Long-acting eldecalciferol soft capsule and preparation method thereof

Abstract

The invention provides a long-acting idedecalciferol soft capsule and a preparation method thereof, and relates to the technical field of pharmaceutical preparations, preparation raw materials comprise a liquid medicine containing idedecalciferol-PLGA chitosan microspheres and a glue solution containing lemon yellow, and the preparation method of the long-acting idedecalciferol soft capsule comprises the steps that a soft capsule machine is used for preparing the long-acting idedecalciferol soft capsule at the glue solution temperature of 50-60 DEG C; and injecting the liquid medicine containing the idedecalciferol-PLGA chitosan microspheres into a glue solution containing lemon yellow to prepare a wet soft capsule, and drying until the water content is controlled to be 8-14% to obtain the long-acting idedecalciferol soft capsule.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical preparations, and in particular to a long-acting edecalcitol soft capsule and a preparation method thereof. Background Art

[0002] Osteoporosis is a common bone disease. With the aging of the population, its incidence rate is increasing year by year. Although traditional osteoporosis treatment drugs can relieve symptoms to a certain extent, they often have problems such as uncertain efficacy and large side effects. Therefore, the development of new, efficient and low-side effect osteoporosis treatment drugs has become an important topic in the medical community. Vitamin D and its analogs play an important role in the treatment of osteoporosis. As a new generation of active vitamin D analogs, idecalcitol has higher biological activity and more precise targeting, providing a new option for the treatment of osteoporosis. Idecalcitol is jointly developed by Chugai Pharmaceutical (Chugai) and Taisho Pharmaceutical (Taisho) of Japan. This product can improve bone metabolism and promote calcium absorption. It is mainly used to treat osteoporosis clinically. As a new generation of active vitamin D analogs, long-acting edecalcitol soft capsules have higher biological activity and more precise targeting effects, which can meet this market demand. There are few studies on long-acting edecalcitol soft capsules, and the existing edecalcitol preparations generally have poor long-term stability, complex preparation process, easy changes in impurities during the preparation process, and difficult control of the viscosity of the gel, resulting in a low product yield. A small number of patients may have allergic reactions to the drug ingredients in the edecalcitol soft capsules, and symptoms such as rashes and itching may occur. The edecalcitol soft capsules are mainly metabolized by the liver and excreted by the kidneys. Long-term use may increase the burden on the liver and kidneys and cause certain damage to liver and kidney function. Idecalcitol has the effect of promoting calcium absorption. Long-term excessive use may lead to increased blood calcium, which in turn causes a series of uncomfortable symptoms. With the intensification of population aging and changes in people's lifestyles, the number of osteoporosis patients continues to increase. This provides a broad market space for osteoporosis treatment drugs such as long-acting edecalcitol soft capsules. Traditional osteoporosis treatment drugs often have problems such as uncertain efficacy and large side effects. Patients and doctors are in urgent need of drugs with definite efficacy and few side effects, so a new long-acting edecalciferol soft capsule and a preparation method thereof are urgently needed in the market. Summary of the invention

[0003] The present invention provides a long-acting idecalcitol soft capsule and a preparation method thereof, which are used to solve the problems raised in the above background technology.

[0004] In order to solve the above technical problems, the present invention discloses a long-acting idecalcitol soft capsule and a preparation method thereof. The long-acting idecalcitol soft capsule comprises a medicinal solution containing idecalcitol-PLGA chitosan microspheres and a colloid containing tartrazine.

[0005] Furthermore, the raw materials for preparing the medicinal solution containing idecalcitol-PLGA chitosan microspheres include idecalcitol-PLGA chitosan microspheres, medium-chain triglycerides and anhydrous ethanol.

[0006] Furthermore, the raw materials for preparing the medicinal solution containing idecalcitol-PLGA chitosan microspheres include idecalcitol-PLGA chitosan microspheres, medium-chain triglycerides and anhydrous ethanol in a mass ratio of (0.13-0.15):(8-9):(0.05-0.08).

[0007] Further, the raw materials for preparing the idecalcitol-PLGA chitosan microspheres include idecalcitol-PLGA blend and chitosan polyvinyl alcohol solution; Preferably, the raw materials for preparing the idecalcitol-PLGA blend solution include PLGA, dichloromethane, green tea extract, d-α-tocopherol, proanthocyanidins and idecalcitol; Preferably, the raw materials for preparing the chitosan polyvinyl alcohol solution include polyvinyl alcohol aqueous solution, chitosan and acetic acid aqueous solution; Preferably, the mass percentage of the polyvinyl alcohol aqueous solution is 2.0%, and the mass percentage of the acetic acid aqueous solution is 1%.

[0008] Furthermore, the preparation method of the idecalcitol-PLGA chitosan microspheres includes: dissolving PLGA in dichloromethane to obtain a PLGA solution, mixing the PLGA solution with green tea extract, d-α-tocopherol, proanthocyanidin and idecalcitol to obtain an idecalcitol-PLGA blended liquid, heating deionized water to 90°C, dissolving polyvinyl alcohol therein, cooling to 40°C to obtain a polyvinyl alcohol aqueous solution, dissolving chitosan in an acetic acid aqueous solution to obtain a chitosan solution, mixing the chitosan solution with the polyvinyl alcohol aqueous solution to obtain a chitosan polyvinyl alcohol solution, adding the obtained idecalcitol-PLGA blended liquid to the obtained chitosan polyvinyl alcohol solution, stirring continuously for 8 hours at a speed of 150 r / min when the vacuum degree is 0.08 MPa, washing 3 times with deionized water, and freeze-drying for 24 hours to obtain idecalcitol-PLGA chitosan microspheres.

[0009] Furthermore, the preparation method of the medicinal solution containing idecalcitol-PLGA chitosan microspheres comprises mixing idecalcitol-PLGA chitosan microspheres, medium-chain triglycerides and anhydrous ethanol in a liquid preparation tank at a temperature of 28° C., filling with nitrogen, maintaining a positive pressure of 0.1-0.2 bar in the tank, stirring fully for 30-150 minutes, and filtering through a 200-mesh sieve to obtain a medicinal solution containing idecalcitol-PLGA chitosan microspheres.

[0010] Furthermore, the raw materials for preparing the tartrazine-containing glue solution include gelatin, sorbitol, glycerin, caramel, titanium dioxide, deionized water and tartrazine.

[0011] Furthermore, the raw materials for preparing the capsule shell liquid include gelatin, sorbitol, glycerin, caramel, titanium dioxide, deionized water and tartrazine in a mass ratio of (100-120): (20-30): (15-30): (6-10): (0.2-0.5): (110-160): (3-5).

[0012] Furthermore, the preparation method of the capsule shell liquid includes adding gelatin, sorbitol, glycerin, caramel, titanium dioxide, deionized water and lemon yellow into a gelling tank, setting the temperature of the gelling tank to 65-75°C and the vacuum degree to -0.4 to -1.0 bar, filtering when the weight reduction ratio of the material in the tank is 5%, and obtaining a gelling liquid containing lemon yellow.

[0013] Furthermore, a method for preparing a long-acting idecalcitol soft capsule comprises using a soft capsule machine, at a gel temperature of 50 to 60° C. and a rotation speed of 1.0 to 2.0 rpm, injecting a drug solution containing idecalcitol-PLGA chitosan microspheres into a gel solution containing tartrazine to prepare a wet soft capsule, drying the soft capsule with a drum dryer at 28 to 35° C. and a humidity of 28% to 35% for 2 to 6 hours, placing the soft capsule on a tray, and continuing to dry the soft capsule at 25 to 30° C. and a humidity of 10 to 30% for 10 to 48 hours until the moisture content is controlled at 8% to 14% to obtain a long-acting idecalcitol soft capsule.

[0014] Further, a method for preparing long-acting idecalcitol soft capsules, the method also includes: When the moisture content of the wet soft capsule is controlled at 8% to 14%, a detection image of the current wet soft capsule is obtained; Obtain the pixel value of each pixel in the detection image, perform brightness analysis on the detection image, and obtain the brightness jump coefficient of the detection image;

[0015] in, To detect the brightness jump coefficient of the image; To detect the length of the image; To detect the width of the image; To detect the image The pixel value at ; To detect the image The pixel value at ; To detect the image The pixel value at ; Compare the brightness jump coefficient of the detected image with a preset brightness jump threshold to obtain a first comparison result; Obtain the color value of each pixel in the detection image in the RGB color space, perform color analysis on the detection image, and obtain the color deviation coefficient of the detection image; wherein the color value includes the R color channel value, the G color channel value, and the B color channel value;

[0016] in, To detect the color deviation coefficient of the image; It is the average value of all pixels in the R color channel of the detection image; is the average value of all pixels in the detection image in the G color channel; It is the average value of all pixels in the detection image in the B color channel; To detect the image The value of a pixel in the R color channel; To detect the image The value of a pixel in the G color channel; To detect the image The value of a pixel in the B color channel; Comparing the color deviation coefficient of the detected image with a preset color deviation threshold to obtain a second comparison result; When it is determined that the first comparison result is that the brightness jump coefficient of the detection image is less than the preset brightness jump threshold and the color deviation coefficient is less than the preset color deviation threshold, the current wet soft capsule is regarded as a qualified long-acting idecalciferol soft capsule; otherwise, it indicates that the current wet soft capsule is an unqualified product.

[0017] Compared with the prior art, the present invention provides a long-acting edecalcitol soft capsule and a preparation method thereof, which has the following beneficial effects: (3) Gelatin in the gelatin solution is the main component of the soft capsule material. Its good film-forming property and plasticity ensure the integrity of the soft capsule during storage and transportation, and prevent the leakage and failure of the drug ingredients. This stability is crucial to maintaining the long-term effectiveness of idecalcitol in the soft capsule. The biocompatibility and degradability of gelatin also ensure the safe use of soft capsules in the human body, reducing potential side effects and adverse reactions. Sorbitol, as a plasticizer, can increase the flexibility and elasticity of the soft capsule shell, reduce the cracking and deformation of the shell caused by external factors (such as temperature and humidity changes), thereby extending the shelf life and long-term effectiveness of the soft capsule. The moisturizing effect of sorbitol also helps to maintain the stability of the internal environment of the soft capsule and protect active ingredients such as idecalcitol from the influence of the external environment. Glycerin, also as a plasticizer, synergizes with sorbitol to further enhance the flexibility and stability of the soft capsule shell. In addition, the hygroscopicity of glycerol can adjust the humidity of the internal environment of the soft capsule, prevent the drug ingredients from becoming ineffective due to excessive or insufficient moisture, thereby ensuring the long-term effectiveness of idecalcitol. Titanium dioxide is widely used as a light-shielding agent in the preparation of soft capsules, which can effectively block the irradiation of ultraviolet rays and visible light, and prevent the drug ingredients from decomposing or deteriorating due to light. Titanium dioxide also has the advantages of being non-toxic, odorless, and chemically stable, and meets the safety requirements of pharmaceutical preparations. Caramel is used as a colorant, and its antioxidant effect also helps to protect the drug ingredients in the soft capsule from oxidative damage, indirectly extending the long-term effectiveness of the soft capsule. Lemon yellow is used as a colorant, and is used in combination with caramel to coordinate the dark color of the caramel, making it more beautiful. It also has good water solubility and stability, and can be well compatible with other ingredients in the gelatin. Titanium dioxide, caramel, and lemon yellow synergize to enhance the stability of the long-acting idecalcitol soft capsule from the dual perspectives of light-shielding agent and colorant. (4) The long-acting property of idecalcitol soft capsules was enhanced from both physical (PLGA-chitosan composite microspheres) and chemical (various formulations) perspectives, while also enhancing the stability and effectiveness of the drug. DETAILED DESCRIPTION

[0018] The preferred embodiments of the present invention are described below. It should be understood that the preferred embodiments described herein are only used to illustrate and explain the present invention, and are not used to limit the present invention.

[0019] In addition, in the present invention, the descriptions of "first", "second", etc. are only used for descriptive purposes, and do not specifically refer to the order or sequence, nor are they used to limit the present invention. They are only used to distinguish components or operations described with the same technical terms, and cannot be understood as indicating or implying their relative importance or implicitly indicating the number of technical features indicated. Therefore, the features defined as "first" and "second" may explicitly or implicitly include at least one of the features. In addition, the technical solutions and technical features between the various embodiments can be combined with each other, but they must be based on the ability of ordinary technicians in the field to implement them. When the combination of technical solutions is contradictory or cannot be implemented, it should be considered that such a combination of technical solutions does not exist and is not within the scope of protection required by the present invention.

[0020] Unless otherwise specified, the examples and comparative examples are parallel tests with the same components, component contents, preparation steps and preparation parameters. The experimental methods in the following examples are conventional methods unless otherwise specified. The test materials used in the following examples are analytical reagents (AR) unless otherwise specified. Parts are parts by weight unless otherwise specified, and the materials are purchased from commercial channels.

[0021] PLGA (FluidicLab, 50 / 50, Mw: 2W); polyvinyl alcohol (PVA, Sigma-Aldrich, P8136-250g); polyethylene glycol is Japanese Aoki, PEG-400 pharmaceutical grade; lemon yellow was purchased from Shandong Yousuo Chemical Technology Co., Ltd., lemon yellow 87, CAS is 1934-21-0, pigment content 87%; green tea extract was purchased from Shaanxi Benhe Bioengineering Co., Ltd., CAS is 989-51-5, effective substance content 50%; proanthocyanidins were purchased from Mac Lin, CAS is 4852-22-6, purity>95%; chitosan was purchased from Huaian Runjie Industry and Trade Co., Ltd., for food use only, CAS is 9012-76-4, deacetylation degree ≥85%, moisture ≤10%, ash ≤1.0%; gelatin was purchased from Shandong Jinchengda Biotechnology Co., Ltd., with a net content of 99%, CAS is 9000-70-8; sorbitol was purchased from Foodchem, with a purity of 70%, CAS is 50-70-4; caramel was purchased from Qingdao Kangerxiang Biotechnology Co., Ltd., food grade, with a net content of 99%.

[0022] Example 1 (1) Dissolving 0.5 g of PLGA in 10 mL of dichloromethane to obtain a 5.0% (wt.) PLGA solution; mixing 10 mL of the PLGA solution with 30 mg of green tea extract, 10 mg of d-α-tocopherol, 10 mg of proanthocyanidin and 75 mg of idecalciferol to obtain an idecalciferol-PLGA blend solution; (2) Heat 100 mL of deionized water to 90°C, dissolve 2 g of polyvinyl alcohol 1788 therein, and cool to 40°C to obtain a 2.0% (wt.) polyvinyl alcohol aqueous solution; dissolve 0.4 g of chitosan in 10 mL of 1% (wt.) acetic acid aqueous solution to obtain a 40% (wt.) chitosan solution; mix 10 mL of the chitosan solution with 100 mL of the polyvinyl alcohol aqueous solution to obtain 110 mL of the chitosan polyvinyl alcohol solution; (3) Add 10 mL of the idecalcitol-PLGA blend obtained in step (1) to 110 mL of the chitosan polyvinyl alcohol solution obtained in step (2), stir continuously at a speed of 150 r / min for 8 h when the vacuum degree is 0.08 MPa, wash three times with deionized water, and freeze-dry for 24 h to obtain idecalcitol-PLGA / chitosan microspheres.

[0023] 2. Preparation of long-acting edecalciferol soft capsules: (1) Preparation of drug solution: 130 g of idecalcitol-PLGA / chitosan microspheres and 8 kg of medium-chain triglycerides were mixed in a liquid preparation tank at 28°C, filled with nitrogen, and the positive pressure in the tank was maintained at 0.1 bar. The mixture was stirred for 60 min, and filtered through a 200-mesh sieve to obtain a drug solution; (2) Gelatinization: Add 100 kg gelatin, 20 kg sorbitol, 15 kg glycerin, 6 kg caramel, 0.2 kg titanium dioxide, 110 kg deionized water and 3 kg lemon yellow into a gelatinization tank. Keep the tank temperature at 70 °C and the vacuum degree at -0.6 bar. When the weight of the material in the tank decreases by 5%, filter to obtain a gelatin solution. (3) Pill pressing: Use a soft capsule machine to inject the drug solution into the gelatin solution at a gelatin solution temperature of 50°C and a rotation speed of 1.0 rpm to make wet soft capsules. Use a drum dryer to dry the soft capsules at 30°C and 29% humidity for 4 hours. Place the soft capsules on a tray and continue drying at 30°C and 28% humidity for 15 hours until the moisture content is controlled at 8% to obtain long-acting edecalciferol soft capsules.

[0024] Example 2 The preparation method of idecalcitol-PLGA chitosan microspheres is consistent with that of Example 1, but different from the preparation method of long-acting idecalcitol soft capsules: (1) Preparing a drug solution containing idecalcitol-PLGA chitosan microspheres: 140 g of idecalcitol-PLGA chitosan microspheres, 8.5 kg of medium-chain triglycerides and 70 g of anhydrous ethanol were mixed in a liquid preparation tank at 28° C., filled with nitrogen, and the positive pressure in the tank was maintained at 0.15 bar. The mixture was stirred for 120 min, and filtered through a 200-mesh sieve to obtain a drug solution containing idecalcitol-PLGA chitosan microspheres. (2) Gelatinization: Add 110 kg gelatin, 25 kg sorbitol, 20 kg glycerin, 8 kg caramel, 0.3 kg titanium dioxide, 130 kg deionized water and 4 kg tartrazine into a gelatinization tank. Keep the tank temperature at 70 °C and the vacuum degree at -0.8 bar. When the weight of the material in the tank decreases by 5%, filter to obtain a gelatin solution containing tartrazine. (3) Pill pressing: Using a soft capsule machine, at a gel temperature of 55°C and a rotation speed of 1.5 rpm, inject the drug solution containing edicalcitol-PLGA chitosan microspheres into a gel solution containing tartrazine to prepare wet soft capsules. Use a drum dryer to dry the pellets at 30°C and 30% humidity for 4 hours, place them on a tray, and continue drying at 28°C and 15% humidity for 20 hours until the moisture content is controlled at 10% to obtain long-acting edicalcitol soft capsules.

[0025] Example 3 The preparation method of idecalcitol-PLGA chitosan microspheres is consistent with that of Example 1, but different from the preparation method of long-acting idecalcitol soft capsules: Example 4 The preparation method of idecalcitol-PLGA chitosan microspheres is consistent with that of Example 1, but different from the preparation method of long-acting idecalcitol soft capsules: Preparation of a liquid containing idecalcitol-PLGA chitosan microspheres: 130 g of idecalcitol-PLGA chitosan microspheres, 9 kg of medium-chain triglycerides and 80 g of anhydrous ethanol were mixed in a liquid preparation tank at a temperature of 28°C, filled with nitrogen, the positive pressure in the tank was maintained at 0.15 bar, stirred thoroughly for 120 min, and filtered through a 200-mesh sieve to obtain a liquid containing idecalcitol-PLGA chitosan microspheres; gelling: 100 kg of gelatin, 30 kg of sorbitol, 30 kg of glycerol, 10 kg of caramel, 0.5 kg of titanium dioxide, 160 kg of deionized water and 5 kg of tartrazine were added to the gelling tank. , make the temperature of the gelling tank 70℃, the vacuum degree -1.0bar, until the weight of the material in the tank decreases by 5%, filter to obtain a gel containing lemon yellow; pill pressing: use a soft capsule machine, at a gel temperature of 55℃, at a speed of 1.5 rpm, inject the drug solution containing edicalcitol-PLGA chitosan microspheres into the gel containing lemon yellow to make wet soft capsules, use a drum dryer at 30℃, 30% humidity for 4 hours, place on a tray, and continue drying at 28℃, 15% humidity for 20 hours, until the moisture content is controlled at 12% to obtain long-acting edicalcitol soft capsules. Example 5 The preparation method of idecalcitol-PLGA chitosan microspheres is consistent with that of Example 1, but different from the preparation method of long-acting idecalcitol soft capsules: Example 6 When the moisture content of the wet soft capsule is controlled at 8% to 14%, a detection image of the current wet soft capsule is obtained; Obtain the pixel value of each pixel in the detection image, perform brightness analysis on the detection image, and obtain the brightness jump coefficient of the detection image;

[0026] in, To detect the brightness jump coefficient of the image; To detect the length of the image; To detect the width of the image; To detect the image The pixel value at ; To detect the image The pixel value at ; To detect the image The pixel value at ; Compare the brightness jump coefficient of the detected image with a preset brightness jump threshold to obtain a first comparison result; Obtain the color value of each pixel in the detection image in the RGB color space, perform color analysis on the detection image, and obtain the color deviation coefficient of the detection image; wherein the color value includes the R color channel value, the G color channel value, and the B color channel value;

[0027] in, To detect the color deviation coefficient of the image; It is the average value of all pixels in the R color channel of the detection image; is the average value of all pixels in the detection image in the G color channel; It is the average value of all pixels in the detection image in the B color channel; To detect the image The value of a pixel in the R color channel; To detect the image The value of a pixel in the G color channel; To detect the image The value of a pixel in the B color channel; Comparing the color deviation coefficient of the detected image with a preset color deviation threshold to obtain a second comparison result; When it is determined that the first comparison result is that the brightness jump coefficient of the detection image is less than the preset brightness jump threshold and the color deviation coefficient is less than the preset color deviation threshold, the current wet soft capsule is regarded as a qualified long-acting idecalciferol soft capsule; otherwise, it indicates that the current wet soft capsule is an unqualified product.

[0028] The working principle of the above technical solution: in the process of preparing long-acting edecalciferol soft capsules, when the moisture content of the wet soft capsules is controlled at 8% to 14%, all the production processes have been completed. At this time, the detection image of the current wet soft capsule is obtained, and the detection image is used for identification to determine whether the current wet soft capsule is a qualified product. In the process of identifying the detection image, the main identification is in two aspects: brightness and color. By obtaining the pixel value of each pixel in the detection image, the detection image is subjected to brightness analysis and processing to obtain the brightness jump coefficient of the detection image; the brightness jump coefficient of the detection image is compared with the preset brightness jump threshold to obtain a first comparison result; the preset brightness jump threshold is the brightness jump coefficient corresponding to the image of the qualified product. The color value of each pixel in the detection image in the RGB color space is obtained, and the detection image is subjected to color analysis and processing to obtain the color deviation coefficient of the detection image; the color deviation coefficient of the detection image is compared with the preset color deviation threshold to obtain a second comparison result; the preset color deviation threshold is the color deviation coefficient corresponding to the image of the qualified product. When it is determined that the first comparison result is that the brightness jump coefficient of the detection image is less than the preset brightness jump threshold and the color deviation coefficient is less than the preset color deviation threshold, the current wet soft capsule is regarded as a qualified long-acting idecalciferol soft capsule; otherwise, it indicates that the current wet soft capsule is an unqualified product.

[0029] The beneficial effects of the above technical solution are as follows: by analyzing the detection image of the current wet soft capsule from the two aspects of brightness and color, it is convenient to accurately judge whether the current wet soft capsule is a qualified product, and the appearance of the obtained long-acting idecalciferol soft capsule is verified to ensure the qualification and uniformity of the product appearance.

[0030] Comparative Example 1 The difference from Example 1 is that when preparing the idecalcitol-PLGA chitosan microspheres, the step of dissolving equal weight portions of chitosan in an acetic acid aqueous solution to obtain the idecalcitol-PLGA microspheres is omitted, and the other steps are the same.

[0031] Comparative Example 2 The difference from Example 1 is that when preparing the long-acting idecalciferol soft capsules, the gelling step lacks an equal weight portion of titanium dioxide, and the rest is the same.

[0032] Comparative Example 3 The difference from Example 1 is that when preparing the long-acting idecalciferol soft capsules, the gelling step lacks an equal weight portion of tartrazine, and the rest is the same.

[0033] The difference from Example 1 is that when preparing the long-acting idecalciferol soft capsules, the gelling step lacks an equal weight portion of tartrazine, and the rest is the same.

[0034] Comparative Example 4 The difference from Example 1 is that an equal weight portion of green tea extract is missing when preparing the idecalcitol-PLGA blend, and the rest is the same.

[0035] Comparative Example 5 The difference from Example 1 is that an equal weight portion of d-α-tocopherol is missing when preparing the idecalcitol-PLGA blend, and the other parts are the same.

[0036] Comparative Example 6 The difference from Example 1 is that when preparing the idecalcitol-PLGA blend solution, an equal weight portion of proanthocyanidins is lacking, and the rest is the same.

[0037] Performance Testing 1. Effect of light exposure test on the stability of long-acting edecalciferol soft capsules The long-acting idecalcitol soft capsules prepared in the example, the idecalcitol soft capsules prepared in the comparative example, and the reference preparation (national medicine standard H20143141) were respectively used as test samples, and the opening was placed in a light box equipped with a fluorescent lamp, and placed under an illumination of 4500lx±500lx for 30 days. Samples were taken on the 0th day, the 10th day, and the 30th day, respectively, to detect the idecalcitol content.

[0038] Table 1 Effect of light test on the content of idecalciferol in idecalciferol soft capsules

[0039] Table 1 shows the effect of light exposure test on the content of idecalcitol in idecalcitol soft capsules. The results show that the long-acting idecalcitol soft capsules prepared by the present invention have high tolerance to light exposure.

[0040] 2. Determination of the release rate of long-acting edecalciferol soft capsules According to the "Guidelines for Sustained and Controlled Release Preparations" in the Appendix of the 2010 edition (Part II) of the Pharmacopoeia of the People's Republic of China, 0.25% sodium lauryl sulfate was used as the release medium, and the long-acting edecalciferol soft capsules prepared in the examples and comparative examples were accurately weighed (about 100 mg), and the peak area was determined by HPLC according to the first method of Appendix XD of the 2010 edition of the Pharmacopoeia of the People's Republic of China, and the drug concentration and cumulative release percentage (in %) were calculated. The determination results are shown in Table 2 (dissolution medium: 0.25% sodium lauryl sulfate).

[0041] Table 2

[0042] It can be seen from Table 2 that the long-acting idecalcitol soft capsules prepared in Example 1 have a slow release rate and are slowly released within 22 hours. The idecalcitol soft capsules have the best long-acting effect.

[0043] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. If these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. A long-acting idecalcitol soft capsule, the preparation raw materials of which include a liquid medicine containing idecalcitol-PLGA chitosan microspheres and a glue containing tartrazine.

2. The long-acting idecalcitol soft capsule according to claim 1, characterized in that: The raw materials for preparing the medicinal solution containing idecalcitol-PLGA chitosan microspheres include idecalcitol-PLGA chitosan microspheres, medium-chain triglycerides and anhydrous ethanol.

3. The long-acting idecalcitol soft capsule according to claim 1 or 2, characterized in that: The raw materials for preparing the medicinal solution containing idecalcitol-PLGA chitosan microspheres include idecalcitol-PLGA chitosan microspheres, medium-chain triglycerides and anhydrous ethanol in a mass ratio of (0.13-0.15):(8-9):(0.05-0.08).

4. The long-acting idecalcitol soft capsule according to any one of claims 1 to 3, characterized in that: The raw materials for preparing the idecalcitol-PLGA chitosan microspheres include idecalcitol-PLGA blend and chitosan polyvinyl alcohol solution; Preferably, the raw materials for preparing the idecalcitol-PLGA blend solution include PLGA, dichloromethane, green tea extract, d-α-tocopherol, proanthocyanidins and idecalcitol; Preferably, the raw materials for preparing the chitosan polyvinyl alcohol solution include polyvinyl alcohol aqueous solution, chitosan and acetic acid aqueous solution; Preferably, the mass percentage of the polyvinyl alcohol aqueous solution is 2.0%, and the mass percentage of the acetic acid aqueous solution is 1%.

5. The long-acting idecalcitol soft capsule according to any one of claims 1 to 4, characterized in that: The preparation method of the idecalcitol-PLGA chitosan microspheres comprises: dissolving PLGA in dichloromethane to obtain a PLGA solution, mixing the PLGA solution with green tea extract, d-α-tocopherol, proanthocyanidin and idecalcitol to obtain an idecalcitol-PLGA mixed solution, heating deionized water to 90°C, dissolving polyvinyl alcohol therein, cooling to 40°C to obtain a polyvinyl alcohol aqueous solution, dissolving chitosan in an acetic acid aqueous solution to obtain a chitosan solution, mixing the chitosan solution with the polyvinyl alcohol aqueous solution to obtain a chitosan polyvinyl alcohol solution, adding the obtained idecalcitol-PLGA mixed solution to the obtained chitosan polyvinyl alcohol solution, continuously stirring at a speed of 150 r / min for 8 hours when the vacuum degree is 0.08 MPa, washing with deionized water for 3 times, and freeze-drying for 24 hours to obtain idecalcitol-PLGA chitosan microspheres.

6. The long-acting idecalcitol soft capsule according to any one of claims 1 to 3, characterized in that: The preparation method of the medicinal solution containing idecalcitol-PLGA chitosan microspheres comprises the steps of mixing idecalcitol-PLGA chitosan microspheres, medium-chain triglycerides and anhydrous ethanol in a liquid preparation tank at a temperature of 28° C., filling with nitrogen, maintaining a positive pressure of 0.1-0.2 bar in the tank, fully stirring for 30-150 minutes, and filtering through a 200-mesh sieve to obtain the medicinal solution containing idecalcitol-PLGA chitosan microspheres.

7. The long-acting idecalcitol soft capsule according to claim 1, characterized in that: The raw materials for preparing the tartrazine-containing glue solution include gelatin, sorbitol, glycerin, caramel, titanium dioxide, deionized water and tartrazine.

8. The long-acting idecalcitol soft capsule according to claim 1 or 7, characterized in that: The raw materials for preparing the capsule shell liquid include gelatin, sorbitol, glycerin, caramel, titanium dioxide, deionized water and tartrazine in a mass ratio of (100-120): (20-30): (15-30): (6-10): (0.2-0.5): (110-160): (3-5).

9. The long-acting idecalcitol soft capsule according to claim 1 or 7, characterized in that: The preparation method of the capsule shell liquid comprises the steps of adding gelatin, sorbitol, glycerin, caramel, titanium dioxide, deionized water and lemon yellow into a gelling tank, setting the temperature of the gelling tank to 65-75° C. and the vacuum degree to -0.4 to -1.0 bar, filtering the tank until the weight reduction ratio of the material in the tank is 5%, and obtaining a gelling liquid containing lemon yellow.

10. A method for preparing the long-acting idecalcitol soft capsule according to any one of claims 1 to 9, characterized in that: The preparation method of the long-acting idecalcitol soft capsule comprises the following steps: using a soft capsule machine, at a gel temperature of 50 to 60° C. and a rotation speed of 1.0 to 2.0 rpm, injecting a drug solution containing idecalcitol-PLGA chitosan microspheres into a gel solution containing tartrazine to prepare a wet soft capsule; using a drum dryer to dry the capsule for 2 to 6 hours at a temperature of 28 to 35° C. and a humidity of 28% to 35%; placing the capsule on a tray; and continuing to dry the capsule for 10 to 48 hours at a temperature of 25 to 30° C. and a humidity of 10 to 30% until the moisture content is controlled at 8% to 14% to obtain a long-acting idecalcitol soft capsule.

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