Low-temperature drying preparation method of pentaaminolevulinic acid sustained-release particles

Abstract

The invention relates to the field of preparation of pharmaceutical preparations, and particularly discloses a low-temperature drying preparation method of pentaaminolevulinic acid sustained-release granules, which comprises the following steps: raw material treatment: respectively sieving 5-aminolevulinic acid hydrochloride, a composite protective agent, a sustained-release framework material and an antioxidant aid, and sequentially mixing 20-30% by mass of 5-aminolevulinic acid hydrochloride, 35-45% by mass of composite protective agent, 30-40% by mass of sustained-release framework material and 0.03-0.07% by mass of antioxidant aid; a mixed material is obtained; granulating and pore-forming: granulating the mixed material by adopting low-temperature high-shear, and spraying a low-temperature adhesive to form wet granules. Oxygen in the preparation process can be isolated through nitrogen protection, an oxidative degradation reaction is avoided, mixing and drying are controlled in a low-temperature environment in the whole process, degradation reactions such as condensation and decarboxylation caused by molecular thermal motion are reduced, uniform migration of water can be accelerated through communicated pore channels formed through supercritical CO2 pore forming, and the moisture content is reduced. The degradation path of the pentaaminolevulinic acid is blocked from multiple dimensions.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical preparation, more particularly, it relates to a low-temperature drying preparation method of pentaaminolevulinic acid sustained-release granules. BACKGROUND

[0002] As an endogenous porphyrin precursor, pentaaminolevulinic acid (5-ALA) has core application value in photodynamic therapy and can be used for treating precancerous lesions of skin cancer, superficial bladder cancer and other diseases. Its drug efficacy depends on the integrity of its own structure. The amino and carboxyl groups in the molecule are easily affected by temperature, oxygen and humidity, and can undergo condensation, oxidation or decarboxylation reactions to generate pyrrolidine derivatives and pentanedioic acid degradation products, resulting in reduced drug efficacy or even toxic side effects. In order to meet the needs of long-term stable drug delivery in the clinic, 5-ALA is often prepared into sustained-release granules to control the slow release of the drug through the sustained-release matrix, thereby maintaining the blood drug concentration within the therapeutic window.

[0003] The existing preparation of pentaaminolevulinic acid sustained-release granules mostly uses high-temperature vacuum drying and hot air drying. Due to the increased thermal motion of 5-ALA molecules, the condensation reaction of amino and carboxyl groups is easily triggered, generating 2,5-diketopyrrolidine derivatives. At the same time, high temperature accelerates the contact between oxygen and 5-ALA, leading to oxidative degradation. As a result, the prepared pentaaminolevulinic acid sustained-release granules cannot meet the requirements of clinical efficacy purity. SUMMARY

[0004] In order to solve the problem that the existing preparation of pentaaminolevulinic acid sustained-release granules mostly uses high-temperature vacuum drying and hot air drying, resulting in pentaaminolevulinic acid sustained-release granules that cannot meet the requirements of clinical efficacy purity, the present application provides a low-temperature drying preparation method of pentaaminolevulinic acid sustained-release granules.

[0005] The present application provides a low-temperature drying preparation method of pentaaminolevulinic acid sustained-release granules, which adopts the following technical solution: A low-temperature drying preparation method of pentaaminolevulinic acid sustained-release granules, comprising the following steps: Raw material processing: 5-aminoacetylpropionic acid hydrochloride, a composite protective agent, a sustained-release matrix material and an antioxidant are sieved respectively, and then mixed in the order of 20-30%, 35-45%, 30-40% and 0.03-0.07% by mass percentage to obtain a mixture; Granulation and pore formation: the mixture is granulated by low-temperature high-shear granulation, sprayed with a low-temperature binder to form wet granules, and then treated with supercritical CO2 to obtain porous wet granules with a porous structure; Freeze-drying: the porous wet granules are sequentially subjected to pre-freezing, sublimation drying and desorption drying to obtain dry granules; Post-processing: After drying the particles, screen and pack them to obtain the sustained-release granules of pentaaminolevulinic acid.

[0006] By adopting the technical scheme, oxygen in the preparation process is isolated by nitrogen protection to avoid oxidative degradation reaction, the whole mixing and drying process is controlled in a low-temperature environment to reduce degradation reactions such as condensation and decarboxylation caused by molecular thermal motion, and the uniform granular matrix formed by high-shear granulation and the connected pores formed by supercritical CO2 pore forming can accelerate the uniform migration of moisture and block the degradation path of pentaaminolevulinic acid from multiple dimensions to avoid degradation caused by local high-humidity environment in the granule and reduce the generation of degradation products, thereby ensuring the efficacy purity of pentaaminolevulinic acid and providing a material basis for stable efficacy in clinical treatment.

[0007] Preferably, in the raw material processing step, the composite protective agent is composed of malt dextrin and chitosan at a mass ratio of 3-5:1, the sustained-release matrix material is composed of hydroxypropyl methyl cellulose K15M and polylactic acid-glycolic acid copolymer at a mass ratio of 2-4:1, and the antioxidant is glutathione.

[0008] By adopting the technical scheme, malt dextrin and chitosan in the composite protective agent can form a dense and stable glassy network to wrap pentaaminolevulinic acid molecules, the swelling property of hydroxypropyl methyl cellulose K15M and the rigidity of polylactic acid-glycolic acid copolymer in the sustained-release matrix material are complementary, which can ensure slow drug dissolution and maintain the integrity of the granule form, and the antioxidant glutathione can specifically inhibit oxidation, and the three components can synergistically act with 5-aminoacetylpropionic acid hydrochloride to not only further reduce the generation of degradation products but also optimize the sustained-release curve to ensure sustained and stable efficacy.

[0009] Preferably, in the raw material processing step, the sieving is performed on 5-aminoacetylpropionic acid hydrochloride, the composite protective agent, the sustained-release matrix material through an 80-mesh sieve, and the antioxidant through a 100-mesh sieve, the mixing is performed in a low-temperature mixer under nitrogen protection, the mixing temperature is 8-12℃, the rotation speed is 12-18 rpm, and the mixing time is 30-60 min.

[0010] By adopting the technical scheme, different raw materials are sieved according to specific mesh numbers to remove impurities and ensure uniform particle size, nitrogen protection can isolate oxygen in the mixing process, and the combination of low temperature, rotation speed and mixing time can not only ensure the fusion of all components but also inhibit molecular thermal motion at low temperature to reduce the degradation risk in the mixing stage and ensure the consistency of particle performance.

[0011] Preferably, in the granulation and pore-forming step, the low-temperature high-shear granulation adopts a top-drive granulator with jacketed temperature control, the granulation temperature is 8-12℃, the stirring paddle speed in the premixing stage is 50-100 rpm, the stirring paddle speed in the granulation stage is 200-400 rpm, the granulation blade speed is 1000-1500 rpm, the low-temperature binder is a 10-14% hydroxypropyl methylcellulose aqueous solution at 4-6℃, the spraying adopts pulse spraying, the atomization pressure is 0.25-0.35 MPa, the spraying rate is 6-10 g / min, the droplet diameter is 45-55 μm, the wet particles have a particle size of 1.0-1.2 mm and a water content of 28-32%.

[0012] By adopting the above technical solution, the jacketed closed granulation environment can maintain low temperature and isolate oxygen, avoiding thermal degradation and oxidation of pentaaminolevulinic acid. The coordinated control of the rotation speed of the stirring paddle and the granulation blade, combined with pulsed low-temperature binder spraying, can ensure that the material is fully wetted to form uniform particles, and can also control the particle density through mechanical shearing action, forming wet particles with uniform particle size and suitable moisture content, thus improving the morphological integrity of the wet particles.

[0013] Preferably, in the granulation and pore-forming step, the supercritical CO2 treatment temperature is 33-37℃, the pressure is 7-9MPa, the treatment time is 25-35min, the depressurization rate is 0.4-0.6MPa / min, and the porosity of the porous wet particles is 0.4-0.5, and the pore size is 2-5μm.

[0014] By adopting the above technical solution, and by combining temperature, pressure and processing time with the depressurization rate, interconnected channels can be formed inside the wet particles. This ensures rapid and uniform migration of moisture during subsequent freeze-drying and provides a stable support structure for the slow-release skeleton.

[0015] Preferably, in the freeze-drying step, the pre-freezing is performed by lowering the temperature from 25°C to -10°C at a rate of 1.5-2.5°C / min and maintaining it for 0.8-1.2 hours, then lowering it to -40°C at a rate of 4.5-5.5°C / min and maintaining it for 2.8-3.2 hours, and finally lowering it to -70°C at a rate of 0.8-1.2°C / min and maintaining it for 1.8-2.2 hours. The spread thickness of the porous wet particles in the freeze dryer tray is ≤10 mm.

[0016] By adopting the above technical solution, the step-cooling rate induces the formation of regular columnar ice crystals inside the particles, avoiding the damage to the slow-release skeleton structure caused by irregular ice crystals generated by uniform cooling. The spreading thickness ensures that all particles in the tray are heated evenly, avoiding pre-freezing differences between edge and center particles, and reducing damage to the internal structure of the particles during the pre-freezing stage.

[0017] Preferably, in the freeze-drying step, the sublimation drying is maintained at 0.08-0.12 mbar for 1.8-2.2 h, then at 0.28-0.32 mbar for 5.8-6.2 h, and finally at 0.18-0.22 mbar for 3.8-4.2 h. At the same time, the shelf temperature is raised from -40°C to -5°C at a rate of 0.4-0.6°C / h, and the particle temperature is kept below the eutectic point of -25°C, so that the moisture content of the porous wet particles is reduced to 7-9%.

[0018] By adopting the above technical solution, dynamic vacuum control is used to adjust the mass transfer efficiency according to the change of particle moisture, avoiding water retention due to excessively low vacuum or skeletal collapse due to excessively high vacuum. By controlling the shelf temperature in conjunction with the particle temperature below the eutectic point, it is ensured that moisture is removed in the form of ice crystal sublimation, avoiding ice crystal melting and damage to the particle structure, and reducing the fluctuation of degradation or slow-release performance caused by uneven moisture migration during the sublimation stage.

[0019] Preferably, in the freeze-drying step, the analytical drying is performed by raising the shelf temperature from -5°C to 33-37°C at a rate of 0.8-1.2°C / h under a vacuum of 0.02-0.04 mbar, which is 25-29°C lower than the glass transition temperature of the composite protective agent. Then, dry nitrogen gas with a dew point ≤ -60°C is introduced to purge for 3.8-4.2h, so that the water activity of the porous wet particles is 0.23-0.27 and the water content is ≤1.5%.

[0020] By adopting the above technical solution, the bound water in the particles is removed by combining high vacuum with slow heating. The temperature is lower than the glass transition temperature of the composite protective agent, which promotes the formation of a stable glassy network of the composite protective agent. The dew point is purged with dry nitrogen, which further reduces the humidity of the environment around the particles. This not only reduces degradation during the desorption stage, but also improves the long-term storage stability of the particles and avoids the decrease in efficacy caused by moisture absorption or molecular migration during storage.

[0021] Preferably, in the post-processing steps, the granulation is carried out using an 18-mesh sieve, the sieving is carried out using a 20-30 mesh grading sieve, and the particle size distribution of the sieved particles is D10=0.8-1.0mm, D50=1.0-1.2mm, and D90=1.2-1.4mm. The packaging is carried out using aluminum-plastic composite film bags.

[0022] By adopting the above technical solutions, the small amount of clumps generated after freeze-drying is removed by granulation, and the particle size distribution is controlled by grading sieves to avoid uneven release rates caused by excessive particle size differences; aluminum-plastic composite film bags reduce the degradation of pentaminolevulinic acid and the moisture absorption of particles during storage.

[0023] Preferably, in the post-processing step, the packaged product is stored at 2-6℃ in the dark.

[0024] By adopting the above technical solutions, the low-temperature environment slows down the thermal motion of pentamirrolic acid molecules, reduces the occurrence of degradation reactions such as condensation and decarboxylation, and the light-protected conditions avoid light-induced oxidation reactions, further reducing the risk of degradation.

[0025] In summary, this application has the following beneficial effects: 1. This application uses nitrogen protection to isolate oxygen during the preparation process, avoiding oxidative degradation reactions. The mixing and drying processes are controlled at low temperatures throughout, reducing degradation reactions such as condensation and decarboxylation caused by molecular thermal motion. The uniform particle matrix formed by high-shear granulation, combined with the interconnected channels formed by supercritical CO2 pore-forming, can accelerate the uniform migration of moisture, blocking the degradation pathway of pentaminolevulinic acid from multiple dimensions, avoiding degradation caused by local high humidity environment inside the particles, reducing the generation of degradation products, ensuring the efficacy and purity of pentaminolevulinic acid, and providing a material basis for stable efficacy in clinical treatment.

[0026] 2. This application utilizes supercritical CO2 to construct interconnected channels within the particles, providing a uniform mass transfer pathway for drug release. The sustained-release framework formed by the compounding of hydroxypropyl methylcellulose K15M and polylactic acid-glycolic acid copolymer, along with the stable glassy network constructed by the composite protectant, can maintain the integrity of the particle structure for a long time, avoiding performance changes caused by framework collapse or deformation during release. This ensures that the pentaaminolevulinic acid sustained-release particles maintain uniform release within a twelve-hour release cycle, reducing the risk of efficacy differences or adverse reactions due to uneven release.

[0027] 3. This application controls the water activity of the particles by analyzing the drying process, so that the moisture content of the particles is maintained at a low level, reducing particle deterioration or drug degradation caused by moisture absorption during storage. By utilizing the stable glassy network formed by maltodextrin and chitosan in the composite protectant, the pentamirrolic acid molecules are locked in the amorphous region, inhibiting their molecular migration and degradation during storage. This makes the particles less prone to performance degradation under normal storage conditions, effectively extending the shelf life of the product and improving the long-term storage stability of the particles. Attached Figure Description

[0028] Figure 1 This is a flowchart of a low-temperature drying method for preparing pentaaminolevulinic acid sustained-release granules proposed in this application. Detailed Implementation

[0029] The present application will be further described in detail below with reference to the accompanying drawings and embodiments.

[0030] Technical Concept: Pentaaminolevulinic acid is a core drug for photodynamic therapy in the treatment of precancerous skin lesions, superficial bladder cancer, and other diseases. Its sustained-release granule formulation is a key form for achieving long-term stable clinical administration. However, existing processes mostly use high-temperature vacuum drying or hot air drying to remove moisture from the granules. The high-temperature environment will significantly aggravate the thermal motion of pentaaminolevulinic acid molecules, causing the amino and carboxyl groups to undergo condensation reactions. At the same time, it will accelerate contact with oxygen and trigger oxidative degradation, resulting in high particle degradation rate and large fluctuations in sustained-release performance, which cannot meet the requirements of clinical efficacy.

[0031] To address the aforementioned issues, this application focuses on the degradation mechanism of pentamirrylpropionic acid (PPA) and the structural and functional requirements of sustained-release particles, conducting a synergistic optimization study of process parameters and excipient systems. First, it was determined that a low-temperature environment is fundamental to inhibiting degradation. The study then explored how to achieve efficient and uniform moisture removal at low temperatures. Supercritical carbon dioxide treatment was used to construct interconnected channels within the particles, solving the problem of slow moisture mass transfer at low temperatures. Simultaneously, regarding the excipient system, maltodextrin and chitosan were selected to form a stable glassy network, which was then combined with hydroxypropyl methylcellulose and polylactic acid-glycolic acid copolymer to construct a complementary sustained-release framework. This was further enhanced by step-by-step pre-freezing to protect the particle structure, nitrogen protection to isolate oxygen, and gradient parameter control during the freeze-drying process, forming a chain of raw material protection, structure construction, and low-temperature drying. This multi-dimensionally blocks the degradation pathway of PPA while ensuring the integrity and uniformity of the sustained-release framework.

[0032] To better understand the above technical solutions, the technical solutions of the present invention will be clearly and completely described below in conjunction with embodiments.

[0033] Unless otherwise specified, all experimental methods used below are conventional methods. All materials, reagents, methods, and instruments used, unless otherwise specified, are conventional materials, reagents, methods, and instruments in this field, which can be obtained commercially or prepared according to literature methods by those skilled in the art.

[0034] The following is a further description with reference to the embodiments: Example 1: A method for preparing sustained-release pentamirrolic acid granules by low-temperature drying includes the following steps: Raw material processing: 5-aminolevulinate salt, composite protective agent, slow-release skeleton material and antioxidant additive are sieved separately and then mixed in sequence at a mass percentage of 25%, 39.95%, 35% and 0.05% to obtain a mixture. Granulation and pore formation: The mixture is granulated at low temperature and high shear, a low temperature binder is sprayed in to form wet particles, and then treated with supercritical CO2 to obtain porous wet particles with a porous structure. Freeze-drying: Porous wet particles are subjected to pre-freezing, sublimation drying and desorption drying in sequence to obtain dried particles; Post-processing: The dried granules are sized, sieved, and packaged to obtain sustained-release granules of pentamirrolic acid.

[0035] In the raw material processing step, the composite protective agent is composed of maltodextrin and chitosan in a mass ratio of 4:1, the slow-release backbone material is composed of hydroxypropyl methylcellulose K15M and polylactic acid-glycolic acid copolymer in a mass ratio of 3:1, and the antioxidant is glutathione.

[0036] In the raw material processing step, 5-aminolevulinate salt, composite protective agent, and slow-release skeleton material are sieved through an 80-mesh sieve, and antioxidant additives are sieved through a 100-mesh sieve. Mixing is carried out in a low-temperature mixer under nitrogen protection at a mixing temperature of 10°C, a rotation speed of 15 rpm, and a mixing time of 45 min.

[0037] In the granulation and pore-forming process, the low-temperature high-shear granulation uses a top-drive granulator with jacketed temperature control. The granulation temperature is 10℃. The stirring paddle speed is 75 rpm in the premixing stage and 300 rpm in the granulation stage. The granulation blade speed is 1250 rpm. The low-temperature binder is a 12% hydroxypropyl methylcellulose aqueous solution at 5℃. The spraying is done by pulse spraying with an atomization pressure of 0.3 MPa, a spraying rate of 8 g / min, a droplet diameter of 50 μm, a wet particle size of 1.1 mm, and a moisture content of 30%.

[0038] In the granulation and pore-forming process, the supercritical CO2 treatment temperature was 35℃, the pressure was 8MPa, the treatment time was 30min, the depressurization rate was 0.5MPa / min, and the porosity of the porous wet particles was 0.45 with a pore size of 3.5μm.

[0039] In the freeze-drying process, the pre-freezing is carried out by lowering the temperature from 25°C to -10°C at a rate of 2°C / min and maintaining it for 1 hour, then lowering it to -40°C at a rate of 5°C / min and maintaining it for 3 hours, and then lowering it to -70°C at a rate of 1°C / min and maintaining it for 2 hours. The spread thickness of the porous wet particles in the freeze dryer tray is ≤10mm.

[0040] In the freeze-drying process, the sublimation drying is maintained at 0.1 mbar for 2 hours, then at 0.3 mbar for 6 hours, and finally at 0.2 mbar for 4 hours. At the same time, the shelf temperature is increased from -40℃ to -5℃ at a rate of 0.5℃ / h, and the particle temperature is kept below the eutectic point of -25℃, so that the moisture content of the porous wet particles is reduced to 8%.

[0041] In the freeze-drying process, the desorption drying involves raising the shelf temperature from -5℃ to 35℃ at a rate of 1℃ / h under a vacuum of 0.03mbar, which is lower than the glass transition temperature of the composite protective agent (27℃). Then, dry nitrogen gas with a dew point ≤ -60℃ is introduced to purge for 4 hours, so that the water activity of the porous wet particles is 0.25 and the water content is ≤ 1.5%.

[0042] In the post-processing steps, granulation is carried out using an 18-mesh sieve, and sieving is carried out using a 20-30 mesh grading sieve. The particle size distribution of the sieved particles is D10=0.9mm, D50=1.1mm, and D90=1.3mm. The particles are then packaged in aluminum-plastic composite film bags.

[0043] In the post-processing steps, after dispensing, store in the dark at 2-6℃.

[0044] Example 2: The difference between this embodiment and Embodiment 1 above is that: A method for preparing sustained-release pentamirrolic acid granules by low-temperature drying includes the following steps: Raw material processing: 5-aminolevulinate salt, composite protective agent, slow-release skeleton material and antioxidant additive are sieved separately and then mixed in sequence at a mass percentage of 30%, 39.97%, 30% and 0.03% to obtain a mixture. Granulation and pore formation: The mixture is granulated at low temperature and high shear, a low temperature binder is sprayed in to form wet particles, and then treated with supercritical CO2 to obtain porous wet particles with a porous structure. Freeze-drying: Porous wet particles are subjected to pre-freezing, sublimation drying and desorption drying in sequence to obtain dried particles; Post-processing: The dried granules are sized, sieved, and packaged to obtain sustained-release pentamirrolic acid granules. Example 3: The difference between this embodiment and Embodiment 1 above is that: A method for preparing sustained-release pentamirrolic acid granules by low-temperature drying includes the following steps: Raw material processing: 5-aminolevulinate salt, composite protective agent, slow-release skeleton material and antioxidant additive are sieved separately and then mixed in sequence at a mass percentage of 20%, 44.97%, 35% and 0.03% to obtain a mixture. Granulation and pore formation: The mixture is granulated at low temperature and high shear, a low temperature binder is sprayed in to form wet particles, and then treated with supercritical CO2 to obtain porous wet particles with a porous structure. Freeze-drying: Porous wet particles are subjected to pre-freezing, sublimation drying and desorption drying in sequence to obtain dried particles; Post-processing: The dried granules are sized, sieved, and packaged to obtain sustained-release granules of pentamirrolic acid.

[0045] Comparative Example 1: The difference between this embodiment and Embodiment 1 above is that: Raw material processing: No nitrogen protection, mixing temperature is 25°C, the rest is the same as in Example 1; Granulation and pore formation: No supercritical CO2 treatment, and the inlet air temperature is 45℃. Spray with 12% hydroxypropyl methylcellulose aqueous solution at 25℃. The wet particle size is 1.1mm, the water content is 30%, and the porosity is 0.2. Drying: Replaced with 45℃ vacuum drying, vacuum degree -0.08MPa, drying for 8 hours until the moisture content is ≤1.5%, without pre-freezing, sublimation drying, or desorption drying steps; Post-processing: Same as in Example 1.

[0046] Comparative Example 2: The difference between this embodiment and Embodiment 1 above is that: Granulation and pore formation: Without supercritical CO2 treatment, the wet particles with a particle size of 1.1 mm, a water content of 30%, and a porosity of 0.25 obtained by low-temperature fluidized bed preparation were directly transferred to freeze drying. The remaining steps were the same as in Example 1.

[0047] Comparative Example 3: The difference between this embodiment and Embodiment 1 above is that: In the raw material processing, the mass ratio of maltodextrin to chitosan in the composite protective agent is 1:1, and the remaining steps are the same as in Example 1.

[0048] Performance testing Total degradation rate (%): Degradation products such as 2,5-diketopyrrolidine derivatives were detected by ultra-high performance liquid chromatography and tandem mass spectrometry. The total degradation rate was calculated by external standard method. A total degradation rate of ≤0.5% was considered excellent, and the lower the rate, the better the stability of 5-ALA.

[0049] 12h cumulative release rate (%): The concentration of 5-ALA at different time points was measured by HPLC using an intelligent dissolution tester, paddle method (50 rpm, 37℃±0.5℃, pH6.8 phosphate buffer 900 mL), and the 12h cumulative release rate was calculated. A 12h release rate of 85-95% is considered excellent, reflecting the sustained-release effect.

[0050] 12h release relative standard deviation (RSD, %): Similar to the dissolution test above, 6 samples were measured in parallel, and the RSD value of the cumulative release rate over 12h was calculated. RSD ≤ 5% is preferred, and the lower the value, the better the sustained-release uniformity. Particle porosity: The pore distribution and total porosity of the dried particles were determined by mercury porosimetry. A porosity of 0.4-0.5 is considered optimal, reflecting mass transfer efficiency. Water activity (Aw): The water activity of the dried particles was measured using a dynamic vapor adsorption analyzer. Aw ≤ 0.3 is preferred, as a lower Aw indicates better long-term storage stability. Table 1

[0051] According to Table 1, and comparing Examples 1 to 3 with Comparative Example 1, the total degradation rate, 12-hour cumulative release rate, 12-hour release RSD, particle porosity, and water activity of Examples 1 to 3 are all superior to those of Comparative Example 1. Specifically, Examples 1 to 3 employ a synergistic process of nitrogen-protected low-temperature mixing, supercritical carbon dioxide pore-forming, and low-temperature freeze-drying: nitrogen can isolate oxygen, reducing the contact between pentaminolevulinic acid and oxygen; the low-temperature environment can inhibit the degradation reaction of pentaminolevulinic acid; supercritical carbon dioxide pore-forming can construct interconnected channels within the particles, helping to uniformly transfer moisture; and the glassy solidification during low-temperature freeze-drying can stably lock in pentaminolevulinic acid molecules. In contrast, Comparative Example 1 uses a high-temperature vacuum drying process, which has a higher drying temperature and does not employ supercritical carbon dioxide pore-forming. The high temperature accelerates the condensation and oxidation reactions of pentaminolevulinic acid, and the lack of effective channels within the particles leads to moisture retention, resulting in uneven sustained-release performance. This demonstrates that the low-temperature synergistic process of this application can solve the degradation of pentaminolevulinic acid and improve its sustained-release performance.

[0052] According to Table 1, and comparing Example 1 and Comparative Example 2, Example 1 demonstrates better control of the overall degradation rate, superior uniformity of release over twelve hours, and higher mass transfer efficiency within the particles, all of which are better than Comparative Example 2. This is because the supercritical carbon dioxide pore-forming process in Example 1 creates interconnected channels within the particles. These channels provide pathways for rapid moisture migration during the freeze-drying stage, preventing localized high-humidity environments that could lead to pentaminolevulinic acid degradation, while also ensuring uniform drug dissolution during release. In contrast, Comparative Example 2 did not undergo supercritical carbon dioxide pore-forming, resulting in no effective mass transfer channels within the particles. Moisture retention exacerbates pentaminolevulinic acid degradation, and the sustained-release matrix exhibits uneven solidification. This indicates that supercritical carbon dioxide pore-forming can maintain a lower degree of pentaminolevulinic acid degradation and more uniform sustained-release.

[0053] According to Table 1, and comparing Example 1 with Comparative Example 3, Example 1 demonstrates better control of the overall degradation rate, superior uniformity of release over twelve hours, and more stable water activity, all of which are better than Comparative Example 3. The principle is that the composite protectant in Example 1, composed of maltodextrin and chitosan in a specific mass ratio, forms a stable glassy network. During the desorption and drying stage, this glassy network stably locks in pentaminolevulinic acid molecules. In contrast, the mass ratio of maltodextrin to chitosan in the composite protectant of Comparative Example 3 deviates from this ratio, leading to decreased stability of the glassy network formed by the composite protectant, making it prone to collapse. This increases the migration rate of pentaminolevulinic acid molecules, resulting in a greater degree of degradation and uneven sustained-release performance.

[0054] According to Table 1, and comparing Examples 1, 2, and 3, Example 1 shows better control of total degradation rate and uniformity of release over twelve hours. Example 2 uses upper limit parameters, i.e., a higher mass ratio of pentaminolevulinic acid and higher supercritical carbon dioxide treatment temperature and pressure. Example 3 uses lower limit parameters, i.e., a lower mass ratio of pentaminolevulinic acid and a lower mass ratio of maltodextrin to chitosan in the composite protectant. The overall performance of both examples is slightly inferior to that of Example 1. The median parameters of Example 1 ensure a good synergy between raw material ratio, process parameters, and glassy network stability: the moderate proportion of pentaminolevulinic acid avoids localized enrichment leading to increased degradation; the supercritical carbon dioxide treatment parameters match the pore formation efficiency; and the proportion of the composite protectant ensures the integrity of the glassy network.

[0055] This specific embodiment is merely an explanation of this application and is not intended to limit it. After reading this specification, those skilled in the art can make modifications to this embodiment without contributing any inventive step, but such modifications are protected by patent law as long as they fall within the scope of the claims of this application.

Claims

1. A method for preparing sustained-release granules of pentamirrolic acid using low-temperature drying, characterized in that, Includes the following steps: Raw material processing: After sieving 5-aminolevulinate, composite protective agent, slow-release skeleton material and antioxidant additive, respectively, they are mixed in sequence at a mass percentage of 20-30%, 35-45%, 30-40% and 0.03-0.07% to obtain a mixture. Granulation and pore formation: The mixture is granulated at low temperature and high shear, a low temperature binder is sprayed in to form wet particles, and then treated with supercritical CO2 to obtain porous wet particles with a porous structure. Freeze-drying: Porous wet particles are subjected to pre-freezing, sublimation drying and desorption drying in sequence to obtain dried particles; Post-processing: The dried granules are granulated, sieved, and packaged to obtain sustained-release granules of pentamirrolic acid.

2. The method for preparing sustained-release pentamirrolic acid granules by low-temperature drying according to claim 1, characterized in that: In the raw material processing step, the composite protective agent is composed of maltodextrin and chitosan in a mass ratio of 3-5:1, the sustained-release backbone material is composed of hydroxypropyl methylcellulose K15M and polylactic acid-glycolic acid copolymer in a mass ratio of 2-4:1, and the antioxidant is glutathione.

3. The method for preparing sustained-release pentamirrolic acid granules by low-temperature drying according to claim 1, characterized in that: In the raw material processing step, the sieving of 5-aminolevulinate salt, composite protective agent, and slow-release skeleton material is done through an 80-mesh sieve, and the antioxidant additive is done through a 100-mesh sieve. The mixing is carried out in a low-temperature mixer under nitrogen protection, with a mixing temperature of 8-12℃, a rotation speed of 12-18 rpm, and a mixing time of 30-60 min.

4. The method for preparing sustained-release pentamirrolic acid granules by low-temperature drying according to claim 1, characterized in that: In the granulation and pore-forming process, the low-temperature high-shear granulation uses a top-drive granulator with jacketed temperature control. The granulation temperature is 8-12℃. The stirring paddle speed is 50-100 rpm in the premixing stage and 200-400 rpm in the granulation stage. The granulation blade speed is 1000-1500 rpm. The low-temperature binder is a 10-14% hydroxypropyl methylcellulose aqueous solution at 4-6℃. The spraying is done using pulse spraying with an atomization pressure of 0.25-0.35 MPa, a spray rate of 6-10 g / min, and a droplet diameter of 45-55 μm. The wet particles have a particle size of 1.0-1.2 mm and a moisture content of 28-32%.

5. The method for preparing sustained-release pentamirrolic acid granules by low-temperature drying according to claim 1, characterized in that: In the granulation and pore-forming process, the supercritical CO2 treatment temperature is 33-37℃, the pressure is 7-9MPa, the treatment time is 25-35min, the depressurization rate is 0.4-0.6MPa / min, and the porosity of the porous wet particles is 0.4-0.5, with a pore size of 2-5μm.

6. The method for preparing sustained-release pentamirrolic acid granules by low-temperature drying according to claim 1, characterized in that: In the freeze-drying process, the pre-freezing involves lowering the temperature from 25°C to -10°C at a rate of 1.5-2.5°C / min and maintaining it for 0.8-1.2 hours, then lowering it to -40°C at a rate of 4.5-5.5°C / min and maintaining it for 2.8-3.2 hours, and finally lowering it to -70°C at a rate of 0.8-1.2°C / min and maintaining it for 1.8-2.2 hours. The spread thickness of the porous wet particles in the freeze dryer tray is ≤10 mm.

7. The method for preparing sustained-release pentamirrolic acid granules by low-temperature drying according to claim 1, characterized in that: In the freeze-drying step, the sublimation drying is carried out at 0.08-0.12 mbar for 1.8-2.2 h, then at 0.28-0.32 mbar for 5.8-6.2 h, and finally at 0.18-0.22 mbar for 3.8-4.2 h. At the same time, the shelf temperature is raised from -40℃ to -5℃ at a rate of 0.4-0.6℃ / h, and the particle temperature is kept below the eutectic point of -25℃, so that the moisture content of the porous wet particles is reduced to 7-9%.

8. The method for preparing sustained-release pentamirrolic acid granules by low-temperature drying according to claim 1, characterized in that: In the freeze-drying step, the analytical drying involves raising the shelf temperature from -5℃ to 33-37℃ at a rate of 0.8-1.2℃ / h under a vacuum of 0.02-0.04 mbar, which is 25-29℃ lower than the glass transition temperature of the composite protective agent. Then, dry nitrogen gas with a dew point ≤ -60℃ is introduced to purge for 3.8-4.2h, so that the water activity of the porous wet particles is 0.23-0.27 and the water content is ≤1.5%.

9. The method for preparing sustained-release pentamirrolic acid granules by low-temperature drying according to claim 1, characterized in that: In the post-processing steps, the granulation is carried out using an 18-mesh sieve, the sieving is carried out using a 20-30 mesh grading sieve, and the particle size distribution of the sieved particles is D10=0.8-1.0mm, D50=1.0-1.2mm, and D90=1.2-1.4mm. The packaging is carried out using aluminum-plastic composite film bags.

10. The method for preparing sustained-release pentamirrolic acid granules by low-temperature drying according to claim 1, characterized in that: In the post-processing steps, the dispensed products are stored at 2-6℃ in the dark.

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