An irregular microsphere sorting screen and sorting device

Abstract

The present application relates to the field of pharmaceutical processing equipment, and discloses an irregular microsphere sorting screen and a sorting device, the sorting screen comprising upper, middle and lower layer screens stacked from top to bottom; each layer screen is composed of at least one square hole screen, and the warp and weft lines of the upper and lower layer screens coincide under the perspective angle, and the warp and weft lines of the middle layer screen form an angle of 30-60° or 120-150° with the upper and lower layer screens; the aperture of the screen in the next layer is not less than that in the previous layer, and the distance between the adjacent two screens is less than or equal to 0.5 mm. The sorting screen is assembled by stacking a certain number of screens with specific screen hole shapes, warp and weft angles and upper and lower distances, which can effectively intercept irregular microspheres and almost does not affect the filtration flux of qualified microsphere products.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical processing equipment, and more particularly to an irregular microsphere sorting sieve and sorting device. Background Technology

[0002] In the field of sterile injectables, microspheres refer to particulate dispersion systems formed by dispersing or adsorbing drugs within a polymer matrix. Microspheres can be administered via intramuscular, subcutaneous, intravitreal, and intra-articular injections, increasing drug retention time, improving local drug concentration, and reducing systemic reactions.

[0003] Common methods for preparing microspheres include solvent evaporation, solvent extraction, complex coagulation, spray drying, and rotary table methods. These methods typically result in microspheres with a wide particle size distribution, and the process often produces irregularly shaped products, such as non-spherical microcapsules or microparticles, including flocculent, rod-shaped, filamentous, and spindle-shaped products, each with at least one protrusion. The presence of these irregular products not only affects the appearance and suspension properties of the microspheres but also poses a high risk of needle blockage during injection, potentially leading to clinical injection failure or inaccurate dosage.

[0004] Patent CN101489539A discloses a spherical or non-spherical microencapsulation agent comprising GLP-1 peptide, its preparation, and its application. However, the described examples all revolve around the preparation and application of spherical microencapsulation agents. The specification only mentions that wherever "spherical" microencapsulation agents are mentioned in the disclosure, "non-spherical" microencapsulation agents can also be provided, prepared, or used. Furthermore, no beneficial effects of the presence of non-spherical microencapsulation agents are disclosed. Patent CN109310975A discloses that in the mass production of monodisperse biodegradable polymer-based microspheres, if the concentration of the biodegradable polymer is less than 5% by weight, microspheres will not form; if the concentration exceeds 30% by weight, the formed microspheres will have a non-spherical shape. Patent KR1020180130344A mentions that due to processes such as emulsification of aqueous and organic phases, the possibility of partial aggregation of particles or the formation of non-spherical microcapsules is high, and it is more difficult to control variable processes when scaling up or even commercializing.

[0005] Irregularities in microsphere products pose a significant challenge, as they are practically impossible to control effectively through initial preparation processes during large-scale microsphere production. To prevent needle clogging during clinical injection, it is necessary to effectively screen for microsphere particle size distribution and morphology, removing excessively large microsphere aggregates and these irregular microsphere products.

[0006] Existing microsphere sieving technologies are broadly classified into two categories based on the three-dimensional structure of the screen: planar screens and cylindrical screens. Based on the microstructure of the screen, they can be divided into single-layer screens or combinations of single-layer screens and support layers. The latter is typically used to prevent damage to the single-layer screen under high filtration pressure. Furthermore, auxiliary measures such as installing the screen at a fixed angle, vibration, rotation, or agitation of the liquid can be employed to increase sieving efficiency and prevent screen clogging during filtration. During the sorting process, selecting the screen aperture can remove or retain microspheres with a specific particle size distribution range. Furthermore, a three-dimensional combination of screens with different apertures can be used to progressively sieve microspheres of different average particle sizes.

[0007] However, irregular products, especially those with particle size distributions not significantly different from normal products, may pass through the sieve along with regular microspheres due to at least one part having a particle size close to or the same as that of regular microspheres, thus failing to be effectively sieved. Such irregular products are highly likely to occur during the preparation of sterile microspheres. Currently, no effective sieving method has been disclosed in the industry for removing these irregular products formed during the sterile production of microspheres. Existing sorting sieves are also not suitable for sieving microspheres (<200µm) in principle and structure.

[0008] To this end, the applicant has made various attempts in the early stages, including separation by centrifugation, density separation, wet sieving, and dry sieving, but the results have been unsatisfactory. Therefore, how to remove irregular products from the microsphere products is a pressing technical problem that needs to be solved. Summary of the Invention

[0009] To address the aforementioned technical problems, this invention provides an irregular microsphere sorting sieve and sorting device. This invention assembles a sorting sieve by stacking a certain number of sieve meshes with specific sieve hole shapes, warp and weft angles, and interlayer spacing. This not only effectively traps irregular microspheres but also hardly affects the filtration throughput of qualified microsphere products.

[0010] The specific technical solution of this invention is as follows:

[0011] In a first aspect, the present invention provides an irregular microsphere sorting sieve, comprising an upper sieve, a middle sieve, and a lower sieve stacked from top to bottom. Each sieve layer consists of at least one identical square-aperture sieve, and from a top-view angle, the warp and weft lines of the upper and lower sieves coincide. The middle sieve forms an angle of 30–60° or 120–150° with the warp and weft lines of the upper and lower sieves. The aperture of the sieve in the next lower layer is not lower than that of the layer above, and the distance between two adjacent sieves is less than 0.5 mm.

[0012] During the exploration of wet sieving, this invention, through extensive experimental and comparative studies, discovered that a sorting sieve composed of a certain number of tightly stacked sieve meshes with specific mesh shapes and warp and weft angles has an unexpectedly significant effect on removing irregular microspheres. This invention further found that factors such as the number of sieve mesh layers and the sieve mesh spacing significantly affect the filtration flux and retention effect of the microsphere products, and the parameters mentioned above in this invention are the optimized results.

[0013] Existing wet sieving techniques can only sieve microspheres with a diameter exceeding the sieve aperture through a single planar structure by adjusting the sieve aperture size. Furthermore, combinations of sieves with different aperture sizes can sieve microspheres with different particle size distributions. This invention, however, innovatively constructs a spatial structure sieving channel that can accommodate irregularly shaped microspheres. This allows the microspheres to develop an orientation during filtration. When the microspheres do not match the spatial structure of the sieving channel, they will be trapped by the sieve. The specific principle is as follows:

[0014] When different screens are tightly stacked together according to the specific method described above, screening channels with a certain spatial structure can be formed. These channels can trap irregular microspheres in space. For conventional spherical products, they can pass smoothly through the screen channels with the spatial structure. Moreover, by combining screens with different apertures, various aperture sizes can be created. The shapes of these apertures are very similar to those of irregular microspheres, but they only allow filtration in a certain fixed flow direction, thus successfully intercepting the irregular microspheres. When the square aperture of each layer of screens from top to bottom is the same, the interception efficiency of these irregular microspheres is even better. However, since there are many apertures that intercept irregular microspheres, once a screen aperture is blocked by irregular microspheres too early, no other microspheres can pass through that aperture, resulting in a lower overall filtration flux. When the aperture of each layer of screen increases from top to bottom, the number of apertures used to intercept irregular microspheres can be appropriately reduced, thereby achieving a balance between interception efficiency and filtration throughput. This means that while ideally intercepting irregular microspheres, high sieving efficiency of conventional microspheres is also ensured.

[0015] Furthermore, we also found that the influence of the spacing between adjacent screen layers in the sorting sieve is as follows: when the spacing between each screen layer of the sorting sieve is greater than the range set by the present invention, it is close to multiple screenings of a multi-layer two-dimensional planar sieve. Due to the large distance between the screens, the three-dimensional spatial structure formed by the present invention is lost, and the interception of irregular microspheres is not significant. When the spacing between each screen layer is infinitely large, there is no difference in filtration effect from a multi-layer planar sieve.

[0016] In summary, the sorting sieve of the present invention can effectively screen and remove irregular microspheres (including flocculent, filamentous, rod-shaped and spindle-shaped products) from microsphere products, especially those whose particle size distribution is similar to that of normal spherical products with no significant difference, and improves screening efficiency, further ensuring the quality stability and safety of microsphere products.

[0017] Preferably, the mesh size, measured by the side length of a square, is 3 to 5 times the diameter of the trapped microspheres.

[0018] The screen aperture can be adjusted according to the diameter of the target irregular microspheres. Based on previous experimental results, this invention optimizes the screen aperture to be 3 to 5 times the diameter of the microspheres to be retained. Specifically, this invention concludes that: when the aperture of each layer of the sorting screen is the same, the retention of irregular microspheres is more thorough, but the filtration flux is lower; when the screen aperture increases from top to bottom, both the retention effect of irregular microspheres and the filtration flux can be improved (see...). Figure 9 and Figure 10 ).

[0019] Preferably, the warp and weft lines of the middle screen are at an angle of 45° or 135° to the warp and weft lines of the upper and lower screens.

[0020] Preferably, the spacing between two adjacent screens is less than 0.2 mm.

[0021] Preferably, the upper, middle and lower screens are each made of 1 to 2 identical screens stacked on top of each other.

[0022] Preferably, the edges of the upper, middle and lower screens are sealed together to form a closed structure. This can be achieved by integral welding or spot welding followed by sealing with an annular sealing ring.

[0023] Secondly, the present invention provides an irregular microsphere sorting device, comprising:

[0024] The filter tank has an inlet at the top and an outlet at the bottom.

[0025] An irregular microsphere sorting sieve is installed inside the filter tank, and its four edges are sealed to the inner wall of the filter tank.

[0026] Preferably, the irregular microsphere sorting sieve is horizontally mounted.

[0027] Preferably, the tank above the irregular microsphere sorting sieve is cylindrical, and the lower part is conical.

[0028] Preferably, the irregular microsphere sorting device is suitable for sieving irregular microspheres with a particle size of 2μm to 1mm, more preferably 2μm to 200μm, and even more preferably 20μm to 100μm.

[0029] Compared with the prior art, the beneficial effects of the present invention are as follows: The present invention assembles a sorting sieve by stacking a certain number of sieve meshes with specific sieve hole shapes, warp and weft angles, and interlayer spacing. This not only effectively screens and removes irregular products (including flocculent, filamentous, rod-shaped, and spindle-shaped products) from microsphere products, especially those with particle size distributions that are similar to normal products and have no significant differences, but also has a high screening efficiency for qualified microsphere products, further ensuring the quality stability and safety of microsphere products. Attached Figure Description

[0030] Figure 1 This is a schematic diagram (top view) of the overall and disassembled structure of the sorting sieve in Embodiment 1 of the present invention.

[0031] Figure 2 This is a schematic diagram (top view) of the overall and disassembled structure of the sorting sieve in Embodiment 2 of the present invention.

[0032] Figure 3 This is a schematic diagram (top view) of the overall and disassembled structure of the sorting sieve in Embodiment 3 of the present invention.

[0033] Figure 4 This is a top view of the overall and disassembled structure of the sorting sieve in Embodiment 4 of the present invention.

[0034] Figure 5 This is a schematic diagram of one structure of the sorting device of the present invention.

[0035] Figure 6 This is a top view of the overall and disassembled structure of the sorting sieve in Comparative Example 1.

[0036] Figure 7 This is a schematic diagram (top view) of the sorting sieve structure for Comparative Example 2.

[0037] Figure 8 This is a top view of the overall and disassembled structure of the screen in Comparative Example 3.

[0038] Figure 9 This is a schematic diagram illustrating the retention effect principle of a sorting sieve (with the same square hole diameter in each layer of sieve from top to bottom) according to the present invention.

[0039] Figure 10 A schematic diagram illustrating the retention effect principle of another sorting sieve of the present invention (the diameter of the square holes in each layer of the sieve increases from top to bottom).

[0040] The attached diagram is labeled as follows: Irregular microsphere sorting sieve 1, upper sieve 11, middle sieve 12, lower sieve 13, filter tank 100, feed inlet 101, and discharge outlet 102. Detailed Implementation

[0041] The present invention will be further described below with reference to embodiments.

[0042] General Implementation Examples

[0043] An irregular microsphere sorting sieve 1, such as Figure 1-4 As shown, the screen comprises an upper screen 11, a middle screen 12, and a lower screen 13 stacked from top to bottom. Each of the upper, middle, and lower screens is composed of one to two identical screens stacked vertically. Each screen layer consists of at least one identical square-hole screen, and from a top-down view, the warp and weft lines of the upper and lower screens coincide. The warp and weft lines of the middle screen form an angle of 30–60° or 120–150° with the warp and weft lines of the upper and lower screens (most preferably 45° and 135°). The aperture of the screen in the next lower layer is not lower than that of the previous layer (the aperture, measured as the side length of a square, is 3–5 times the diameter of the trapped microspheres), and the distance between two adjacent screens is less than 0.5 mm (more preferably less than 0.2 mm). The edges of the upper, middle and lower screens are sealed together to form a closed structure. This can be achieved by integral welding or spot welding followed by sealing with an annular sealing ring.

[0044] An irregular microsphere sorting device, such as Figure 5 As shown, it includes:

[0045] The filter tank 100 has an inlet 101 at its top and an outlet 102 at its bottom.

[0046] The irregular microsphere sorting sieve 1 is horizontally mounted inside the filter tank, and its four edges are sealed to the inner wall of the filter tank.

[0047] The filter tank, located above the irregular microsphere sorting sieve, is cylindrical, while the lower portion is conical. This irregular microsphere sorting device is suitable for sorting irregular microspheres with a particle size of 2μm to 1mm, more specifically 2μm to 200μm, and even more preferably 20μm to 100μm.

[0048] In the following specific embodiments, the microsphere set will be screened, with the microsphere particle size range being 2 to 200 μm and the target microsphere particle size range being 2 to 70 μm.

[0049] Example 1 (Preferred Example)

[0050] An irregular microsphere sorting sieve 1, such as Figure 1As shown, the structure consists of three square mesh screens stacked one on top of the other. The first screen (upper screen 11) has a mesh diameter of 150 μm (measured by one side of the square mesh, the same applies below), the second screen (middle screen 12) has a mesh diameter of 150 μm, and the third screen (lower screen 13) has a mesh diameter of 150 μm. From a top-down view, the latitude and longitude of the first and third screens coincide, while the latitude and longitude of the second screen are at a 45° angle to the first and third screens. The spacing between each screen is 0.15 mm. The edges of each screen are sealed and welded together to form a closed structure.

[0051] An irregular microsphere sorting device 100, such as Figure 5 As shown, it includes: a filter tank (with an inlet 101 at the top and an outlet 102 at the bottom) and an irregular microsphere sorting screen. The irregular microsphere sorting screen is horizontally mounted inside the filter tank, and its four edges are sealed to the inner wall of the filter tank. The portion of the filter tank above the irregular microsphere sorting screen is cylindrical, and the portion below it is conical.

[0052] During operation, the microsphere suspension is injected through the feed inlet and discharged and collected through the outlet.

[0053] Sorting effect: Spherical products and a small portion of irregular products pass through the screen, while excessively large microspheres or irregular products are retained. The screening throughput is relatively large.

[0054] Example 2

[0055] An irregular microsphere sorting sieve 1, such as Figure 2 As shown, the structure consists of five square mesh screens stacked one on top of the other. The first, second, third, fourth, and fifth screens each have a 200μm aperture. From a top-down view, the upper screen 11 (the first and second screens) and the lower screen 13 (the fourth and fifth screens) have the same latitude and longitude, while the middle screen 12 (the third screen) maintains a 45° angle with both the upper and lower screens. The spacing between each screen is 0.2mm. The edges of each screen are sealed and welded together, forming a closed structure.

[0056] An irregular microsphere sorting device, which differs from Example 1 in that it uses the irregular microsphere sorting sieve of Example 2.

[0057] Sorting effect: Microspheres with excessively large particle size, a small portion of spherical products, and almost all irregular products are retained. The sieve throughput is relatively low.

[0058] Example 3 (Preferred Example)

[0059] An irregular microsphere sorting sieve 1, such as Figure 3As shown, the structure consists of three square mesh screens stacked one on top of the other. The first screen (upper screen 11) has a mesh size of 100 μm, the second screen (middle screen 12) has a mesh size of 150 μm, and the third screen (lower screen 13) has a mesh size of 300 μm. Viewed from above, the first and third screens are aligned in latitude and longitude, while the second screen forms a 45° angle with both the first and third screens. The spacing between each screen is 0.1 mm. The edges of each screen are sealed and welded together to form a closed structure.

[0060] An irregular microsphere sorting device, which differs from Example 1 in that it uses the sorting sieve of Example 3.

[0061] Sorting effect: Spherical products and a very small number of irregular products pass through the screen, while microspheres or irregular products with excessively large particle sizes are retained. The screening throughput is relatively large.

[0062] Example 4 (Preferred Example)

[0063] An irregular microsphere sorting sieve, such as Figure 4 As shown, the structure consists of four square mesh screens stacked one on top of the other. The first screen has a mesh size of 100μm, the second 150μm, the third 200μm, and the fourth 200μm. From a top-down view, the upper screen 11 (the first screen) and the middle screen 12 (the second screen) maintain a 45° angle in latitude and longitude, and the middle screen (the second screen) and the lower screen 13 (the third and fourth screens) also maintain a 45° angle in latitude and longitude (i.e., the upper and lower screens coincide in latitude and longitude). The spacing between each screen is 0.15mm. The edges of each screen are sealed and welded together to form a closed structure.

[0064] An irregular microsphere sorting device, which differs from Example 1 in that it uses the sorting sieve of Example 4.

[0065] Sorting effect: Spherical products and a small portion of irregular products pass through the screen, while excessively large microspheres or irregular products are retained. The screening throughput is moderate.

[0066] Comparative Example 1

[0067] An irregular microsphere sorting sieve, such as Figure 6As shown, the structure consists of three square mesh screens stacked one on top of the other. The first screen (upper screen 11) has a mesh size of 150 μm, the second screen (middle screen 12) has a mesh size of 150 μm, and the third screen (lower screen 13) has a mesh size of 150 μm. From a top-down view, the first and second screens maintain a 30° angle in latitude and longitude, the second and third screens maintain a 30° angle in latitude and longitude, and the first and third screens maintain a 60° angle in latitude and longitude. The spacing between each screen is 0.15 mm. The edges of each screen are integrally sealed and welded to form a closed structure.

[0068] Sorting results: Some spherical products passed through the sieve smoothly, while microspheres with excessively large particle sizes, irregular products, and some spherical products were retained. The sieve throughput was relatively low. Over-screening of irregular products resulted in the retention of some samples.

[0069] Comparative Example 2

[0070] An irregular microsphere sorting sieve, such as Figure 7 As shown, the structure consists of three square mesh screens stacked one on top of the other. The first screen (upper screen 11) has a mesh size of 150 μm, the second screen (middle screen 12) has a mesh size of 150 μm, and the third screen (lower screen 13) has a mesh size of 150 μm. From a top-down view, the latitude and longitude of the first and second screens coincide, as do the latitude and longitude of the second and third screens. The spacing between each screen is 0.15 mm. The edges of each screen are sealed and welded together to form a closed structure.

[0071] Sorting effect: Spherical products and most irregular products pass through the screen smoothly, while excessively large microspheres or a small portion of irregular products are retained. The screening throughput is relatively high. However, the sorting effect on irregular products is low.

[0072] Comparative Example 3

[0073] A sorting sieve, such as Figure 8 As shown, it consists of a single square mesh screen with a mesh size of 150μm.

[0074] Sorting effect: Spherical products and most irregular products pass through the screen smoothly, while excessively large microspheres or a small number of irregular products are retained. The screening throughput is relatively high. There is no sorting effect on irregular products.

[0075] Comparative Example 4

[0076] An irregular microsphere sorting sieve consists of three square mesh screens stacked one on top of the other. The first, second, and third screens each have a 150μm aperture. Viewed from above, the first and third screens are aligned in latitude and longitude, while the second screen forms a 45° angle with both the first and third screens. The spacing between each screen is 2mm. The edges of all screens are integrally sealed and welded together, forming a closed structure.

[0077] Sorting effect: No significant difference compared to single-layer screens. High throughput. No sorting effect on irregular products.

[0078] Comparative Example 5

[0079] An irregular microsphere sorting sieve consists of three square mesh screens stacked one on top of the other. The first, second, and third screens each have a 150μm aperture. Viewed from above, the first and third screens are aligned in latitude and longitude, while the second screen forms a 45° angle with both the first and third screens. The spacing between each screen is 1mm. The edges of all screens are integrally sealed and welded together, forming a closed structure.

[0080] Sorting effect: Compared with single-layer screens, it can intercept excessively long irregular products. The screening throughput is relatively large. However, it has only limited sorting effect on irregular products.

[0081] The table below compares the screening effects of the sorting sieves used in Examples 1-4 and Comparative Examples 1-5, as detailed below:

[0082]

[0083]

[0084] Note: The above retention efficiency percentages are the percentages of spherical and irregular products, respectively. Before screening, spherical products still account for the majority of the product, while irregular products account for only a small portion.

[0085] The data comparison in the table above shows that:

[0086] In Comparative Example 1, the warp and weft angles of each screen are different, resulting in an excessively curved spatial structure. This causes too many irregular products to be trapped and clog the screen, thus affecting the throughput of normal products. After over-screening irregular products, some normal spherical samples are also trapped.

[0087] In Comparative Example 2, the warp and weft threads of each screen overlap, resulting in a spatial structure that is not curved enough. When some irregular products pass through the screen, they can pass smoothly through the three layers of screens along the fluid direction, resulting in a large throughput and low sorting effect for irregular products.

[0088] Comparative Example 3 is a single-layer screen, which does not have a spatial structure and is no different from a flat screen, so it cannot effectively distinguish between spherical and irregular products.

[0089] In Comparative Example 4, the wide vertical spacing between each screen causes irregular products to adjust their screening direction further in line with the fluid flow when passing through the first screen, thus allowing them to pass through the second or even third screen. Therefore, its screening efficiency is low.

[0090] In Comparative Example 5, the spacing between each screen is narrower than in Comparative Example 4, but it is still larger than the ideal spacing, and therefore does not have a high sorting effect. The reason is still that the spatial structure it forms is too loose, allowing most irregular products to escape and not be successfully intercepted.

[0091] Unless otherwise specified, the raw materials and equipment used in this invention are all commonly used in the field; unless otherwise specified, the methods used in this invention are all conventional methods in the field.

[0092] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Any simple modifications, alterations, and equivalent transformations made to the above embodiments based on the technical essence of the present invention shall still fall within the protection scope of the present invention.

Claims

1. An irregular microsphere sorting sieve, characterized in that: It includes an upper layer of screens, a middle layer of screens, and a lower layer of screens stacked from top to bottom; Each layer of screen consists of at least one identical square-hole screen, and when viewed from above, the warp and weft threads of the upper and lower screens coincide. The middle screen forms an angle of 30-60° or 120-150° with the warp and weft threads of the upper and lower screens. The spacing between two adjacent screens is less than 0.5mm. The mesh size of the screen in the next layer is not smaller than that in the layer above; The mesh size, measured by the side length of a square, is 3 to 5 times the diameter of the trapped microspheres.

2. The irregular microsphere sorting sieve as described in claim 1, characterized in that: The middle layer screen forms an angle of 45° or 135° with the warp and weft lines of the upper and lower layers screens.

3. The irregular microsphere sorting sieve as described in claim 1, characterized in that: The spacing between two adjacent screens should be less than 0.2mm.

4. The irregular microsphere sorting sieve as described in claim 1, characterized in that: The upper, middle, and lower screens are each made of 1 to 2 identical screens stacked together.

5. The irregular microsphere sorting sieve as described in claim 1, characterized in that: The edges of the upper, middle, and lower screens are sealed together.

6. An irregular microsphere sorting device, characterized in that: include: The filter tank has an inlet at the top and an outlet at the bottom. The irregular microsphere sorting sieve as described in any one of claims 1-5 is installed inside the filter tank and its four edges are sealed to the inner wall of the filter tank.

7. The irregular microsphere sorting device as described in claim 6, characterized in that: The tank above the irregular microsphere sorting sieve is cylindrical, and the lower part is conical.

8. The application of the irregular microsphere sorting device as described in claim 6 or 7 in screening irregular microspheres, characterized in that: The irregular microspheres have a particle size of 2μm to 1mm.

9. The application as described in claim 8, characterized in that: The irregular microspheres have a particle size of 2μm to 200μm.

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