Preparation process of semaglutide microspheres

Abstract

The invention discloses a semaglutide microsphere preparation process, and belongs to the technical field of medicines. The semaglutide injection is prepared from the following components: 15g of semaglutide, 6g of cane sugar, 195g of water for injection, 300g of PLGA, 4.5 kg of dichloromethane, 4.5 kg of dimeticone, 73.8 kg of n-heptane, 8.1 kg of ethanol, 30kg of n-heptane and 30kg of n-heptane. The semaglutide injection has longer onset time, higher safety and easiness in amplified production, the preparation process is good in stability and reproducibility, and the preparation price is reduced; the left receiving tank base and the right receiving tank base abut against each other through force application of the electric push rods on the two sides, the S-shaped elastic piece is clamped between the left tank cavity and the right tank cavity, the electric control magnetic force generator generates intermittent magnetic force to attract and release the stainless steel balls, and the main control motor drives the platform base to rotate. During use, ingredients stored in the first storage tank and the second storage tank enter the left tank cavity and the right tank cavity, due to rotation of the platform base, the left receiving tank base and the right receiving tank base rotate along with the platform base, the proportioning and mixing effects are achieved, and the S-shaped elastic piece is matched with the rusted steel balls, so that liquid materials are evenly mixed on the inner side of the tank body.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical preparation, and specifically relates to a process for preparing semaglutide microspheres. Background Art

[0002] Type 2 diabetes is a chronic metabolic disorder that accounts for more than 90% of diabetes and has become a serious public health problem worldwide. Its main characteristics are persistent hyperglycemia, positive urine sugar, and impaired glucose tolerance. There are many types of diabetes treatment drugs currently on the market, and the treatment mechanisms are also different, but the goal of diabetes treatment is to improve the patient's blood sugar level throughout the day and reduce it to a normal range. Traditional hypoglycemic drugs have significant side effects and other factors, which limit the use of drugs by diabetic patients. Common clinical hypoglycemic drugs have adverse reactions such as hypoglycemia, gastrointestinal reactions, liver damage, allergic reactions, and increased heart burden.

[0003] In recent years, GLP-1 receptor agonists with new mechanisms of action have become one of the hot spots in the field of drug development for the treatment of type 2 diabetes. Compared with traditional drugs, GLP-1 receptor agonists have the characteristics of reducing blood sugar in a blood sugar-dependent concentration, which can significantly reduce the risk of hypoglycemia in patients, and can also reduce the weight of patients, and may also have potential effects on the cardiovascular, pancreatic and other tissues of patients. GLP-1 receptor agonists are analogs of glucagon-like peptide-1 (GLP-1), which have the effects of protecting pancreatic β cells, promoting insulin synthesis and secretion, and inhibiting glucagon secretion, so they are effective in regulating blood sugar. And the effects of GLP-1 in promoting insulin secretion and inhibiting glucagon secretion are related to glucose concentration, that is, the higher the blood sugar, the stronger its effect. In addition, GLP-1 can also increase satiety and reduce food intake by acting on the central nervous system, and inhibit gastric and duodenal motility by acting on the vagus nerve, reduce gastric acid secretion, delay gastric emptying, and thus reduce appetite, resulting in no weight gain or weight loss in patients.

[0004] Compliance with drug treatment is a basic condition for achieving the best treatment outcome, especially for chronic diseases such as diabetes that require long-term or even lifelong medication to control symptoms and prevent complications. In addition, diabetic patients are generally elderly people who are prone to missing medication, and traditional diabetes treatment drugs have adverse reactions. In addition, the common adverse reaction of GLP-1 receptor agonists such as semaglutide is nausea, which is mild to moderate and occurs frequently when patients start treatment and increase the dose. However, nausea is transient and will be alleviated or disappear as the treatment time increases. This may be caused by the stimulation of the body by the drug during the initial administration and when the dose is increased. When the patient develops tolerance to the drug, the adverse reaction will disappear. Since the GLP-1 molecule is easily degraded by DPP-4 in the body and loses its activity, its half-life in the body is extremely short, which limits its clinical application. Therefore, in order to improve the efficacy, reduce toxic side effects, and increase patient compliance with medication, the research and development direction of GLP-1 receptor agonists is mainly anti-enzymatic mutation and long-term effect.

[0005] There are currently no public reports on long-acting preparations or microencapsulation technologies such as semaglutide microspheres. Oral semaglutide preparations need to be administered once a day and the dosage is relatively large, and semaglutide injections need to be injected once a week. No matter what excipients are selected, the longest duration is only one day, and the oral effective dosage is as high as 40 mg. Compared with other anti-diabetic drugs that are administered once a week, there is no obvious advantage and the cost of disease treatment is bound to be expensive.

[0006] Therefore, the development of a longer-acting semaglutide microsphere preparation that can sustain stable release and has a low burst release rate can further reduce the number of dosing times, improve patient medication compliance and quality of life, and thus avoid treatment failure.

[0007] Furthermore, the functionality of the receiving tank in the current preparation process is insufficient and needs to be improved.

[0008] To this end, the applicant has conducted useful explorations and attempts, and found solutions to the above-mentioned problems, which can achieve multiple functions. The technical solution to be introduced below was produced in this context. Summary of the invention

[0009] The present invention mainly solves the technical problems existing in the above-mentioned prior art and provides a process for preparing semaglutide microspheres.

[0010] The above technical problems of the present invention are mainly solved by the following technical solutions: a process for preparing semaglutide microspheres, wherein the preparation ingredients include semaglutide 15g, sucrose 6g, water for injection 195g, PLGA 300g, dichloromethane 4.5kg, dimethicone 4.5kg, n-heptane 73.8kg, ethanol 8.1kg, n-heptane 30kg and n-heptane 30kg;

[0011] The preparation process comprises the following steps:

[0012] Step A, weigh the formula amount of semaglutide API, sucrose, and water for injection, dissolve them in a 1L dissolution tank, and then sterilize and filter them through a secondary 0.22um filter membrane into a 1L receiving tank;

[0013] Step B, weighing the formulated amount of PLGA and dichloromethane into the oil phase tank, stirring at 300 r / min for two hours, and then filtering through a secondary 0.22 um filter membrane to enter the colostrum tank;

[0014] Step C, transfer the 1L receiving tank material in step A to the colostrum tank, stir at 3000r / min for two minutes immediately after the transfer, and transfer to the coagulation tank immediately after stirring;

[0015] Step D, pour dimethicone into the silicone oil preparation tank, transfer to the silicone oil receiving tank through secondary 0.22um filter membrane sterilization filtration, immediately add the dimethicone in the silicone oil receiving tank prepared in advance into the colostrum tank of step C, add 4.5kg dimethicone within 2.5min-3.5min, immediately transfer to a curing tank containing 73.8kg n-heptane and 8.1kg anhydrous ethanol mixed solution and controlled at 2-5°C, and stir at 300r / min for 1 hour;

[0016] Step E: After completion, transfer to an oscillating screen, discharge the solidified liquid from the oscillating screen, and leave the microspheres on the sieve. Add 30 kg of n-heptane at a temperature of 2-5° C. to the oscillating screen for cleaning, and oscillate at 500 r / min for 30 min.

[0017] Step F: After completion, discharge the cleaning liquid from the oscillating screen, add 30 kg of n-heptane at a temperature of 2-5° C. to the oscillating screen for cleaning, and oscillate at 500 r / min for 30 min.

[0018] Step G: After completion, all the microspheres are transferred to a microsphere collecting tank, and the powder in the microsphere collecting tank is placed in a freeze dryer for freeze drying.

[0019] Preferably, it comprises a left receiving tank seat and a right receiving tank seat, a platform seat is arranged under the left receiving tank seat and the right receiving tank seat, two slide rails are arranged in parallel on the upper surface of the platform seat, the left receiving tank seat and the right receiving tank seat are both slidably arranged on the two slide rails, a left tank cavity is opened on the side of the left receiving tank seat close to the right receiving tank seat, a right tank cavity is opened on the side of the right receiving tank seat close to the left receiving tank seat, the left tank cavity and the right tank cavity are arranged opposite to each other, an S-shaped elastic member is arranged between the left tank cavity and the right tank cavity, an electric push rod is arranged on the side of the left receiving tank seat and the right receiving tank seat away from each other, and the electric push rod body is fixed to the upper surface of the platform seat;

[0020] Wherein, a base is arranged below the platform seat, a main control motor is arranged in the middle of the base, the rotating shaft of the main control motor is connected to the center of the lower surface of the platform seat through a universal joint transmission, and floating support seats are arranged on both sides of the base, and the two floating support seats are respectively supported on both sides of the platform seat;

[0021] Wherein, the upper surfaces of the left receiving tank seat and the right receiving tank seat where they are close to each other are both provided with a first input pipe, and the upper surfaces of the left receiving tank seat and the right receiving tank seat where they are far away from each other are both provided with a second input pipe, the two first input pipes are respectively corresponding to the left tank cavity and the right tank cavity, the two second input pipes are respectively corresponding to the left tank cavity and the right tank cavity, solenoid valves are respectively provided on the two first input pipes and the two second input pipes, the upper ends of the two first input pipes are both provided with a storage tank 1, and the upper ends of the two second input pipes are both provided with a storage tank 2, and the inner walls of the left tank cavity and the right tank cavity are uniformly provided with a plurality of electromagnetic heating coils, which are used for heat preservation, and the storage tank 1 and the storage tank 2 can selectively store the semaglutide API, sucrose and water for injection in step A;

[0022] Wherein, stainless steel balls are stored in the left tank cavity and the right tank cavity, and an electrically controlled magnetic force generator is arranged at one end of the left tank cavity and the right tank cavity which are away from each other.

[0023] Preferably, adjustment plates are provided on the inner sides of the left tank cavity and the right tank cavity, and two positioning slide rods are provided on the sides of the two adjustment plates away from each other. The two positioning slide rods located on the left tank cavity side pass through the outer side of the left receiving tank seat, and the two positioning slide rods located on the right tank cavity side pass through the outer side of the right receiving tank seat. An adjusting screw is provided at the center of the sides of the two adjustment plates away from each other, and the two adjusting screws respectively pass through the outer sides of the left receiving tank seat and the right receiving tank seat and are threadedly connected.

[0024] Preferably, a drag slide is fixedly provided on the side of the left receiving tank seat and the right receiving tank seat that are away from each other, and an adjusting motor is provided on both drag slides. The rotating shafts of the two adjusting motors are respectively connected to the adjusting screws, and the two adjusting motors are slidably connected to the corresponding drag slides left and right.

[0025] Preferably, sealing rings are provided on the side surface of the left receiving tank seat on the outer side of the left tank cavity and on the side surface of the right receiving tank seat on the outer side of the right tank cavity, and the two sealing rings are staggered.

[0026] Preferably, the floating support seat includes a hydraulic push rod, a support fork arm arranged at the upper end of the hydraulic push rod and an I-shaped ring rail arranged on the lower surface of the platform seat, upper guide wheels are arranged on both sides of the inside of the support fork arm, the upper guide wheels are arranged on both sides of the lower end of the I-shaped ring rail, and a bottom support guide wheel is provided in the middle of the lower side of the I-shaped ring rail.

[0027] Preferably, both sides of the lower end of the I-shaped ring rail are in a downwardly curved arc shape, and the bottom support guide wheel is located at the arc-shaped concave bottom of the bottom of the I-shaped ring rail.

[0028] Preferably, an annular cavity is provided on the inner wall of the left tank cavity and the right tank cavity, the annular cavity is connected with the first input pipe, a swivel is provided on the inner side of the annular cavity, the swivel is rotatably arranged in the annular cavity, a plurality of blades are evenly arranged on the outer surface of the swivel, a plurality of air delivery holes are evenly opened on the swivel, and the air delivery holes are shrinkage holes.

[0029] The present invention has the beneficial effects:

[0030] The semaglutide microsphere preparation process of the present invention has a longer onset time, higher safety, is easy to scale up production, has good stability and reproducibility in the preparation process, and reduces the preparation price.

[0031] In the preparation process of the present invention, the left receiving tank seat and the right receiving tank seat are pressed against each other by the force of the electric push rods on both sides, so that the S-shaped elastic member is clamped between the left tank cavity and the right tank cavity, and the electric-controlled magnetic force generator generates intermittent magnetic force to absorb and release the stainless steel balls. The main control motor drives the platform seat to rotate, and the ingredients stored in the first storage tank and the second storage tank enter the left tank cavity and the right tank cavity. Due to the rotation of the platform seat, the left receiving tank seat and the right receiving tank seat follow the rotation, which plays a role in proportioning and mixing. The S-shaped elastic member cooperates with the stainless steel balls to evenly mix the liquid material inside the tank body;

[0032] By controlling the thrust of the electric push rod on one side to be greater than the thrust of the electric push rod on the other side, the left receiving tank seat and the right receiving tank seat are close to each other and offset to one side. When the platform seat rotates, the liquid offset inside it changes due to eccentricity, which accelerates mixing.

[0033] 2. By rotating the adjusting screw to displace the position of the adjusting plate, the compression amount of the S-shaped elastic member is controlled to achieve the desired space inside the tank.

[0034] 3. Move the support fork arm upward or downward through the hydraulic push rod to tilt the platform seat, so as to control the position of the stainless steel balls in the left tank cavity and the right tank cavity, so as to adjust the stainless steel balls on both sides. By controlling the two hydraulic push rods to move up and down, the stainless steel balls can be fully mixed with the drug liquid;

[0035] When the platform seat rotates, the two upper guide wheels and the bottom support guide wheel are buckled on the lower end of the I-shaped ring rail, which is convenient for controlling the position of the platform seat. The arc-shaped lower end of the I-shaped ring rail is convenient for the upper guide wheel to roll on its upper side, and the platform seat can also rotate when it is tilted. The bottom support guide wheel is located at the bottom of the arc concave, providing better support.

[0036] 4. After the drug liquid in the storage tank is input into the annular cavity, it drives the blades to rotate the rotating ring. After the annular cavity is full, the drug liquid is output through the delivery hole. At this time, the drug liquid flows into the tank, and the rotating rotating ring can mix the drug liquid more fully. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 It is a side view structural schematic diagram of the present invention;

[0038] Figure 2 It is a structural schematic diagram of the left tank cavity and the right tank cavity of the present invention;

[0039] Figure 3 It is a schematic diagram of the position structure of the sealing ring of the present invention;

[0040] Figure 4 yes Figure 1 A schematic diagram of a structure enlarged in the middle A part;

[0041] Figure 5 It is a schematic diagram of a structure in the ring cavity of the present invention;

[0042] Figure 6 It is a structural schematic diagram of the lower surface of the platform seat of the present invention.

[0043] In the figure: 1. Left receiving tank seat; 2. Right receiving tank seat; 3. Platform seat; 4. Slide rail; 5. Left tank cavity; 6. Right tank cavity; 7. Electric push rod; 8. Base; 9. Main control motor; 10. Universal joint; 11. Floating support seat; 12. First input pipe; 13. Second input pipe; 14. Storage tank one; 15. Storage tank two; 16. Electromagnetic heating coil; 17. Adjustment plate; 18. Positioning slide rod; 19. Adjustment screw; 20. Drag plate; 21. Adjustment motor; 22. Sealing ring; 23. Hydraulic push rod; 24. Support fork arm; 25. I-shaped ring rail; 26. Upper guide wheel; 27. Bottom support guide wheel; 28. Ring cavity; 29. ​​Rotating ring; 30. Blade; 31. Air delivery hole; 32. Stainless steel ball; 33. S-shaped elastic member; 34. Electric controlled magnetic generator. DETAILED DESCRIPTION

[0044] The following are examples and the attached Figure 1-Figure 6 , the technical solution of the present invention is further specifically described.

[0045] Embodiment: A process for preparing semaglutide microspheres, the preparation ingredients comprising semaglutide 15 g, sucrose 6 g, water for injection 195 g, PLGA 300 g, dichloromethane 4.5 kg, dimethicone 4.5 kg, n-heptane 73.8 kg, ethanol 8.1 kg and n-heptane 30 kg;

[0046] The preparation process comprises the following steps:

[0047] Step A, weigh the formula amount of semaglutide API, sucrose, and water for injection, dissolve them in a 1L dissolution tank, and then sterilize and filter them through a secondary 0.22um filter membrane into a 1L receiving tank;

[0048] Step B, weighing the formulated amount of PLGA and dichloromethane into the oil phase tank, stirring at 300 r / min for two hours, and then filtering through a secondary 0.22 um filter membrane to enter the colostrum tank;

[0049] Step C, transfer the 1L receiving tank material in step A to the colostrum tank, stir at 3000r / min for two minutes immediately after the transfer, and transfer to the coagulation tank immediately after stirring;

[0050] Step D, pour dimethicone into the silicone oil preparation tank, transfer to the silicone oil receiving tank through secondary 0.22um filter membrane sterilization filtration, immediately add the dimethicone in the silicone oil receiving tank prepared in advance into the colostrum tank of step C, add 4.5kg dimethicone within 2.5min-3.5min, immediately transfer to a curing tank containing 73.8kg n-heptane and 8.1kg anhydrous ethanol mixed solution and controlled at 2-5°C, and stir at 300r / min for 1 hour;

[0051] Step E: After completion, transfer to an oscillating screen, discharge the solidified liquid from the oscillating screen, and leave the microspheres on the sieve. Add 30 kg of n-heptane at a temperature of 2-5° C. to the oscillating screen for cleaning, and oscillate at 500 r / min for 30 min.

[0052] Step F: After completion, discharge the cleaning liquid from the oscillating screen, add 30 kg of n-heptane at a temperature of 2-5° C. to the oscillating screen for cleaning, and oscillate at 500 r / min for 30 min.

[0053] Step G: After completion, all the microspheres are transferred to a microsphere collecting tank, and the powder in the microsphere collecting tank is placed in a freeze dryer for freeze drying.

[0054] The freeze-drying procedure is shown in the table below.

[0055] temperature time Vacuum degree 3℃ 1080min 0.2mbar 25℃ 1440min 0.2mbar 30℃ 360min 0.2mbar

[0056] The receiving tank in step A comprises a left receiving tank seat 1 and a right receiving tank seat 2, a platform seat 3 is arranged under the left receiving tank seat 1 and the right receiving tank seat 2, two slide rails 4 are arranged in parallel on the upper surface of the platform seat 3, the left receiving tank seat 1 and the right receiving tank seat 2 are both slidably arranged on the two slide rails 4, a left tank cavity 5 is provided on the side of the left receiving tank seat 1 close to the right receiving tank seat 2, a right tank cavity 6 is provided on the side of the right receiving tank seat 2 close to the left receiving tank seat 1, the left tank cavity 5 and the right tank cavity 6 are arranged opposite to each other, an S-shaped elastic member 33 is arranged between the left tank cavity 5 and the right tank cavity 6, an electric push rod 7 is arranged on the side of the left receiving tank seat 1 and the right receiving tank seat 2 away from each other, and the body of the electric push rod 7 is fixed to the upper surface of the platform seat 3;

[0057] A base 8 is provided below the platform seat 3, a main control motor 9 is provided in the middle of the base 8, the rotating shaft of the main control motor 9 is connected to the center of the lower surface of the platform seat 3 through a universal joint 10, and floating support seats 11 are provided on both sides of the base 8, and the two floating support seats 11 are supported on both sides of the platform seat 3 respectively;

[0058] Among them, the upper surfaces of the left receiving tank seat 1 and the right receiving tank seat 2 where they are close to each other are each provided with a first input pipe 12, and the upper surfaces of the left receiving tank seat 1 and the right receiving tank seat 2 where they are far away from each other are each provided with a second input pipe 13, the two first input pipes 12 are respectively connected to the left tank cavity 5 and the right tank cavity 6, and the two second input pipes 13 are respectively connected to the left tank cavity 5 and the right tank cavity 6, solenoid valves are respectively provided on the two first input pipes 12 and the two second input pipes 13, the upper ends of the two first input pipes 12 are each provided with a material storage tank 14, and the upper ends of the two second input pipes 13 are each provided with a material storage tank 2 15, and the inner walls of the left tank cavity 5 and the right tank cavity 6 are evenly provided with a plurality of electromagnetic heating coils 16, which are used for heat preservation, and the material storage tank 14 and the material storage tank 2 15 can selectively store the semaglutide API, sucrose and water for injection in step A.

[0059] Stainless steel balls 32 are stored in the left tank cavity 5 and the right tank cavity 6 , and an electrically controlled magnetic force generator 34 is provided at one end of the left tank cavity 5 and the right tank cavity 6 away from each other.

[0060] An adjustment plate 17 is provided at the inner side of the left tank cavity 5 and the right tank cavity 6, and two positioning slide bars 18 are provided at the sides of the two adjustment plates 17 away from each other. The two positioning slide bars 18 located on the side of the left tank cavity 5 penetrate the outer side of the left receiving tank seat 1, and the two positioning slide bars 18 located on the side of the right tank cavity 6 penetrate the outer side of the right receiving tank seat 2. An adjustment screw 19 is provided at the center of the side of the two adjustment plates 17 away from each other, and the two adjustment screws 19 respectively penetrate the outer sides of the left receiving tank seat 1 and the right receiving tank seat 2 and are threadedly connected;

[0061] A drag slide 20 is fixedly provided on the side of the left receiving tank seat 1 and the right receiving tank seat 2 that are away from each other, and an adjusting motor 21 is provided on the two drag slides 20. The rotating shafts of the two adjusting motors 21 are respectively connected to the adjusting screw 19, and the two adjusting motors 21 are slidably connected to the corresponding drag slides 20 left and right.

[0062] Sealing rings 22 are arranged on the side surface of the left receiving tank seat 1 on the outer side of the left tank cavity 5 and on the side surface of the right receiving tank seat 2 on the outer side of the right tank cavity 6, and the two sealing rings 22 are arranged alternately.

[0063] The floating support seat 11 includes a hydraulic push rod 23, a support fork arm 24 arranged at the upper end of the hydraulic push rod and an I-shaped ring rail 25 arranged on the lower surface of the platform seat 3, and upper guide wheels 26 are arranged on both sides of the inside of the support fork arm 24. The upper guide wheels 26 are arranged on both sides of the lower end of the I-shaped ring rail 25, and a bottom support guide wheel 27 is provided in the middle of the lower side of the I-shaped ring rail 25.

[0064] Both sides of the lower end of the I-shaped ring rail 25 are in a downwardly curved arc shape, and the bottom support guide wheel 27 is located at the arc-shaped concave bottom of the bottom of the I-shaped ring rail 25 .

[0065] An annular cavity 28 is provided on the inner wall of the left tank cavity 5 and the right tank cavity 6. The annular cavity 28 is communicated with the first input pipe 12. A swivel 29 is provided on the inner side of the annular cavity 28. The swivel 29 is rotatably provided in the annular cavity 28. A plurality of blades 30 are evenly distributed on the outer surface of the swivel 29. A plurality of gas delivery holes 31 are evenly distributed on the swivel 29. The gas delivery holes 31 are shrinkage holes.

[0066] In the preparation process of the present invention, the left receiving tank seat and the right receiving tank seat are pressed against each other by the force of the electric push rods on both sides, so that the S-shaped elastic member is clamped between the left tank cavity and the right tank cavity, and the electric-controlled magnetic force generator generates intermittent magnetic force to absorb and release the stainless steel balls. The main control motor drives the platform seat to rotate, and the ingredients stored in the first storage tank and the second storage tank enter the left tank cavity and the right tank cavity. Due to the rotation of the platform seat, the left receiving tank seat and the right receiving tank seat follow the rotation, which plays a role in proportioning and mixing. The S-shaped elastic member cooperates with the stainless steel balls to evenly mix the liquid material inside the tank body;

[0067] By controlling the thrust of the electric push rod on one side to be greater than the thrust of the electric push rod on the other side, the left receiving tank seat and the right receiving tank seat are close to each other and offset to one side. When the platform seat rotates, the liquid offset inside it changes due to eccentricity, which accelerates mixing.

[0068] The position of the adjusting plate is displaced by rotating the adjusting screw, thereby controlling the compression amount of the S-shaped elastic member to obtain the desired space inside the tank.

[0069] By moving the support fork arm upward or downward through the hydraulic push rod, the platform seat is tilted to control the position of the stainless steel balls in the left tank cavity and the right tank cavity, so as to adjust the stainless steel balls on both sides. By controlling the two hydraulic push rods to move up and down, the stainless steel balls can be fully mixed with the drug liquid.

[0070] When the platform seat rotates, the two upper guide wheels and the bottom support guide wheel are buckled on the lower end of the I-shaped ring rail, which is convenient for controlling the position of the platform seat. The arc-shaped lower end of the I-shaped ring rail is convenient for the upper guide wheel to roll on its upper side, and the platform seat can also rotate when it is tilted. The bottom support guide wheel is located at the bottom of the arc concave, providing better support.

[0071] After the drug liquid in the storage tank is input into the annular cavity, it drives the blades to rotate the rotating ring. After the annular cavity is full, the drug liquid is output through the delivery hole. At this time, the drug liquid flows into the tank, and the rotating rotating ring can mix the drug liquid more fully.

[0072] Finally, it should be pointed out that the above embodiments are only representative examples of the present invention. Obviously, the present invention is not limited to the above embodiments, and there are many variations. Any simple modification, equivalent changes and modifications made to the above embodiments based on the technical essence of the present invention should be considered to belong to the protection scope of the present invention.

Claims

1. A process for preparing semaglutide microspheres, characterized in that The preparation ingredients include 15g of semaglutide, 6g of sucrose, 195g of water for injection, 300g of PLGA, 4.5kg of dichloromethane, 4.5kg of dimethicone, 73.8kg of n-heptane, 8.1kg of ethanol, 30kg of n-heptane and 30kg of n-heptane; The preparation process comprises the following steps: Step A, weigh the formula amount of semaglutide API, sucrose, and water for injection, dissolve them and put them into a 1L dissolution tank, and then sterilize and filter them through a secondary 0.22um filter membrane into a 1L receiving tank; Step B, weighing the formulated amount of PLGA and dichloromethane into the oil phase tank, stirring at 300 r / min for two hours, and then filtering through a secondary 0.22 um filter membrane to enter the colostrum tank; Step C, transfer the 1L receiving tank material in step A to the colostrum tank, stir at 3000r / min for two minutes immediately after the transfer, and transfer to the coagulation tank immediately after stirring; Step D, pour dimethicone into the silicone oil preparation tank, transfer to the silicone oil receiving tank through secondary 0.22um filter membrane sterilization filtration, immediately add the dimethicone in the silicone oil receiving tank prepared in advance into the colostrum tank of step C, add 4.5kg dimethicone within 2.5min-3.5min, immediately transfer to a curing tank containing 73.8kg n-heptane and 8.1kg anhydrous ethanol mixed solution and controlled at 2-5°C, and stir at 300r / min for 1 hour; Step E: After completion, transfer to an oscillating screen, discharge the solidified liquid from the oscillating screen, and leave the microspheres on the sieve. Add 30 kg of n-heptane at a temperature of 2-5° C. to the oscillating screen for cleaning, and oscillate at 500 r / min for 30 min. Step F: After completion, discharge the cleaning liquid from the oscillating screen, add 30 kg of n-heptane at a temperature of 2-5° C. to the oscillating screen for cleaning, and oscillate at 500 r / min for 30 min. Step G: After completion, all the microspheres are transferred to a microsphere collecting tank, and the powder in the microsphere collecting tank is placed in a freeze dryer for freeze drying.

2. The process for preparing semaglutide microspheres according to claim 1, characterized in that The receiving tank in step A comprises a left receiving tank seat (1) and a right receiving tank seat (2), a platform seat (3) is arranged below the left receiving tank seat (1) and the right receiving tank seat (2), two slide rails (4) are arranged in parallel on the upper surface of the platform seat (3), the left receiving tank seat (1) and the right receiving tank seat (2) are both slidably arranged on the two slide rails (4), a left tank cavity (5) is provided on the side of the left receiving tank seat (1) close to the right receiving tank seat (2), and a right tank cavity (6) is provided on the side of the right receiving tank seat (2) close to the left receiving tank seat (1), the left tank cavity (5) and the right tank cavity (6) are arranged opposite to each other, an S-shaped elastic member (33) is arranged between the left tank cavity (5) and the right tank cavity (6), and an electric push rod (7) is arranged on the side of the left receiving tank seat (1) and the right receiving tank seat (2) away from each other, and the body of the electric push rod (7) is fixed to the upper surface of the platform seat (3); A base (8) is provided below the platform seat (3), a main control motor (9) is provided in the middle of the base (8), a rotating shaft of the main control motor (9) is connected to the center of the lower surface of the platform seat (3) by a universal joint (10), and floating support seats (11) are provided on both sides of the base (8), and the two floating support seats (11) are respectively supported on both sides of the platform seat (3); Wherein, the upper surfaces of the left receiving tank seat (1) and the right receiving tank seat (2) where they are close to each other are both provided with a first input pipe (12), and the upper surfaces of the left receiving tank seat (1) and the right receiving tank seat (2) where they are far away from each other are both provided with a second input pipe (13), the two first input pipes (12) respectively correspondingly pass through the left tank cavity (5) and the right tank cavity (6), the two second input pipes (13) respectively correspondingly pass through the left tank cavity (5) and the right tank cavity (6), and the two first input pipes (12) and the two Each of the second input pipes (13) is provided with an electromagnetic valve, each of the upper ends of the two first input pipes (12) is provided with a storage tank 1 (14), each of the upper ends of the two second input pipes (13) is provided with a storage tank 2 (15), and a plurality of electromagnetic heating coils (16) are evenly distributed on the inner walls of the left tank cavity (5) and the right tank cavity (6), and the electromagnetic heating coils (16) are used for heat preservation. The storage tank 1 (14) and the storage tank 2 (15) can selectively store the semaglutide API, sucrose and water for injection in step A. Wherein, stainless steel balls (32) are stored in the left tank cavity (5) and the right tank cavity (6), and an electrically controlled magnetic force generator (34) is arranged at one end of the left tank cavity (5) and the right tank cavity (6) which are away from each other.

3. The process for preparing semaglutide microspheres according to claim 2, characterized in that An adjustment plate (17) is provided on the inner side of the left tank cavity (5) and the right tank cavity (6), and two positioning slide bars (18) are provided on the side of the two adjustment plates (17) away from each other. The two positioning slide bars (18) located on the left tank cavity (5) side penetrate the outer side of the left receiving tank seat (1), and the two positioning slide bars (18) located on the right tank cavity (6) side penetrate the outer side of the right receiving tank seat (2). An adjustment screw (19) is provided at the center of the side of the two adjustment plates (17) away from each other. The two adjustment screws (19) respectively penetrate the outer sides of the left receiving tank seat (1) and the right receiving tank seat (2) and are threadedly connected. A dragging plate (20) is fixedly provided on the side of the left receiving tank seat (1) and the right receiving tank seat (2) that are away from each other, and an adjusting motor (21) is provided on each of the two dragging plates (20). The rotating shafts of the two adjusting motors (21) are respectively connected to the adjusting screw rods (19), and the two adjusting motors (21) are slidably connected to the corresponding dragging plates (20) left and right.

4. The process for preparing semaglutide microspheres according to claim 3, characterized in that A sealing ring (22) is provided on the side of the left receiving tank seat (1) on the outer side of the left tank cavity (5) and on the side of the right receiving tank seat (2) on the outer side of the right tank cavity (6), and the two sealing rings (22) are arranged alternately.

5. The process for preparing semaglutide microspheres according to claim 2, characterized in that The floating support seat (11) comprises a hydraulic push rod (23), a support fork arm (24) arranged at the upper end of the hydraulic push rod and an I-shaped ring rail (25) arranged on the lower surface of the platform seat (3), upper guide wheels (26) are arranged on both sides of the interior of the support fork arm (24), the upper guide wheels (26) are arranged on both sides of the lower end of the I-shaped ring rail (25), and a bottom support guide wheel (27) is provided in the middle of the lower side of the I-shaped ring rail (25).

6. The process for preparing semaglutide microspheres according to claim 5, characterized in that Both sides of the lower end of the I-shaped ring rail (25) are in a downwardly curved arc shape, and the bottom support guide wheel (27) is located at the arc-shaped concave bottom of the bottom of the I-shaped ring rail (25).

7. The process for preparing semaglutide microspheres according to claim 2, characterized in that An annular cavity (28) is provided on the inner wall of the left tank cavity (5) and the right tank cavity (6). The annular cavity (28) is communicated with the first input pipe (12). A rotating ring (29) is provided on the inner side of the annular cavity (28). The rotating ring (29) is rotatably arranged in the annular cavity (28). A plurality of blades (30) are evenly arranged on the outer surface of the rotating ring (29). A plurality of gas delivery holes (31) are evenly arranged on the rotating ring (29). The gas delivery holes (31) are shrinkage holes.

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