Colchicine sustained-release pellet and preparation method thereof

Abstract

The invention belongs to the technical field of sustained-release preparations, and discloses colchicine sustained-release pellets and a preparation method thereof. The colchicine sustained-release pellet comprises a blank pellet core, a colchicine medicine layer, a shading layer and a sustained-release layer from inside to outside, the shading layer comprises an opacifying agent and a suspending aid; and the opacifying agent is one or more of Fe2O3 (ferric oxide), Fe2O3.H2O (ferric oxide) and Fe3O4 (ferric oxide). According to the colchicine preparation, iron oxide is added into the colchicine preparation, compared with titanium dioxide, the colchicine preparation has a more remarkable protection effect, has an unexpected inhibition effect on photochemical degradation of colchicine and has higher safety, and the effect is optimal by adding iron oxide as an independent shading 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 a colchicine sustained-release micropill 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 dramatically. In 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, when preparing colchicine preparations, researchers mostly add sunscreens to reduce the photodegradation of colchicine.

[0003] The colchicine tablets approved by the US FDA have titanium dioxide, a sunscreen, added to their film coating. Some colchicine preparations available in China are packaged in double-sided aluminum to ensure that the drug does not undergo photodegradation. But there are still some problems. First, research results in recent years have shown that titanium dioxide has potential genotoxic risks. 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 EU currently classifies certain forms of titanium dioxide (TiO2) as suspected carcinogens by inhalation (category 2), which will take effect on October 1, 2021. Based on the EFSA announcement and its own assessment, the EU announced on January 14, 2022 that it will completely ban the addition of titanium dioxide to food after a six-month period (Eropean Commission (2022), Foodsafety: Food additive Titanium Dioxide banned as of this summer). Following the EU's footsteps, the Gulf Standards Organization, including Saudi Arabia, Yemen, Qatar and other countries, has also decided to ban titanium dioxide. Switzerland, South Korea and other countries have also made the same decision (China Nutrition and Health Food Association (2022), International News | Titanium Dioxide: The ban is spreading (translation)). In addition, the use of double-sided aluminum packaging may require measures such as light protection during the production process. The light protection effect is uncertain, which may cause the product to be unqualified, and the packaging cost of double-sided aluminum is also high.

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

[0005] The object of the present invention is to provide a colchicine sustained-release pellet 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 micro-pill, which comprises, from inside to 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 microcapsules, 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.

[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 microcapsules, 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, methyl cellulose, 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 pore-forming agent 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) colchicine is mixed with water to obtain a colchicine solution;

[0018] The sunscreen agent, the suspending agent and the 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 are sequentially coated onto the blank pellet cores, and the pellets are sieved to obtain colchicine sustained-release pellets.

[0021] Preferably, in the preparation method of the colchicine sustained-release microcapsules, the air inlet temperature during coating in step (2) 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.

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

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

[0024] Iron oxide is added to the colchicine preparation. Compared with 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 oxides of different colors and adds iron oxide in different preparation steps. The results show that there is no significant difference in the protective effect of photochemical degradation of iron oxides 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, which has 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 drawings required to be used in the description of the embodiments or the prior art are briefly introduced below.

[0026] Figure 1 The schematic diagram is a structural diagram of the colchicine sustained-release micropellets obtained in the present invention. DETAILED DESCRIPTION

[0027] The present invention provides a colchicine sustained-release micro-pill, which comprises, from inside to 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 familiar 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 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 pill 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 acid resin II, polyacrylic acid resin III, polyacrylic acid resin IV, Eudragit NE 30D, Eudragit RS 30D and Eudragit RL 30D, more 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 types and sources of the ethyl cellulose aqueous dispersion and the hydroxypropyl methylcellulose, and any materials familiar to those skilled in the art can be used. Specifically, in the embodiments of the present invention, the ethyl cellulose aqueous dispersion is preferably Sulis E-7-19040 (Type B); the hydroxypropyl cellulose is preferably HPLC-E5; the manufacturer of Sulis E-7-19040 (Type B) and the 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 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) colchicine is mixed with water to obtain a colchicine solution;

[0049] The sunscreen agent, the suspending agent and the 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 are sequentially coated onto the blank pellet cores, and the pellets are sieved to obtain colchicine sustained-release pellets.

[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 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 core in step (2) also 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 meshes.

[0056] The technical solutions in the embodiments of the present invention are described clearly and completely below. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work 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] Fixed 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 (1 / 100,000, BT125D, Sartorius, Switzerland).

[0064] Reagents used

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

[0066] Blank pellet core: 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] Ethyl cellulose: Sulis 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 & Pigment Technology Co., Ltd., Batch No.: 5752646;

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

[0072] Red iron oxide: Manufacturer: Senxin Flavor & 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) 250 mL of distilled water was measured and placed in a 1000 mL beaker, placed on a magnetic stirrer, stirred until completely dissolved, and then 2.5 g of colchicine was added, the beaker was sealed with plastic wrap and continued to be stirred until the colchicine was completely dissolved to obtain a colchicine solution;

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

[0079] 7.44 g of HPMC-E5 was dissolved in 273.86 g of distilled water, and stirred on a mechanical stirrer until completely dissolved. Then, it was added to 290.23 g of Sulis E-7-19040 (Type B) with a solid content of 25%, and 68.47 g of distilled water was added. The mixture was stirred for 30 minutes to obtain a sustained-release layer liquid 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 pan of the fluidized bed, and coat the colchicine on the sugar pills according to the parameters of inlet air temperature of 60° C., inlet air volume of 34 Pasca / s, guide tube height of 27 mm, atomization pressure of 2.0 bar, liquid inlet speed of 15 mL / min, drying temperature of 60° C., and drying time of 5 min. The mass of colchicine is 0.5% of the sugar pills, and drug-loaded micropellets are obtained;

[0081] Take 500g of drug-loaded pellets, spray the prepared light-shielding layer liquid into the fluidized bed bottom spray coating pan, and coat the light-shielding layer on the drug-loaded pellets according to the parameters of inlet temperature 60°C, inlet air volume 34Pasca / s, guide tube height 27mm, atomization pressure 2.0bar, liquid inlet speed 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 pan, and coat the sustained-release layer on the light-shielding layer according to the parameters of inlet temperature 68°C, inlet air volume 34Pasca / s, guide tube height 27mm, atomization pressure 2.0bar, liquid inlet speed 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 microcapsules, which is different from Example 1 in that the preparation of the shading layer liquid in step (1) and the step of coating the shading layer liquid in step (2) are deleted, and the other parameter conditions are the same as those in Example 1.

[0084] Detection Methods

[0085] Weigh 300 mg of different samples and place them in 10 mL vials, place them in a light test box, and expose them to light at 4500±500 lx for 24 h or 48 h. Different samples are 2 cm apart and 3 cm away 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 make up to the mark. Take 2 mL of the 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 membrane.

[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, make up to the mark with distilled water, shake well, and filter through a 0.22 μm filter membrane.

[0088] The luminous 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, running time: 45 min.

[0089] The light-containing 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 illumination

[0091]

[0092] From the data in Table 1, it can be seen that the colchicine raw material contains about 0.04% of photodegradable impurities. When preparing colchicine-loaded pellets, the required drug loading is reduced (colchicine is 0.5% of the weight of the blank pellet core), the preparation process is short, and no photodegradation occurs; and when the drug-loaded pellets are subjected to sustained-release coating to prepare sustained-release pellets, the coating time is long, which is 4 times the time required for preparing the drug-loaded pellets, causing the drug to be exposed to light for a long time, and then photodegradation occurs. After sustained-release coating, the photodegradable impurities increase sharply from 0.04% to 0.76%, an increase of about 20 times, and if the production batch increases, the coating time will be extended, the light exposure time will also be extended, and then the photodegradation products will also increase. Therefore, sunscreens must be added during the production process to shield light, protect drugs, and avoid degradation.

[0093] Embodiments 2 to 5

[0094] Examples 2 to 5 respectively provide a method for preparing colchicine sustained-release microcapsules, which differ from Example 1 in 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 microcapsules respectively, and 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 microcapsules, 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 microcapsules respectively. The other parameter conditions are the same as those in Example 1.

[0097] The commonly used sunscreen titanium dioxide was selected as a light protectant 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, the effect is very limited. After 48 hours of illumination, the peak area percentage of the photodegradation product still increases significantly, and the main peak area percentage decreases significantly; and with the increase in the amount of titanium dioxide, the photodegradation product decreases slightly, but not significantly. The amount of titanium dioxide 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 the photodegradation product 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 selects iron oxide as a photoprotectant to inhibit the degradation of colchicine, and the test results are shown in Table 3. When the amount of red iron oxide is 1% of the weight of the drug-loaded pill core, it has shown a significant photodegradation inhibition effect. The percentage of photodegradation products after 48 hours of illumination without adding iron oxide is 13.41%. When the amount of red iron oxide is 1%, the percentage of photodegradation products is reduced to 1.53%, and as the amount of red iron oxide increases, the content of photodegradation products gradually decreases. When the amount is 4%, the sustained-release micropills are at the same level as the test results of the batch of raw materials used without illumination after 48 hours of illumination, indicating that red iron oxide can almost completely inhibit the generation of late photodegradation products of colchicine.

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

[0103]

[0104] Embodiments 6 to 10

[0105] Examples 6 to 10 respectively provide a method for preparing colchicine sustained-release microcapsules, which differ from Example 1 in that the Fe2O3 sunscreen in step (1) is completely replaced by Fe2O3·H2O sunscreen (yellow 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 microcapsules 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 microcapsules, 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 microcapsules respectively. The other parameter conditions are the same as those in Example 1.

[0108] The experiments of Examples 1 to 5 confirm that iron oxide sunscreens can effectively protect colchicine drugs from photodegradation. Upon investigation, the Chinese Pharmacopoeia contains a total of 5 colors of iron oxide: red iron oxide, yellow iron oxide, black iron oxide, purple iron oxide, and brown iron oxide. Among them, purple iron oxide and brown iron oxide are the first three kinds of iron oxide mixed in different proportions. The present invention selects the first three basic iron oxides to examine their protective effects on drugs, and the test results are shown in Tables 3 to 4.

[0109] The results showed that there was no significant difference in the protective effect of the three colors of iron oxide on the drug, and the dosage must reach more than 4% to maximize the protection of the drug and avoid photodegradation. However, after yellow iron oxide coating, the micro-pellets are prone to color difference, affecting the appearance of the product; black iron oxide gives people a poor visual experience, so red iron oxide is preferred as the sunscreen for colchicine sustained-release micro-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 desired effect. The proportion can be adjusted as needed to obtain the desired coloring effect, and the light protection effect is 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 microcapsules, which is different from Example 5 in that the preparation of the shading layer liquid in step (1) and the step of coating the shading layer liquid in step (2) are deleted; after the colchicine in step (1) is completely dissolved, the following process is added: 20g of red iron oxide sunscreen is added, and stirring is continued for 30min until it is evenly dispersed to obtain a colchicine solution; the air intake volume when preparing the drug-loaded microcapsules in step (2) is changed to 30Pasca / s, and the guide tube height is changed to 30mm, and 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 microcapsules, which is different from Example 5 in that the preparation of the shading layer liquid in step (1) and the step of coating the shading 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% in step (1), the following process is added: 20g of red iron oxide shading agent 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 pellets, which is different from Example 5 in that in step (2), after the preparation of the drug-loaded pellets is completed, the sustained-release layer liquid is first coated on the drug-loaded pellets, and then the light-shielding layer liquid is coated on the outermost layer of the sustained-release coating film.

[0119] The effects of the addition of red iron oxide on the photostability of colchicine drug-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 still 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 sunscreen layer (i.e., Example 5), the drugs can be protected to the maximum 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 hours; 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, 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 as the illumination time increases, the amount of degradation products also increases significantly. 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 sunscreen role, but since complete light protection cannot be guaranteed during the preparation of the micropills, some drugs have undergone photodegradation before the sunscreen 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 microcapsules 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 component of which is colchicine.

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

[0126] Light experiment design: The prepared samples were placed in a light test box 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 HPLC.

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

[0128]

[0129] It can be seen from the experimental results in Table 6 that before receiving light, the photodegradable impurity content of the commercially available tablet A and the sample of Example 5 is basically at the same level, but the commercially available sample is still slightly higher than Example 5; however, with the extension of the light exposure time, the photodegradable impurities of the commercially available tablet A increase sharply. After only one day of light exposure, the photodegradable impurities increase by about 44 times, which is 71 times that of Example 5. After 10 days of light exposure, the increment of photodegradable products is about 125 times, which is 250 times that of Example 5. The commercially available tablet A uses a light-proof double-sided aluminum package. The experiment examined samples of different batches, and the test results were slightly different. The same batch was tested at different times, and the results were slightly different and irregular, which may be caused by different light intensity or operation time during the inspection process, which also brings uncertainty to quality control. It can be inferred that no light-proof measures are taken in the prescription of the commercially available sample or the light-proof measures are improper, so light-proof operation is still required during the production and inspection process to avoid drug degradation, which not only causes inconvenience but also increases costs, and the light-proof effect is uncertain, which is very likely to lead to unqualified products. However, the photodegradation impurity content of the sample of Example 5 prepared by the present invention did not change significantly after irradiation for 10 days under the same conditions as the commercially available tablet A, indicating that the colchicine sustained-release microcapsules prepared by the technical solution of the present invention can be operated normally during the production and inspection process, without the need to take 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 principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A colchicine sustained-release pellet, characterized in that: From inside to 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, characterized in that: 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, characterized in that: 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 mass 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) colchicine is mixed with water to obtain a colchicine solution; The sunscreen agent, the suspending agent and the 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 are sequentially coated onto the blank pellet cores, and the pellets are sieved to obtain colchicine sustained-release pellets.

9. The method for preparing colchicine sustained-release pellets according to claim 8, characterized in that: 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.

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