Colchicine sustained-release micropill and preparation method thereof

Abstract

The present invention belongs to the technical field of sustained-release preparations and discloses colchicine sustained-release micropellets and their preparation method. The colchicine sustained-release micropellets comprise, from the inside out, a blank core, a colchicine drug layer, a light-shielding layer, and a sustained-release layer. The light-shielding layer includes a light-shielding agent and a suspending agent; the light-shielding agent is one or more of Fe2O3, Fe2O3·H2O, and Fe3O4. Adding iron oxide to the colchicine preparation has a more significant protective effect than titanium dioxide, unexpectedly inhibiting the photochemical degradation of colchicine and providing greater safety. The optimal effect is achieved when iron oxide is added as an independent light-shielding layer between the drug layer and the sustained-release layer.

Description

Technical Field

[0001] The present invention relates to the technical field of sustained-release preparations, and in particular to colchicine sustained-release micropills and a preparation method thereof. Background Art

[0002] During the research process, it was found that colchicine preparations are very easy to degrade under light conditions, and under different light conditions, the degradation products are relatively concentrated, and with the increase of light intensity and light duration, the degree of degradation also increases relatively (Lv Bai et al., Study on the photochemical degradation law of colchicine raw materials. Military Medicine, 2022, 46(3): 219-224). Especially after being prepared into micropellets, since the raw materials are evenly attached to the surface of the pellet core carrier, the specific surface area becomes larger, and the drug degradation increases sharply. During the preparation production process, as well as the transportation and storage of semi-finished products or intermediates, colchicine is inevitably exposed to different light intensities. The degradation of the drug is difficult to avoid, and the degree of drug degradation is uncontrollable, resulting in uncontrollable quality of the drug preparation. Therefore, researchers mostly add sunscreens to reduce the photodegradation of colchicine when preparing colchicine preparations.

[0003] The colchicine tablets approved for marketing by the US FDA contain titanium dioxide, a sunscreen, in their film coating. Some colchicine preparations available in China are packaged in double-sided aluminum to prevent the drug from photodegradation. However, there are still some problems. First, recent research results have shown that titanium dioxide has a potential genotoxic risk. An assessment by the European Food Safety Authority (EFSA) in May 2021 revealed the potential for genotoxicity of titanium dioxide, and the agency believes it is necessary to ban the use of titanium dioxide in food (Safety assessment of titanium dioxide (E171) as a food additive. EFSA Panel on Food Additives and Flavourings (FAF). EFSAJ. 2021May 6; 19(5): e06585. doi: 10.2903 / j.efsa.2021.6585. PMID: 33976718; PMCID: PMC8101360). The European Union currently classifies certain forms of titanium dioxide (TiO2) as a suspected carcinogen by inhalation (Category 2), with this ban effective October 1, 2021. Based on EFSA's announcement and its own assessment, the EU announced on January 14, 2022, that it would completely ban the addition of titanium dioxide to food after a six-month period (Eropean Commission (2022), Food safety: Food additive titanium dioxide banned as of this summer). Following the EU's lead, the Gulf Standards Organization, which includes countries such as Saudi Arabia, Yemen, and Qatar, has also decided to ban titanium dioxide. Switzerland, South Korea, and other countries have also made similar decisions (China Nutrition and Health Food Association (2022), International News | Titanium Dioxide: Bans are Spreading (Translation)). Furthermore, double-sided aluminum packaging may require light shielding measures during the production process, but the effectiveness of this shielding is uncertain, potentially resulting in substandard products. Furthermore, double-sided aluminum packaging is costly.

[0004] Therefore, it is urgent to provide a colchicine preparation that does not contain titanium dioxide and can simultaneously ensure that the degree of colchicine degradation is reduced. Summary of the Invention

[0005] The purpose of the present invention is to provide a colchicine sustained-release micropill and a preparation method thereof, so as to solve the problem that the degradation degree of existing colchicine preparations is too high.

[0006] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0007] The present invention provides a colchicine sustained-release micropill, which comprises, from the inside to the outside: a blank pellet core, a colchicine drug layer, a light-shielding layer, and a sustained-release layer;

[0008] The light-shielding layer includes a light-shielding agent and a suspending agent;

[0009] The sunscreen is one or more of Fe2O3, Fe2O3·H2O and Fe3O4.

[0010] Preferably, in the colchicine sustained-release micropellets, the blank pellet core is a sugar pellet, a microcrystalline cellulose pellet or a starch pellet; and the particle size of the blank pellet core is 150 to 1500 μm.

[0011] Preferably, in the colchicine sustained-release pellets, the mass of colchicine in the colchicine drug layer is 0.2-1% of the mass of the blank pellet core, and the colchicine drug layer does not contain a binder.

[0012] Preferably, in the colchicine sustained-release pellets, the mass of the sunscreen and the suspending agent is independently 0.1 to 10% of the sum of the mass of the blank pellet core and the colchicine drug layer.

[0013] Preferably, in the colchicine sustained-release micropellets, the sustained-release layer comprises a sustained-release material and a pore-forming agent; the sustained-release material is an ethyl cellulose or polymethacrylate polymer; the suspending agent and the pore-forming agent independently comprise hydroxypropyl methylcellulose, methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose or povidone.

[0014] Preferably, in the colchicine sustained-release pellets, the mass of the sustained-release layer is 5 to 30% of the sum of the masses of the blank pellet core and the colchicine drug layer.

[0015] Preferably, in the colchicine sustained-release pellets, the mass of the sustained-release material is 70-100% of the sustained-release layer, and the mass of the porogen is 0-30% of the sustained-release layer.

[0016] The present invention also provides a method for preparing the colchicine sustained-release pellets, comprising the following steps:

[0017] (1) mixing colchicine with water to obtain a colchicine solution;

[0018] The sunscreen agent, the suspending agent and water are mixed and dispersed to obtain a sunscreen layer liquid;

[0019] The sustained-release material, the pore-forming agent and water are mixed and dispersed to obtain a sustained-release layer liquid;

[0020] (2) The colchicine solution, the light-shielding layer solution, and the sustained-release layer solution were sequentially coated onto the blank pellet cores and sieved to obtain colchicine sustained-release micropellets.

[0021] Preferably, in the preparation method of the colchicine sustained-release microcapsules, the air inlet temperature during the coating in step (2) is independently 60-68°C, the liquid inlet speed during the coating is independently 5-15 mL / min, the air inlet volume during the coating is independently 28-36 Pasca / s, the atomization pressure during the coating is independently 1-2.5 bar, and the guide tube height during the coating is independently 27-30 mm.

[0022] Preferably, in the preparation method of the colchicine sustained-release micropellets, the particle size of the colchicine sustained-release micropellets in step (2) is 20 to 40 meshes.

[0023] It can be seen from the above technical solutions that compared with the prior art, the present invention has the following beneficial effects:

[0024] Iron oxide is added to colchicine preparations. Compared to titanium dioxide, iron oxide has a more significant protective effect, and has an unexpected inhibitory effect on the photochemical degradation of colchicine. The iron oxide of the present invention can well replace titanium dioxide as a sunscreen for colchicine sustained-release pellets, and has higher safety. The present invention also compares iron oxide of different colors and adds iron oxide in different preparation steps. The results show that there is no significant difference in the photochemical degradation protective effect of iron oxide of different colors, but iron oxide is added in different preparation steps, and iron oxide is added between the drug layer and the sustained-release layer as an independent light-shielding layer, with the best effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for describing the embodiments or the prior art.

[0026] Figure 1 Schematic diagram of the structure of the colchicine sustained-release pellets obtained in the present invention. DETAILED DESCRIPTION

[0027] The present invention provides a colchicine sustained-release micropill, which comprises, from the inside to the outside: a blank pellet core, a colchicine drug layer, a light-shielding layer, and a sustained-release layer;

[0028] The light-shielding layer includes a light-shielding agent and a suspending agent;

[0029] The sunscreen is one or more of Fe2O3, Fe2O3·H2O and Fe3O4.

[0030] In the present invention, the sunscreen is preferably Fe2O3 or a combination of two or three of Fe2O3, Fe2O3·H2O and Fe3O4, more preferably Fe2O3 or a combination of two of Fe2O3 and Fe2O3·H2O, and more preferably Fe2O3.

[0031] The present invention does not limit the sources of the Fe2O3, the Fe2O3 and the Fe2O3·H2O, and any manufacturer known to those skilled in the art can be used. Specifically in the embodiments of the present invention, the manufacturer of the Fe2O3, the Fe2O3 and the Fe2O3·H2O is preferably Senxin Flavor and Pigment Technology Co., Ltd.

[0032] In the present invention, the blank pill core is preferably a sugar pill, a microcrystalline cellulose pill or a starch pill, more preferably a sugar pill or a starch pill, and more preferably a sugar pill.

[0033] The present invention does not limit the source of the sugar pills, and any material well known to those skilled in the art can be used. Specifically in the embodiment of the present invention, the manufacturer of the sugar pills is preferably Hangzhou Gaocheng Biological Nutrition Technology Co., Ltd.

[0034] In the present invention, the particle size of the blank pellet core is preferably 150 to 1500 μm, more preferably 400 to 1000 μm, and even more preferably 500 to 600 μm.

[0035] In the present invention, the mass of colchicine in the colchicine drug layer is preferably 0.2-1% of the mass of the blank pill core, more preferably 0.5-1%, and even more preferably 0.5%.

[0036] In the present invention, the colchicine drug layer does not contain a binder.

[0037] The present invention does not limit the source of the colchicine, and any source well known to those skilled in the art may be used.

[0038] In the present invention, the mass of the sunscreen and the suspending agent is independently preferably 0.1-10% of the sum of the mass of the blank pellet core and the colchicine drug layer, more preferably 1-5%, and even more preferably 4%.

[0039] In the present invention, the sustained-release layer comprises a sustained-release material and a pore-forming agent.

[0040] In the present invention, the sustained-release material is preferably an ethyl cellulose or polymethacrylate polymer.

[0041] The present invention does not limit the state of the ethyl cellulose, but preferably includes ethyl cellulose powder, ethyl cellulose aqueous dispersion, and ethyl cellulose organic solution, and more preferably ethyl cellulose aqueous dispersion.

[0042] In the present invention, the polymethacrylate polymer preferably includes one or more of polyacrylic resin II, polyacrylic resin III, polyacrylic resin IV, Eudragit NE 30D, Eudragit RS 30D and Eudragit RL 30D, further preferably one or more of Eudragit NE 30D, Eudragit RS 30D and Eudragit RL 30D, and more preferably Eudragit RL 30D.

[0043] In the present invention, the suspending agent and the porogen independently preferably comprise hydroxypropyl methylcellulose, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl cellulose or povidone, further preferably comprise hydroxypropyl methylcellulose, hydroxypropyl cellulose or povidone, more preferably hydroxypropyl methylcellulose.

[0044] The present invention does not limit the type and source of the aqueous ethylcellulose dispersion and the hydroxypropyl methylcellulose; materials familiar to those skilled in the art may be used. Specifically, in the embodiments of the present invention, the aqueous ethylcellulose dispersion is preferably Surelease E-7-19040 (Type B); the hydroxypropyl cellulose is preferably HPLC-E5; and the manufacturer of Surelease E-7-19040 (Type B) and HPLC-E5 is preferably Shanghai Colorcon Coating Technology Co., Ltd.

[0045] In the present invention, the mass of the sustained-release layer is preferably 5-30% of the sum of the masses of the blank pill core and the colchicine drug layer, more preferably 16-30%, and even more preferably 16%.

[0046] In the present invention, the mass of the sustained-release material is preferably 70-100% of the sustained-release layer, more preferably 80-100%, and more preferably 91%; the mass of the porogen is preferably 0-30% of the sustained-release layer, more preferably 0-20%, and more preferably 9%.

[0047] The present invention also provides a method for preparing the colchicine sustained-release pellets, comprising the following steps:

[0048] (1) mixing colchicine with water to obtain a colchicine solution;

[0049] The sunscreen agent, the suspending agent and water are mixed and dispersed to obtain a sunscreen layer liquid;

[0050] The sustained-release material, the pore-forming agent and water are mixed and dispersed to obtain a sustained-release layer liquid;

[0051] (2) The colchicine solution, the light-shielding layer solution, and the sustained-release layer solution were sequentially coated onto the blank pellet cores and sieved to obtain colchicine sustained-release micropellets.

[0052] In the present invention, the total solid content of the sustained-release layer liquid in step (1) is preferably 8-18%, more preferably 10-15%, and even more preferably 12.5%.

[0053] In the present invention, the air inlet temperature during coating in step (2) is independently preferably 60-68°C, the liquid inlet speed during coating is independently preferably 5-15 mL / min, the air inlet volume during coating is independently preferably 28-36 Pasca / s, the atomization pressure during coating is independently preferably 1-2.5 bar, and the guide tube height during coating is independently preferably 27-30 mm.

[0054] In the present invention, the process of sequentially coating the colchicine solution, the light-shielding layer solution, and the sustained-release layer solution onto the blank pill cores in step (2) further includes: drying after each coating is completed; the drying temperature is independently preferably 55 to 65° C., and the drying time is independently preferably 5 to 20 minutes.

[0055] In the present invention, the particle size of the colchicine sustained-release micropellets in step (2) is preferably 20-40 mesh.

[0056] The following is a clear and complete description of the technical solutions in the embodiments of the present invention. Obviously, the embodiments described are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making any creative efforts are within the scope of protection of the present invention.

[0057] Instruments used

[0058] fluidized bed (GPCG 1, Glatt, Germany);

[0059] Magnetic stirrer (DF-101S, Yingyu Yuhua Instrument Factory, Gongyi City, Henan Province);

[0060] Stationary screw air compressor (BLT-15A-12, Shanghai Baolete Compressor Co., Ltd.);

[0061] electronic balance (1%, BS323S, Sartorius, Switzerland);

[0062] electronic balance (1 / 10,000, BSA224S, Sartorius, Switzerland);

[0063] Electronic balance (100,000, BT125D, Sartorius, Switzerland).

[0064] Reagents used

[0065] Colchicine: Manufacturer: Indena, Batch No.: 21S0134800;

[0066] Blank pellets: Manufacturer: Hangzhou Gaocheng Bio-Nutrition Technology Co., Ltd., batch number: 20211215;

[0067] Hydroxypropyl cellulose: HPMC-E5: Manufacturer: Shanghai Colorcon Coating Technology Co., Ltd., batch number: PDR548736;

[0068] Ethylcellulose: Surelease E-7-19040 (Type B) aqueous dispersion: Manufacturer: Shanghai Colorcon Coating Technology Co., Ltd., Batch No.: IN548398;

[0069] Titanium dioxide: Manufacturer: Merck, Germany, batch number: K51803005;

[0070] Yellow iron oxide: Manufacturer: Senxin Flavor and Color Technology Co., Ltd., Batch No.: 5752646;

[0071] Black iron oxide: Manufacturer: Senxin Flavor and Color Technology Co., Ltd., Batch No.: K51803005;

[0072] Red iron oxide: Manufacturer: Senxin Flavor and Pigment Technology Co., Ltd., Batch No.: 5752646;

[0073] Acetonitrile: Manufacturer: Fisher Chemical, Lot No.: F22MAC202;

[0074] Distilled water: Manufacturer: Watsons, Batch number: 20221025.

[0075] Example 1

[0076] This embodiment provides a method for preparing colchicine sustained-release pellets, comprising the following steps:

[0077] (1) Measure 250 mL of distilled water and place it in a 1000 mL beaker. Place it on a magnetic stirrer and stir until it is completely dissolved. Then, add 2.5 g of colchicine, seal the beaker with plastic wrap and continue stirring until the colchicine is completely dissolved to obtain a colchicine solution.

[0078] Measure 400 mL of distilled water into a 1000 mL beaker and stir on a mechanical stirrer. Add 25 g of HPMC-E5 and wait until it is completely dissolved. Then add 25 g of Fe2O3 sunscreen (red iron oxide) and 100 mL of distilled water and continue stirring for about 30 min to evenly disperse the sunscreen in the solution to obtain a sunscreen liquid.

[0079] Dissolve 7.44 g of HPMC-E5 in 273.86 g of distilled water and stir on a mechanical stirrer until completely dissolved. Then add the mixture to 290.23 g of Surelease E-7-19040 (Type B) with a solid content of 25%. Continue to add 68.47 g of distilled water and continue stirring for 30 minutes to mix thoroughly to obtain a sustained-release layer solution with a total solid content of 12.5%.

[0080] (2) Start the fluidized bed, take 500 g of 500-600 μm sugar pills, spray the prepared colchicine solution into the bottom spray coating pot of the fluidized bed, and coat the colchicine onto the sugar pills according to the parameters of inlet air temperature 60°C, air volume 34 Pasca / s, guide tube height 27 mm, atomization pressure 2.0 bar, liquid feed rate 15 mL / min, drying temperature 60°C, and drying time 5 min. The mass of colchicine is 0.5% of the sugar pills to obtain drug-loaded micropellets;

[0081] Take 500g of drug-loaded pellets, spray the prepared light-shielding layer liquid into the fluidized bed bottom spray coating pot, and coat the light-shielding layer on the drug-loaded pellets according to the parameters of inlet temperature 60°C, air volume 34Pasca / s, guide tube height 27mm, atomization pressure 2.0bar, liquid feed rate 15mL / min, drying temperature 60°C, and drying time 5min. Stop when the light-shielding agent is 5% of the mass of the drug-loaded pellets; then spray the prepared sustained-release layer liquid into the fluidized bed bottom spray coating pot, and coat the sustained-release layer on the light-shielding layer according to the parameters of inlet temperature 68°C, air volume 34Pasca / s, guide tube height 27mm, atomization pressure 2.0bar, liquid feed rate 15mL / min, drying temperature 60°C, and drying time 20min. The mass of the sustained-release layer is 16% of the drug-loaded pellets, and sieve to obtain 20-40 mesh colchicine sustained-release pellets.

[0082] Comparative Example 1

[0083] This comparative example provides a method for preparing colchicine sustained-release micropellets, which differs from Example 1 in that the preparation of the light-shielding layer liquid in step (1) and the step of coating the light-shielding layer liquid in step (2) are deleted, and the other parameter conditions are the same as those in Example 1.

[0084] Detection method

[0085] Weigh 300 mg of different samples and place them in 10 mL vials. Place them in a light test chamber and expose them to 4500 ± 500 lx for 24 or 48 hours. The samples are spaced 2 cm apart and 3 cm from the light source.

[0086] Reference solution: Accurately weigh 10 mg of colchicine and place it in a 25 mL volumetric flask. Add distilled water and sonicate for 10 min to adjust the volume to the mark. Take 2 mL of this solution and place it in a 5 mL volumetric flask, dilute it to the mark with distilled water, shake well, and filter through a 0.22 μm filter.

[0087] Experimental solution: Grind the sample in the vial and transfer it to a 10 mL volumetric flask. Add appropriate amount of distilled water, sonicate for 20 min, dilute to the mark with distilled water, shake well, and filter through a 0.22 μm filter.

[0088] The luminescent substances were detected according to the following chromatographic conditions: stationary phase: CSMOSIL Packed Column 5C8-MS (4.6×250 mm, 5 μm), mobile phase: acetonitrile:water = 25:75, detection wavelength: 254 nm, flow rate: 1 mL / min, column temperature: 15°C, injection volume: 100 μL, and run time: 45 min.

[0089] The light-producing substance content of the colchicine raw material, the drug-loaded pellets obtained in Comparative Example 1, and the colchicine sustained-release pellets before irradiation was tested, and the results are shown in Table 1.

[0090] Table 1. Test results of colchicine drug and the drug-loaded pellets and colchicine sustained-release pellets obtained in Comparative Example 1 before light exposure

[0091]

[0092] The data in Table 1 show that the colchicine API contains approximately 0.04% photodegradable impurities. When preparing colchicine-loaded pellets, the required drug loading was reduced (colchicine was 0.5% of the blank pellet weight), resulting in a shorter preparation process and no photodegradation. However, when applying sustained-release coating to the pellets, the coating time was extended—four times the time required for preparation—exposing the drug to light for extended periods, leading to photodegradation. After sustained-release coating, the photodegradable impurities increased dramatically from 0.04% to 0.76%, an increase of approximately 20-fold. Furthermore, as the production batch size increases, the coating time must be extended, which in turn increases the exposure time, leading to an increase in photodegradation products. Therefore, the addition of a sunscreen during production is essential to shield the drug from light and prevent degradation.

[0093] Examples 2 to 5

[0094] Examples 2 to 5 respectively provide a method for preparing colchicine sustained-release micropellets. The difference from Example 1 is that the end point of the light-shielding layer liquid coating in step (2) is changed to 1%, 2%, 3%, and 4% of the mass of the drug-loaded micropellets respectively. The other parameter conditions are the same as those in Example 1.

[0095] Comparative Examples 2 to 6

[0096] Comparative Examples 2 to 6 respectively provide a method for preparing colchicine sustained-release micropellets, which differ from Example 1 in that the Fe2O3 sunscreen in step (1) is completely replaced by a TiO2 sunscreen, and the end point of the sunscreen liquid coating in step (2) is changed to 1%, 2%, 3%, 4%, and 5% of the mass of the drug-loaded micropellets respectively. The other parameter conditions are the same as those in Example 1.

[0097] Titanium dioxide, a commonly used sunscreen, was selected as a photoprotective agent to investigate the effect of titanium dioxide dosage on the photostability of colchicine. The results are shown in Table 2.

[0098] Table 2. Test results of samples of comparative examples 2 to 6 after 48 hours of illumination

[0099]

[0100] The results in Table 2 show that although titanium dioxide has a protective effect on the photodegradation of drugs, its effect is very limited. After 48 hours of illumination, the peak area percentage of photodegradation products still significantly increases, while the main peak area percentage significantly decreases. Moreover, as the titanium dioxide dosage increases, the photodegradation products slightly decrease, but not significantly. The titanium dioxide dosage reaches 5% of the drug-loaded pill core, which is approximately equivalent to 10 times the amount of colchicine. After 48 hours of illumination, the percentage of photodegradation products is still greater than 7%. It can be seen that titanium dioxide cannot effectively protect colchicine, which is not expected by those skilled in the art.

[0101] The present invention uses iron oxide as a photoprotectant to inhibit the degradation of colchicine. The test results are shown in Table 3. When the red iron oxide dosage was 1% of the weight of the drug-loaded pellet core, it showed a significant photodegradation inhibitory effect. Without the addition of iron oxide, the percentage of photodegradation products after 48 hours of illumination was 13.41%. When the red iron oxide dosage was 1%, the percentage of photodegradation products decreased to 1.53%. Furthermore, the content of photodegradation products gradually decreased with increasing red iron oxide dosage. At a dosage of 4%, the sustained-release pellets after 48 hours of illumination showed the same level of performance as the unilluminated batch of the API, indicating that red iron oxide can almost completely inhibit the formation of late-stage photodegradation products of colchicine.

[0102] Table 3. Test results of samples of Examples 1 to 5 after 48 hours of illumination

[0103]

[0104] Examples 6 to 10

[0105] Examples 6 to 10 respectively provide a method for preparing colchicine sustained-release micropellets, which differ from Example 1 in that the Fe2O3 sunscreen in step (1) is completely replaced by Fe2O3·H2O sunscreen (yellow ferric oxide), and the end point of the sunscreen liquid coating in step (2) is changed to 1%, 2%, 3%, 4%, and 5% of the mass of the drug-loaded micropellets respectively. The other parameter conditions are the same as those in Example 1.

[0106] Examples 11 to 15

[0107] Examples 11 to 15 respectively provide a method for preparing colchicine sustained-release micropellets, which differ from Example 1 in that the Fe2O3 sunscreen in step (1) is completely replaced by Fe3O4 sunscreen (black iron oxide), and the end point of the sunscreen liquid coating in step (2) is changed to 1%, 2%, 3%, 4%, and 5% of the mass of the drug-loaded micropellets respectively. The other parameter conditions are the same as those in Example 1.

[0108] The experiments in Examples 1-5 confirmed that iron oxide sunscreens can effectively protect colchicine from photodegradation. The Chinese Pharmacopoeia lists five colors of iron oxide: red, yellow, black, violet, and brown. Violet and brown are mixtures of the first three types of iron oxide in varying proportions. The present invention selected the first three basic iron oxides to investigate their protective effects on the drug, with the test results shown in Tables 3-4.

[0109] Results showed no significant difference in the protective effects of the three colors of iron oxide on the drug, and a dosage of 4% or more was required to maximize drug protection against photodegradation. However, yellow iron oxide coating can lead to color variations in the pellets, affecting the product's appearance. Black iron oxide also presents a poor visual experience, so red iron oxide is the preferred sunscreen for colchicine sustained-release pellets.

[0110] From the above results, it can be seen that single-color iron oxide can effectively inhibit the photodegradation of colchicine, and mixed-color purple iron oxide and brown iron oxide can also achieve the expected effect. The proportion can be adjusted as needed to obtain the desired coloring effect, and their photoprotection effects are consistent.

[0111] Table 4. Test results of samples of Examples 6 to 15 after 48 hours of illumination

[0112]

[0113] Comparative Example 7

[0114] This comparative example provides a method for preparing colchicine sustained-release micropills, which differs from Example 5 in that the preparation of the light-shielding layer liquid in step (1) and the step of coating the light-shielding layer liquid in step (2) are deleted; after the colchicine in step (1) is completely dissolved, the following process is added: 20 g of red iron oxide sunscreen is added and stirred for 30 minutes until uniformly dispersed to obtain a colchicine solution; the air intake volume during the preparation of the drug-loaded micropills in step (2) is changed to 30 Pasca / s and the guide tube height is changed to 30 mm. The other parameter conditions are the same as those in Example 5.

[0115] Comparative Example 8

[0116] This comparative example provides a method for preparing colchicine sustained-release micropellets, which differs from Example 5 in that the preparation of the light-shielding layer liquid in step (1) and the step of coating the light-shielding layer liquid in step (2) are deleted; after adding it to 290.23g of Sulis E-7-19040 (Type B) with a solid content of 25% as described in step (1), the following process is added: 20g of red iron oxide sunscreen is added; the other parameter conditions are the same as those in Example 5.

[0117] Comparative Example 9

[0118] This comparative example provides a method for preparing colchicine sustained-release micropellets, which is different from Example 5 in that in step (2), after the preparation of the drug-loaded micropellets is completed, the sustained-release layer liquid is first coated on the drug-loaded micropellets, and then the light-shielding layer liquid is coated on the outermost layer of the sustained-release coating film.

[0119] The effects of different addition methods of red iron oxide on the photostability of colchicine loaded micropellets were compared, and the results are shown in Table 5. The experimental results in Table 5 show that when the sunscreen is added to the drug-loaded layer (i.e., Comparative Example 7), the sunscreen fails to protect all drugs, causing some drugs to be exposed to light, and the drugs will still undergo photodegradation, and the content of photodegradable impurities increases significantly over time; when the sunscreen is used as an independent light-shielding layer (i.e., Example 5), the drugs can be protected to the greatest extent to avoid photodegradation. After 10 days of drug illumination, the content of photodegradable impurities remains unchanged and is at the same level as when the drug is illuminated for 0 h; when the sunscreen is added to the sustained-release layer (i.e., Comparative Example 8), due to the large amount of sustained-release coating material used, the unit density of the sunscreen in the sustained-release layer is reduced, and the light transmittance increases. In addition, some drugs still undergo photodegradation, and the amount of degradation products increases significantly as the illumination time increases. In addition, since a large amount of insoluble sunscreen is added to the sustained-release layer, the quality and stability of the sustained-release coating may be affected; when the sunscreen is added to the outermost layer of the sustained-release coating as an independent sunscreen layer (i.e., Comparative Example 9), the sunscreen layer can also play a good light-shielding role, but since complete light protection cannot be guaranteed during the preparation of the micropills, some drugs have already undergone photodegradation before the light-shielding coating is performed, and as the production batch increases and the coating time is prolonged, the amount of degradation products generated will also increase, which is uncontrollable during the production process.

[0120] In summary, the sunscreen of colchicine sustained-release micropellets is added between the drug layer and the sustained-release layer as an independent sunscreen layer, which has the best sunscreen effect and can completely prevent drug degradation.

[0121] Table 5. Test results of samples of Comparative Examples 7 to 9 and Example 5 after 10 days of illumination

[0122]

[0123] Comparative Example 10

[0124] The colchicine preparation of this comparative example is commercially available tablet A, the main ingredient of which is colchicine.

[0125] The samples prepared in Example 5 and the samples in Comparative Example 10 were subjected to a light irradiation experiment to compare their stability under the same light irradiation conditions.

[0126] Light irradiation experiment design: The prepared samples were placed in a light test chamber according to the strong light irradiation test method in the 2020 edition of the "Chinese Pharmacopoeia" Stability Guidelines for Active Pharmaceutical Ingredients and Preparations. Samples were taken at 0 days, 1 day, 5 days, and 10 days, and the changes in related substances in the samples were determined by high-performance liquid chromatography.

[0127] Table 6. Comparative test results of samples of Comparative Example 10 and Example 5 after 10 days of illumination

[0128]

[0129] As shown in the experimental results in Table 6, before exposure to light, the photodegradable impurity content of commercially available tablets A and Example 5 samples was essentially the same, but the commercially available sample was slightly higher than that of Example 5. However, as the exposure time increased, the photodegradable impurities of commercially available tablets A increased dramatically. After only one day of exposure, the photodegradable impurities increased by approximately 44 times, which was 71 times that of Example 5. After 10 days of exposure, the increase in photodegradable products was approximately 125 times, which was 250 times that of Example 5. Commercially available tablets A were packaged in light-proof, double-sided aluminum packaging. The experimental test results for different batches of samples were slightly different. The results of the same batch tested at different times also varied slightly and were irregular. This may be due to different light intensity or operating time during the testing process, which also introduces uncertainty into quality control. It can be speculated that the commercially available sample formulations did not take light-proof measures or the light-proof measures were inappropriate. Therefore, light-proofing operations are still required during the production and testing process to prevent drug degradation, which is inconvenient and increases costs. Moreover, the light-proofing effect is uncertain, which is very likely to lead to product failure. However, the sample of Example 5 prepared by the present invention did not show a significant change in the content of photodegradable impurities after 10 days of illumination under the same conditions as the commercially available tablet A, indicating that the colchicine sustained-release micropellets prepared by the technical solution of the present invention can be operated normally during the production and inspection process, without the need for light-proof measures or light-proof sample packaging, which greatly increases the convenience of production and reduces production costs.

[0130] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. A colchicine sustained-release pellet, characterized in that: From the inside to the outside, it includes: blank pill core, colchicine drug layer, light-shielding layer, and sustained-release layer; The light-shielding layer includes a light-shielding agent and a suspending agent; The sunscreen is one or more of Fe2O3, Fe2O3·H2O and Fe3O4.

2. The colchicine sustained-release pellets according to claim 1, wherein The blank pill core is a sugar pill, a microcrystalline cellulose pill or a starch pill; and the particle size of the blank pill core is 150 to 1500 μm.

3. The colchicine sustained-release pellets according to claim 1 or 2, characterized in that The mass of colchicine in the colchicine drug layer is 0.2-1% of the mass of the blank pill core, and the colchicine drug layer does not contain a binder.

4. The colchicine sustained-release pellets according to claim 3, wherein The mass of the sunscreen and the suspending agent is independently 0.1-10% of the sum of the mass of the blank pill core and the colchicine drug layer.

5. The colchicine sustained-release pellets according to claim 1, 2 or 4, characterized in that: The sustained-release layer comprises a sustained-release material and a pore-forming agent; the sustained-release material is an ethyl cellulose or polymethacrylate polymer; the suspending agent and the pore-forming agent independently comprise hydroxypropyl methylcellulose, methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose or povidone.

6. The colchicine sustained-release pellets according to claim 5, characterized in that The mass of the sustained-release layer is 5-30% of the sum of the masses of the blank pill core and the colchicine drug layer.

7. The colchicine sustained-release pellets according to claim 6, characterized in that: The mass of the sustained-release material is 70-100% of the sustained-release layer, and the mass of the porogen is 0-30% of the sustained-release layer.

8. The method for preparing the colchicine sustained-release pellets according to any one of claims 1 to 7, characterized in that: The following steps are involved: (1) mixing colchicine with water to obtain a colchicine solution; The sunscreen agent, the suspending agent and water are mixed and dispersed to obtain a sunscreen layer liquid; The sustained-release material, the pore-forming agent and water are mixed and dispersed to obtain a sustained-release layer liquid; (2) The colchicine solution, the light-shielding layer solution, and the sustained-release layer solution were sequentially coated onto the blank pellet cores and sieved to obtain colchicine sustained-release micropellets.

9. The method for preparing colchicine sustained-release pellets according to claim 8, wherein: In step (2), the air inlet temperature during coating is independently 60-68°C, the liquid inlet speed during coating is independently 5-15 mL / min, the air inlet volume during coating is independently 28-36 Pasca / s, the atomization pressure during coating is independently 1-2.5 bar, and the guide tube height during coating is independently 27-30 mm.

10. The method for preparing colchicine sustained-release pellets according to claim 8 or 9, characterized in that: The particle size of the colchicine sustained-release micropellets in step (2) is 20 to 40 meshes.

Images