An alfacalcidol soft capsule composition and a method for preparing the same

Abstract

The present application relates to the field of new drug preparations, and specifically discloses a kind of alfacalcidol soft capsule composition and preparation method thereof, the alfacalcidol soft capsule composition is prepared from alfacalcidol content drug liquid and soft capsule shell, wherein the soft capsule content drug liquid includes alfacalcidol co-crystal, oily base, the soft capsule shell is made of gelatin, plasticizer, purified water and light shielding agent;The alfacalcidol soft capsule composition prepared by the present application has high stability, and improves the problems of low solubility of raw material, easy oxidation and poor water solubility, the preparation method of the alfacalcidol soft capsule composition is simple and easy to operate, low in cost, and easy to mass production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparations, and specifically discloses an alfacalcidol soft capsule composition and its preparation method. Background Technology

[0002] Alfacalcidol, (5Z,7E)-9,10-open-cholest-5,7,10(19)-trien-1α,3β-diol, has the molecular formula C 27 H 44 O2, the structural formula is as follows:

[0003] .

[0004] After oral absorption, alfacalcidol is rapidly converted into 1,25-dihydroxyvitamin D3 in the liver. This substance is the active metabolite of vitamin D3 and can regulate the balance of calcium and phosphorus in the body. When the kidneys fail to produce enough endogenous 1,25-dihydroxyvitamin D3, it can lead to mineral metabolism disorders, which can be seen in renal osteodystrophy, hypoparathyroidism, and vitamin D-dependent rickets.

[0005] Alfacalcidol is a white crystalline powder that is easily degraded by light, moisture, and heat, and is almost insoluble in water. Studies have shown that one of the main reasons why the efficacy of oral solid dosage forms cannot be fully realized is the poor water solubility of oral drugs. After oral administration, these drugs easily precipitate in the gastrointestinal environment, resulting in low dissolution and consequently poor bioavailability. Therefore, there is an urgent need for a technology to improve the solubility and stability of alfacalcidol to address its existing problems.

[0006] Drug cocrystals refer to crystals formed by the active pharmaceutical ingredient (API) and cocrystal former (CCF) in a certain proportion through non-covalent intermolecular interactions. The formation of cocrystals does not require the formation of new covalent bonds between the API and CCF, nor does it involve molecule disruption; it is simply the self-assembly of binary or multi-component components after rearrangement. Selecting appropriate cocrystal ligands to form cocrystals with the active pharmaceutical ingredient holds great potential for enhancing the solubility, permeability, bioavailability, and stability of active pharmaceutical ingredients.

[0007] Erythritol, a widely distributed natural active substance, is abundant in seaweed, fungi such as mushrooms, and fruits such as melons and grapes. Erythritol possesses antioxidant activity, is highly stable to acids, alkalis, and heat, and does not undergo the Maillard reaction. Compared to other sugar alcohols, its greatest advantage is its good tolerability; after absorption, it is not metabolized and is excreted from the body, not participating in sugar metabolism or blood glucose fluctuations, making it suitable for diabetic patients. Erythritol exhibits good compatibility with various drugs and can be widely used in coating, tableting excipients, and inhalation carriers / excipients. Furthermore, erythritol possesses low-calorie, anti-caries, and antioxidant biological properties, making it a pharmaceutical excipient with multiple excellent characteristics. Adding an appropriate amount of erythritol to soft capsules can prevent soft capsule adhesion, significantly shorten the drying time of gelatin soft capsules, and save drying costs.

[0008] Glycine is one of the most commonly used amino acid antioxidants / stabilizers in the amino acid series. It has the simplest structure, and its amino and carboxyl groups can form hydrogen bonds or electrostatic interactions with the peptide chains of gelatin, repairing defects in the gelatin network structure and reducing the damage to the gelatin molecular chains caused by moisture and oxygen. This delays the hardening and cracking of the capsule shell caused by hydrolysis and oxidation. Studies have shown that glycine can reduce the denaturation rate of gelatin under high temperature and high humidity conditions, prolong the retention time of the shell's mechanical properties, and extend the shelf life of soft capsules.

[0009] Soft capsule materials are generally made alone or in combination from capsule gelatin, glycerin, or other suitable pharmaceutical excipients. Gelatin is the preferred film-forming material for soft capsule formulations due to its excellent film-forming ability and stable physical properties. However, due to the unevenness of gelatin molecular chain breakage and its own hydrophilicity, the barrier capacity of a single gelatin film is poor. Stability phenomena such as capsule shell disintegration and delayed dissolution during soft capsule storage are common problems in soft capsule products. The main reasons for these phenomena are the hygroscopicity and cross-linking aging of the gelatin in the soft capsule shell.

[0010] Patent CN104800187B discloses an alfacalcidol soft capsule and its preparation method. The contents mainly consist of alfacalcidol, polyethylene glycol, a penetration enhancer, glycerin, and a thickener, with the aim of improving drug bioavailability. Patent CN109568287A discloses an alfacalcidol soft capsule and its preparation method. The contents mainly consist of alfacalcidol, an antioxidant, and an oily matrix. The preparation process involves formulation under light-protected and nitrogen-protected conditions, with the main purpose of improving product stability and reducing the defect of low product bioavailability. However, neither of these patents mentions how to solve the problems of alfacalcidol's own stability and the slow disintegration and dissolution caused by the aging of the soft capsule shell.

[0011] Patent CN111214453B discloses an alfacalcidol soft capsule and its preparation method. It involves a method of preparing alfacalcidol soft capsules by uniformly mixing alfacalcidol, medium-chain triglycerides, ascorbyl palmitate, gliadin, polyethylene glycol, phospholipids, and monoglycerides of laurate. The purpose is to improve the stability and bioavailability of alfacalcidol soft capsules. However, it does not propose solutions to problems such as shell aging and instability of active ingredients that occur during long-term storage of soft capsules.

[0012] Patent CN118252813B discloses an alfacalcidol soft capsule and its preparation method. The capsule shell is prepared using modified hydroxypropyl methylcellulose and starch, and the soft capsule contents are prepared using ultrasonic emulsification technology, with the aim of improving product stability and bioavailability. However, since alfacalcidol raw material is unstable at high temperatures, and high-temperature emulsification is used in the emulsion preparation process, this may be detrimental to the long-term stability of the alfacalcidol soft capsules. Furthermore, the plant matrix capsule material preparation process used in this patent is cumbersome and complex, requiring a large amount of organic solvents, which poses certain difficulties for industrial-scale production.

[0013] Patent CN119405615A discloses a method for preparing rapid-release alfacalcidol soft capsules containing PLGA microspheres with vitamin D3 and a capsule shell liquid containing β-cyclodextrin. Although this preparation method can achieve rapid release of alfacalcidol, it does not analyze the stability of the soft capsules during long-term storage and their cross-linking aging. In addition, its preparation process is relatively complex and poses certain challenges to industrial production.

[0014] Patent CN119488148A discloses a seamless soft capsule, its preparation method, and its uses. The film-forming composition mainly comprises a first gelling agent, high-ester pectin, a plasticizer, and water. The plasticizer is primarily composed of one or more of glycerol, sorbitol, xylitol, erythritol, maltitol, and lactitol, with glycerol being preferred. The main objective is to research and develop a plant-based seamless soft capsule with a uniform appearance, low oil leakage rate, and satisfactory disintegration test after drying. Although the application of plant-based colloidal materials such as hydroxypropyl methylcellulose (HPMC) in soft capsules has been studied to some extent, problems remain, such as inferior mechanical strength, elasticity, density, and thermal stability compared to traditional gelatin. Furthermore, for products with high barrier requirements, complex processes, and cost control, plant-based colloidal materials cannot currently completely replace traditional gelatin.

[0015] In summary, none of the above patented technologies have addressed the inherent stability of alfacalcidol raw material and the cross-linking aging and stability of its soft capsule shell during long-term storage.

[0016] While the methods described above can achieve the preparation of alfacalcidol soft capsules, they fail to address how to improve the stability of the active pharmaceutical ingredient and its formulation. Current patents, although addressing issues such as improving light stability, do not explain how to prevent disintegration and delayed dissolution caused by soft capsule shell cross-linking aging. In fact, soft capsule shell aging leads to prolonged disintegration time, decreased dissolution rate, and even complete insolubility, which can prevent the drug from fully exerting its active ingredient activity. Therefore, developing an alfacalcidol soft capsule with high stability, delayed shell cross-linking aging, and suitability for industrial-scale production could, to some extent, improve the shortcomings of existing soft capsules. Summary of the Invention

[0017] This invention addresses the shortcomings of existing technologies by providing an alfacalcidol soft capsule composition and its preparation method. The alfacalcidol soft capsule composition is prepared from an alfacalcidol content solution and a soft capsule shell. The soft capsule content solution includes alfacalcidol cocrystals and an oily matrix, while the soft capsule shell is composed of gelatin, a plasticizer, purified water, and a light-blocking agent. The alfacalcidol cocrystal preparation method provided by this invention is simple, does not alter the properties of the active pharmaceutical ingredient, and produces a product with good stability. It is convenient, safe, and has strong process operability and low cost, making it suitable for industrial production. By adding a compound composition of glycerol, erythritol, and glycine to the soft capsule shell, the barrier properties of the gelatin film are improved, as are its antioxidant properties, the generation of aldehydes in the capsule shell, and the aging of the capsule shell. This improves the problems of disintegration and delayed dissolution of soft capsules after long-term storage, thereby enhancing the long-term stability of the product.

[0018] The specific technical solution provided by this invention is as follows:

[0019] An alfacalcidol soft capsule composition is prepared from an alfacalcidol content solution and a soft capsule shell; wherein the alfacalcidol content solution comprises alfacalcidol eutectic and an oily matrix, and the pure alfacalcidol content solution accounts for 0.0001~0.1% by weight; the final alfacalcidol soft capsules are specified to contain 0.25μg, 0.5μg, or 1.0μg of pure alfacalcidol per soft capsule.

[0020] The cocrystallization ligand in the alfacalcidol cocrystallization is selected from nicotinamide, proline, tyrosine, arginine and L-alanine, with nicotinamide being preferred; the oily matrix is ​​one or more of medium-chain triglycerides, sesame oil, olive oil, castor oil, oleic acid and monolinolenic acid glycerides, with medium-chain triglycerides and / or sesame oil being preferred.

[0021] The soft capsule shell is composed of gelatin, plasticizer, purified water and light-blocking agent, wherein the weight ratio of gelatin, plasticizer, purified water and light-blocking agent is (0.7~1.0):(0.12~0.6):(0.6~1.2):(0.0018~0.09), preferably, the weight ratio of gelatin, plasticizer, purified water and light-blocking agent is 1:0.46:1:0.015;

[0022] The plasticizer is a composition of glycerol, erythritol, and glycine, wherein the weight ratio of glycerol, erythritol, and glycine is (0.05~5):(0.02~3):(0.001~1.5). If the weight ratio of the three components in the plasticizer exceeds the above-mentioned limit range, there is a risk that the erythritol in the soft capsule shell may precipitate and crystallize, thereby increasing the brittleness of the product shell. Preferably, the weight ratio of the three components is 1.875:1:0.2.

[0023] The light-blocking agent is one or more of titanium dioxide, red iron oxide, and yellow iron oxide, preferably titanium dioxide.

[0024] Another object of the present invention is to provide a method for preparing the alfacalcidol soft capsule composition, comprising the following steps:

[0025] (1) Preparation of alfacalcidol cocrystal: Weigh out the powders of alfacalcidol and the cocrystal ligand respectively; then dissolve the powders in the reaction solvent to form a clear solution of alfacalcidol and the cocrystal ligand; while stirring, add 0.1 to 15 times the amount of purified water of the reaction solvent dropwise to crystallize; after the addition is complete, filter the mixed suspension to crystallize at low temperature or room temperature, filter, and dry to obtain a white crystalline solid, which is the alfacalcidol cocrystal;

[0026] (2) Preparation of alfacalcidol contents solution: The alfacalcidol eutectic obtained in step (1) was added to the oily matrix and stirred to obtain the alfacalcidol contents solution;

[0027] (3) Preparation of alfacalcidol soft capsules:

[0028] ① Disperse the light-shielding agent evenly with 10-15% of the prescribed amount of purified water and set aside. Dissolve the plasticizer in water and place it in a gelling tank. Add the suspension of the above-mentioned light-shielding agent, stir and disperse evenly, and heat in a water bath to 55-60℃. After adding gelatin, heat to 65-72℃, evacuate the vacuum (≤-0.08Mpa), and after the weight of the gelatin solution in the gelling tank decreases by 3-10%, filter and keep warm at 50-60℃ to obtain the soft capsule material.

[0029] When dissolving the above plasticizer, erythritol and glycine should be completely dissolved first, and then glycerol should be added and completely dissolved.

[0030] ② The contents of alfacalcidol and the soft capsule material are pressed into soft capsules using a fully automatic soft capsule machine, dried at 18℃~33℃, and shaped at 20~27℃ to obtain alfacalcidol soft capsules.

[0031] The specifications are that each soft capsule contains 0.25 μg, 0.5 μg, or 1.0 μg of pure alfacalcidol.

[0032] Furthermore, in step (1), the cocrystallized ligand is selected from nicotinamide, proline, tyrosine, arginine, and L-alanine, preferably nicotinamide. All selected cocrystallized ligands contain hydrogen bond donors (e.g., -NH, -OH, -COOH) and hydrogen bond acceptors (e.g., C=O, -N=, -OH), which can form a hydrogen bond network with drug molecules, stabilize the cocrystallized structure, and improve the dissolution rate of poorly soluble drugs. Based on the advantages of nicotinamide, such as hydrogen bond stabilization, high solubility, and antioxidant properties, nicotinamide is preferred as the cocrystallized ligand to further improve the stability of the alfacalcidol cocrystallization.

[0033] Furthermore, in step (1), the molar ratio of alfacalcidol to the cocrystal ligand is 1:(0.5~2.5), preferably 1:1. If the cocrystal ligand ratio is too low, the alfacalcidol molecules cannot be fully encapsulated or interact, resulting in incomplete cocrystal formation. This may lead to a mixture of free alfacalcidol and the cocrystal, rather than a simple homogeneous phase. In addition, free alfacalcidol may cause phase separation, precipitation, or uneven crystallinity, affecting the homogeneity of the formulation. The improvement in the solubility of the cocrystal depends on the synergistic effect of the cocrystal ligand; if the ratio is insufficient, it may not significantly improve the dissolution performance of alfacalcidol. If the cocrystal ligand ratio is too high, the excess cocrystal ligand may exist in a free form, leading to an increase in impurities in the formulation, which may affect the purity of the drug or cause side reactions.

[0034] Furthermore, in step (1), after alfacalcidol and the cocrystal ligand are completely dissolved in the reaction solvent to form a clear solution of alfacalcidol and the cocrystal ligand, 0.1 to 10 times the volume of purified water is added dropwise under stirring conditions.

[0035] Furthermore, the reaction solvent in step (1) is one or any two of ethanol, methanol, isopropanol and acetonitrile, preferably ethanol.

[0036] Furthermore, in step (1), the volume-to-mass ratio of the reaction solvent to alfacalcidol is 0.1~100 mL / g. Insufficient reaction solvent may lead to incomplete dissolution, insufficient contact between the cocrystallized ligand and the drug molecule, and a low cocrystallization yield. Excessive reaction solvent, while ensuring sufficient dissolution, results in high production costs, potentially slow cocrystallization rates, and the introduction of impurities or solvent residue. More preferably, the volume-to-mass ratio of the reaction solvent to alfacalcidol is 0.1~65 mL / g.

[0037] Furthermore, the low temperature or room temperature conditions in step (1) are -20℃ to 25℃, ensuring that no more crystals precipitate; the drying conditions are 30 to 50℃, drying until the moisture content is <1.0%.

[0038] Furthermore, in step (2), the stirring speed is 100~2000 rpm and the stirring time is 10~120 min.

[0039] The present invention uses electron microscopy and differential scanning calorimetry (DSC) to characterize the prepared alfacalcidol eutectic. The electron microscopy image shows the formation of new crystals (different from alfacalcidol and the eutectic ligand), and the DSC shows that the eutectic has only one characteristic melting peak, which further confirms the formation of the eutectic.

[0040] The mechanism by which the alfacalcidol eutectic improves solubility in this invention is as follows:

[0041] (1) Crystal structure reconstruction: When the eutectic is formed, alfacalcidol and the eutectic ligand are combined through non-covalent bonds such as hydrogen bonds and π-π stacking, which changes the crystal stacking mode, reduces the lattice energy, thereby reducing the energy required for drug molecules to release from the lattice and improving apparent solubility.

[0042] (2) Introducing hydrophilic ligands: The eutectic ligands are hydrophilic, which can improve the wettability of the overall eutectic, enhance the penetration of water molecules, and thus improve solubility.

[0043] The mechanism by which the alfacalcidol eutectic prepared in this invention promotes stability is as follows:

[0044] (1) Steric hindrance effect: The eutectic ligands encapsulate the active groups (such as hydroxyl groups) of alfacalcidol through intermolecular interactions (such as hydrogen bond networks), reducing its contact with light, oxygen and moisture in the environment, thereby delaying degradation reactions such as photo-oxidation and hydrolysis.

[0045] (2) Suppressing crystal transformation: Eutectic may form a more compact packing pattern, reduce lattice defects, reduce hygroscopicity or suppress amorphous phase transformation, thereby improving physical stability.

[0046] Compared with the prior art, the beneficial effects of the present invention are:

[0047] (1) Compared with the alfacalcidol raw material, the alfacalcidol cocrystal prepared by the present invention has high solubility and good stability, and exhibits good stability under high temperature, high humidity and strong light conditions. In addition, the preparation method of the alfacalcidol cocrystal described in the present invention is simple and easy to implement, does not change the properties of the active pharmaceutical ingredient itself, has strong process operability, low cost, and is suitable for industrial production;

[0048] (2) Compared with soft capsules prepared by conventional plasticizers, the present invention uses a novel compound plasticizer, which combines glycerol, erythritol and glycine in a certain proportion as the soft capsule shell, to prevent capsule adhesion and shorten the drying time of soft capsules. It not only improves the barrier properties of gelatin film, but also increases the antioxidant properties of gelatin film, inhibits the generation of aldehydes in the capsule shell, and delays the cross-linking aging of soft capsule shell, thereby improving the problems of disintegration and delayed dissolution of gelatin soft capsules after long-term storage, and improving the efficacy and product stability.

[0049] (3) The preparation method of the alfacalcidol soft capsule composition of the present invention is simple, easy to implement, low in cost, and easy to scale up for production. Attached Figure Description

[0050] Figure 1 Comparison of the results of alfacalcidol active pharmaceutical ingredient, cocrystal ligand nicotinamide, and alfacalcidol-nicotinamide cocrystal prepared in Example 1 under an electron microscope (200×), where A is an electron microscope image of alfacalcidol active pharmaceutical ingredient, B is an electron microscope image of cocrystal ligand nicotinamide, and C is an electron microscope image of alfacalcidol-nicotinamide cocrystal prepared in Example 1;

[0051] Figure 2 The differential scanning calorimetry (DSC) analysis chromatogram of the alfacalcidol-nicotinamide cocrystal prepared in Example 1 is shown below.

[0052] Figure 3 This image shows the disintegration phenomenon of alfacalcidol soft capsules under strong light irradiation for 20 days. In this image, A represents the reference formulation, Ivan. ® (LEO Pharma A / S), B is the alfacalcidol soft capsule prepared in Example 1;

[0053] Figure 4 This image shows the rupture phenomenon of alfacalcidol soft capsules under strong light irradiation for 20 days. In this image, A represents the reference formulation, Ivan. ® (LEO Pharma A / S), B is the alfacalcidol soft capsule prepared in Example 1. Detailed Implementation

[0054] To better understand the present invention, the following description, in conjunction with embodiments and accompanying drawings, further clarifies the content of the invention. Obviously, the described embodiments are merely some, not all, of the embodiments of the present invention. The specific embodiments described herein are only used to explain the present invention and are not intended to limit the invention. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0055] To better understand the invention and not to limit its scope, all figures indicating amounts, percentages, and other numerical values ​​used in this application should, in all cases, be understood to be modified by the word "approximately." Each numerical parameter should at least be considered as obtained based on reported significant figures and through conventional rounding methods.

[0056] Example 1: An alfacalcidol soft capsule composition and its preparation method

[0057] (1) Preparation of alfacalcidol-nicotinamide eutectic

[0058] Weigh 1 mmol (400 mg) of alfacalcidol powder (purity: 100.30%) and 1 mmol (122 mg) of nicotinamide into a beaker. Add 5.06 mL of ethanol to the beaker and dissolve completely to obtain a clear solution. While stirring at room temperature, slowly add 2.3 mL of purified water dropwise to crystallize. Cool the resulting milky white suspension at 2-8 °C. After 24 hours, white crystals are obtained. Dry under vacuum at 40 °C until the moisture content is less than 1.0%, which is the alfacalcidol-nicotinamide cocrystal.

[0059] Figure 1 Comparative electron microscope (200×) images of alfacalcidol active pharmaceutical ingredient, cocrystal ligand nicotinamide, and the alfacalcidol-nicotinamide cocrystal prepared in Example 1. In image A, the alfacalcidol active pharmaceutical ingredient shows rod-shaped crystals; in image B, the cocrystal ligand nicotinamide also shows rod-shaped crystals; and in image C, the alfacalcidol-nicotinamide cocrystal from Example 1 shows numerous tiny needle-like crystals. The comparison shows that image C demonstrates the formation of a new crystal form, and the reduction in cocrystal size indicates a reconstruction of the molecular packing structure.

[0060] Figure 2 The differential scanning calorimetry (DSC) analysis chromatogram of the alfacalcidol-nicotinamide eutectic prepared in Example 1 shows that the alfacalcidol eutectic has a characteristic melting peak with a peak temperature of 144.52 ± 0.2 °C.

[0061] (2) Preparation of alfacalcidol contents solution

[0062] Table 1. Components of the soft capsule contents

[0063] Components Prescription quantity Alfacalcidol pure substance 2.5mg Sesame oil 0.5kg medium-chain triglycerides 0.5kg

[0064] The prescribed amount of alfacalcidol-nicotinamide cocrystal was added to a mixture of medium-chain triglycerides and sesame oil, and stirred at 800 rpm for 30 minutes to obtain a colorless to pale yellow oily solution of alfacalcidol contents.

[0065] (3) Preparation of alfacalcidol cocrystal soft capsules

[0066] Table 2. Components of the soft capsule shell

[0067] Components Prescription quantity gelatin 12.5kg glycerin 3.75kg Erythritol 2kg glycine 0.4kg Purified water 12.5kg Titanium dioxide 0.1875kg

[0068] ① Disperse the prescribed amount of titanium dioxide evenly in 1.25 kg of purified water and set aside; then completely dissolve erythritol and glycine in water, then dissolve glycerol completely in a gelling tank, then add the titanium dioxide suspension, stir and disperse evenly, and heat in a water bath to 60℃; after adding gelatin, heat to 70℃, vacuum, vacuum degree ≤ -0.08Mpa, after the weight of the gel solution in the gelling tank decreases by 3~10%, stop vacuuming, filter, and keep warm at 55℃ to obtain the soft capsule material.

[0069] ② Capsule compression: The temperature and humidity of the preparation room are controlled to be below 25℃ and below 45%; the temperature of the glue box is 55℃ and the temperature of the sprayer is 40℃; the thickness of the glue sheet is controlled to be maintained at 0.7~0.8mm. The alfacalcidol contents are filled into the feed hopper, and soft capsules are compressed. After shaping at 20~22℃ and drying at 24~29℃, alfacalcidol soft capsules are obtained. Each soft capsule contains 100mg of contents and 0.25μg of pure alfacalcidol.

[0070] Example 2: An alfacalcidol soft capsule composition and its preparation method

[0071] (1) Preparation of alfacalcidol-nicotinamide eutectic

[0072] Weigh 1 mmol (400 mg) of alfacalcidol powder (purity: 100.30%) and 1.3 mmol (158 mg) of nicotinamide into a beaker. Add 7.8 mL of ethanol to the beaker and dissolve completely to obtain a clear solution. Slowly add 3.3 mL of purified water dropwise while stirring at room temperature to induce crystallization. Cool the resulting milky white suspension at 2-8°C. After 24 hours, white crystals are obtained. Dry under vacuum at 40°C until the moisture content is below 1.0% to obtain the alfacalcidol-nicotinamide cocrystal.

[0073] (2) Preparation of alfacalcidol contents solution

[0074] Table 3. Components of the soft capsule contents

[0075] Components Prescription quantity Alfacalcidol pure substance 2.5mg medium-chain triglycerides 1.0kg

[0076] The prescribed amount of alfacalcidol-nicotinamide cocrystal was added to medium-chain triglycerides, and the mixture was stirred at 1000 rpm for 30 minutes to obtain a colorless to slightly yellow oily solution of alfacalcidol contents.

[0077] (3) Preparation of alfacalcidol soft capsules

[0078] Table 4. Components of the soft capsule shell

[0079] Components Prescription quantity gelatin 12.5kg glycerin 3.625kg Erythritol 1.5875kg glycine 0.55kg Purified water 14.9kg Titanium dioxide 0.2375kg

[0080] ① Disperse the prescribed amount of titanium dioxide evenly in 1.49 kg of purified water and set aside. First, completely dissolve erythritol and glycine in water, then dissolve glycerol completely in a gelling tank, then add the titanium dioxide suspension, stir and disperse evenly, and heat in a water bath at 60°C. After adding gelatin, heat to 70°C, and apply vacuum (≤-0.08 MPa). After the weight of the gelling solution in the gelling tank decreases by 3-10%, stop applying vacuum, filter, and keep warm at 55°C to obtain the soft capsule material.

[0081] ② Capsule compression: The temperature and humidity of the preparation chamber are controlled to be below 25℃ and below 45%; the temperature of the glue box is 55℃ and the temperature of the sprayer is 40℃; the thickness of the glue sheet is controlled to be maintained at 0.7~0.8mm. Alfacalcidol solution is filled into the feed hopper for soft capsule compression, and the capsules are shaped at 20~23℃ and dried at 25~30℃ to obtain alfacalcidol soft capsules. Each soft capsule contains 100mg of contents and 0.25μg of pure alfacalcidol.

[0082] Example 3: An alfacalcidol soft capsule composition and its preparation method

[0083] (1) Preparation of alfacalcidol-nicotinamide eutectic

[0084] Weigh 1 mmol (400 mg) of alfacalcidol powder (purity: 100.30%) and 2 mmol (244 mg) of nicotinamide into a beaker. Add 6.84 mL of ethanol to the beaker and dissolve completely to obtain a clear solution. Slowly add 2.7 mL of purified water dropwise while stirring at room temperature to induce crystallization. Cool the resulting milky white suspension at 2-8°C. After 24 hours, white crystals are obtained. Dry under vacuum at 40°C until the moisture content is below 1.0% to obtain the alfacalcidol-nicotinamide cocrystal.

[0085] (2) Preparation of alfacalcidol contents solution

[0086] Table 5. Components of the soft capsule contents

[0087] Components Prescription quantity Alfacalcidol pure substance 10mg Sesame oil 1.0kg

[0088] The prescribed amount of alfacalcidol-nicotinamide cocrystal was added to sesame oil and stirred at 2000 rpm for 25 minutes to obtain a colorless to pale yellow oily alfacalcidol contents solution.

[0089] (3) Preparation of alfacalcidol soft capsules

[0090] Table 6. Components of the soft capsule shell

[0091] Components Prescription quantity gelatin 12.5kg glycerin 3.906kg Erythritol 2.344kg glycine 0.36kg Purified water 13.8kg Titanium dioxide 0.195kg

[0092] ① Disperse the prescribed amount of titanium dioxide evenly in 1.38 kg of purified water and set aside. First, completely dissolve erythritol and glycine in water, then dissolve glycerol completely in a gelling tank, then add the titanium dioxide suspension, stir and disperse evenly, and heat in a water bath at 60°C. After adding gelatin, heat to 70°C, and apply vacuum (≤-0.08 MPa). After the weight of the gelling solution in the gelling tank decreases by 3-10%, stop applying vacuum, filter, and keep warm at 55°C to obtain the soft capsule material.

[0093] ② Capsule compression: The temperature and humidity of the preparation chamber are controlled to be below 25℃ and below 45%; the temperature of the glue box is 55℃ and the temperature of the sprayer is 40℃; the thickness of the glue sheet is controlled to be maintained at 0.7~0.8mm. Alfacalcidol solution is filled into the feed hopper for soft capsule compression, and the capsules are shaped at 20~23℃ and dried at 25~29℃ to obtain alfacalcidol soft capsules. Each soft capsule contains 100mg of contents, including 1.0μg of pure alfacalcidol.

[0094] Example 4: An alfacalcidol soft capsule composition and its preparation method

[0095] (1) Preparation of alfacalcidol-nicotinamide eutectic

[0096] Weigh 1 mmol (400 mg) of alfacalcidol powder (purity: 100.30%) and 1.3 mmol (158 mg) of nicotinamide into a beaker. Add 7.8 mL of ethanol to the beaker and dissolve completely to obtain a clear solution. Slowly add 3.3 mL of purified water dropwise while stirring at room temperature to induce crystallization. Cool the resulting milky white suspension at 2-8°C. After 24 hours, white crystals are obtained. Dry under vacuum at 40°C until the moisture content is below 1.0% to obtain the alfacalcidol-nicotinamide cocrystal.

[0097] (2) Preparation of alfacalcidol contents solution

[0098] Table 7. Components of the soft capsule contents

[0099] Components Prescription quantity Alfacalcidol pure substance 5mg olive oil 1.0kg

[0100] Add the prescribed amount of alfacalcidol-nicotinamide cocrystal to olive oil, stir at 800 rpm for 45 minutes to obtain a colorless to pale yellow oily solution of alfacalcidol contents.

[0101] (3) Preparation of alfacalcidol soft capsules

[0102] Table 8. Components of the soft capsule shell

[0103] Components Prescription quantity gelatin 12.5kg glycerin 3.625kg Erythritol 1.5875kg glycine 0.55kg Purified water 14.9kg Titanium dioxide 0.2375kg

[0104] ① Disperse the prescribed amount of titanium dioxide evenly in 1.49 kg of purified water and set aside. First, completely dissolve erythritol and glycine in water, then dissolve glycerol completely in a gelling tank, then add the titanium dioxide suspension, stir and disperse evenly, and heat in a water bath at 60°C. After adding gelatin, heat to 70°C, and apply vacuum (≤-0.08 MPa). After the weight of the gelling solution in the gelling tank decreases by 3-10%, stop applying vacuum, filter, and keep warm at 55°C to obtain the soft capsule material.

[0105] ② Capsule compression: The temperature and humidity of the preparation chamber are controlled to be below 25℃ and below 45%; the temperature of the glue box is 55℃ and the temperature of the sprayer is 40℃; the thickness of the glue sheet is controlled to be maintained at 0.7~0.8mm. Alfacalcidol solution is filled into the feed hopper for soft capsule compression, and the capsules are shaped at 20~23℃ and dried at 25~30℃ to obtain alfacalcidol soft capsules. Each soft capsule contains 100mg of contents, including 0.5μg of pure alfacalcidol.

[0106] Comparative Example 1: An Alfacalcidol Soft Capsule Composition and Its Preparation Method

[0107] (1) Preparation of alfacalcidol-nicotinamide eutectic

[0108] Weigh 1 mmol (400 mg) of alfacalcidol powder (purity: 100.30%) and 1.5 mmol (183 mg) of nicotinamide into a beaker. Add 5.83 mL of ethanol to the beaker and dissolve completely to obtain a clear solution. Slowly add 2.14 mL of purified water dropwise while stirring at room temperature to induce crystallization. Cool the resulting milky white suspension at 2-8 °C. After 24 hours, white crystals are obtained. Dry under vacuum at 40 °C until the moisture content is below 1.0% to obtain the alfacalcidol-nicotinamide cocrystal.

[0109] (2) Preparation of alfacalcidol contents solution

[0110] Table 9. Components of the soft capsule contents

[0111] Components Prescription quantity Alfacalcidol pure substance 10mg Sesame oil 0.5kg medium-chain triglycerides 0.5kg

[0112] The prescribed amount of alfacalcidol-nicotinamide cocrystal was added to a mixture of sesame oil and medium-chain triglycerides. The mixture was stirred at 1000 rpm for 20 minutes to obtain a colorless to pale yellow oily solution of alfacalcidol contents.

[0113] (3) Preparation of alfacalcidol soft capsules

[0114] Table 10 Components of Soft Capsule Shells

[0115] Components Prescription quantity gelatin 12.5kg glycerin 5.5kg Purified water 13.0kg Titanium dioxide 0.1625kg

[0116] ① Disperse the prescribed amount of titanium dioxide evenly in 1.3 kg of purified water and set aside. Place the purified water in a gelling tank, add glycerin to dissolve it completely, then add the titanium dioxide suspension, stir and disperse evenly, and heat in a water bath at 60°C. After adding gelatin, heat to 70°C, and apply a vacuum with a vacuum degree ≤ -0.08 MPa. After the weight of the gelling solution in the gelling tank decreases by 3~10%, stop applying the vacuum, filter, and keep warm at 55°C to obtain the soft capsule material.

[0117] ② Capsule compression: The temperature and humidity of the preparation chamber are controlled to be below 25℃ and below 45%; the temperature of the glue box is 55℃ and the temperature of the sprayer is 39℃; the thickness of the glue sheet is controlled to be maintained at 0.7~0.8mm. Alfacalcidol solution is filled into the feed hopper for soft capsule compression, and the capsules are shaped at 21~24℃ and dried at 25~30℃ to obtain alfacalcidol soft capsules. Each soft capsule contains 100mg of contents and 1.0μg of pure alfacalcidol.

[0118] Comparative Example 2: An Alfacalcidol Soft Capsule Composition and Its Preparation Method

[0119] (1) Preparation of alfacalcidol-nicotinamide eutectic

[0120] Weigh 1 mmol (400 mg) of alfacalcidol powder (purity: 100.30%) and 1 mmol (122 mg) of nicotinamide into a beaker. Add 5.06 mL of ethanol to the beaker and dissolve completely to obtain a clear solution. Slowly add 2.3 mL of purified water dropwise while stirring at room temperature to induce crystallization. Cool the resulting milky white suspension at 2-8°C for 24 hours to obtain white crystals. Dry under vacuum at 30°C until the moisture content is less than 1.0%, thus obtaining the alfacalcidol-nicotinamide cocrystal.

[0121] (2) Preparation of alfacalcidol contents solution

[0122] Table 11 Components of the Soft Capsule Contents

[0123] Components Prescription quantity Alfacalcidol pure substance 2.5mg medium-chain triglycerides 1.0kg

[0124] The prescribed amount of alfacalcidol-nicotinamide cocrystal was added to the medium-chain triglyceride, and the mixture was stirred at 1200 rpm for 35 minutes to obtain a colorless to slightly yellow oily solution of alfacalcidol contents.

[0125] (3) Preparation of alfacalcidol soft capsules

[0126] Table 12 Components of Soft Capsule Shells

[0127] Components Prescription quantity gelatin 12.5kg glycerin 6.0kg Erythritol 2.83kg Purified water 12.5kg Titanium dioxide 0.2kg

[0128] ① Disperse the prescribed amount of titanium dioxide evenly in 1.25 kg of purified water and set aside. Place the purified water in a gelling tank, add glycerin and erythritol to dissolve, then add the titanium dioxide suspension, stir and disperse evenly, and heat in a water bath at 60°C. After adding gelatin, heat to 70°C, and apply a vacuum with a vacuum degree ≤ -0.08 MPa. After the weight of the gelling solution in the gelling tank decreases by 3~10%, stop applying the vacuum, filter, and keep warm at 55°C to obtain the soft capsule material.

[0129] ② Capsule compression: The temperature and humidity of the preparation chamber are controlled to be below 25℃ and below 45%; the temperature of the glue box is 55℃ and the temperature of the sprayer is 40℃; the thickness of the glue sheet is controlled to be maintained at 0.7~0.8mm. Alfacalcidol solution is filled into the feed hopper for soft capsule compression, and the capsules are shaped at 21~24℃ and dried at 25~30℃ to obtain alfacalcidol soft capsules. Each soft capsule contains 100mg of contents and 0.25μg of pure alfacalcidol.

[0130] Comparative Example 3: An Alfacalcidol Soft Capsule Composition and Its Preparation Method

[0131] (1) Preparation of alfacalcidol contents solution

[0132] Table 13 Components of the Soft Capsule Contents

[0133] Components Prescription quantity Alfacalcidol 5mg Sesame oil 1.0kg

[0134] Add the prescribed amount of alfacalcidol to sesame oil, stir at 1000 rpm, at a temperature below 25°C, away from light, and stir for 120 minutes until completely dissolved to obtain a colorless to pale yellow oily alfacalcidol solution.

[0135] (2) Preparation of alfacalcidol soft capsules

[0136] Table 14 Components of Soft Capsule Shells

[0137] Components Prescription quantity gelatin 12.5kg glycerin 5.529kg glycine 0.56kg Purified water 12.02kg Titanium dioxide 0.15kg

[0138] ① Disperse the prescribed amount of titanium dioxide evenly with 1.202 kg of purified water and set aside. Place the purified water in a gelling tank, add glycerol and glycine to dissolve, then add the titanium dioxide suspension, stir and disperse evenly, and heat in a water bath at 60℃. After adding gelatin, heat to 70℃, and apply vacuum with a vacuum degree ≤ -0.08 MPa. After the weight of the gelling solution in the gelling tank decreases by 3~10%, stop applying vacuum, filter, and keep warm at 55℃ to obtain the soft capsule material.

[0139] ② Capsule compression: The temperature and humidity of the preparation chamber are controlled to be below 25℃ and below 45%; the temperature of the glue box is 55℃ and the temperature of the sprayer is 40℃; the thickness of the glue sheet is controlled to be maintained at 0.7~0.8mm. Alfacalcidol solution is filled into the feed hopper for soft capsule compression, and the capsules are shaped at 21~24℃ and dried at 25~30℃ to obtain alfacalcidol soft capsules. Each soft capsule contains 100mg of contents, including 0.5μg of alfacalcidol.

[0140] Comparative Example 4: An Alfacalcidol Soft Capsule Composition and Its Preparation Method

[0141] (1) Preparation of alfacalcidol contents solution

[0142] Table 15 Components of the Soft Capsule Contents

[0143] Components Prescription quantity Alfacalcidol 2.5mg medium-chain triglycerides 1.0kg

[0144] The prescribed amount of alfacalcidol was added to the medium-chain triglycerides, stirred at 1000 rpm, at a temperature below 25°C, protected from light, for 150 min, to obtain a colorless to slightly yellow oily solution of alfacalcidol.

[0145] (3) Preparation of alfacalcidol soft capsules

[0146] Table 16 Components of Soft Capsule Shells

[0147] Components Prescription quantity gelatin 12.5kg glycerin 5.8kg Purified water 12.5kg Titanium dioxide 0.25kg

[0148] ① Disperse the prescribed amount of titanium dioxide evenly in 1.25 kg of purified water and set aside. Place the purified water in a gelling tank, add glycerin and stir until well mixed, then add the titanium dioxide suspension and stir until evenly dispersed. Heat in a water bath to 60°C. After adding gelatin, heat to 70°C, and apply a vacuum with a vacuum degree ≤ -0.08 MPa. After the weight of the gelling liquid in the gelling tank decreases by 3~10%, stop applying the vacuum, filter, and keep warm at 55°C to obtain the soft capsule material.

[0149] ② Capsule compression: The temperature and humidity of the preparation chamber are controlled to be below 25℃ and below 45%; the temperature of the glue box is 55℃ and the temperature of the sprayer is 39℃; the thickness of the glue sheet is controlled to be maintained at 0.7~0.8mm. Alfacalcidol solution is filled into the feed hopper for soft capsule compression, and the capsules are shaped at 21~24℃ and dried at 25~30℃ to obtain alfacalcidol soft capsules. Each soft capsule contains 100mg of contents, including 0.25μg of alfacalcidol.

[0150] The inventors compared the embodiments and comparative examples, and the specific results are as follows:

[0151] (1) Comparative Example 1: Soft capsules were prepared using the eutectic prepared in Example 1. The difference is that the soft capsule shell plasticizer used in the comparative example is ordinary plasticizer-glycerin, which has the following characteristics: long drying time, capsule adhesion during drying, product instability, cross-linking aging after long-term storage, and affecting drug release.

[0152] (2) Comparative Example 2, the contents are alfacalcidol-nicotinamide cocrystal. The difference is that glycine (as an antioxidant / stabilizer) was not added to the soft capsule shell. Its long-term stability and anti-crosslinking aging effect are not obvious, and long-term storage may affect drug release.

[0153] (3) Comparative Example 3: The active pharmaceutical ingredient was not treated in any way, and there were problems such as instability of the active pharmaceutical ingredient, long dissolution time, and uneven dissolution. The capsule shell was similar to that of Comparative Example 2, except that a small amount of glycine was added to the soft capsule shell, but no erythritol was added. Its disadvantages are that slight adhesion occurs during the drying process of the soft capsule, the drying time is long, which is not conducive to the stability of the alfacalcidol active pharmaceutical ingredient; and slight cross-linking and aging may also occur during long-term storage.

[0154] (4) Comparative Example 4: The active pharmaceutical ingredient was similar to that of Comparative Example 3 and was not treated in any way. It had problems such as long dissolution time, uneven dissolution, and content degradation. In addition, the capsule shell was made of conventional plasticizer glycerin, which caused the capsules to stick together during the drying process, the drying time to be long, the active pharmaceutical ingredient to degrade during the drying process, the soft capsules to be unstable after long-term storage, the capsule shell to cross-link and age, and the drug release to be affected.

[0155] The following experimental example will further verify this:

[0156] Experimental Example 1: Stability Study of Alfacalcidol Eutectic

[0157] The alfacalcidol cocrystal products prepared in Examples 1-3 of this invention, as well as the alfacalcidol active pharmaceutical ingredient, were investigated under high temperature, high humidity, and strong light irradiation for 10 days. The influencing factor test followed the "Guidelines for Stability Testing of Raw Materials and Preparations" (Part IV, 2020 Edition of the Chinese Pharmacopoeia). 100 mg samples were placed under high temperature (60±2℃), high humidity (95%±5%RH), and strong light (4500lx±500lx) conditions, and samples were taken at 0, 5, and 10 days to examine the appearance and purity. The results are shown in Table 17.

[0158] Table 17 Summary of Alfacalcidol Cocrystallization Stability Study Results

[0159]

[0160] The results showed that the formation of a cocrystal between alfacalcidol and the cocrystal ligand could effectively reduce the degradation rate of alfacalcidol active pharmaceutical ingredient and improve the stability of the product in high temperature, high humidity and strong light irradiation environments.

[0161] Experimental Example 2: Gelatin Equilibrium Swelling Amount S eq Measurement

[0162] Gelatin is a macromolecular hydrophilic colloidal compound. When gelatin swells to its limit, the equilibrium swelling amount corresponds to the degree of cross-linking; the greater the degree of cross-linking, the smaller the equilibrium swelling amount. Therefore, the equilibrium swelling amount can be used to indirectly evaluate the degree of cross-linking of gelatin. The finite swelling process of gelatin conforms to the second-order kinetic equation ①: ds / dt=k(S eq -S) 2 In the formula: ds / dt is the swelling rate at a certain time, k is the swelling rate constant, and S eq To balance the swelling amount, S is the expansion rate. Where S = (W s -W i ) / W i In the formula: W s W is the weight of the film at time t. i Let be the initial dry weight of the rubber. Integrating and simplifying formula ①, we obtain formula ②: t / s = A + Bt, where A = 1 / (k × S) eq 2 B=1 / S eq Therefore, S eq The value of can be determined by the slope B of the line t / s→t.

[0163] Take films of the same size and weight (0.8 mm thick, 1.5 cm in diameter) prepared in Examples 1-3 and Comparative Examples 1-4, place them in 100 mL beakers, add distilled water, and remove them at 20°C for 0, 1, 2, 2.5, 3, 3.5, and 4 hours. Wipe them clean with filter paper and weigh them accurately. Take another 3 films and dry them at 105°C to constant weight. Measure the initial dry weight of the films and calculate the swelling rate of the films at different time points. Calculate the equilibrium swelling amount according to formula ②.

[0164] The greater the degree of cross-linking, the smaller the equilibrium swelling amount; the smaller the degree of cross-linking, the larger the equilibrium swelling amount. The equilibrium swelling amounts S of Examples 1-3 and Comparative Examples 1-4 are shown in Table 18. eq Test results show that conventional gelatin soft capsule shells with only glycerin added as a plasticizer have S eq The relatively small size indicates a relatively high degree of cross-linking of the capsule shell; adding erythritol or glycine alone, S eq A slight increase indicates a relatively reduced degree of cross-linking in the capsule shell; however, after simultaneously adding erythritol and glycine to the soft capsule shell, S... eq The increase in volume and decrease in the degree of cross-linking of the capsule shell indicate that the compound plasticizer of glycerol, erythritol and glycine can significantly reduce the cross-linking aging of gelatin soft capsule shells to a certain extent and improve product stability.

[0165] Table 18 Gelatin Soft Capsules with Different Formulations (S) eq Measurement results

[0166] .

[0167] Experimental Example 3: Determination of Peroxide Value in Soft Capsules

[0168] Oil oxidation is the main cause of rancidity. To verify the antioxidant properties of the alfacalcidol soft capsules of the present invention, the peroxide value of the soft capsules prepared in Examples 1-3 and Comparative Examples 1-4 was determined. The soft capsules prepared in Examples 1-3 and Comparative Examples 1-4 were placed in a constant temperature incubator at 30℃±2℃ and 65%±5%RH for one month. The peroxide value of the contents of the soft capsules in Examples 1-3 and Comparative Examples 1-4 was then determined according to the first titration method of GB 5009.227-2023 "National Food Safety Standard - Determination of Peroxide Value in Food". The determination method was as follows: Under light-protected conditions, the soft capsules were longitudinally cut open, and the contents of each sample were squeezed out and thoroughly mixed. 3g of the contents were weighed into a 250mL iodine flask, and 30mL of a chloroform-glacial acetic acid mixture was added. The flask was gently shaken to completely dissolve the sample. 1mL of saturated potassium iodide solution was accurately added, the cap was tightly sealed, and the flask was gently shaken for 30 seconds. After standing in the dark for 3 minutes, 100mL of deionized water was added, and the mixture was shaken well. Immediately afterward, the solution was titrated with sodium thiosulfate until a pale yellow color was reached. Then, 1mL of starch indicator was added, and the titration continued while shaking vigorously until the blue color disappeared. A blank test was performed simultaneously, and the peroxide value was determined colorimetrically. The test results are shown in Table 19 below.

[0169] Table 19 Results of Peroxide Value Determination for Soft Capsules

[0170] sample Peroxide value (meq / kg) Example 1 0.32 Example 2 0.38 Example 3 0.45 Comparative Example 1 0.97 Comparative Example 2 0.85 Comparative Example 3 0.89 Comparative Example 4 1.01

[0171] The lower the peroxide value, the stronger the antioxidant performance and the better the product stability; conversely, the higher the peroxide value, the weaker the antioxidant performance and the worse the product stability. Comparative peroxide value test results from Examples 1-3 and Comparative Examples 1-4 show that the prepared alfacalcidol cocrystal and the addition of the novel compound plasticizer of glycerol, erythritol, and glycine to the soft capsule shell significantly improved the antioxidant properties of the oils in the soft capsules, further improving the product stability after long-term storage.

[0172] Experiment Example 4: Accelerated Stability Experiment

[0173] The alfacalcidol soft capsules prepared in Examples 1-3 and Comparative Examples 1-4 of this invention were investigated under accelerated testing conditions for 6 months. The accelerated testing followed the "Guidelines for Stability Testing of Raw Materials and Preparations" (Part IV, 2020 Edition of the Chinese Pharmacopoeia). Samples were placed at 40℃±2℃ and 75%±5%RH for 6 months, and samples were taken at 0, 1, 2, 3, and 6 months to test for properties, content, and disintegration time.

[0174] The results of Examples 1-3 and Comparative Examples 1-4 (see Table 20) show that the content of the products in Comparative Examples 1-4 decreased significantly with the increase of acceleration time, and the disintegration time was prolonged; while the properties, content and disintegration time of the products obtained in Examples 1-3 of the present invention did not change significantly, indicating that the addition of the novel compound plasticizer can increase the stability of the products.

[0175] Table 20 Comparison of Product Accelerated Stability

[0176] .

[0177] Experiment Example 5: Stability Experiment under Strong Light

[0178] The alfacalcidol soft capsules prepared in Examples 1-2 of this invention and the reference formulation Ivan ® (LEO PharmaA / S) The sample was sealed in a transparent bottle to examine its stability. The strong light test was performed according to the "Guidelines for Stability Testing of Raw Materials and Preparations" in Part IV of the 2020 edition of the Chinese Pharmacopoeia, with the sample exposed to strong light at an illuminance of 5000±500 Lux, and the total illuminance of the light source not less than 1.2×10⁻⁶. 6 The samples were placed under Lux·hr conditions for 20 days, and samples were taken at 0, 10 and 20 days to test the properties, content, disintegration and breakage time.

[0179] Examples 1-2 containing alfacalcidol and the reference formulation Ivan ® The results from (LEO Pharma A / S) (see Table 21) show that, with prolonged light exposure, the efficacy of Examples 1-3 and the reference formulation Ivan increased. ® The product properties and content of (LEO Pharma A / S) showed no significant changes; however, their disintegration and rupture times were correspondingly prolonged. Compared to Examples 1-2, the reference formulation, Ivan, showed no significant changes. ® (LEO Pharma A / S) Products exhibit a swollen, thin, tough, and elastic water-insoluble film on the surface of soft capsules as the exposure time increases. This film prolongs the disintegration and rupture time of the soft capsules in disintegration and rupture tests. However, this phenomenon is not observed in Examples 1-2, which incorporate a novel compound plasticizer. This indicates that the novel compound plasticizer can delay the aging of the capsule shell, thereby improving problems such as delayed disintegration, rupture, and dissolution of soft capsules after long-term storage.

[0180] Figure 3 The disintegration test results of alfacalcidol soft capsules under strong light irradiation for 20 days are shown. In this test, A represents the reference formulation, Ivan. ® (LEO Pharma A / S) The disintegration test of the sample under strong light irradiation for 20 days showed that a layer of insoluble cross-linked film appeared on the soft capsule shell; B is the disintegration test of the sample of Example 1 under strong light irradiation for 20 days.

[0181] The results showed that after 20 days of strong light irradiation, the soft capsules of Example 1 became moistened and floated on the surface of the medium. The capsule shell gradually softened, partially ruptured, and the contents slowly seeped out. Finally, the capsule shell completely dissolved or disintegrated, and the remaining shell fragments passed completely through the disintegration apparatus sieve. The reference formulation, after strong light irradiation, showed cross-linking, and a wrinkled, water-insoluble gelatin film appeared on the surface of the capsule shell, making it difficult for the shell to disintegrate or disintegrate.

[0182] Figure 4 The image shows the rupture phenomenon of alfacalcidol soft capsules under strong light irradiation for 20 days. In this image, A represents the reference formulation, Ivan. ® (LEO Pharma A / S) The test phenomenon of sample rupture after 20 days of strong light irradiation for 1.0 h: a dense water-insoluble film appeared on the surface of the soft capsule, indicating that the soft capsule shell was severely cross-linked; B is the sample rupture test phenomenon of Example 1 under strong light irradiation for 20 days.

[0183] The results showed that after 20 days of strong light irradiation, the soft capsules of Example 1 became wetted upon placement in a settling basket, and the capsule shell began to gradually dissolve. Subsequently, "transparent pearl" droplets appeared on the surface of the capsule shell, gradually increasing in size and number until the soft capsule shell completely dissolved, and the contents floated on the surface of the medium. In contrast, the reference formulation exhibited severe cross-linking of the capsule shell after strong light irradiation, resulting in a swollen, thin, tough, and elastic water-insoluble film on the surface of the shell, preventing the contents from flowing out and affecting drug release.

[0184] In summary Figure 3 and 4 The comparison shows that, compared with the reference formulation, the technical solution of the present invention further reduces the risk of light instability of soft capsules and cross-linking of the capsule shell by adding compound plasticizers, improves the storage stability of the product, and enables the product to fully exert its efficacy.

[0185] Table 21 Comparison of Product Stability under Strong Light

[0186]

[0187] In the table, "—*" indicates that the capsule shell has aged and a water-insoluble film has formed on its surface. No time was observed for complete dissolution of the capsule shell.

[0188] The specific embodiments of the present invention have been described above. It should be understood that the present invention is not limited to the specific embodiments described above. Those skilled in the art can make various modifications or variations within the scope of the claims, which do not affect the substantive content of the present invention.

Claims

1. An alfacalcidol soft capsule composition prepared from an alfacalcidol content liquid and a soft capsule shell, characterized in that, The alfacalcidol content medicine liquid comprises alfacalcidol co-crystal and an oily base, wherein the content of alfacalcidol pure substance in the content medicine liquid is 0.0001-0.1% by weight; The co-crystal ligand in the alfacalcidol co-crystal is selected from nicotinamide; The preparation method of the alfacalcidol co-crystal comprises the following steps: separately weighing the powders of alfacalcidol and co-crystal ligand; then dissolving the powders in a reaction solvent to form a clear solution of alfacalcidol and co-crystal ligand; adding purified water in an amount of 0.1-15 times the reaction solvent drop by drop during stirring to induce crystallization; after the dropwise addition is completed, placing the mixed suspension in low temperature or room temperature to induce crystallization, filtering, and drying to obtain white crystalline solid, which is the alfacalcidol co-crystal; wherein the molar ratio of the alfacalcidol to the co-crystal ligand is 1:1, and the reaction solvent is ethanol.

2. The alfacalcidol softgel capsule composition according to claim 1, wherein, The oily base is one or more of medium-chain triglyceride, sesame oil, olive oil, castor oil, oleic acid, and monolinoleate glyceride; the soft capsule shell is composed of gelatin, plasticizer, purified water, and light shielding agent, and the weight ratio of the gelatin, plasticizer, purified water, and light shielding agent is (0.7-1.0):(0.12-0.6):(0.6-1.2):(0.0018-0.09).

3. The alfacalcidol softgel capsule composition according to claim 2, wherein, The oily base is medium-chain triglyceride and / or sesame oil; the weight ratio of the gelatin, plasticizer, purified water, and light shielding agent is 1:0.46:1:0.

015.

4. The alfacalcidol softgel capsule composition according to claim 2 or 3, characterized in that, The plasticizer is a combination of glycerol, erythritol, and glycine, and the weight ratio of the glycerol, erythritol, and glycine is (0.05-5):(0.02-3):(0.001-1.5); the light shielding agent is one or more of titanium dioxide, red iron oxide, and yellow iron oxide.

5. The alfacalcidol softgel capsule composition according to claim 4, wherein, The weight ratio of the glycerol, erythritol, and glycine is 1.875:1:0.2; the light shielding agent is titanium dioxide.

6. A process for preparing the soft capsule composition of alfacalcidol according to claim 1, characterized in that, The method comprises the following steps: (1) Preparation of alfacalcidol co-crystal: separately weighing the powders of alfacalcidol and co-crystal ligand; then dissolving the powders in a reaction solvent to form a clear solution of alfacalcidol and co-crystal ligand; adding purified water in an amount of 0.1-15 times the reaction solvent drop by drop during stirring to induce crystallization; after the dropwise addition is completed, placing the mixed suspension in low temperature or room temperature to induce crystallization, filtering, and drying to obtain white crystalline solid, which is the alfacalcidol co-crystal; wherein the molar ratio of the alfacalcidol to the co-crystal ligand is 1:1, and the reaction solvent is ethanol; (2) Preparation of alfacalcidol content medicine liquid: adding the alfacalcidol co-crystal obtained in step (1) into an oily base, and stirring to obtain the alfacalcidol content medicine liquid; (3) Preparation of alfacalcidol soft capsule: ①Dispersing the light shielding agent in an amount of 10-15% of the prescription amount in water, and then reserving; dissolving the plasticizer in water, and then placing in a gelatinizing tank; adding the suspension of the light shielding agent, and stirring to disperse uniformly; heating to 55-60°C in a water bath; adding gelatin, and heating to 65-72°C; vacuumizing, and the vacuum degree is ≤-0.08 Mpa; after the weight of the gelatinizing tank decreases by 3-10%, filtering, and keeping at 50-60°C, the soft capsule shell is obtained; ii) The alfacalcidol content liquid and soft capsule material are pressed into soft capsules by using a full-automatic soft capsule machine, dried at 18-33°C, and shaped at 20-27°C to obtain alfacalcidol soft capsules.

7. The method of making the alfacalcidol softgel capsule composition according to claim 6, wherein, The specification of the alfacalcidol soft capsules is that each soft capsule contains 0.25 μg or 0.5 μg or 1.0 μg of alfacalcidol pure substance.

8. The method of making the alfacalcidol softgel capsule composition according to claim 6, wherein, The volume / mass ratio of the reaction solvent to alfacalcidol in step (1) is 0.1-100 mL / g; the low-temperature or room-temperature condition in step (1) is -20-25°C, ensuring that no more crystals are precipitated; and the drying condition is 30-50°C, and the drying is stopped until the moisture content is less than 1.0%.

9. The method of making the alfacalcidol softgel capsule composition according to claim 6, wherein, The stirring speed in step (2) is 100-2000 rpm, and the stirring time is 10-120 min.

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