Edecalciferol pharmaceutical composition and preparation method thereof

Abstract

The invention relates to an idedecalciferol pharmaceutical composition and a preparation method thereof. The idedecalciferol pharmaceutical composition comprises an active ingredient, grease and a stabilizer, the active ingredient is idedecalciferol or pharmaceutically acceptable salt thereof, the grease comprises medium-chain triglyceride, and the anisidine value in the medium-chain triglyceride is smaller than or equal to 0.2. The preparation method comprises the following steps: putting an active component, grease and a stabilizer into a blending tank for blending to obtain the idedecalciferol pharmaceutical composition, and controlling the residual oxygen content in the blending tank to be less than or equal to 1.3% in the blending process. Under the condition that the curative effect of the eldecalciferol pharmaceutical composition is consistent with that of the original developed preparation, the eldecalciferol capsule prepared from the eldecalciferol pharmaceutical composition provided by the invention has higher quality stability, and the quality of the medicine is ensured.

Description

Technical Field

[0001] This application relates to the technical field of drug preparation, and particularly to an eldecalcitol pharmaceutical composition and a preparation method thereof. Background Art

[0002] Postmenopausal osteoporosis is the most common type of primary osteoporosis. According to statistics in 2000, there were 740 million postmenopausal women worldwide. Cardiovascular diseases and osteoporosis are common diseases and the main causes of death in postmenopausal women. The risk of osteoporotic fractures in women's lifetime is about 40%, higher than the sum of breast cancer, endometrial cancer and ovarian cancer. The treatment goal of postmenopausal osteoporosis is to regulate bone metabolism according to the bone turnover state, increase bone density, relieve pain, prevent and reduce the incidence of fractures. In this process, abnormal Ca metabolism and abnormal bone metabolism play important roles. Research shows that active vitamin D3 can act through vitamin D receptors: ① It can directly promote the absorption of calcium and phosphorus in the small intestine; ② It acts on the distal renal tubules to regulate the reabsorption of calcium ions to maintain the plasma calcium ion concentration; ③ It regulates the plasma calcium ion level to maintain stability by regulating the bone resorption of osteoclasts.

[0003] Eldecalcitol is a new generation of active vitamin D3 drug with skeletal selectivity. The eldecalcitol soft capsules (Edirol ® ), developed by Chugai Pharmaceutical under Roche, were first launched in Japan in 2011 for the treatment of osteoporosis. After being launched in Japan, the efficacy evaluation was relatively high. In 2015, the Japanese Osteoporosis Guidelines pointed out that the clinical trials of eldecalcitol covered a wide range of ages and disease severities, and had better efficacy compared with traditional active vitamin D. It could effectively increase bone density and had an inhibitory effect on vertebral fractures, and was recommended for all osteoporosis patients. In the treatment of primary osteoporosis, eldecalcitol had better efficacy than alfacalcidol, could significantly increase the bone mineral density of patients, and had similar safety to alfacalcidol. The original research eldecalcitol was launched in China in December 2020, with the trade name Aidiluo ® , and was approved for the treatment of postmenopausal women with osteoporosis. However, the quality stability of this drug still needs to be further improved. Summary of the Invention

[0004] Based on this, it is necessary to provide an eldecalcitol pharmaceutical composition and a preparation method thereof to improve the quality stability of the product.

[0005] In one aspect of this application, an eldecalcitol pharmaceutical composition is provided, which includes an active ingredient, an oil and a stabilizer;

[0006] The active ingredient is eldecalcitol or a pharmaceutically acceptable salt thereof, the oil includes medium-chain triglycerides, and the p-anisidine value of the medium-chain triglycerides is ≤0.2.

[0007] In some embodiments, the p-anisidine value of the medium-chain triglycerides is ≤0.09; and / or

[0008] The stabilizer includes at least one of nitrite, sulfite, thiosulfate, α-dimercaptopropanol, 1,3-butanediol, mercaptoacetic acid and its salts, thiomalate, thiourea, thiolactic acid, edetate, dichloroisocyanurate, citric acid, cysteine and its salts, benzotriazole, 2-mercaptobenzimidazole, isoascorbic acid and its salts, ascorbic acid and its ester compounds, phospholipids, metal chelating agents and their salts, tartaric acid and its salts, polyphenols, glutathione, dibutylhydroxytoluene, butylhydroxyanisole, propyl gallate, tocopherol and derivatives of tocopherol;

[0009] Optionally, the stabilizer is selected from at least one of racemic α-tocopherol and its acetate derivatives.

[0010] In the second aspect of the present application, an eldecalcitol capsule is provided, which includes a capsule shell and contents, and the contents include the eldecalcitol pharmaceutical composition of the first aspect.

[0011] In some embodiments, the capsule shell includes gelatin, the gel strength of the gelatin solution is 160-180, and the tensile strength of the gelatin film is 0.4 MPa-0.7 MPa; optionally, the gelatin is RXL gelatin;

[0012] Further optionally, the gelatin is selected from 180bloom RXL gelatin; and / or

[0013] The capsule shell includes a plasticizer, and the plasticizer includes one or more of glycerol, sorbitol, maltose, glucose, maltitose, sucrose, xylitol, mannitol, erythritol and polyethylene glycol;

[0014] Optionally, the plasticizer is selected from sorbitol; and / or

[0015] The capsule shell further includes a colorant, and the colorant includes one or more of caramel, caramel syrup, FD&C Red No. 3 Aluminum Lake, FD&C Yellow No. 4 Aluminum Lake, FD&C Yellow No. 5 Aluminum Lake, FD&C Green No. 3 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake and sodium copper chlorophyllin;

[0016] Optionally, the colorant is selected from caramel.

[0017] The third aspect of the present application provides a method for preparing an eldecalcitol pharmaceutical composition, which includes the following steps:

[0018] Place the active ingredient, oil and stabilizer in a batching tank to prepare a eldecalcitol pharmaceutical composition, and control the residual oxygen content in the batching tank during the liquid preparation process to be ≤ 1.3%; the active ingredient is eldecalcitol or a pharmaceutically acceptable salt thereof, the oil includes medium-chain triglycerides, and the p-anisidine value of the medium-chain triglycerides is ≤ 0.2.

[0019] In some embodiments, the p-anisidine value of the medium-chain triglycerides is ≤ 0.09; and / or

[0020] The step of controlling the residual oxygen content in the batching tank during the liquid preparation process to be ≤ 1.3% includes:

[0021] Add oil to the batching tank, and perform at least one vacuum pumping treatment and at least one nitrogen replacement treatment; and

[0022] Dissolve the active ingredient and stabilizer in a solvent and then add them to the batching tank, pump vacuum and perform at least one vacuum pumping treatment and at least one nitrogen replacement treatment.

[0023] The fourth aspect of the present application further provides the eldecalcitol pharmaceutical composition prepared by the preparation method of the eldecalcitol pharmaceutical composition in the third aspect.

[0024] The fifth aspect of the present application provides a preparation method of an eldecalcitol capsule, including the following steps;

[0025] Prepare an eldecalcitol pharmaceutical composition by using the preparation method of the eldecalcitol pharmaceutical composition in the third aspect; and

[0026] Prepare a capsule shell and inject the eldecalcitol pharmaceutical composition into the capsule shell to form a capsule.

[0027] In some embodiments, the step of preparing the capsule shell and injecting the eldecalcitol pharmaceutical composition into the capsule shell to form a capsule adopts a pressing method, and the pressing method includes: injecting the eldecalcitol pharmaceutical composition between rubber sheets through a nozzle to form a capsule, and the temperature of the nozzle is 35°C to 43°C;

[0028] Optionally, the temperature of the nozzle is 37°C to 43°C.

[0029] The sixth aspect of the present application provides an eldecalcitol capsule prepared by the preparation method of the eldecalcitol capsule in the fifth aspect.

[0030] Compared with the prior art, the present application has at least the following beneficial effects:

[0031] (1) By controlling the p-anisidine value of the medium-chain triglyceride in the excipient oil, the quality stability of eldecalcitol pharmaceutical composition products is improved. Under the condition of achieving the same efficacy as the original developed formulation, the eldecalcitol capsules prepared with the eldecalcitol pharmaceutical composition provided in this application have higher quality stability, ensuring the quality and safety of the drug, and further providing a more cost-effective choice for domestic osteoporosis patients. Detailed implementation manners

[0032] To facilitate the understanding of this application, the following will provide a more comprehensive description of this application and give the preferred embodiments of this application. However, this application can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the understanding of the disclosed content of this application more thorough and comprehensive.

[0033] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the technical field to which this application belongs. The terms used in the specification of this application herein are only for the purpose of describing specific embodiments and are not intended to limit this application. The term "and / or" used herein includes any and all combinations of one or more of the related listed items.

[0034] In this application, "the first aspect", "the second aspect", "the third aspect", etc. are only for descriptive purposes and cannot be understood as indicating or implying relative importance or quantity, nor can they be understood as implicitly indicating the importance or quantity of the indicated technical features.

[0035] In this application, among the technical features described in an open-ended manner, there are included closed technical solutions composed of the listed features, as well as open technical solutions including the listed features.

[0036] In this application, "one or more" means any one, any two or any two or more of the listed items.

[0037] In this application, regarding the numerical range, unless otherwise specified, the above numerical range is regarded as continuous and includes the minimum value and the maximum value of this range, as well as each value between such minimum value and maximum value. Further, when the range refers to an integer, it includes each integer between the minimum value and the maximum value of this range. In addition, when multiple ranges are provided to describe features or characteristics, these ranges can be combined. In other words, unless otherwise specified, all ranges disclosed herein should be understood to include any and all sub-ranges subsumed therein.

[0038] The percentage content involved in this application, unless otherwise specified, refers to the mass percentage for solid-liquid mixing and solid-solid mixing, and refers to the volume percentage for liquid-liquid mixing.

[0039] In this application, the percentage concentration, unless otherwise specified, refers to the final concentration. The final concentration refers to the proportion of the added component in the system after adding the component.

[0040] In this application, the temperature parameter, unless otherwise specified, allows for both constant temperature treatment and treatment within a certain temperature range. The constant temperature treatment allows the temperature to fluctuate within the accuracy range controlled by the instrument.

[0041] The method steps in this application that do not emphasize temperature usually refer to the method steps carried out at normal temperature or room temperature. In this text, normal temperature and room temperature are interchangeable, and the specific temperature refers to 22°C to 25°C.

[0042] If there is no special instruction, all the embodiments and optional embodiments of this application can be combined with each other to form new technical solutions.

[0043] If there is no special instruction, all the technical features and optional technical features of this application can be combined with each other to form new technical solutions.

[0044] If there is no special instruction, all the steps of this application can be carried out in sequence or randomly. For example, the method includes steps (a) and (b), which means that the method can include steps (a) and (b) carried out in sequence, or can also include steps (b) and (a) carried out in sequence. For example, when it is mentioned that the method may further include step (c), it means that step (c) can be added to the method in any order. For example, the method can include steps (a), (b) and (c), or can also include steps (a), (c) and (b), or can also include steps (c), (a) and (b), etc.

[0045] If there is no special instruction, the "including" and "comprising" mentioned in this application mean open-ended, and can also be closed-ended. For example, the "including" and "comprising" can mean that other components not listed can also be included or comprised, or can also only include or comprise the listed components.

[0046] If there is no special instruction, in this application, the term "or" is inclusive. For example, the phrase "A or B" means "A, B, or both A and B". More specifically, any of the following conditions satisfies the condition "A or B": A is true (or exists) and B is false (or does not exist); A is false (or does not exist) while B is true (or exists); or both A and B are true (or exist).

[0047] Alfacalcidol has the following chemical structural formula:

[0048] 。

[0049] There are mainly three impurities in eldecalcitol, including thermal isomers, namely precursor impurities (Pre), tachysterol-type isomer impurities (Tachy), and trans-type isomer impurities (IPB). Eldecalcitol is unstable, which is very unfavorable to the product stability.

[0050] Based on this, in the first aspect of the present application, a eldecalcitol pharmaceutical composition is provided, including an active ingredient, an oil, and a stabilizer; the active ingredient is eldecalcitol or a pharmaceutically acceptable salt thereof, the oil includes medium-chain triglycerides, and the p-anisidine value of the medium-chain triglycerides is ≤0.2.

[0051] In some embodiments, the p-anisidine value of the medium-chain triglycerides is ≤0.09.

[0052] In some embodiments, in the eldecalcitol pharmaceutical composition, the mass ratio of the active ingredient can be 0.0007% - 0.001%, the mass ratio of the oil is 98% - 99.5%, and the mass ratio of the stabilizer is 0.01% - 0.05%.

[0053] Without limitation, the stabilizer includes at least one of nitrite, sulfite, thiosulfate, α-dimercaptopropanol, 1,3-butanediol, mercaptoacetic acid and its salts, thiomalate, thiourea, thiolactic acid, edetate, dichloroisocyanurate, citric acid, cysteine and its salts, benzotriazole, 2-mercaptobenzimidazole, isoascorbic acid and its salts, ascorbic acid and its ester compounds, phospholipids, metal chelating agents and their salts, tartaric acid and its salts, polyphenols, glutathione, dibutylhydroxytoluene, butylhydroxyanisole, propyl gallate, tocopherol and derivatives of tocopherol.

[0054] It should be noted that tocopherol is also known as vitamin E. According to its source, it mainly includes two categories: RRR-α-tocopherol (alpha-tocopherol or d-tocopherol) produced in natural plants, that is, tocopherol in natural form, also known as natural vitamin E; and synthetic tocopherol (also known as racemic-α-tocopherol, all-rac-α-tocopherol, all-rac vitamin E or dl-tocopherol).

[0055] Furthermore, synthetic tocopherol has eight stereoisomers, including: RRR, RRS, RSS, SSS, RSR, SRS, SRR, and SSR.

[0056] The above-mentioned tocopherol can be a single form of tocopherol, or a mixture of multiple forms or isomers. The mixture of various forms of tocopherol, that is, the mixture of multiple tocopherols, is mixed concentrated tocopherol.

[0057] Furthermore, synthetic tocopherols can exist in the form of ester derivatives, such as acetic acid derivatives of tocopherol, also known as tocopheryl acetate.

[0058] In some embodiments, the stabilizer is selected from at least one of racemic α-tocopherol and its acetate derivatives.

[0059] In some embodiments, the stabilizer is selected from racemic α-tocopherol.

[0060] One embodiment of the present application provides an eldecalcitol capsule, which includes a capsule shell and contents. The contents include the eldecalcitol pharmaceutical composition of the first aspect.

[0061] It is understandable that the contents are arranged inside the capsule shell, and the capsule shell wraps the contents.

[0062] In some embodiments, the capsule shell includes gelatin.

[0063] As the matrix of the capsule shell, gelatin affects the gel strength and disintegration time limit of the capsule shell. The amino acid composition or content in different gelatins is different, and some amino acids in gelatin may undergo cross-linking reactions with aldehydes, further affecting the cross-linking degree of the capsule shell under high-temperature conditions, and thus affecting the disintegration performance of the product.

[0064] In some embodiments, the capsule shell includes gelatin. Optionally, the gel strength of the gelatin solution is 160-180, and the tensile strength of the gelatin film is 0.4 MPa-0.7 MPa. The capsule shell made of gelatin within this range can further improve the product quality and stability.

[0065] In some embodiments, the gelatin is RXL gelatin, and further optionally 180 bloom RXL gelatin. The capsule shell made of 180 bloom RXL gelatin can further improve the product quality and stability.

[0066] Similarly, 180 bloom RXL gelatin also has the meaning known in the art. 180 bloom means that the gel strength of the gelatin solution is 180. Specifically, the gel strength of 180 bloom RXL gelatin solution is about 180 bloom, and the tensile strength of the gelatin film is about 0.7 MPa.

[0067] In some embodiments, the capsule shell includes a plasticizer. Optionally, the plasticizer includes one or more of glycerol, sorbitol, maltose, glucose, maltitose, sucrose, xylitol, mannitol, erythritol, and polyethylene glycol. Further optionally, the plasticizer is selected from sorbitol.

[0068] In some embodiments, the capsule shell further comprises a colorant. Optionally, the colorant comprises one or more of caramel, caramel syrup, FD&C Red No. 3 Aluminum Lake, FD&C Yellow No. 4 Aluminum Lake, FD&C Yellow No. 5 Aluminum Lake, FD&C Green No. 3 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, and sodium copper chlorophyllin. Further optionally, the colorant is selected from caramel.

[0069] In some embodiments, eldecalcitol capsules comprise a content and a capsule shell. The content comprises the active ingredient eldecalcitol or a pharmaceutically acceptable salt thereof, the above medium-chain triglyceride, and racemic α-tocopherol, wherein the p-anisidine value of the medium-chain triglyceride is ≤0.20. The capsule shell comprises 180 bloom RXL gelatin, sorbitol, and caramel.

[0070] In another embodiment of the present application, a method for preparing an eldecalcitol pharmaceutical composition is further provided, comprising the following step S10:

[0071] Step S10: Place the active ingredient, oil, and stabilizer in a batching tank for liquid preparation to obtain an eldecalcitol pharmaceutical composition, and control the residual oxygen content in the batching tank during the liquid preparation process to be ≤1.3%; the active ingredient is eldecalcitol or a pharmaceutically acceptable salt thereof, the oil comprises medium-chain triglyceride, and the p-anisidine value of the medium-chain triglyceride is ≤0.2.

[0072] By controlling the residual oxygen content in the batching tank during the liquid preparation process, the content of related impurities, especially degradation impurities, in the finished product is reduced, and the product quality is further improved.

[0073] In some embodiments, the p-anisidine value of the medium-chain triglyceride is ≤0.09.

[0074] In some embodiments, the step of controlling the residual oxygen content in the batching tank during the liquid preparation process to be ≤1.3% comprises:

[0075] S121, adding oil to the batching tank, performing at least one vacuum pumping treatment and at least one nitrogen replacement treatment; and

[0076] S121, dissolving the active ingredient and stabilizer in a solvent and then adding them to the batching tank, performing at least one vacuum pumping treatment and at least one nitrogen replacement treatment.

[0077] In one embodiment of the present application, an eldecalcitol pharmaceutical composition prepared by the above method for preparing an eldecalcitol pharmaceutical composition is further provided.

[0078] In one embodiment of the present application, a method for preparing eldecalcitol capsules is further provided, comprising the following steps S20 to S30.

[0079] Step S20: Prepare an eldecalcitol pharmaceutical composition by using the above method for preparing an eldecalcitol pharmaceutical composition.

[0080] Step S30: Prepare the capsule shell and inject the eldecalcitol pharmaceutical composition into the capsule shell to form a capsule.

[0081] It can be understood that when the eldecalcitol pharmaceutical composition is injected into the capsule shell, the eldecalcitol pharmaceutical composition is the content.

[0082] In some embodiments, the step of preparing the capsule shell and injecting the eldecalcitol pharmaceutical composition into the capsule shell to form a capsule in step S30 adopts the pressing method. The method of preparing the capsule by pressing includes injecting the eldecalcitol pharmaceutical composition between the rubber sheets through a nozzle to form the capsule shell. The temperature of the nozzle can be 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, and the range between any two of the above values. Optionally, the temperature of the nozzle in the pill-making step is 37°C - 43°C. By controlling the temperature of the nozzle during the pill-making process, the content of related impurities in the finished product can be further reduced, and the product quality can be improved.

[0083] In some embodiments, it further includes the step of preparing the rubber sheet. The step of preparing the rubber sheet includes steps of rubber melting, vacuum degassing, rubber solution heat preservation, and skin making. These steps can all adopt the methods well-known to those skilled in the art. For example, the skin making is completed by a capsule machine. It should be noted that the rubber sheet refers to the state before the formation of the capsule shell. The rubber solution forms a solid state (rubber sheet) from a liquid state through the capsule agent, and then the rubber sheet encloses the content and is sutured to form the capsule skin, and finally the capsule is obtained.

[0084] In some embodiments, the method for preparing the eldecalcitol capsule further includes one or more of the steps of drying, pill selection, and packaging.

[0085] An embodiment of the present application also provides an eldecalcitol capsule prepared by the method for preparing the eldecalcitol capsule described above.

[0086] The following are specific examples. The purpose is to further elaborate on the present application to help those skilled in the art and researchers further understand the present application. The relevant technical conditions do not constitute any limitation to the present application. Any form of modification within the scope of the claims of the present application is within the protection scope of the claims of the present application.

[0087] Unless otherwise specified, the raw materials and reagents used in the following examples are all commercially available products, or can be prepared by known methods. The experimental methods without specific conditions noted in the examples are carried out under conventional conditions, such as the conditions described in the literature, books, or the methods recommended by the manufacturers.

[0088] The following English names have the following meanings:

[0089] Tachy: tachysterol isomer impurity; IPB: trans isomer impurity; Pre: idecalciferol thermal isomer or precursor impurity.

[0090] Table 1 Prescription table

[0091]

[0092] Note: Purified water and anhydrous ethanol are solvents removed during the preparation process and are almost non-existent in the final product.

[0093] Table 2 Ingredients and prescription of Ai Decalcitol Capsules

[0094]

[0095] Note: Purified water and anhydrous ethanol are solvents removed during the preparation process. They only serve as mixing media during the preparation process and are almost non-existent in the final product. Therefore, the mass of purified water or anhydrous ethanol is not included in the "Total" column in Table 2 above. Furthermore, "appropriate amount" means that purified water or anhydrous ethanol can soak and mix other raw materials. Among them, based on the total mass of the raw materials for preparing the capsule shell (including purified water), the mass proportion of purified water can be 45%~65%, and based on the total mass of the raw materials for preparing the core liquid (including anhydrous ethanol), the mass proportion of anhydrous ethanol can be 0.5%~2%.

[0096] Comparative Example 1

[0097] The idecalcitol capsules were prepared according to the following steps using the formulation of idecalcitol capsules shown in Table 1:

[0098] Dissolve idecalciferol and dl-α-tocopherol in anhydrous ethanol respectively, add to medium-chain triglycerides (methoxyaniline value 0.18), and stir evenly to obtain liquid medicine. Add sorbitol and caramel to purified water to dissolve, stir and heat, add gelatin (select RXL gelatin model) to start gelatinization after reaching the appropriate gelatinization temperature, and stir evenly to obtain gelatin solution. Use a soft capsule machine to fill the liquid medicine and gelatin into soft capsules by dripping method, dry the soft capsules and then pack them in aluminum-plastic packaging, and then use polyester / aluminum / polyethylene medicinal composite film pillow to pack the finished aluminum-plastic packaging medicine plate into a paper box.

[0099] 1. Drug quality

[0100] 1.1 Residual oxygen control in batching tank

[0101] Embodiment 1~3

[0102] The idecalcitol capsules were prepared according to the following steps using the formulation of idecalcitol capsules shown in Table 1:

[0103] (1)Gelatinization: Weigh the gelatin for capsules, sorbitol, caramel syrup, and purified water. Add purified water, sorbitol, and caramel syrup to the gelatinization tank in sequence, stir and heat simultaneously. After reaching the appropriate gelatinization temperature, add gelatin to start gelatinization. After the gelatin is completely dissolved, perform degassing until the color of the glue solution is uniform and there are no visible bubbles (select gelatin type 180 bloom RXL).

[0104] (2)Solution preparation: Weigh eldecalcitol, racemic α - tocopherol, absolute ethanol, and medium - chain triglyceride. Add the prescribed amount of medium - chain triglyceride to the batching tank, evacuate and perform one nitrogen replacement. Dissolve racemic α - tocopherol and eldecalcitol separately with appropriate absolute ethanol and add them to the batching tank in sequence. After performing one nitrogen replacement in the same way, evacuate and start stirring. After the liquid medicine is mixed evenly, fill it with nitrogen, protect it from light, and store it sealed below 25°C (the p - anisidine value of medium - chain triglyceride is 0.09, and the residual oxygen content in the batching tank during the solution preparation process is shown in Table 3 below).

[0105] (3)Pellet making: Use a rotary - die soft capsule machine and a spherical - like mold to press the pills. Specifically, add the prepared liquid medicine to the hopper, pump the glue solution to the soft capsule machine through a glue delivery pipe, complete the preparation of the rubber shell, quantitative filling of the content, and press the rubber shell and the content into capsules through the mold. Among them, the temperature of the nozzle is controlled at 40.0°C.

[0106] (4)Drying: After shaping the pills in a rotating cage, transfer them to a tray for static drying until the drying loss of the capsule shell meets the requirements.

[0107] (5)Pill selection: Pick out soft capsules with different sizes, abnormal shapes, thin walls, obvious screen prints, flat pills, pills with air bubbles, pills with black spots, and pills with oil leakage after drying.

[0108] (6)Packaging: Use solid pharmaceutical hard PVC sheets and pharmaceutical aluminum foils to perform blister packaging on the pills, then use polyester / aluminum / polyethylene composite films for pharmaceutical packaging to perform pillow packaging on the medicine boards, and box them after completing the pillow packaging.

[0109] Table 3 Control of Residual Oxygen Content in the Batching Tank

[0110]

[0111] If vacuum evacuation and nitrogen replacement operations are not carried out during the solution preparation process, the residual oxygen content in the tank will be relatively high, resulting in a relatively high level of related substances in the finished product and affecting the quality of the finished product. By adding operations such as vacuum evacuation and nitrogen replacement during the solution preparation process to control the residual oxygen content in the tank, especially controlling the residual oxygen content in the tank ≤ 1.3%, the level of related substances in the obtained finished product is lower than that of Comparative Example 1.

[0112] 1.2 Control of the Temperature of the Nozzle during Pellet Making

[0113] Examples 4 - 6

[0114] The preparation methods of Examples 4 to 6 are basically the same as that of Example 3, except that the temperatures of the pill-making nozzle are replaced with the temperatures listed in Table 4 below.

[0115] Table 4 Control of the nozzle temperature in the pill-making process

[0116]

[0117] The calculation formula for the average suture rate of the capsule is: the average thickness of the capsule shell at the joint / the average thickness of the capsule shell away from the joint * 100%. Specific test method: Take the soft capsule, cut a ring-shaped capsule shell about 1 mm thick perpendicular to the joint direction in the middle, observe and measure the thickness of the capsule shell at the joint and the thickness of the capsule shell away from the joint through a microscope, repeat the measurement 2 times and take the average value to obtain the average thickness of the capsule shell at the joint and the average thickness of the capsule shell away from the joint.

[0118] When the nozzle temperature of the soft capsule machine is controlled within the range of 35°C to 43°C, all indexes of the related substances of the obtained finished product are better than those of Comparative Example 1. Considering comprehensively, it is advisable to preferably control the temperature of the pill-making nozzle within the range of 37 to 43°C.

[0119] 2. Product stability

[0120] 2.1 Selection of gelatin type

[0121] Examples 7 to 9

[0122] The preparation methods of Examples 7 to 9 are basically the same as that of Example 3, except that the type of gelatin is replaced with the types listed in Table 5 below.

[0123] Table 5 Selection of gelatin type

[0124]

[0125] The disintegration time limit tests of the capsules prepared in Example 3, Examples 7 to 9 and Comparative Example 1 were carried out at 0 day and under accelerated conditions. The specific test conditions are as follows:

[0126] 0 day: It means that the sample is taken out for detection directly without being placed under accelerated conditions. The storage conditions after production and warehousing are protected from light and sealed, and stored at no more than 25°C. The detection time is within 1 month after production. That is, the 0-day sample is taken out for detecting the disintegration time limit within 1 month under the conditions of being protected from light and sealed and stored at no more than 25°C;

[0127] The disintegration test of this product examines the capsule shell rupture time of the soft capsule in the water medium at 37°C ± 1°C. The capsule shell rupture time refers to the time when the oil droplets of the content are just observed to be released from the rupture of the capsule shell.

[0128] The results are shown in Table 6.

[0129] Table 6 Comparison of the disintegration time limit of finished products of different gelatin models at 0 day and under accelerated conditions

[0130]

[0131] Note: RH represents relative humidity.

[0132] During the drying process of the capsules, due to the loss of moisture, the capsule shell will shrink. In Example 7, the gelatin model is 160 bloom. Some capsules rupture during the drying and shrinking process because the gel strength and tensile strength of the capsule shell are relatively low, resulting in a decrease in the finished product yield. Gelatin models with higher gel strength and tensile strength indicators, such as 180 bloom, 200 bloom, and 180 bloom RXL, will not rupture.

[0133] By comparing the disintegration time of the finished products prepared from different models of gelatin with the samples of Comparative Example 1 at 0 day and after 1 month of acceleration (40°C, 75% RH) in water, it was found that the capsule shell rupture time and disintegration time of the finished products prepared from common model gelatin (160 bloom, 180 bloom, 200 bloom) in Examples 7 - 9 were significantly slower after 1 month of acceleration compared to 0 day, and the average disintegration time limit in Examples 8 - 9 was greater than 20 min. However, for the finished products prepared from anti-crosslinking model gelatin (180 bloom RXL) in Example 3, the capsule shell rupture time and disintegration time showed no significant change after 1 month of acceleration compared to 0 day, and were basically the same as those of Comparative Example 1. Considering comprehensively, the preferred gelatin model is 180 bloom RXL.

[0134] 2.2 Control of p - anisidine value in medium - chain triglycerides

[0135] Examples 10 - 11

[0136] The preparation methods of Examples 10 - 11 are basically the same as those of Example 3, except that medium - chain triglycerides with different p - anisidine values are used. The specific p - anisidine values are listed in Table 7 below.

[0137] Table 7 Comparison of influencing factors and stability data of finished products at different p - anisidine value levels

[0138]

[0139] Note: 0 day means that the samples are directly detected without being placed under high temperature or accelerated conditions. The storage conditions before detection are protected from light, sealed, and stored at no more than 25°C.

[0140] In Comparative Example 1, only Pre exceeded the limit after being placed under severe conditions (high temperature of 60°C, naked exposure after the liquid medicine was drawn out) for 2 days, and no impurities exceeded the limit under the accelerated conditions (40°C, 75% RH, with packaging) for 6 months; in Example 10, impurities Tachy, Pre, and IPB all exceeded the limit after being placed under severe conditions (high temperature of 60°C, naked exposure after the liquid medicine was drawn out) for 2 days, and only impurity Tachy exceeded the limit under the accelerated conditions (40°C, 75% RH, with packaging) for 6 months; in Example 11, only Pre exceeded the limit after being placed under severe conditions (high temperature of 60°C, naked exposure after the liquid medicine was drawn out) for 2 days, no impurities exceeded the limit under the accelerated conditions (40°C, 75% RH, with packaging) for 6 months, and there was no significant difference in stability from Comparative Example 1. In Example 3, only Pre exceeded the limit after being placed under severe conditions (high temperature of 60°C, naked exposure after the liquid medicine was drawn out) for 2 days, and Tachy and IPB were significantly lower than those in Comparative Example 1. The stability under the accelerated conditions (40°C, 75% RH, with packaging) for 6 months was significantly better than that in Comparative Example 1, indicating that controlling the p-anisidine value in medium-chain triglycerides ≤ 0.20 can make the stability of the finished product equivalent to that in Comparative Example 1; more preferably, controlling the p-anisidine value in medium-chain triglycerides ≤ 0.09 can make the stability of the finished product better than that in Comparative Example 1.

[0141] The technical features of the above-described embodiments can be combined arbitrarily. For the sake of brevity of description, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, it should be considered as within the scope described in this specification.

[0142] The above-described embodiments merely represent several implementation manners of this application, which are convenient for understanding the technical solutions of this application specifically and in detail, but should not be construed as a limitation on the protection scope of the invention patent. It should be noted that for those of ordinary skill in the art, without departing from the concept of this application, several modifications and improvements can still be made, and these all belong to the protection scope of this application. It should be understood that the technical solutions obtained by those skilled in the art through logical analysis, reasoning, or limited experiments based on the technical solutions provided in this application are all within the protection scope of the appended claims of this application. Therefore, the protection scope of this patent application should be subject to the content of the appended claims, and the specification can be used to explain the content of the claims.

Claims

1. An eldecalcitol pharmaceutical composition, characterized in that, It includes an active ingredient, an oil and a stabilizer, The active ingredient is eldecalcitol or a pharmaceutically acceptable salt thereof, the oil includes medium-chain triglycerides, and the medium-chain triglycerides have a p-anisidine value ≤ 0.

2.

2. The eldecalcitol pharmaceutical composition according to claim 1, wherein The medium-chain triglycerides have a p-anisidine value ≤ 0.09; and / or The stabilizer includes at least one of nitrite, sulfite, thiosulfate, α-dimercaptopropanol, 1,3-butanediol, mercaptoacetic acid and its salts, thiomalate, thiourea, thiolactic acid, edetate, dichloroisocyanurate, citric acid, cysteine and its salts, benzotriazole, 2-mercaptobenzimidazole, isascorbic acid and its salts, ascorbic acid and its ester compounds, phospholipids, metal chelating agents and their salts, tartaric acid and its salts, polyphenols, glutathione, dibutylhydroxytoluene, butylhydroxyanisole, propyl gallate, tocopherol and derivatives of tocopherol; Optionally, the stabilizer is selected from at least one of racemic α-tocopherol and its acetate derivatives.

3. An eldecalcitol capsule, characterized in that, It includes a capsule shell and a content, and the content includes the eldecalcitol pharmaceutical composition according to any one of claims 1 to 2.

4. The eldecalcitol capsule according to claim 3, wherein, The capsule shell includes gelatin, the gel strength of the gelatin solution is 160 to 180, and the tensile strength of the gelatin film is 0.4 MPa to 0.7 MPa; optionally, the gelatin is RXL gelatin; Further optionally, the gelatin is selected from 180bloom RXL gelatin; and / or The capsule shell includes a plasticizer, and the plasticizer includes one or more of glycerol, sorbitol, maltose, glucose, maltitose, sucrose, xylitol, mannitol, erythritol and polyethylene glycol; Optionally, the plasticizer is selected from sorbitol; and / or The capsule shell further includes a colorant, and the colorant includes one or more of caramel, caramel syrup, FD&C Red No. 3 Aluminum Lake, FD&C Yellow No. 4 Aluminum Lake, FD&C Yellow No. 5 Aluminum Lake, FD&C Green No. 3 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake and sodium copper chlorophyllin; Optionally, the colorant is selected from caramel.

5. A method for preparing an eldecalcitol pharmaceutical composition, characterized in that, It includes the following steps: Place the active ingredient, the oil and the stabilizer in a dosing tank to prepare a liquid to obtain the eldecalcitol pharmaceutical composition, and control the residual oxygen content in the dosing tank during the liquid preparation process ≤ 1.3%; the active ingredient is eldecalcitol or a pharmaceutically acceptable salt thereof, the oil includes medium-chain triglycerides, and the medium-chain triglycerides have a p-anisidine value ≤ 0.

2.

6. The preparation method of the eldecalcitol pharmaceutical composition according to claim 5, characterized in that, The medium-chain triglycerides have a p-anisidine value ≤ 0.09; and / or The step of controlling the residual oxygen content in the dosing tank during the liquid preparation process ≤ 1.3% includes: Add the oil to the dosing tank, and perform at least one vacuum pumping treatment and at least one nitrogen replacement treatment; and Dissolve the active ingredient and the stabilizer in a solvent and then add them to the dosing tank, pump vacuum and perform at least one vacuum pumping treatment and at least one nitrogen replacement treatment.

7. The eldecalcitol pharmaceutical composition prepared by the preparation method of the eldecalcitol pharmaceutical composition according to any one of claims 5 to 6.

8. A preparation method of eldecalcitol capsules, characterized in that, It includes the following steps; Preparing an eldecalcitol pharmaceutical composition by using the preparation method of the eldecalcitol pharmaceutical composition according to any one of claims 6 to 7; and Preparing a capsule shell and injecting the eldecalcitol pharmaceutical composition into the capsule shell to form a capsule.

9. The preparation method of eldecalcitol capsules according to claim 8, characterized in that, The step of preparing the capsule shell and injecting the eldecalcitol pharmaceutical composition into the capsule shell to form a capsule adopts a pressing method, and the pressing method includes: injecting the eldecalcitol pharmaceutical composition between rubber sheets through a nozzle to form a capsule, and the temperature of the nozzle is 35°C to 43°C; Optionally, the temperature of the nozzle is 37°C to 43°C.

10. An eldecalcitol capsule prepared by the preparation method of the eldecalcitol capsule according to any one of claims 8 to 9.

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