Microcrystal suspension multi-ball soft capsule as well as preparation method and application thereof
The microcrystalline suspended multi-sphere soft capsule structure solves the problems of drug particle sedimentation and single drug release control, achieving stable drug suspension and slow release, and is suitable for oral drug formulations.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- 山东润安生物科技有限公司
- Filing Date
- 2026-01-26
- Publication Date
- 2026-04-17
AI Technical Summary
Existing soft capsule technology suffers from the problem that drug particles are prone to sedimentation and clumping during storage and transportation, resulting in uneven content and affecting the stability of efficacy; sustained-release drugs have a single release control method, and it is difficult to ensure the stability of the formulation in industrial production.
The microcrystalline suspended multi-sphere soft capsule structure consists of an outer shell, a temperature-sensitive hydrogel, and drug-loaded microcrystalline spheres. The drug-loaded microcrystalline spheres are prevented from settling under the spatial constraint of the temperature-sensitive hydrogel. When the outer shell disintegrates rapidly, the temperature-sensitive hydrogel slowly dissolves, the drug-loaded microcrystalline spheres are slowly released, and the drug nanocrystals are steadily dissolved.
It achieves stable drug suspension and slow release, avoids drug sedimentation and aggregation, meets the needs of large-scale production, and ensures stable drug dissolution and therapeutic stability.
Smart Images
Figure CN121868240A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of oral pharmaceutical formulation technology, specifically relating to a microcrystalline suspended multi-sphere soft capsule and its preparation method and application. Background Technology
[0002] Oral soft capsules, as a commonly used drug carrier, are widely used for the delivery of lipid-soluble and easily oxidized drugs due to their advantages such as good taste masking and high bioavailability. However, existing soft capsule technology has significant drawbacks: (1) If the contents are a drug-loaded particle suspension, the particles are prone to sedimentation and clumping during storage and transportation, resulting in uneven content and affecting the stability of efficacy. (2) For drugs requiring sustained release, most soft capsules rely on the direct release of the drug after the outer shell disintegrates, resulting in a single drug release control method.
[0003] (3) Some controlled-release soft capsules use complex carriers (such as nanocomposite gels), which require special production equipment and are difficult to balance the needs of industrial production with the stability of the formulation. Summary of the Invention
[0004] In view of the problems in the background art, the present invention provides a microcrystalline suspended multi-sphere soft capsule, its preparation method and application.
[0005] The technical solution of the present invention is as follows: This invention provides a microcrystalline suspended multisphere soft capsule, which comprises, from the outside in, a shell and a composite system, wherein the composite system is encapsulated by the shell. The composite system is formed by dispersing multiple drug-loaded microspheres in the thermosensitive hydrogel; The temperature-sensitive hydrogel has a three-dimensional porous network structure, is liquid below 28°C, and transforms into a gel above 36°C. The drug-loaded microspheres are three-dimensional porous spherical particles, with the drug dispersed in the three-dimensional porous structure in the form of nanocrystals.
[0006] Furthermore, the particle size of the drug-loaded microspheres is 1-5 μm, and the particle size of the nanocrystals is no greater than 200 nm.
[0007] The temperature-sensitive hydrogel has a pore size of 10-50 μm, and the pore channels connect adjacent pores, with an inner diameter of 2-5 μm.
[0008] The outer shell is in the form of an elliptical or spherical soft capsule, with a thickness of 0.15-0.2 mm.
[0009] This invention also provides a method for preparing the aforementioned microcrystalline suspended multi-sphere soft capsules, comprising the following steps: (1) The dispersed drug is subjected to high-pressure homogenization to obtain a drug nanocrystal suspension; The drug nanocrystal suspension was sequentially atomized and freeze-dried to obtain drug-loaded microspheres; (2) Poloxamer was stirred in purified water at 2-5℃ until it became a viscous liquid, and then refrigerated to obtain a thermosensitive hydrogel premix. (3) Disperse the drug-loaded microspheres in a thermosensitive hydrogel premix solution stirred at the first temperature to obtain a composite system; (4) Using gelatin liquid as the outer shell substrate and composite system as the contents, the capsules are press-filled at the second temperature and dried to obtain microcrystalline suspension multisphere soft capsules.
[0010] Furthermore, the refrigeration temperature in step (2) is 2-5℃, and the first temperature in step (3) is 2-5℃.
[0011] The process of obtaining the drug nanocrystal suspension in step (1) is as follows: The drug and stabilizer are dissolved together in an organic solvent to form an organic phase; Use purified water containing surfactant at 2-5℃ as the aqueous phase; After injecting the organic phase into the aqueous phase under high-speed shearing, the mixed solution is circulated and homogenized multiple times under a pressure of 800-1500 bar to obtain a drug nanocrystal suspension.
[0012] Step (4) The second temperature is 10-15℃.
[0013] Step (3) The mass ratio of the thermosensitive hydrogel premix to the drug-loaded microspheres is 10-8:1.
[0014] The present invention also provides an application of the aforementioned microcrystalline suspended multisphere soft capsule in oral pharmaceutical formulations.
[0015] Beneficial effects The microcrystalline suspended multi-sphere soft capsule of this invention comprises a three-tiered structure consisting of a shell, a thermosensitive hydrogel, and drug-loaded microcrystalline spheres. The drug-loaded microcrystalline spheres are prevented from settling or moving freely due to the spatial constraint of the thermosensitive hydrogel. After oral administration, the shell rapidly disintegrates, the thermosensitive hydrogel slowly dissolves, and the drug-loaded microcrystalline spheres are released, ensuring stable dissolution of the drug nanocrystals. Furthermore, the preparation process of this invention only requires conventional equipment, such as a high-pressure homogenizer and a soft capsule press, without the need for special nanosynthesis or cross-linking processes; the preparation process is easily controlled and meets the needs of large-scale production. Attached Figure Description
[0016] Figure 1 This is a schematic diagram of the structure of a microcrystalline suspended multi-sphere soft capsule provided by the present invention.
[0017] The attached figures are labeled as follows: 1-Outer shell, 2-Composite system, 21-Thermosensitive hydrogel, 22-Drug-loaded microspheres. Detailed Implementation
[0018] The following examples are intended to illustrate the present invention, and not to further limit the invention.
[0019] This invention provides a microcrystalline suspended multi-sphere soft capsule, such as... Figure 1 As shown, from the outside in, it includes an outer shell 1 and a composite system 2, and the composite system 2 is encapsulated by the outer shell 1; The composite system 2 is formed by dispersing a plurality of drug-loaded microspheres 22 in the thermosensitive hydrogel 21; The thermosensitive hydrogel 21 has a three-dimensional porous network structure, which is liquid below 28°C and transforms into a gel above 36°C. The drug-loaded microspheres 22 are three-dimensional porous spherical particles, and the drug is dispersed in the three-dimensional porous structure in the form of nanocrystals.
[0020] Specifically, the drug-loaded microspheres 22 have a particle size of 1-5 μm, and the nanocrystals have a particle size of no more than 200 nm. Because the drug-loaded microspheres 22 are loosely porous spherical particles with uniform particle size and pore size distribution, the drug can be uniformly dispersed in the porous framework in the form of nanocrystals, achieving a drug loading of ≥85%.
[0021] The temperature-sensitive hydrogel 21 has a pore size of 10-50 μm, and the pore channels connect adjacent pores, with an inner diameter of 2-5 μm.
[0022] The particle size (1-5μm) of the drug-loaded microspheres 22 matches the size of the mesh (10-50μm) and mesh channels (2-5μm) of the thermosensitive hydrogel 21, allowing the drug-loaded microspheres 22 to enter the mesh. The inner diameter of the mesh channels is close to the particle size of the microspheres, forming a spatial constraint. In addition, since the thermosensitive hydrogel 21 is a continuous phase, the drug-loaded microspheres 22 are uniformly dispersed in the gel network as a dispersed phase, without local aggregation, thus facilitating the formation of a stable composite system.
[0023] In addition, the outer shell 1 is in the form of an elliptical or spherical soft capsule, and the thickness of the outer shell is 0.15-0.2mm.
[0024] This invention also provides a method for preparing the aforementioned microcrystalline suspended multi-sphere soft capsules, comprising the following steps: (1) The dispersed drug is subjected to high-pressure homogenization to obtain a drug nanocrystal suspension; The drug nanocrystal suspension was sequentially atomized and freeze-dried to obtain drug-loaded microspheres; (2) Poloxamer was stirred in purified water at 2-5℃ until it became a viscous liquid, and then refrigerated to obtain a thermosensitive hydrogel premix. (3) Disperse the drug-loaded microspheres in a thermosensitive hydrogel premix solution stirred at the first temperature to obtain a composite system; (4) Using gelatin liquid as the outer shell substrate and composite system as the contents, the capsules are press-filled at the second temperature and dried to obtain microcrystalline suspension multisphere soft capsules.
[0025] Specifically, the process of obtaining the drug nanocrystal suspension in step (1) is as follows: The drug and stabilizer (such as povidone K30) are dissolved together in an organic solvent to form an organic phase; Use purified water containing surfactant at 2-5℃ as the aqueous phase; After injecting the organic phase into the aqueous phase under high-speed shearing, the mixed solution is circulated and homogenized 10-20 times under a pressure of 800-1500 bar to obtain a drug nanocrystal suspension.
[0026] This invention utilizes high-pressure shearing and impact forces to break down large drug crystals, forming nanoscale drug microcrystals. Simultaneously, stabilizer molecules are adsorbed onto the surface of the drug microcrystals through hydrophobic interactions and hydrogen bonds, preventing the nanocrystals from re-aggregating. The drug nanocrystal suspension is atomized into micron-sized droplets, which are then instantly sprayed into a liquid nitrogen cold trap at -80 to -100°C. The water in the droplets rapidly freezes into ice crystals, and the drug nanocrystals and stabilizers are fixed within these ice crystals, forming spherical ice crystal particles. These particles are then freeze-dried in a vacuum environment for 12-16 hours. The ice crystals directly sublimate into water vapor and detach, leaving behind a porous spherical framework composed of drug nanocrystals and stabilizers—the drug-loaded microspheres.
[0027] In preparing the temperature-sensitive hydrogel premix, this invention uses poloxamer 407 as the main functional material, compounded with poloxamer 188, wherein the concentration of poloxamer 407 is 18% (w / v) and the concentration of poloxamer 188 is 5% (w / v). The specific operation is as follows: In a cold storage environment at 2-8℃, weigh 18% (w / v) poloxamer 407 and 5% (w / v) poloxamer 188, and slowly add them to cold purified water at 2-5℃ with stirring at a stirring speed of 200-300 rpm. To avoid generating bubbles, continue magnetic stirring for 30-45 minutes until the solution becomes clear and transparent, forming a viscous liquid. The viscous liquid was placed in a refrigerator at 2-5℃ and left to stand for 12-16 hours to complete hydration and degassing, resulting in a temperature-sensitive hydrogel premix.
[0028] The thermosensitive hydrogel of this invention has a critical phase transition temperature of 28-32℃. Below 28℃, it remains stable as a liquid with good fluidity, facilitating subsequent preparation and meeting the requirements of soft capsule filling processes. Above 32℃, it gradually gels, reducing its fluidity. Above 36℃, it completes the gel transformation within 5-10 minutes, thus completing gelation. Soft capsules prepared from this thermosensitive hydrogel do not require additional cold chain transportation or special temperature control equipment; they only need to follow conventional oral formulation storage standards, such as avoiding direct sunlight and keeping away from high-temperature heat sources.
[0029] The specific steps for preparing the composite system are as follows: The thermosensitive hydrogel premix is kept at a first temperature of 2-5℃. Under slow magnetic stirring, drug-loaded microspheres are slowly sprinkled into the premix. Preferably, the mass ratio of the thermosensitive hydrogel premix to the drug-loaded microspheres is 10-8:1. Continue stirring for 20-30 minutes until the drug-loaded microspheres are completely dispersed, forming a uniform suspension without visible particles. Maintain a low temperature of 2-5℃ throughout the process to prevent premature gel formation and obtain a composite system.
[0030] In this composite system, the spatial constraint of the gel network and the synergistic effect of surface hydrogen bonding prevent drug-loaded microspheres from agglomerating due to gravity or collisions during storage and transportation. In vivo, the gradual dissolution of the gel network and the restriction of its pore channels allow for the slow release of drug-loaded microspheres, avoiding burst drug release; simultaneously, the porous structure of the drug-loaded microspheres works in conjunction with the gel network to ensure the stable dissolution of drug nanocrystals.
[0031] In the final encapsulation stage, the present invention weighs pharmaceutical gelatin, glycerin, and water according to a preset mass ratio, adds 0.5%-1% opacifier (such as titanium dioxide), and melts the gel at 60-70℃ for 30-45 minutes, and keeps it at 50℃ for later use.
[0032] Using gelatin liquid as the outer shell substrate and a composite system as the contents, the contents delivery pipeline and storage tank of the soft capsule compression machine are cooled to a second temperature of 10-15℃. The composite system is then injected into the storage tank and the capsules are filled according to the preset filling amount.
[0033] The filled soft capsules are transferred to an environment of 20-25℃ for drying for 1-2 hours to perform in-situ gelation, raising the temperature of the internal composite system to 36.5-37.5℃. The thermosensitive hydrogel transforms into a semi-solid gel within 5-10 minutes, fixing the drug-loaded microspheres. If drying is performed directly, the high water content and slow thermal conductivity of the outer shell in the initial stage of drying, before the temperature of the contents reaches the phase transition point, will cause the drug-loaded microspheres to move along with the direction of water evaporation, leading to sedimentation and stratification. In addition, after in-situ gelation, although the thermosensitive hydrogel can reversibly transform into a liquid state, the drug-loaded microspheres are still wrapped by the gel molecular chains and will not undergo rapid sedimentation.
[0034] After drying at 40-45℃ for 4-6 hours, microcrystalline suspension multisphere oral soft capsules were obtained.
[0035] In the preparation process of this invention, the liquid gel used is easy to mix with drug-loaded microspheres and fill soft capsules, while the semi-solid gel can fix the microspheres in vivo, preventing them from being lost rapidly in the gastrointestinal tract and ensuring the stability of drug delivery in vivo.
[0036] The present invention also provides an application of the aforementioned microcrystalline suspended multisphere soft capsule in oral pharmaceutical formulations.
[0037] The microcrystalline suspended multi-sphere soft capsule of this invention comprises a three-tiered structure consisting of a shell, a thermosensitive hydrogel, and drug-loaded microcrystalline spheres. The drug-loaded microcrystalline spheres are prevented from settling or moving freely due to the spatial constraint of the thermosensitive hydrogel. After oral administration, the shell rapidly disintegrates, the thermosensitive hydrogel slowly dissolves, and the drug-loaded microcrystalline spheres are released, ensuring stable dissolution of the drug nanocrystals. Furthermore, the preparation process of this invention only requires conventional equipment, such as a high-pressure homogenizer and a soft capsule press, without the need for special nanosynthesis or cross-linking processes; the preparation process is easily controlled and meets the needs of large-scale production.
[0038] Example 1 This embodiment provides a method for preparing microcrystalline suspended multi-sphere soft capsules, including: (1) Dissolve 10g of paclitaxel raw material and 3.33g of povidone K30 together in 100mL of anhydrous ethanol, stir, and form a clear organic phase.
[0039] Add 0.5g of sodium dodecyl sulfate to 200mL of purified water at 4℃ and stir until completely dissolved. This aqueous phase is then prepared for use.
[0040] After the organic phase was injected into the aqueous phase under high-speed shearing, the mixed solution was circulated and homogenized 20 times under a pressure of 1200 bar. After each cycle, the particle size was measured to obtain a drug nanocrystal suspension.
[0041] The drug nanocrystal suspension was sprayed into a liquid nitrogen cold trap at -90℃ and freeze-dried to obtain drug-loaded microspheres with a particle size of 2-5 μm and a drug loading of 87%.
[0042] (2) In a 5℃ cold storage environment, weigh 18% (w / v) poloxamer 407 and 5% (w / v) poloxamer 188, slowly add them to cold purified water at 4℃ with stirring, stir at 250 rpm for 45 min until the solution is clear and forms a viscous liquid. The viscous liquid was placed in a refrigerator at 4°C and left to stand for 15 hours to complete hydration and degassing, resulting in a temperature-sensitive hydrogel premix.
[0043] (3) At 4℃, take 100g of temperature-sensitive hydrogel premix and slowly add 12.5g of paclitaxel drug-loaded microspheres while stirring magnetically at 300rpm.
[0044] Continue stirring for 30 minutes until the drug-loaded microspheres are completely dispersed, forming a uniform suspension without visible particles. Maintain a low temperature of 4°C throughout the process to prevent premature gel formation and obtain a composite system.
[0045] (4) 40g of pharmaceutical gelatin, 20g of glycerin, 40g of purified water, add 0.8g of titanium dioxide, gelatinize at 65℃ for 40min, and keep warm at 50℃ for later use.
[0046] Using gelatin liquid as the outer shell substrate and a composite system as the contents, the contents delivery pipeline and storage tank of the soft capsule compression machine are cooled to 10°C, the composite system is injected into the storage tank, and the capsules are filled at a composite system filling amount of 0.6g / capsule.
[0047] The filled soft capsules were transferred to a 25°C constant temperature drying oven and dried for 2 hours to perform in-situ gelation.
[0048] After drying at 40℃ for 6 hours, microcrystalline suspension multisphere oral soft capsules were obtained.
[0049] Example 2 This embodiment provides a method for preparing microcrystalline suspended multi-sphere soft capsules, including: (1) Dissolve 10g of paclitaxel raw material and 3.33g of povidone K30 together in 100mL of anhydrous ethanol, stir, and form a clear organic phase.
[0050] Add 0.5g of sodium dodecyl sulfate to 200mL of purified water at 4℃ and stir until completely dissolved. This aqueous phase is then prepared for use.
[0051] After the organic phase was injected into the aqueous phase under high-speed shearing, the mixed solution was circulated and homogenized 20 times under a pressure of 1200 bar. After each cycle, the particle size was measured to obtain a drug nanocrystal suspension.
[0052] The drug nanocrystal suspension was sprayed into a liquid nitrogen cold trap at -90℃ and freeze-dried to obtain drug-loaded microspheres with a particle size of 2-5 μm and a drug loading of 87%.
[0053] (2) In a 5℃ cold storage environment, weigh 18% (w / v) poloxamer 407 and 5% (w / v) poloxamer 188, slowly add them to cold purified water at 4℃ with stirring, stir at 250 rpm for 45 min until the solution is clear and forms a viscous liquid. The viscous liquid was placed in a refrigerator at 4°C and left to stand for 15 hours to complete hydration and degassing, resulting in a temperature-sensitive hydrogel premix.
[0054] (3) At 4℃, take 100g of temperature-sensitive hydrogel premix and slowly add 12.5g of paclitaxel drug-loaded microspheres while stirring magnetically at 300rpm.
[0055] Continue stirring for 30 minutes until the drug-loaded microspheres are completely dispersed, forming a uniform suspension without visible particles. Maintain a low temperature of 4°C throughout the process to prevent premature gel formation and obtain a composite system.
[0056] (4) 40g of pharmaceutical gelatin, 20g of glycerin, 40g of purified water, add 0.8g of titanium dioxide, gelatinize at 65℃ for 40min, and keep warm at 50℃ for later use.
[0057] Using gelatin liquid as the outer shell substrate and a composite system as the contents, the contents delivery pipeline and storage tank of the soft capsule compression machine are cooled to 10°C, the composite system is injected into the storage tank, and the capsules are filled at a composite system filling amount of 0.6g / capsule.
[0058] After drying at 40℃ for 6 hours, microcrystalline suspension multisphere oral soft capsules were obtained.
[0059] Comparative Example 1 Weigh 10.0g of paclitaxel and 5.0g of polysorbate 80, add 200mL of purified water, and sonicate for 30min to form a suspension. Using the suspension as the contents and gelatin liquid as the outer shell material, the contents delivery pipeline and storage tank of the soft capsule compression machine are cooled to 10°C, the composite system is injected into the storage tank, and the capsules are filled at a composite system filling amount of 0.6g / capsule.
[0060] After drying at 40℃ for 6 hours, soft capsules were obtained.
[0061] Comparative Example 2 (1) Dissolve 10g of paclitaxel raw material and 3.33g of povidone K30 together in 100mL of anhydrous ethanol, stir, and form a clear organic phase.
[0062] Add 0.5g of sodium dodecyl sulfate to 200mL of purified water at 4℃ and stir until completely dissolved. This aqueous phase is then prepared for use.
[0063] After the organic phase was injected into the aqueous phase under high-speed shearing, the mixed solution was circulated and homogenized 20 times under a pressure of 1200 bar. After each cycle, the particle size was measured to obtain a drug nanocrystal suspension.
[0064] The drug nanocrystal suspension was directly poured into a petri dish with a layer thickness of 5 mm, and then freeze-dried to obtain block particles. These particles were then crushed and sieved, and particles with a diameter of 2-5 μm were collected as drug-loaded microspheres with a drug loading of 72.5%.
[0065] (2) In a 5℃ cold storage environment, weigh 18% (w / v) poloxamer 407 and 5% (w / v) poloxamer 188, slowly add them to cold purified water at 4℃ with stirring, stir at 250 rpm for 45 min until the solution is clear and forms a viscous liquid. The viscous liquid was placed in a refrigerator at 4°C and left to stand for 15 hours to complete hydration and degassing, resulting in a temperature-sensitive hydrogel premix.
[0066] (3) At 4℃, take 100g of temperature-sensitive hydrogel premix and slowly add 12.5g of paclitaxel drug-loaded microspheres while stirring magnetically at 300rpm.
[0067] Continue stirring for 30 minutes until the drug-loaded microspheres are completely dispersed, forming a uniform suspension without visible particles. Maintain a low temperature of 4°C throughout the process to prevent premature gel formation and obtain a composite system.
[0068] (4) 40g of pharmaceutical gelatin, 20g of glycerin, 40g of purified water, add 0.8g of titanium dioxide, gelatinize at 65℃ for 40min, and keep warm at 50℃ for later use.
[0069] Using gelatin liquid as the outer shell substrate and a composite system as the contents, the contents delivery pipeline and storage tank of the soft capsule compression machine are cooled to 10°C, the composite system is injected into the storage tank, and the capsules are filled at a composite system filling amount of 0.6g / capsule.
[0070] The filled soft capsules were transferred to a 25°C constant temperature drying oven and dried for 2 hours to perform in-situ gelation.
[0071] After drying at 40℃ for 6 hours, microcrystalline suspension multisphere oral soft capsules were obtained.
[0072] Experimental results 1. Detection indicators Drug loading: Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0512, High Performance Liquid Chromatography (HPLC).
[0073] Agglomeration rate or sedimentation rate: Refer to the guidelines for drug and formulation stability testing in General Chapter 9001 of the 2020 edition of the Chinese Pharmacopoeia, Part IV. After storage at 40℃ and 75% relative humidity in the dark for 3 months, the soft capsules of Examples 1 and 2 were cut open, and the contents were taken out. The particle size distribution was detected using a laser particle size analyzer, with the detection range set at 0.01-3000 μm. The volume percentage of particles with a diameter >10 μm was recorded as the agglomeration rate. Three parallel tests were performed, and the average value was taken. The soft capsules of Examples 2 and 1 were cut open, and the contents were taken out, poured into a graduated cylinder, and the total height was recorded. The mixture was allowed to stand at room temperature for 24 hours until the particles completely settled. The height of the sedimentation layer was recorded, and the sedimentation rate was calculated. Three parallel tests were performed, and the average value was taken.
[0074] In vitro drug release rates at 0.5h and 12h: Determination of dissolution and release rate, Part IV, General Chapter 0931, Chinese Pharmacopoeia 2020 Edition.
[0075] 2. Test Results Various indicators were tested on the drug-loaded microspheres and soft capsules of Examples 1 and 2 and Comparative Examples 1 and 2. The test results are shown in Table 1.
[0076] Table 1 Test Results As shown in Table 1, compared with Comparative Examples 1 and 2, Examples 1 and 2, which use spray freeze-drying to prepare drug-loaded microspheres, have sufficient drug-loading space and high drug loading capacity. Furthermore, in terms of accelerated aggregation rate at 3 months and in vitro drug release rates at 0.5 h and 12 h, the microcrystalline suspension multisphere oral soft capsules prepared using the method of this invention exhibit anti-sedimentation, anti-agglomeration, and sustained-release effects.
[0077] The above description is only a preferred embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any changes or substitutions that can be easily conceived by those skilled in the art within the scope of the technology disclosed in the present invention should be included within the scope of protection of the present invention.
Claims
1. A microcrystalline suspension multi-sphere soft capsule characterized by, From the outside in, it includes an outer shell and a composite system, and the composite system is encapsulated by the outer shell; The composite system is formed by dispersing multiple drug-loaded microspheres in the thermosensitive hydrogel; The temperature-sensitive hydrogel has a three-dimensional porous network structure, is liquid below 28°C, and transforms into a gel above 36°C. The drug-loaded microspheres are three-dimensional porous spherical particles, with the drug dispersed in the three-dimensional porous structure in the form of nanocrystals.
2. The microcrystalline suspension multi-sphere soft capsule according to claim 1, wherein The particle size of the drug-loaded microspheres is 1-5 μm, and the particle size of the nanocrystals is no greater than 200 nm.
3. The microcrystalline suspension multi-sphere soft capsule according to claim 1, wherein The temperature-sensitive hydrogel has a pore size of 10-50 μm, and the pore channels connect adjacent pores, with an inner diameter of 2-5 μm.
4. The microcrystalline suspended multi-sphere soft capsule according to claim 1, characterized in that, The outer shell is in the form of an elliptical or spherical soft capsule, with a thickness of 0.15-0.2 mm.
5. A method for preparing microcrystalline suspended multi-sphere soft capsules as described in claim 1, characterized in that, Includes the following steps: (1) The dispersed drug is subjected to high-pressure homogenization to obtain a drug nanocrystal suspension; The drug nanocrystal suspension was sequentially atomized and freeze-dried to obtain drug-loaded microspheres; (2) Poloxamer was stirred in purified water at 2-5℃ until it became a viscous liquid, and then refrigerated to obtain a thermosensitive hydrogel premix. (3) Disperse the drug-loaded microspheres in a thermosensitive hydrogel premix solution stirred at the first temperature to obtain a composite system; (4) Using gelatin liquid as the outer shell substrate and composite system as the contents, the capsules are press-filled at the second temperature and dried to obtain microcrystalline suspension multisphere soft capsules.
6. The preparation method according to claim 5, characterized in that, The refrigeration temperature in step (2) is 2-5℃, and the first temperature in step (3) is 2-5℃.
7. The preparation method according to claim 5, characterized in that, The process of obtaining the drug nanocrystal suspension in step (1) is as follows: The drug and stabilizer are dissolved together in an organic solvent to form an organic phase; Use purified water containing surfactant at 2-5℃ as the aqueous phase; After injecting the organic phase into the aqueous phase under high-speed shearing, the mixed solution is circulated and homogenized multiple times under a pressure of 800-1500 bar to obtain a drug nanocrystal suspension.
8. The preparation method according to claim 5, characterized in that, Step (4) The second temperature is 10-15℃.
9. The preparation method according to claim 5, characterized in that, Step (3) The mass ratio of the thermosensitive hydrogel premix to the drug-loaded microspheres is 10-8:
1.
10. The application of a microcrystalline suspended multisphere soft capsule as described in claim 1 or a microcrystalline suspended multisphere soft capsule prepared by the preparation method as described in claim 5 in oral pharmaceutical formulations.