivery pipe 64, and the switching component 7.

[0049] Further, such as Fig.12 , Fig.13As shown, a rack 65 is provided at the edge of the circulation groove 60, and clamping grooves 650 are provided on both sides of the rack 65. A U-shaped frame 66 is slidably clamped in the clamping groove 650, and a matching gear 68 is rotatably installed in the U-shaped frame 66. The matching gear 68 and the rack 65 are meshed with each other, and the matching gear 68 is connected to a drive motor 1 67. A vertical frame 69 is provided on the top of the U-shaped frame 66, and a drive motor 2 610 is provided on the vertical frame 69. The drive motor 2 610 is connected to a rotating shaft 611, and a swing frame 612 is provided on the rotating shaft 611. A heating roller 613 is horizontally installed at the end of the swing frame 612.

[0050] Specifically, when there is residual dichloromethane in the receiving tank 63, the heating roller 613 is driven by the driving motor 67 to move along the inside of the receiving tank 63 to accelerate the volatilization of dichloromethane, and is sent into the preparation tank 1 through the conveying pipe 64, so that the preparation tank 1 is filled with dichloromethane, thereby reducing the volatilization rate of the liquid dichloromethane injected into the preparation tank 1 in the early stage.

[0051] Further, such as Fig.14 As shown, the switching assembly 7 includes a telescopic tube 170 connected to the end of the connecting duct 10, a mounting column 71 is provided on the inner wall of the circulation cylinder 2, a rotating motor 72 is horizontally mounted on the mounting column 71, the rotating motor 72 is connected to a mounting ring 73, a connecting tube 2 74 is fixedly installed in the mounting ring 73, one end of the connecting tube 2 74 is connected to the telescopic tube 170, the other end of the connecting tube 2 74 is provided with a telescopic tube 2 79, the telescopic tube 2 79 is connected to a docking joint 77, a mounting plate 75 is provided on the mounting ring 73, a telescopic motor 76 is provided on the mounting plate 75, the telescopic motor 76 is connected to a clamping frame 78, the clamping frame 78 is clamped with the docking joint 77, and the docking joint 77 is respectively docked with the ends of the intake pipe 53 and the delivery pipe 64.

[0052] Specifically, during the solidification stage, when it is necessary to send the volatilized gaseous dichloromethane in the preparation tank 1 into the condensation and liquefaction mechanism 5 for condensation and liquefaction, the telescopic motor 76 in the switching assembly 7 drives the docking joint 77 to dock with the end of the air inlet pipe 53, and then the vacuum machine 3 and the condensation and liquefaction mechanism 5 are started to send the gaseous dichloromethane in the preparation tank 1 into the liquefaction tank 50 for liquefaction and collection; when preparing the oil phase O, the rotating motor 72 drives the mounting ring 73 to rotate, and the telescopic motor 76 drives the docking joint 77 to dock with the end of the conveying pipe 64, thereby sending the liquid dichloromethane into the preparation tank 1.

[0053] The working principle of the embodiment of the present invention is: like Figure 1-Figure 14As shown, the oil phase O is configured in the preparation tank 1. When in use, dichloromethane liquid is introduced into the preparation tank 1 through the connecting conduit 10, and stirred and mixed evenly. During the fixing process, the dichloromethane in the emulsion is separated from the gaseous state by the stirring and volatilizing mechanism 4, and the dichloromethane is transformed into a liquid state again by combining with the condensation and liquefaction mechanism 5, and stored in the condensation and liquefaction mechanism 5. When dichloromethane is reused for the preparation of the oil phase O, the liquid dichloromethane in the condensation and liquefaction mechanism 5 is extracted by the recycling mechanism 6 and sent to the preparation tank 1 in combination with the switching component 7. In the curing stage, the stirring shaft 41 is driven to rotate by the stirring motor 40, and the suspension cable 414 is driven to be retracted and released in combination with the winding motor 416, so as to control the connection disc 411 and the annular frame 49, the blowing pipe 410, and the stirring blade 44 to rise and fall, so as to stir and introduce hot air in combination with the height of the liquid level in the preparation tank 1 to accelerate the volatilization of dichloromethane. When the stirring shaft 41 rotates, it synchronously drives the matching sleeve 45 to rotate, and then drives the stirring blade 44 to rotate. At the same time, the clamping ring 48 is rotatably installed with the annular clamping groove 46 on the outside of the matching sleeve 45. When the stirring shaft 41 rotates, it will not drive the clamping ring 48 and the annular frame 49 to rotate synchronously. At the same time, the top connecting plate is rotatably installed with the stirring shaft 41. When the suspension cable 414 is retracted and released, the blowing pipe 410 will be adjusted to rise and fall, and the rotation of the bottom stirring blade 44 will not be interfered. After the dichloromethane is combined with the stirring and volatilizing mechanism 4 to form a gas in the preparation tank 1, it is sent to the condensation and liquefaction mechanism 5 through the connecting conduit 10 and the switching component 7. The condenser 58 sends the low-temperature water along the cold water pipe 59 into the U-shaped condenser 57, and then it is discharged from the other end of the U-shaped condenser 57, and is sent back to the condenser 58 by the return pipe 510 for reuse. The gaseous dichloromethane reaches the branch pipe 54 and the shunt pipe 55 along the air inlet pipe 53, and then disperses into the vertically arranged liquefaction pipe 56. When the condensed water enters the U-shaped condenser 57, it encounters the gaseous dichloromethane in the liquefaction pipe 56, and the dichloromethane is liquefied and attached to the outer wall of the U-shaped condenser 57, and finally drips into the liquefaction tank 50 along the outer wall of the U-shaped condenser 57. The vacuum machine 3 is connected with the liquefaction tank 50 in combination with the exhaust pipe 30, the liquefaction pipe 56, the air inlet pipe 53, the switching component 7, and the connecting conduit 10, so that a vacuum environment is also formed in the preparation tank 1, thereby accelerating the volatilization speed of the dichloromethane in the preparation tank 1, and at the same time sending the volatilized gaseous dichloromethane into the condensation and liquefaction mechanism 5 for re-condensation, liquefaction and collection, which is convenient for subsequent reuse. When dichloromethane is used to prepare the oil phase O, the liquid dichloromethane in the liquefaction tank 50 is extracted through the suction pump 62 and the extraction pipe 61, sent to the receiving tank 63, and then sent to the preparation tank 1 in combination with the suction pump, the delivery pipe 64, and the switching component 7.When there is residual dichloromethane in the receiving tank 63, the heating roller 613 is driven by the driving motor 67 to move along the inside of the receiving tank 63 to accelerate the volatilization of dichloromethane, and is sent into the preparation tank 1 through the delivery pipe 64, so that the preparation tank 1 is filled with dichloromethane, thereby reducing the volatilization rate of the liquid dichloromethane injected into the preparation tank 1 in the early stage. In the solidification stage, when it is necessary to send the volatilized gaseous dichloromethane in the preparation tank 1 into the condensation and liquefaction mechanism 5 for condensation and liquefaction, the telescopic motor 76 in the switching component 7 drives the docking joint 77 to dock with the end of the air inlet pipe 53, and then the vacuum machine 3 and the condensation and liquefaction mechanism 5 are started to send the gaseous dichloromethane in the preparation tank 1 into the liquefaction tank 50 for liquefaction and collection; when preparing the oil phase O, the rotating motor 72 drives the mounting ring 73 to rotate, and the telescopic motor 76 drives the docking joint 77 to dock with the end of the delivery pipe 64, so as to send the liquid dichloromethane into the preparation tank 1.

[0054] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modification, equivalent substitution, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention. Any reference numeral in a claim shall not be regarded as limiting the claim involved.

[0055] In addition, it should be understood that although the present specification is described according to implementation modes, not every implementation mode contains only one independent technical solution. This description of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment may also be appropriately combined to form other implementation modes that can be understood by those skilled in the art.

Claims

1. A process for preparing leuprorelin acetate microspheres for injection, characterized in that: The following steps are involved: S1. Calculate by weight: 5-30 parts of leuprorelin acetate, 45-270 parts of lactide-glycolide copolymer, 10-50 parts of mannitol, and 4-8 parts of polyvinyl alcohol; S2. Prepare the external aqueous phase W1: Place leuprolide acetate in a preparation tank, add water for injection to dissolve, and shake until completely dissolved; S3, preparing oil phase O: adding dichloromethane to the lactide-glycolide copolymer to dissolve, and stirring until the mixture is uniform; S4, preparing the internal aqueous phase W2: dissolving polyvinyl alcohol in water for injection, stirring until completely dissolved, to prepare a polyvinyl alcohol aqueous solution; S5, preparing colostrum: mixing the oil phase O and the external water phase W1, and high-speed shear emulsification to obtain W1 / O colostrum; S6, preparing a double emulsion: injecting the obtained W1 / O colostrum into the internal water phase W2, and obtaining a W1 / O / W2 type double emulsion by high-speed shear emulsification; S7, solidification: volatilize the dichloromethane in the emulsion by stirring and vacuuming to form porous microspheres; S8, collecting microspheres: removing large particles by sieving, and collecting precipitated microspheres by centrifugation; S9. Preparation of lyophilized protective agent: dissolve mannitol in water for injection and stir until mixed evenly; S10, freeze drying: adding the prepared mannitol solution to the collected microspheres, mixing evenly and freeze drying to obtain leuprolide acetate microspheres for injection; The equipment used in the above-mentioned preparation process comprises a preparation tank (1), wherein a stirring and volatilizing mechanism (4) is arranged in the preparation tank (1), wherein the preparation tank (1) is connected to a circulation cylinder (2) via a connecting conduit (10), wherein a condensation and liquefaction mechanism (5) and a recycling mechanism (6) are arranged in the circulation cylinder (2), wherein a vacuum machine (3) is arranged between the condensation and liquefaction mechanism (5) and the preparation tank (1) via the circulation cylinder (2), and a switching component (7) is arranged between the connecting conduit (10) and the condensation and liquefaction mechanism (5) and the recycling mechanism (6).

2. The preparation process of leuprorelin acetate microspheres for injection according to claim 1, characterized in that: The stirring and volatilizing mechanism (4) comprises a stirring motor (40) arranged on the top of the preparation tank (1); the stirring motor (40) is connected to a stirring shaft (41); the outer side of the stirring shaft (41) is evenly provided with matching grooves (43); a matching sleeve (45) is slidably mounted on the stirring shaft (41); the bottom of the matching sleeve (45) is connected to a stirring blade (44); the outer side of the matching sleeve (45) is provided with an annular clamping groove (46); the outer side of the annular clamping groove (46) is rotatably provided with a clamping ring (48); An annular frame (49) is arranged outside the clamping ring (48), and air blowing pipes (410) are evenly arranged on the annular frame (49). The air blowing pipes (410) are interconnected. A connecting disc (411) is arranged at the center of the annular frame (49), and a heating air pump (413) is arranged on the connecting disc (411). The connecting disc (411) is rotatably mounted between the stirring shaft (41), and the heating air pump (413) is connected to an air guide pipe (412), and the air guide pipe (412) is connected to the air blowing pipe (410).

3. The preparation process of leuprolide acetate microspheres for injection according to claim 2, characterized in that: The connecting disc (411) is connected to a suspension cable (414), a winding drum (415) is rotatably mounted on the lower side of the top of the preparation tank (1), the suspension cable (414) is connected to the winding drum (415), and the winding drum (415) is connected to a winding motor (416).

4. The preparation process of leuprorelin acetate microspheres for injection according to claim 2, characterized in that: The bottom of the stirring shaft (41) is evenly provided with heating scrapers (42), and the heating scrapers (42) are in contact with the bottom inner wall of the preparation tank (1).

5. The preparation process of leuprolide acetate microspheres for injection according to claim 1, characterized in that: The condensation and liquefaction mechanism (5) comprises a liquefaction tank (50) arranged in a circulation cylinder (2), a top cover (52) being arranged on the top of the liquefaction tank (50), an air intake pipe (53) being arranged between the liquefaction tank (50) and the top cover (52), the air intake pipe (53) being connected to a connecting pipe (10) via a switching assembly (7), a branch pipe (54) being connected to one end of the air intake pipe (53) located in the liquefaction tank (50), a flow divider (55) being evenly arranged on the branch pipe (54), a vertical liquefaction pipe (56) being evenly arranged on the flow divider (55), and the liquefaction pipe (56) being The liquefaction pipe (56) is connected to the shunt pipe (55), the upper and lower ends of the liquefaction pipe (56) are open, a U-shaped condenser pipe (57) is inserted into the liquefaction pipe (56), a condenser (58) is arranged on the top cover (52), and the condenser (58) is connected to a cold water pipe (59) and a return water pipe (510), a section of the U-shaped condenser pipe (57) located inside the liquefaction pipe (56) is connected to the cold water pipe (59), and a section of the U-shaped condenser pipe (57) located outside the liquefaction pipe (56) is connected to the return water pipe (510), and the upper end of the liquefaction pipe (56) and the U-shaped condenser pipe (57) are sealed.

6. The preparation process of leuprorelin acetate microspheres for injection according to claim 5, characterized in that: The vacuum machine (3) is connected to an exhaust pipe (30), the exhaust pipe (30) is connected to a connecting pipe 1 (31) in the circulation cylinder (2), and the end of the connecting pipe 1 (31) extends into the liquefaction tank (50).

7. The preparation process of leuprolide acetate microspheres for injection according to claim 5, characterized in that: The recycling mechanism (6) comprises a circulation tank (60) arranged adjacent to the liquefaction tank (50), a suction pump (62) being arranged at the bottom of the liquefaction tank (50), the suction pump (62) being connected to an extraction pipe (61), the end of the extraction pipe (61) being arranged in the circulation tank (60), a receiving tank (63) being arranged in the circulation tank (60) below the end of the extraction pipe (61), the top of the circulation tank (60) being connected to a delivery pipe (64), the bottom of the delivery pipe (64) being provided with a suction pump in a lifting manner, and the delivery pipe (64) being connected to a switching assembly (7).

8. The preparation process of leuprorelin acetate microspheres for injection according to claim 7, characterized in that: A rack (65) is provided at the edge of the circulation groove (60), and engaging grooves (650) are provided on both sides of the rack (65). A U-shaped frame (66) is slidably engaged in the engaging groove (650), and a matching gear (68) is rotatably installed in the U-shaped frame (66). The matching gear (68) and the rack (65) are meshed with each other, and the matching gear (68) is connected to a driving motor 1 (67). A vertical frame (69) is provided at the top of the U-shaped frame (66), and a driving motor 2 (610) is provided on the vertical frame (69). The driving motor 2 (610) is connected to a rotating shaft (611), and a swing frame (612) is provided on the rotating shaft (611). A heating roller (613) is horizontally installed at the end of the swing frame (612).

9. The preparation process of leuprorelin acetate microspheres for injection according to claim 8, characterized in that: The switching assembly (7) comprises a telescopic tube 1 (70) connected to the end of the connecting duct (10); a mounting column (71) is provided on the inner wall of the circulation cylinder (2); a rotating motor (72) is horizontally mounted on the mounting column (71); the rotating motor (72) is connected to a mounting ring (73); a connecting tube 2 (74) is fixedly mounted in the mounting ring (73); one end of the connecting tube 2 (74) is connected to the telescopic tube 1 (70); a telescopic tube 2 (79) is provided at the other end of the connecting tube 2 (74); the telescopic tube 2 (79) is connected to a docking joint (77); a mounting plate (75) is provided on the mounting ring (73); a telescopic motor (76) is provided on the mounting plate (75); the telescopic motor (76) is connected to a clamping frame (78); the clamping frame (78) is clamped with the docking joint (77); the docking joint (77) is docked with the ends of the air intake pipe (53) and the delivery pipe (64), respectively.

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