Device for preparing pharmaceutical composition for slowly releasing somatostatin analogue

Abstract

The utility model discloses a device for preparing a pharmaceutical composition for slowly releasing somatostatin analogues, and relates to the technical field of medicines. The problems that in the production process of the composition for slowly releasing the somatostatin analogue, dissolution is incomplete, bubbles are likely to be mixed, residues are serious, and the equipment sealing performance and the mixing effect are poor are solved. The device comprises a mounting bracket, and a powder pushing mechanism, a solvent pushing mechanism and a three-way mixing structure which are arranged on the mounting bracket, the powder pushing mechanism comprises a powder barrel, a powder piston push rod and a powder driving system; the solvent pushing mechanism comprises a solvent cylinder, a solvent piston push rod and a solvent driving system; the powder cylinder is communicated with the solvent cylinder through a three-way mixing structure; the three-way mixing structure is communicated with an external vacuum system; the powder driving system can drive the powder piston push rod to reciprocate; the solvent driving system can drive the solvent piston push rod to reciprocate. The performance of the device for preparing the medicine composition for slowly releasing the somatostatin analogue is improved.

Description

Technical Field

[0001] The present application relates to the field of medical technology, and in particular to a device for preparing a pharmaceutical composition for sustained-release somatostatin analogs. Background Art

[0002] Lanreotide is a representative of the pharmaceutical composition of sustained-release somatostatin analogs. We know that its marketed product dosage form is a semisolid gel preparation, and the route of administration is injection. Unlike ordinary topical gels, this type of high-viscosity preparation for injection has higher requirements for content uniformity and bubbles. The prior art generally prepares high-viscosity sustained-release peptide preparations (emulsions, suspensions, gels) through a stirring, dissolving and mixing process. The disadvantage of this method is that there are obvious problems that the raw materials cannot be fully dissolved, the mixing is uneven, a large number of bubbles cannot be discharged, and the residual loss of the stirring paddle and the container is serious, and the stable production of such pharmaceutical compositions cannot be achieved. Utility Model Content

[0003] The embodiments of the present application provide a device for preparing a pharmaceutical composition for sustained-release somatostatin analogs, which solves the problems of incomplete dissolution, easy mixing of bubbles, serious residues, poor equipment sealing and mixing effect in the production process of the composition for sustained-release somatostatin analogs.

[0004] To achieve the above-mentioned objectives, an embodiment of the present application provides a device for preparing a pharmaceutical composition for sustained-release somatostatin analogs, comprising a mounting bracket and a powder pushing mechanism, a solvent pushing mechanism and a three-way mixing structure arranged on the mounting bracket; the powder pushing mechanism comprises a powder cylinder, a powder piston push rod and a powder driving system; the solvent pushing mechanism comprises a solvent cylinder, a solvent piston push rod and a solvent driving system; the powder cylinder is connected to the solvent cylinder through a three-way mixing structure; the three-way mixing structure is connected to an external vacuum system; the powder driving system can drive the powder piston push rod to reciprocate; the solvent driving system can drive the solvent piston push rod to reciprocate.

[0005] Furthermore, the powder driving system includes a servo motor and a linear electric cylinder arranged in sequence along the axial direction; the fixed end of the linear electric cylinder is connected to the mounting bracket, and the telescopic end is connected to the powder piston push rod; a pressure sensor is provided between the linear electric cylinder and the powder piston push rod; the solvent driving system has the same structure as the powder driving system.

[0006] Furthermore, a heat-insulating interlayer is provided in the powder cylinder; and the solvent cylinder has the same structure as the powder cylinder.

[0007] Furthermore, the bottom surface of the cavity of the powder cylinder is a conical surface or a hemispherical surface, and the ratio of the inner diameter of the cavity to the height of the conical surface is 2:1 to 8:1.

[0008] Furthermore, the three-way mixing structure is made of polytetrafluoroethylene; the powder cylinder is made of polymethyl methacrylate or anodized aluminum or SUS304 stainless steel and the inner wall thereof is plated with a PTFE film.

[0009] Furthermore, the powder piston push rod comprises a push rod and a conical piston connected to the end of the push rod; a fluororubber sealing ring and a wear-resistant ring are sequentially arranged on the conical piston along the axial direction.

[0010] Furthermore, it also includes a guide assembly; the guide assembly includes a guide rod and a push rod support seat; the two ends of the guide rod are fixedly connected to the mounting bracket, and the middle part is sleeved in the push rod support seat; one end of the push rod support seat is connected to the pressure sensor, and the other end is connected to the powder piston push rod or the solvent piston push rod.

[0011] Furthermore, the powder pushing mechanism and the solvent pushing mechanism are both arranged in the vertical direction, and the two are arranged side by side; the three-way mixing structure is a three-way valve; the powder cylinder and the solvent cylinder are both connected to the three-way valve through a connecting pipeline; the ratio of the inner diameter of the cavity of the powder cylinder or the solvent cylinder to the diameter of the valve core of the three-way valve is 3:1 to 9:1; the ratio of the inner diameter of the cavity of the powder cylinder or the solvent cylinder to the diameter of the connecting pipeline is also 3:1 to 9:1.

[0012] Furthermore, the powder pushing mechanism and the solvent pushing mechanism are arranged in an "I" shape along the horizontal direction, and the powder cylinder and the solvent cylinder together form an "I"-shaped double cavity; the two cavities of the "I"-shaped double cavity are connected through a three-way mixing structure; the three-way mixing structure includes a three-way structure and a three-way valve core arranged in the three-way structure; the ratio of the inner diameter of the cavity of the "I"-shaped double cavity to the diameter of the valve core of the three-way valve core is 3:1 to 9:1.

[0013] Compared with the prior art, this application has the following beneficial effects:

[0014] 1. The pharmaceutical composition preparation device for sustained-release somatostatin analogs of the embodiment of the present application connects the three ports of the three-way mixing structure to the powder cylinder, the solvent cylinder and the vacuum system respectively, and sets the ratio of the cylinder diameter to the diameter of the valve core of the three-way mixing structure to 3:1-9:1, selects PMMA as the cylinder material, selects PTFE as the material of the three-way valve, sets the cavity bottom surfaces of the powder cylinder and the solvent cylinder to conical surfaces or hemispherical surfaces, and sets the ratio of the inner diameter of the cavity to the height of the conical surface to 2:1-8:1, thereby solving the problems of incomplete dissolution, easy mixing of bubbles, serious residue, poor equipment sealing and mixing effect in the production process of high-viscosity products.

[0015] 2. The apparatus for preparing a pharmaceutical composition for sustained-release somatostatin analogs in the embodiment of the present application can control the temperature of the material in the inner cavity by providing a heat-insulating interlayer in the powder cylinder and the solvent cylinder and by introducing a circulating medium into the interlayer.

[0016] 3. The pharmaceutical composition preparation device for sustained-release somatostatin analogs in the embodiment of the present application improves the sealing performance and service life of the device by arranging a conical piston at the end of the push rod and arranging a fluororubber sealing ring and a wear-resistant ring in sequence along the axial direction on the conical piston.

[0017] 4. The pharmaceutical composition preparation device for sustained-release somatostatin analogs in the embodiment of the present application realizes real-time monitoring of pressure / resistance changes during the mixing process by setting a servo motor and a linear electric cylinder to push and pull the push rod, and setting a pressure sensor between the linear electric cylinder and the push rod, thereby indirectly providing feedback on the mixing degree of the materials and further improving the mixing effect of the powder and the solvent.

[0018] 5. The device for preparing the pharmaceutical composition of sustained-release somatostatin analogs in the embodiment of the present application can meet the requirements for both small-scale trials and scale-up, and obtain a uniform product that meets expectations. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In order to more clearly illustrate the embodiments of the present application or the technical solutions in the prior art, the drawings required for use in the embodiments or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0020] Figure 1 This is a schematic diagram of a three-dimensional structure of an embodiment of the present application;

[0021] Figure 2 This is a front view of an embodiment of the present application;

[0022] Figure 3 A side view of an embodiment of the present application;

[0023] Figure 4 This is a schematic diagram of the structure of a powder cylinder in one embodiment of the present application;

[0024] Figure 5 This is a schematic diagram of a three-dimensional structure of another embodiment of the present application;

[0025] Figure 6 This is an appearance diagram of a "I"-shaped double cavity in another embodiment of the present application;

[0026] Figure 7 This is a cross-sectional view of an I-shaped double cavity in another embodiment of the present application. DETAILED DESCRIPTION

[0027] The following will be combined with the drawings in the embodiments of the present application to clearly and completely describe the technical solutions in the embodiments of the present application. Obviously, the described embodiments are only part of the embodiments of the present application, not all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of this application.

[0028] In the description of the present application, it should be understood that the terms "center", "up", "down", "front", "back", "left", "right", "vertical", "horizontal", "top", "bottom", "inside", "outside", etc., indicating orientations or positional relationships, are based on the orientations or positional relationships shown in the accompanying drawings, and are only for the convenience of describing the present application and simplifying the description, and 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 should not be understood as a limitation on the present application.

[0029] In the description of the present application, it should be noted that, unless otherwise clearly specified and limited, the terms "installed", "connected" and "connected" should be understood in a broad sense. For example, it can be a fixed connection, a detachable connection, or an integral connection. For ordinary technicians in this field, they can understand the specific meanings of the above terms in this application according to specific circumstances.

[0030] The terms "first" and "second" 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. Thus, a feature defined as "first" or "second" can explicitly or implicitly include one or more of the features. In the description of this application, unless otherwise specified, "plurality" means two or more.

[0031] Reference Figures 1 to 4 An embodiment of the present application provides a device for preparing a pharmaceutical composition for sustained-release somatostatin analogs, comprising a mounting bracket 1 and a powder pushing mechanism 2, a solvent pushing mechanism 3 and a three-way mixing structure 4 arranged on the mounting bracket 1.

[0032] The mounting bracket 1 includes a bottom plate 11a, which is a rectangular plate, and a foot 12 is provided at each of the four corners of the lower surface of the bottom plate 11a. Four long support rods 13 and two short support rods 14 are fixedly connected to the upper surface of the bottom plate 11. The top of the long support rod 13 is fixedly connected to the electric cylinder fixing plate 15. The middle of the long support rod 13 is fixedly connected to the upper fixing plate 16 and the lower fixing plate 17 of the cylinder from top to bottom. The top of the short support rod 14 is fixedly connected to the reinforcing plate 18, and the left and right sides of the reinforcing plate 18 are fixedly connected to the corresponding long support rod 13 to enhance the stability of the entire device.

[0033] The powder pushing mechanism 2 and the solvent pushing mechanism 3 have the same structure, and the powder pushing mechanism 2 and the solvent pushing mechanism 3 are both arranged side by side in the vertical direction.

[0034] Reference Figure 1 and Figure 4 The powder pushing mechanism 2 includes a powder cylinder 21, a powder piston push rod 22 and a powder driving system 23. The cavity bottom surface of the powder cylinder 21 is a conical surface or a hemispherical surface. When the cavity bottom surface is a conical surface, the ratio of the inner diameter of the cavity to the height of the conical surface is 2:1 to 8:1. In this way, the dead volume of the mixing process can be effectively reduced and the pushing resistance can be reduced. The two ends of the powder cylinder 21 are respectively connected to the upper cylinder fixing plate 16 and the lower cylinder fixing plate 17 in the mounting bracket 1.

[0035] A heat-insulating interlayer 211 is provided in the powder cylinder 21 , and the temperature of the material in the inner cavity can be controlled by introducing a circulating medium into the heat-insulating interlayer 211 .

[0036] The powder piston push rod 22 includes a push rod 221 and a conical piston 222 connected to the end of the push rod 221. A fluororubber seal ring 223 and a wear-resistant ring 224 are sequentially arranged on the conical piston 222 along the axial direction. Thus, it can be ensured that the powder still has good sealing performance during high-pressure extrusion, and it is not easy to deform and leak under high-intensity pressure, and the friction resistance during the sliding process can also be reduced.

[0037] The powder driving system 23 includes a servo motor 231 and a linear electric cylinder 232 connected to the lower end of the servo motor 231. The fixed end of the linear electric cylinder 232 is connected to the electric cylinder fixing plate 15, and the telescopic end is connected to the powder piston push rod 22. A pressure sensor 24 is provided between the linear electric cylinder 232 and the powder piston push rod 22. Thus, the pressure / resistance changes during the mixing process can be monitored in real time, and the mixing degree of the materials can be indirectly fed back.

[0038] The solvent pushing mechanism 3 comprises a solvent cylinder 31, a solvent piston push rod 32 and a solvent driving system 33. The structure and working principle of the solvent pushing mechanism 3 are the same as those of the powder pushing mechanism 2, and will not be described in detail here.

[0039] Since the powder pushing mechanism 2 is a slender rod structure, in order to improve its guiding performance and prevent lateral bending, the device also includes two groups of guiding components 25. The two groups of guiding components 25 are arranged side by side on the left and right, and each group of guiding components 25 includes two guide rods 251 and a push rod support seat 252. The middle part of the guide rod 251 is sleeved in the push rod support seat 252, and the two ends are respectively fixed to the electric cylinder fixing plate 15 and the cylinder upper fixing plate 16. The pressure sensor 24 is connected to the upper surface of the push rod support seat 252, and the powder piston push rod 22 or the solvent piston push rod 32 is connected to the lower surface. Therefore, during the extension and retraction process of the linear electric cylinder 232, the push rod support seat 252 can slide up and down along the axial direction of the guide rod 251, thereby preventing the powder piston push rod 22 or the solvent piston push rod 32 from lateral bending.

[0040] In the embodiment, the three-way mixing structure 4 is a three-way valve. The powder cylinder 21 and the solvent cylinder 31 are both connected to two ports of the three-way valve through the connecting pipeline 5, and the third port of the three-way valve is connected to the external vacuum system. The ratio of the inner diameter of the cavity of the powder cylinder 21 to the diameter of the valve core of the three-way valve and the diameter of the connecting pipeline 5 is 3:1 to 9:1. Among them, the diameter of the three-way valve core and the inner diameter of the connecting pipeline 5 are close to 1:1. In this way, it can not only ensure a better shear mixing effect, reduce the mixing time and number, but also avoid the problem of excessive resistance during the mixing process, resulting in the equipment reaching the pressure limit and being unable to continue mixing or leakage during the mixing process of the equipment.

[0041] In addition, the connecting pipeline 5 is preferably arc-shaped. The volume of the pipeline is preferably no more than 10% of the total volume of the solvent. This helps to reduce the initial residual solvent, so that as much solvent as possible enters the powder to wet the powder, thereby improving the initial powder wetting effect, reducing the time required for static hydration, and avoiding the problem of blockage caused by undissolved powder, thereby causing excessive pushing resistance.

[0042] The powder cylinder 21 and the solvent cylinder 31 are both made of polymethyl methacrylate (PMMA), and the three-way mixing structure 4 is made of polytetrafluoroethylene. The advantage of using PMMA as the cavity is that the preparation process is visualized, and the two materials are used together to have good sealing. The cavity can also be made of anodized aluminum or SUS304 stainless steel, and the inner wall is plated with PTFE film to ensure that the internal sealing and sliding properties meet the mixing requirements. In addition, the inner wall of the cavity should be smooth.

[0043] The vacuum system includes a vacuum pump (not shown), a vacuum gauge (not shown) and a sieve plate (not shown) at the inlet end of the vacuum pump for throttling fine solid powder. The sieve plate is made of ultra-high molecular weight polyethylene (UHMW-PE) material with a pore size not exceeding 5 μm.

[0044] Since the powder pushing mechanism 2, the solvent pushing mechanism 3 and the connecting pipeline 5 in the embodiment of the present application are arranged in a "U" shape, the space requirement is small and can meet the needs of mass production.

[0045] Reference Figures 5 to 7 In other embodiments, in order to meet the needs of both small-batch and large-batch production, the powder cylinder and the solvent cylinder are coaxially arranged to form a "one"-shaped double cavity 6, and the three-way mixing structure 4 is arranged between the powder cylinder and the solvent cylinder, which is used to connect the cavity of the powder cylinder and the cavity of the solvent cylinder. The powder pushing mechanism 2 is arranged at one end of the powder cylinder away from the three-way mixing structure 4. Similarly, the solvent pushing mechanism 3 is arranged at one end of the solvent cylinder away from the three-way mixing structure 4. Among them, the three-way mixing structure 4 includes a three-way structure 7 and a three-way valve core 8 arranged in the three-way structure, and the three-way structure 7 is a horizontal hole and a vertical hole that are interconnected. A vent 61 and a vacuum hole 62 are provided on the side wall of the "one"-shaped double cavity 6. Rotating the three-way valve core 8 can make the two cavities of the "one"-shaped double cavity 6 connected or isolated, and can also make the vent 61 and the vacuum hole 62 connected or isolated from the outside. It should be noted that the three-way valve core 8 includes all the parts of the three-way valve after the valve body is removed.

[0046] In this embodiment, the ratio of the inner diameter of the cavity of the "I"-shaped double cavity 6 to the diameter of the three-way valve core 8 and the diameter of the connecting pipeline is 3:1 to 9:1. Among them, the diameter of the three-way valve core and the inner diameter of the connecting pipeline are close to 1:1. The connecting pipeline here refers to the hole connecting the two cavities of the "I"-shaped double cavity 6.

[0047] Specifically, in this embodiment, the mounting bracket 1 includes a bottom plate 11b and two cylinder fixing seats 19 and two electric cylinder fixing seats 110 arranged on the bottom plate 11b. The bottom plate 11b is also a rectangular plate. The two electric cylinder fixing seats 110 are respectively fixedly connected to the left and right ends of the bottom plate 11b, and the fixed ends of the two linear electric cylinders 232 are fixedly connected to the bottom plate 11b through the electric cylinder fixing seats 110. The two ends of the "I"-shaped double cavity 6 are fixedly connected to the bottom plate 11b through the cylinder fixing seats 19.

[0048] The guide assembly 25 includes two guide rods 251 and two push rod support seats 252. The two push rod support seats 252 are symmetrically arranged on both sides of the "I"-shaped double cavity 6. The middle part of the guide rod 251 is sleeved in the two push rod support seats 252, and the two ends are respectively fixed to the corresponding electric cylinder fixing seat 110. That is, the two groups of guide assemblies 25 share a set of guide rods 251. The outer surface of the push rod support seat 252 is connected to the pressure sensor 24, and the inner surface is connected to the powder piston push rod 22 or the solvent piston push rod 32.

[0049] The embodiments of the present application also provide a method for preparing a pharmaceutical composition for sustained-release somatostatin analogs, comprising the following steps:

[0050] Step S1, loading of raw and auxiliary materials:

[0051] A preset amount of bulk drug powder to be dissolved is placed in the powder cylinder and compacted.

[0052] Step S2, solvent loading:

[0053] Place the prescribed amount of solvent in the solvent cylinder and ensure that there are no bubbles by manual exhaust, vacuum-assisted exhaust or simulated syringe drawing; the volume ratio of the raw material powder to the solvent is 1:1.

[0054] Step S3, vacuuming:

[0055] The three-way valve is controlled to connect the powder cylinder with the vacuum pump, and the vacuum pump is controlled to extract the vacuum in the powder gap for at least 10 minutes.

[0056] Step S4, wetting:

[0057] The three-way valve is controlled to connect the powder cylinder with the solvent cylinder, and the solvent completely enters the powder and preliminarily wets the powder, which lasts for at least 1 hour.

[0058] Step S5, mixing:

[0059] The powder driving system and the solvent driving system drive the powder piston push rod and the solvent piston push rod to reciprocate respectively. The wetted material is mixed by pumping back and forth between the two cavities. The reciprocating pumping is controlled by a semi-automatic or automatic program.

[0060] The effects of the present application are verified through multiple embodiments below.

[0061] Example 1: Study on the ratio of cavity inner diameter to three-way valve core and connecting pipe inner diameter

[0062] The preparation device with "I"-shaped structure was selected for the experiment. The ratio of the inner diameter of the cylinder: the inner diameter of the three-way valve core and the connecting pipeline is shown in the table below, where the cylinder volume is 100ml and the fixed cavity diameter is 30mm. By adjusting the size of the three-way valve core and the pipeline size, devices with different ratios can be obtained.

[0063] The total length between the bottoms of the two cylinders is 26 mm. The cylinder and the connecting pipe 5 are made of PMMA, and the three-way valve is made of PTFE, so that the whole experimental process can be visualized.

[0064] Prescription composition: 7.31 g of lanreotide acetate and 19.29 g of acidified water for injection to ensure that the pH of the finished product meets the requirements.

[0065] Preparation process:

[0066] Step 1: Loading raw materials and excipients: Place the raw material powder to be dissolved in the cavity, and gently press it while adding. It is preferred that the volume of the powder after compression is about 1.1:1 to the volume of the solvent.

[0067] Step 2 Solvent loading: Place the prescribed amount of solvent in another cavity and manually exhaust the air by pushing the cavity piston to ensure that there are as few bubbles as possible.

[0068] Step 3: Vacuuming: Control the three-way valve to connect the powder chamber and the vacuum pump, and remove as much air as possible from the powder by vacuuming. The vacuuming time should be at least 10 minutes.

[0069] Step 3: Wetting: Rotate the three-way valve, close the vacuum line, connect the powder and the solvent chamber, and allow the solvent to enter the powder and preliminarily wet the powder. The solvent is preferably added vertically and statically wetted for at least 1 hour.

[0070] Step 4: Mixing: The moistened material is pumped back and forth between the two cavities through a semi-automatic program control to achieve the final mixing of the material.

[0071] test:

[0072] Record the moment when the solvent enters the powder and the infiltration effect of the powder; record whether there are bubbles introduced during the mixing process that cause the translucent gel to turn white; record whether there is leakage at the connection of the equipment; record the sliding force during the mixing process; record the main component content detection of samples taken from the front, middle and back stages of the cavity from the same direction, and the reciprocating cycle is counted as one mixing.

[0073] The content of this product is determined by ultra-high performance liquid chromatography. The chromatographic conditions are as follows: octadecylsilane bonded silica gel is used as filler (waters ACQUITY UPLC HSS T3, 2.1mm*100mm, 1.8um, or a chromatographic column with equivalent column efficiency); flow rate: 0.3ml / min; column temperature: 25℃; sample plate temperature: 10C; injection volume: 3uL; detection wavelength 280nm; mobile phase A: take 6g of sodium perchlorate and add 1.0ml of phosphoric acid, add 2L of water to fully dissolve; mobile phase B: take 6g of perchloric acid and add 1.0ml of phosphoric acid, add 101ml of methanol, add 1107ml of acetonitrile, and then add 800ml of water to fully mix. Elution is carried out according to the following gradient:

[0074]

[0075] Take an appropriate amount of this product, add 0.1mol / L acetic acid solution and quantitatively dilute to make a solution containing about 0.1mg of lanreotide base per 1mL as the test solution; take an appropriate amount of lanreotide acetate reference substance, accurately weigh, add 0.1mol / L acetic acid solution and quantitatively dilute to make a solution containing about 0.1 lanreotide base per 1mL as the reference solution (prepare two in parallel). Accurately measure 3uL of the test solution and the reference solution, respectively, inject them into the liquid chromatograph, record the chromatogram, and calculate the content of lanreotide acetate by the external standard method.

[0076] The results of Examples 1-1 to 1-5 show that the ratio of the inner diameter of the cavity: the inner diameter of the three-way valve core and the pipeline directly affects the function of the equipment. When the ratio is 3:1 to 9:1, the pushing resistance, sealing and mixing uniformity of the preparation process are at a better level.

[0077] Table 1. Different cavity inner diameters: ratio of three-way valve core and pipeline inner diameter

[0078]

[0079] Table 2. Sliding thrust and content uniformity during mixing of equipment with different diameter ratios

[0080]

[0081] Example 2: Study on the ratio of cavity inner diameter to cone height

[0082] A device with a "U"-shaped structure was selected for the experiment. The powder cylinder 21 and the solvent cylinder 31 consist of two cavities for containing the API powder and the solvent respectively, a three-way valve and a connecting pipe 5 that is as short as possible; the inner diameter of the inner cavity of the cylinder: the inner diameter ratio of the three-way valve core and the connecting pipe 4 is 4:1, where the cavity volume is 125mL, the cavity diameter is 40mm, and the inner diameter of the three-way valve core size and the pipe size is 10mm. The total length of the distance between the two cavities is 36mm. The cylinder and the connecting pipe 5 are made of PMMA, and the three-way valve is made of PTFE, so that the entire experimental process can be visualized. The bottom of the cavity adopts a conical design, and the inner diameter of the cavity: the height of the cone is in accordance with the proportion in the table below, where the fixed inner diameter of the cavity is 40mm.

[0083] Prescription composition: 14.61g lanreotide acetate, 38.59g acidified water for injection to ensure that the pH of the finished product meets the requirements.

[0084] Preparation process: Same as Example 1.

[0085] Detection method: Same as Example 1. Record the sliding force during the mixing process; record whether there is obvious powder remaining on the conical inner wall that cannot be sheared and dissolved during the mixing process; record the content of the sample scraped from the conical inner wall of the powder loading cavity.

[0086] The results of Examples 2-1 to 2-5 show that the ratio of the cavity inner diameter to the cone height directly affects the function of the equipment. When the ratio of the cavity inner diameter to the cone height is 2:1 to 8:1, the pushing resistance of the preparation process, the residual dead volume in the conical area and the mixing effect are at a better level.

[0087] Table 3. Sliding thrust and content uniformity during mixing of equipment with different cavity diameters and cone height ratios

[0088]

[0089] Example 3: Batch Scaling

[0090] A device with a "U"-shaped structure was selected for the experiment. The powder cylinder 21 and the solvent cylinder 31 are composed of two cavities for containing the API powder and the solvent respectively, a three-way valve and a connecting pipe 5 that is as short as possible. The two cylinders are made of SUS304 stainless steel with better pressure resistance and wear resistance, and are plated with PTFE film on their inner walls to ensure that the internal sealing and sliding properties meet the mixing requirements. The ratio of the inner diameter of the cavity: the inner diameter of the three-way valve core and the inner diameter of the pipeline is 5:1, of which the cavity volume is 6L and the diameter is 150mm. The inner diameter of the three-way valve core size and the inner diameter of the pipeline size is 30mm; the total length of the distance between the two cavities is 50mm; the bottom of the cavity adopts a conical design, and the inner diameter of the cavity: the height of the cone is 6:1, that is, the height of the bottom of the cone is 25mm.

[0091] Prescription composition: 730.56g of lanreotide acetate and 1929.44g of acidified water for injection to ensure that the pH of the finished product meets the requirements.

[0092] Preparation process: same as Example 1, prepare three batches. Simultaneously, add three batches for heat preservation control, and control the jacket temperature to 50°C ± 5°C.

[0093] Detection method: Same as Example 1. Record the sliding force during mixing; record the content uniformity of the sample; record the appearance of the product.

[0094] The results of Examples 3-1 to 3-6 show that the production scale-up effect of the equipment is good.

[0095] Table 4. Sliding thrust and content uniformity during mixing of equipment with different diameter ratios

[0096]

[0097] The above are only specific implementations of the present application, but the protection scope of the present application is not limited thereto, and any changes or substitutions within the technical scope disclosed in the present application should be included in the protection scope of the present application. Therefore, the protection scope of the present application should be based on the protection scope of the claims.

Claims

1. A device for preparing a pharmaceutical composition for sustained-release somatostatin analogs, characterized in that: It includes a mounting bracket and a powder pushing mechanism, a solvent pushing mechanism and a three-way mixing structure arranged on the mounting bracket; the powder pushing mechanism includes a powder cylinder, a powder piston push rod and a powder driving system; the solvent pushing mechanism includes a solvent cylinder, a solvent piston push rod and a solvent driving system; the powder cylinder is connected to the solvent cylinder through a three-way mixing structure; the three-way mixing structure is connected to an external vacuum system; the powder driving system can drive the powder piston push rod to reciprocate; the solvent driving system can drive the solvent piston push rod to reciprocate.

2. The device for preparing a pharmaceutical composition for sustained-release somatostatin analogs according to claim 1, characterized in that: The powder driving system includes a servo motor and a linear electric cylinder arranged in sequence along the axial direction; the fixed end of the linear electric cylinder is connected to the mounting bracket, and the telescopic end is connected to the powder piston push rod; a pressure sensor is provided between the linear electric cylinder and the powder piston push rod; the solvent driving system has the same structure as the powder driving system.

3. The device for preparing a pharmaceutical composition for sustained-release somatostatin analogs according to claim 2, characterized in that: The powder cylinder is provided with a heat-insulating interlayer; the solvent cylinder has the same structure as the powder cylinder.

4. The device for preparing a pharmaceutical composition for sustained-release somatostatin analogs according to claim 3, characterized in that: The bottom surface of the cavity of the powder cylinder is a conical surface or a hemispherical surface, and the ratio of the inner diameter of the cavity to the height of the conical surface is 2:1 to 8:

1.

5. The device for preparing a pharmaceutical composition for sustained-release somatostatin analogs according to claim 4, characterized in that: The three-way mixing structure is made of polytetrafluoroethylene; the powder cylinder is made of polymethyl methacrylate or anodized aluminum or SUS304 stainless steel and the inner wall thereof is plated with a PTFE film.

6. The device for preparing a pharmaceutical composition for sustained-release somatostatin analogs according to claim 5, characterized in that: The powder piston push rod comprises a push rod and a conical piston connected to the end of the push rod; a fluororubber sealing ring and a wear-resistant ring are sequentially arranged on the conical piston along the axial direction.

7. The device for preparing a pharmaceutical composition for sustained-release somatostatin analogs according to claim 6, characterized in that: It also includes a guide assembly; the guide assembly includes a guide rod and a push rod support seat; the two ends of the guide rod are fixedly connected to the mounting bracket, and the middle part is sleeved in the push rod support seat; one end of the push rod support seat is connected to the pressure sensor, and the other end is connected to the powder piston push rod or the solvent piston push rod.

8. The device for preparing a pharmaceutical composition for sustained-release somatostatin analogs according to claim 7, characterized in that: The powder pushing mechanism and the solvent pushing mechanism are both arranged in the vertical direction, and the two are arranged side by side; the three-way mixing structure is a three-way valve; the powder cylinder and the solvent cylinder are both connected to the three-way valve through a connecting pipeline; the ratio of the inner diameter of the cavity of the powder cylinder or the solvent cylinder to the diameter of the valve core of the three-way valve is 3:1 to 9:1; the ratio of the inner diameter of the cavity of the powder cylinder or the solvent cylinder to the diameter of the connecting pipeline is also 3:1 to 9:1; the connecting pipeline is arc-shaped.

9. The device for preparing a pharmaceutical composition for sustained-release somatostatin analogs according to claim 7, characterized in that: The powder pushing mechanism and the solvent pushing mechanism are arranged in an "I" shape along the horizontal direction, and the powder cylinder and the solvent cylinder together form an "I"-shaped double cavity; the two cavities of the "I"-shaped double cavity are connected through a three-way mixing structure; the three-way mixing structure includes a three-way structure and a three-way valve core arranged in the three-way structure; the ratio of the inner diameter of the cavity of the "I"-shaped double cavity to the diameter of the valve core of the three-way valve core is 3:1 to 9:1.

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