Alfacalcidol soft capsule composition and preparation method thereof

Abstract

The invention relates to the field of novel pharmaceutical preparations, and particularly discloses an alfacalcidol soft capsule composition and a preparation method thereof.The alfacalcidol soft capsule composition is prepared from alfacalcidol content liquid medicine and a soft capsule shell, the soft capsule content liquid medicine comprises alfacalcidol eutectic crystals and an oily matrix, and the oily matrix is a mixture of alfacalcidol eutectic crystals and the oily matrix. The soft capsule shell is prepared from gelatin, a plasticizer, purified water and an opacifying agent; the alfacalcidol soft capsule composition prepared by the invention has high stability, the problems of low solubility, easy oxidation and poor water solubility of raw material medicines are solved, and the preparation method of the alfacalcidol soft capsule composition is simple and easy to implement, low in cost and easy for large-scale production and preparation.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical preparations, and specifically discloses an alfacalcidol soft capsule composition and a preparation method thereof. BACKGROUND

[0002] Alfacalcidol, (5Z,7E)-9,10-secocholesta-5,7,10(19)-trien-1α,3β-diol, has a molecular formula of C 27 H 44 O2, and a structural formula as follows: .

[0003] After oral absorption of alfacalcidol, it is rapidly converted into 1,25-dihydroxyvitamin D3 in the liver, which is an active metabolite of vitamin D3 and can regulate the balance of calcium and phosphorus in the body. Mineral metabolism disorders can occur when there is insufficient endogenous 1,25-dihydroxyvitamin D3 production in the kidneys, which can be seen in renal osteopathy, hypoparathyroidism, and vitamin D-dependent rickets.

[0004] Alfacalcidol is a white crystalline powder, which is easily deteriorated under light, moisture and heat, and is almost insoluble in water. Studies have shown that one of the main reasons why the pharmacological activity of oral solid preparations cannot be fully exerted is that the oral drug has poor water solubility, is easily precipitated in the gastrointestinal environment after oral administration, and has low dissolution, thereby resulting in poor bioavailability. Therefore, a technology that can improve the solubility and stability of alfacalcidol is urgently needed to solve the existing problems of alfacalcidol.

[0005] A pharmaceutical cocrystal refers to a crystal formed by a certain proportion of an active pharmaceutical ingredient (API) and a cocrystal former (CCF) through intermolecular non-covalent interaction. The formation of a cocrystal does not require the generation of a new covalent bond between the API and the CCF, or the destruction of the molecules, but is only a self-assembly after rearrangement of binary or multi-component components. The selection of a suitable cocrystal former and an active pharmaceutical ingredient to form a cocrystal has great potential in enhancing the solubility, permeability, bioavailability and stability of the raw drug, etc.

[0006] Erythritol is a natural active substance widely exists in nature, widely exists in seaweed, mushrooms and other fungi, and melon, grapes and other fruits. Erythritol has antioxidant activity, is very stable to acid, alkali and heat, and does not undergo Maillard reaction. Compared with other sugar alcohols, the biggest feature of erythritol is good tolerance, which is not metabolized and discharged from the body after absorption, does not participate in sugar metabolism and blood sugar changes, and is suitable for diabetic patients to eat. Erythritol has good compatibility with various drugs, and can be widely used in coating, tabletting auxiliary materials, inhalation carrier / excipient and other fields. At the same time, erythritol has low heat, anticaries, antioxidant and other biological characteristics, is a pharmaceutical excipient with many excellent properties, and adding appropriate amount of erythritol in soft capsules can prevent soft capsules from sticking together, significantly shorten the drying time of gelatin soft capsules, and save drying cost.

[0007] Glycine is the most commonly used amino acid antioxidant / stabilizer in the amino acid series, and has the simplest structure. Because the amino and carboxyl groups in its molecule can form hydrogen bonds or electrostatic interactions with the peptide chains of gelatin, it can repair the defects of gelatin network structure, reduce the damage of water and oxygen to gelatin molecular chain, and thus delay the hardening and brittle fracture of 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 mechanical property maintenance time of the shell and the shelf life of the soft capsule.

[0008] Soft capsule materials are generally made of gelatin, glycerol or other suitable pharmaceutical excipients alone or in combination. Gelatin is the first choice for soft capsule preparation because of its good film-forming ability and stable physical properties. Due to the unevenness of gelatin molecular chain breakage and its own hydrophilicity, the barrier ability of single gelatin film is poor, and the stability problems such as shell disintegration and dissolution delay during the storage of soft capsules are common problems in soft capsule products, and the main reason for these problems is the hygroscopicity and crosslinking aging of gelatin in the soft capsule shell.

[0009] Patent CN104800187B discloses a soft capsule of alfacalcidol and a preparation method thereof, and the content mainly consists of alfacalcidol, polyethylene glycol, penetration enhancer, glycerol and thickening agent, which is used to improve the bioavailability of the drug; patent CN109568287A discloses a soft capsule of alfacalcidol and a preparation method thereof, and the content mainly consists of alfacalcidol, antioxidant and oily base, and the preparation process is carried out in the dark under nitrogen protection, which is mainly used to improve the stability of the product and reduce the defect of low bioavailability of the product. However, both of the above patents do not mention how to solve the problems of alfacalcidol itself stability, shell disintegration and slow dissolution caused by shell aging of soft capsule.

[0010] Patent CN111214453B discloses a soft capsule of alfacalcidol and a preparation method thereof, which relates to a method for preparing a soft capsule of alfacalcidol by uniformly mixing alfacalcidol, medium-chain triglyceride, ascorbic acid palmitate, zein, polyethylene glycol, phospholipid and lauric acid monoglyceride. The purpose is to improve the stability and bioavailability of the soft capsule of alfacalcidol, but it does not provide a solution to the phenomena of capsule shell aging and instability of active ingredients during long-term storage of the soft capsule.

[0011] Patent CN118252813B discloses a soft capsule of alfacalcidol and a preparation method thereof, in which the capsule shell is prepared from modified hydroxypropyl methylcellulose and starch, and the content of the soft capsule is prepared by ultrasonic emulsification technology. The purpose is to improve the stability and bioavailability of the product. Since the raw material drug of alfacalcidol is unstable at high temperature, and high-temperature emulsification is used in the preparation of the emulsion, it may not be conducive to the stability of the soft capsule of alfacalcidol during long-term storage. In addition, the preparation process of the plant matrix capsule material used in this patent is complex and requires a large amount of organic solvent, which makes it difficult for industrial production.

[0012] Patent CN119405615A discloses a preparation method of a soft capsule of alfacalcidol containing vitamin D3 PLGA microspheres and a capsule shell liquid containing β-cyclodextrin. Although this preparation method can achieve rapid release of alfacalcidol, it does not analyze the stability and cross-linking aging of the soft capsule during long-term storage. In addition, the preparation process is relatively complex, which poses a certain challenge to industrial production.

[0013] Patent CN119488148A discloses a seamless soft capsule and a preparation method and use thereof. The film-forming composition mainly includes a first gelling agent, high-ester pectin, a plasticizer and water, and the plasticizer mainly consists of one or more of glycerol, sorbitol, xylitol, erythritol, maltitol and lactitol, preferably glycerol. The main purpose is to develop a plant-based seamless soft capsule with uniform appearance, low oil leakage rate and qualified disintegration test after drying. Although there have been some studies on the application of plant-based gel materials such as hydroxypropyl methylcellulose (HPMC) in soft capsules, there are still problems such as mechanical strength, elasticity, compactness and thermal stability, which are not as good as traditional gelatin. For products with high barrier requirements, complex process and high control cost, plant-based gel materials cannot completely replace traditional gelatin.

[0014] In summary, the above patent technologies do not pay attention to the stability of alfacalcidol raw material and the cross-linking aging and stability of the capsule shell during long-term storage of the soft capsule of alfacalcidol.

[0015] The above method can realize the preparation of alfacalcidol soft capsules, but cannot indicate how to improve the stability of the raw drug and its preparation. Although some patents can improve the light stability of the product, they do not explain how to prevent the disintegration and dissolution delay caused by the crosslinking aging of the soft capsule shell. In fact, the aging of the soft capsule shell leads to the prolongation of the disintegration time, the decrease of the dissolution rate, and even the complete insolubility, which will cause the insufficient effect of the active ingredient. Therefore, developing an alfacalcidol soft capsule with high stability, delaying the crosslinking aging of the capsule shell and suitable for industrialized production can improve the shortcomings of the existing soft capsules to a certain extent. SUMMARY

[0016] The present application provides an alfacalcidol soft capsule composition and a preparation method thereof. The alfacalcidol soft capsule composition is prepared from an alfacalcidol content drug liquid and a soft capsule shell. The soft capsule content drug liquid comprises alfacalcidol co-crystals and an oily base. The soft capsule shell is composed of gelatin, a plasticizer, purified water and a light shielding agent. The preparation method of the alfacalcidol co-crystals is simple, does not change the properties of the active ingredient itself, has good product stability, is convenient and safe to use, has strong process operability, is low in cost, and is suitable for industrial production. The addition of a compound composition of glycerol, erythritol and glycine in the soft capsule shell not only improves the barrier property of the gelatin film, but also increases the antioxidant property of the gelatin film, inhibits the generation of aldehyde substances in the capsule skin, delays the aging of the capsule skin, thereby improving the disintegration and dissolution delay of the soft capsule after long-term storage, and further improving the long-term storage stability of the product.

[0017] The specific technical solutions provided by the present application are as follows: An alfacalcidol soft capsule composition is prepared from an alfacalcidol content drug liquid and a soft capsule shell. The alfacalcidol content drug liquid comprises alfacalcidol co-crystals and an oily base. The weight percentage of alfacalcidol pure substance in the content drug liquid is 0.0001-0.1%. The final alfacalcidol soft capsule has a specification that each soft capsule contains 0.25 μg or 0.5 μg or 1.0 μg of alfacalcidol pure substance.

[0018] The co-crystal ligand in the alfacalcidol co-crystals is selected from nicotinamide, proline, tyrosine, arginine and L-alanine, preferably nicotinamide. The oily base is one or more of medium-chain triglycerides, sesame oil, olive oil, castor oil, oleic acid and monolinoleate glyceride, preferably medium-chain triglycerides and / or sesame oil.

[0019] 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), preferably, the weight ratio of the gelatin, plasticizer, purified water and light shielding agent is 1:0.46:1:0.015; 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). If the weight ratio of the three exceeds the above range, the erythritol in the soft capsule shell may be at risk of crystallization, thereby increasing the brittleness of the product shell. Preferably, the weight ratio of the three is 1.875:1:0.2.

[0020] The light shielding agent is one or several of titanium dioxide, red iron oxide and yellow iron oxide, preferably titanium dioxide.

[0021] Another object of the present application is to provide a preparation method of the alfacalcidol soft capsule composition, comprising the following steps: (1) Preparation of alfacalcidol co-crystal: the powders of alfacalcidol and co-crystal ligand are weighed respectively; then the powders are dissolved in a reaction solvent to form a clear solution of alfacalcidol and co-crystal ligand; 0.1-15 times of purified water of the reaction solvent is added dropwise during stirring to induce crystallization; after the dropwise addition is completed, the mixed suspension is filtered, and the filtrate is crystallized at low temperature or room temperature; after filtration and drying, a white crystalline solid is obtained, which is the alfacalcidol co-crystal; (2) Preparation of alfacalcidol content drug solution: the alfacalcidol co-crystal obtained in step (1) is added to an oily base, and stirred to obtain the alfacalcidol content drug solution; (3) Preparation of alfacalcidol soft capsule: ①The light shielding agent is dispersed uniformly with 10-15% of the prescription amount of purified water, and the plasticizer is dissolved in water and placed in a gelatinizing tank. The suspension of the light shielding agent is added and stirred to disperse uniformly. The gelatinizing tank is heated to 55-60°C in a water bath. After the gelatin is added and heated to 65-72°C, vacuum is applied, and the vacuum degree is ≤-0.08 MPa. After the weight of the gel in the gelatinizing tank decreases by 3-10%, the gelatinizing tank is filtered, and the temperature is maintained at 50-60°C, thereby obtaining the soft capsule shell; The erythritol and glycine are completely dissolved before the glycerol is added and completely dissolved; ②The alfacalcidol content drug solution and the soft capsule shell are pressed into soft capsules by using a full-automatic soft capsule machine, dried at 18-33°C, and shaped at 20-27°C, thereby obtaining the alfacalcidol soft capsule.

[0022] The specifications are that each soft capsule contains 0.25 μg or 0.5 μg or 1.0 μg of alfacalcidol pure substance.

[0023] Further, the co-crystal ligand in step (1) is selected from nicotinamide, proline, tyrosine, arginine and L-alanine, preferably the co-crystal ligand is nicotinamide; the selected co-crystal ligand contains hydrogen bond donors (such as: -NH, -OH, -COOH) and hydrogen bond acceptors (such as: C=O, -N=, -OH), which can form a hydrogen bond network with the drug molecule, stabilize the co-crystal structure, and improve the dissolution rate of the poorly soluble drug. Based on the advantages of nicotinamide, such as hydrogen bond stabilization, high solubility and antioxidant properties, nicotinamide is preferably used as a co-crystal ligand, which can further improve the stability of the alfacalcidol co-crystal.

[0024] Further, the molar ratio of alfacalcidol to co-crystal ligand in step (1) is 1: (0.5-2.5), preferably the molar ratio of alfacalcidol to co-crystal ligand is 1:1; if the co-crystal ligand is too low, the alfacalcidol molecules cannot be fully wrapped or interacted, resulting in incomplete co-crystal formation, which may form a mixture of free alfacalcidol and co-crystal, rather than a simple homogeneous phase; in addition, free alfacalcidol may cause phase separation, precipitation or uneven crystallinity, affecting the uniformity of the preparation; the solubility of the co-crystal depends on the synergistic effect of the co-crystal ligand, and the proportion is insufficient to significantly improve the dissolution performance of alfacalcidol. If the co-crystal ligand is too high, the excess co-crystal ligand may exist in a free form, resulting in an increase in impurities in the preparation, which may affect the drug purity or induce side reactions.

[0025] Further, after the alfacalcidol and the co-crystal ligand are completely dissolved in the reaction solvent to form a clear solution of alfacalcidol and the co-crystal ligand in step (1), 0.1-10 volumes of purified water are added dropwise under stirring.

[0026] Further, the reaction solvent in step (1) is one or any two of ethanol, methanol, isopropyl alcohol and acetonitrile, preferably the reaction solvent is ethanol.

[0027] Further, the volume-to-mass ratio of the reaction solvent to alfacalcidol in step (1) is 0.1-100 mL / g; if the amount of the reaction solvent is too small, it may not be completely dissolved, the co-crystal ligand may not be in sufficient contact with the drug molecules, and the co-crystal yield may be low. If the amount of the reaction solvent is too large, although it can be fully dissolved, the production cost is high, the co-crystal precipitation rate may be too slow, and impurities or solvent residues may be introduced. Further preferably, the volume-to-mass ratio of the reaction solvent to alfacalcidol is 0.1-65 mL / g.

[0028] Further, the low temperature or room temperature condition in step (1) is -20℃ to 25℃, which ensures that no more crystals are precipitated; and the drying condition is 30 to 50℃, and the drying is performed until the moisture content is less than 1.0%.

[0029] Further, the stirring speed in step (2) is 100 to 2000 rpm, and the stirring time is 10 to 120 min.

[0030] The prepared alfacalcidol co-crystals are respectively subjected to structure characterization by using an electron microscope and differential scanning calorimetry (DSC), and the electron microscope image shows that new crystals (different from alfacalcidol and the co-crystal ligand) are formed, and the co-crystal has only one characteristic melting peak in the DSC, thereby further confirming the formation of the co-crystal.

[0031] The mechanism of the prepared alfacalcidol co-crystals for promoting solubility is as follows: (1) Crystal structure reconstruction: when the co-crystal is formed, alfacalcidol and the co-crystal ligand are combined by hydrogen bonds, π-π stacking and other non-covalent bonds, the crystal packing mode is changed, the crystal lattice energy is reduced, and thus the energy required for the release of drug molecules from the crystal lattice is reduced, and the apparent solubility is improved.

[0032] (2) Introduction of hydrophilic ligand: the co-crystal ligand has hydrophilicity, which can improve the wettability of the whole co-crystal and enhance the penetration of water molecules, thereby improving the solubility.

[0033] The mechanism of the prepared alfacalcidol co-crystals for promoting stability is as follows: (1) Steric hindrance effect: the co-crystal ligand wraps the active groups (such as hydroxyl groups) of alfacalcidol through intermolecular interactions (such as hydrogen bond networks), reduces the contact of the active groups with light, oxygen and water in the environment, and thus delays the degradation reactions such as photo-oxidation and hydrolysis.

[0034] (2) Inhibition of crystal transformation: the co-crystal may form a more compact packing mode, reduce crystal lattice defects, reduce hygroscopicity or inhibit amorphous phase transformation, and thus improve the physical stability.

[0035] Compared with the prior art, the present application has the following beneficial effects: (1) Compared with alfacalcidol raw material, the prepared alfacalcidol co-crystals have high solubility and good stability, and have good stability under high temperature, high humidity and strong light conditions. In addition, the preparation method of the alfacalcidol co-crystals is simple and easy to operate, does not change the nature of the active ingredient of the drug itself, has strong process operability, low cost and is suitable for industrial production. (2) Compared with the soft capsules prepared by the conventional general plasticizer, the new compound plasticizer of glycerol, erythritol and glycine in a certain proportion as the soft capsule shell of the application can prevent capsule adhesion and shorten the drying time of the soft capsule, not only improve the barrier property of the gelatin film, but also increase the antioxidant property of the gelatin film, inhibit the generation of aldehyde substances in the capsule skin, delay the crosslinking aging of the soft capsule skin, thereby improving the disintegration and dissolution delay problems of the gelatin soft capsule after long-term storage, improving the drug efficacy and product stability; (3) The preparation method of the alfacalcidol soft capsule composition is simple and easy to operate, low in cost and easy to produce on a large scale. BRIEF DESCRIPTION OF DRAWINGS

[0036] Figure 1 The comparative result graphs of alfacalcidol raw material, co-crystal ligand nicotinamide and alfacalcidol-nicotinamide co-crystal prepared in example 1 under an electron microscope (200x), wherein A is the electron microscope graph of alfacalcidol raw material, B is the electron microscope graph of co-crystal ligand nicotinamide, and C is the electron microscope graph of alfacalcidol-nicotinamide co-crystal of example 1; Figure 2 The differential scanning calorimetry (DSC) analysis graph of alfacalcidol-nicotinamide co-crystal prepared in example 1; Figure 3 The sample disintegration test phenomenon graph of alfacalcidol soft capsules under the condition of strong light irradiation for 20 days, wherein A is the reference preparation Roferon-A (LEO Pharma A / S), and B is the alfacalcidol soft capsule prepared in example 1; ® (LEO Pharma A / S), and B is the alfacalcidol soft capsule prepared in example 1. Figure 4 The sample rupture test phenomenon graph of alfacalcidol soft capsules under the condition of strong light irradiation for 20 days, wherein A is the reference preparation Roferon-A (LEO Pharma A / S), and B is the alfacalcidol soft capsule prepared in example 1. ® (LEO Pharma A / S), and B is the alfacalcidol soft capsule prepared in example 1. DETAILED DESCRIPTION

[0037] In order to better understand the present application, the content of the present application will be further illustrated below in combination with examples and drawings. Obviously, the described examples are only a part of the examples of the present application, rather than all the examples. The specific examples described herein are only used to explain the present application, and are not used to limit the present application. Based on the examples in the present application, all other examples obtained by those skilled in the art without creative labor belong to the scope of protection of the present application.

[0038] For a better understanding of the present application without restricting the scope thereof, all numbers expressing quantities of components, percentages, and other numerical values used in this application are to be understood as modified in all instances by the term "about." Each of the individual parameters is intended to be stood on its own as an amount that is approximated.

[0039] Example 1 A soft capsule composition of alfacalcidol and a method for preparing the same (1) Preparation of alfacalcidol-nicotinamide co-crystal Take 1 mmol (400 mg) of alfacalcidol powder (purity: 100.30%) and 1 mmol (122 mg) of nicotinamide, put them in a beaker, add 5.06 mL of ethanol to the beaker, and obtain a clear solution after complete dissolution. Slowly add 2.3 mL of purified water drop by drop during stirring at room temperature to crystallize. Place the obtained milky white suspension in a 2-8°C cooling condition, and obtain white crystals after 24 hours. Dry at 40°C under vacuum until the moisture is less than 1.0%, and obtain the alfacalcidol-nicotinamide co-crystal.

[0040] Figure 1 The comparative results of alfacalcidol raw material, co-crystal ligand nicotinamide, and the alfacalcidol-nicotinamide co-crystal prepared in Example 1 under an electron microscope (200x) are shown in the figure, wherein A is the electron microscope image of the alfacalcidol raw material, and the electron microscope observation is a rod-shaped crystal; B is the electron microscope image of the co-crystal ligand nicotinamide, and the electron microscope observation is a rod-shaped crystal; C is the electron microscope image of the alfacalcidol-nicotinamide co-crystal of Example 1, and the electron microscope observation is a large amount of fine needle-shaped crystals. It can be known from the comparison that the C figure proves the generation of a new crystal form, and at the same time the co-crystal crystal size is reduced, indicating that the molecular packing mode is reconstructed.

[0041] Figure 2 The differential scanning calorimetry (DSC) analysis diagram of the alfacalcidol-nicotinamide co-crystal prepared in Example 1 is shown in the figure. It can be seen that the alfacalcidol co-crystal has one characteristic melting peak, and the peak temperature is 144.52±0.2°C.

[0042] (2) Preparation of alfacalcidol content drug solution Table 1 Composition table of soft capsule content drug solution Ingredients Amount Alfacalcidol pure substance 2.5 mg Sesame oil 0.5 kg Medium chain triglycerides 0.5 kg Add the prescription amount of alfacalcidol-nicotinamide co-crystal to the mixture of medium-chain triglyceride and sesame oil, and stir at a speed of 800 rpm for 30 min to obtain a colorless to light yellow oily alfacalcidol content drug solution.

[0043] (3) Preparation of alfacalcidol co-crystal soft capsule Table 2 Composition table of soft capsule shell Ingredients Amount Gelatin 12.5 kg Glycerin 3.75 kg Erythritol 2 kg Glycine 0.4 kg Purified water 12.5 kg Titanium dioxide 0.1875 kg ①The prescription amount of titanium dioxide is dispersed uniformly with 1.25 kg of purified water and then stored for use; erythritol and glycine are completely dissolved in water, and then glycerol is dissolved in the gel-making tank, and then the titanium dioxide suspension is added, stirred and dispersed uniformly, and heated to 60°C in a water bath; after adding gelatin, heat to 70°C, vacuumize, vacuum degree ≤-0.08 Mpa, when the weight of the gel in the gel-making tank decreases by 3-10%, stop vacuumizing, filter, and keep at 55°C to obtain the soft capsule shell.

[0044] ② Pill pressing: adjust and control the temperature in the preparation room to be lower than 25°C and the humidity to be lower than 45%; the temperature of the gel box is 55°C, and the temperature of the spraying body is 40°C; adjust and control the thickness of the gelatin to be 0.7-0.8 mm, fill the alfacalcidol content liquid into the hopper, press the soft capsules, and then shape at 20-22°C and dry at 24-29°C to obtain the alfacalcidol soft capsules. Each soft capsule contains 100 mg of content, and contains 0.25 μg of alfacalcidol pure substance.

[0045] Example 2: An alfacalcidol soft capsule composition and a preparation method thereof (1) Preparation of alfacalcidol-nicotinamide co-crystals Take 1 mmol (400 mg) of alfacalcidol powder (purity: 100.30%) and 1.3 mmol (158 mg) of nicotinamide, and place them in a beaker. Add 7.8 mL of ethanol to the beaker, and completely dissolve to obtain a clear solution. Slowly add 3.3 mL of purified water drop by drop during room temperature stirring, and then cool the obtained milky white suspension at 2-8°C. After 24 hours, white crystals are obtained, which are vacuum dried at 40°C until the moisture content is less than 1.0%, to obtain the alfacalcidol-nicotinamide co-crystals.

[0046] (2) Preparation of alfacalcidol content solution Table 3: Composition table of soft capsule content liquid Ingredients Amount Alfacalcidol pure substance 2.5 mg Medium chain triglycerides 1.0 kg Add the prescription amount of alfacalcidol-nicotinamide co-crystals to the medium-chain triglyceride, stir at a speed of 1000 rpm for 30 min, and obtain the alfacalcidol content liquid in the form of colorless to slightly yellow oil.

[0047] (3) Preparation of alfacalcidol soft capsules Table 4: Composition table of soft capsule shell Ingredients Amount Gelatin 12.5 kg Glycerin 3.625 kg Erythritol 1.5875 kg Glycine 0.55 kg Purified water 14.9 kg Titanium dioxide 0.2375 kg ①The prescription amount of titanium dioxide is dispersed uniformly with 1.49 kg of purified water, and then erythritol and glycine are completely dissolved in water, and then glycerol is completely dissolved in the gelatinizing tank, and then the titanium dioxide suspension is added, stirred and uniformly dispersed, and heated in water bath at 60°C; after adding gelatin, heat to 70°C, vacuumize, vacuum degree ≤-0.08 Mpa, when the weight of the gel in the gelatinizing tank decreases by 3-10%, stop vacuumizing, filter, and keep at 55°C to obtain the soft capsule shell.

[0048] ②Punching: adjust and control the temperature in the preparation room to be lower than 25°C and the humidity to be lower than 45%; the temperature of the gel box is 55°C, the temperature of the spraying body is 40°C; adjust and control the thickness of the gelatin to be 0.7-0.8 mm, fill the alfacalcidol solution into the hopper, and then punch the soft capsules, and then shape at 20-23°C and dry at 25-30°C to obtain the alfacalcidol soft capsules. Each soft capsule contains 100 mg of content, and contains 0.25 μg of alfacalcidol pure substance.

[0049] Example 3: An alfacalcidol soft capsule composition and a preparation method thereof (1) Preparation of alfacalcidol-nicotinamide co-crystals Take 1 mmol (400 mg) of alfacalcidol powder (purity: 100.30%) and 2 mmol (244 mg) of nicotinamide, and place them in a beaker. Add 6.84 mL of ethanol to the beaker, and completely dissolve to obtain a clear solution. Slowly add 2.7 mL of purified water drop by drop during room temperature stirring, and then cool the obtained milky white suspension at 2-8°C. After 24 hours, white crystals are obtained, and then vacuum dry at 40°C until the moisture content is less than 1.0%, to obtain the alfacalcidol-nicotinamide co-crystals.

[0050] (2) Preparation of alfacalcidol content solution Table 5: Composition table of soft capsule content solution Ingredients Amount Alfacalcidol pure substance 10 mg Sesame oil 1.0 kg Add the prescription amount of alfacalcidol-nicotinamide co-crystals to sesame oil, stir at a speed of 2000 rpm for 25 min, and obtain colorless to light yellow oil-shaped alfacalcidol content solution.

[0051] (3) Preparation of alfacalcidol soft capsules Table 6: Composition table of soft capsule shell Ingredients Amount Gelatin 12.5 kg Glycerin 3.906 kg Erythritol 2.344 kg Glycine 0.36 kg Purified water 13.8 kg Titanium dioxide 0.195 kg ①The prescription amount of titanium dioxide is dispersed uniformly with 1.38 kg of purified water, and then erythritol and glycine are completely dissolved in water, and then glycerol is completely dissolved in the gelatinizing tank, and then the titanium dioxide suspension is added, stirred and uniformly dispersed, and heated in water bath at 60°C; after adding gelatin, heat to 70°C, vacuumize, vacuum degree ≤-0.08 Mpa, when the weight of the gelatin in the gelatinizing tank decreases by 3-10%, stop vacuumizing, filter, and keep at 55°C to obtain the soft capsule shell.

[0052] ②Punching: adjust and control the temperature in the preparation room to be lower than 25°C and the humidity to be lower than 45%; the temperature of the gelatin box is 55°C, the temperature of the spraying body is 40°C; adjust and control the thickness of the gelatin to be 0.7-0.8 mm, fill the alfacalcidol solution into the hopper, punch the soft capsules, and then shape at 20-23°C and dry at 25-29°C to obtain the alfacalcidol soft capsules. Each soft capsule contains 100 mg of content, and contains 1.0 μg of alfacalcidol pure substance.

[0053] Example 4: An alfacalcidol soft capsule composition and a preparation method thereof (1) Preparation of alfacalcidol-nicotinamide co-crystal Take 1 mmol (400 mg) of alfacalcidol powder (purity: 100.30%) and 1.3 mmol (158 mg) of nicotinamide, and place them in a beaker. Add 7.8 mL of ethanol to the beaker, and completely dissolve to obtain a clear solution. Slowly add 3.3 mL of purified water drop by drop during room temperature stirring, and then cool the obtained milky white suspension at 2-8°C. After 24 hours, white crystals are obtained, which are vacuum dried at 40°C until the moisture content is less than 1.0%, to obtain the alfacalcidol-nicotinamide co-crystal.

[0054] (2) Preparation of alfacalcidol content solution Table 7: Composition table of soft capsule content solution Ingredients Amount Alfacalcidol pure substance 5 mg Olive oil 1.0 kg Add the prescription amount of alfacalcidol-nicotinamide co-crystal to olive oil, stir at a speed of 800 rpm for 45 min, and obtain colorless to light yellow oil-shaped alfacalcidol content solution.

[0055] (3) Preparation of alfacalcidol soft capsules Table 8: Composition table of soft capsule shell Ingredients Amount Gelatin 12.5 kg Glycerin 3.625 kg Erythritol 1.5875 kg Glycine 0.55 kg Purified water 14.9 kg Titanium dioxide 0.2375 kg ①The prescription amount of titanium dioxide is dispersed uniformly with 1.49 kg of purified water, and then erythritol and glycine are completely dissolved in water, and then glycerol is completely dissolved in the gelatinizing tank, and then the titanium dioxide suspension is added, stirred and uniformly dispersed, and heated in water bath at 60°C; after adding gelatin, heat to 70°C, vacuumize, vacuum degree ≤-0.08 Mpa, when the weight of the gel in the gelatinizing tank decreases by 3-10%, stop vacuumizing, filter, and keep at 55°C to obtain the soft capsule shell.

[0056] ②Punching: adjust and control the temperature in the preparation room to be lower than 25°C and the humidity to be lower than 45%; the temperature of the gel box is 55°C, the temperature of the spraying body is 40°C; adjust and control the thickness of the gelatin to be 0.7-0.8 mm, fill the alfacalcidol solution into the hopper, and then punch the soft capsules, and then shape at 20-23°C and dry at 25-30°C to obtain the alfacalcidol soft capsules. Each soft capsule contains 100 mg of content, and contains 0.5 μg of alfacalcidol pure substance.

[0057] Comparative Example 1: An alfacalcidol soft capsule composition and a preparation method thereof (1) Preparation of alfacalcidol-nicotinamide co-crystal Take 1 mmol (400 mg) of alfacalcidol powder (purity: 100.30%) and 1.5 mmol (183 mg) of nicotinamide, and place them in a beaker. Add 5.83 mL of ethanol to the beaker, and completely dissolve to obtain a clear solution. Slowly add 2.14 mL of purified water drop by drop during stirring at room temperature to crystallize. Place the obtained milky white suspension in a 2-8°C cooling condition, and obtain white crystals after 24 hours. Dry at 40°C under vacuum until the moisture content is less than 1.0%, to obtain the alfacalcidol-nicotinamide co-crystal.

[0058] (2) Preparation of alfacalcidol content solution Table 9: Composition table of soft capsule content solution Ingredients Amount Alfacalcidol pure substance 10 mg Sesame oil 0.5 kg Medium chain triglycerides 0.5 kg Add the prescription amount of alfacalcidol-nicotinamide co-crystal to the mixture of sesame oil and medium-chain triglyceride, and stir at a speed of 1000 rpm for 20 min to obtain a colorless to light yellow oily alfacalcidol content solution.

[0059] (3) Preparation of alfacalcidol soft capsules Table 10: Composition table of soft capsule shell Ingredients Amount Gelatin 12.5 kg Glycerin 5.5 kg Purified water 13.0 kg Titanium dioxide 0.1625 kg ①Dispersion of the prescribed amount of titanium dioxide with 1.3 kg purified water, then add glycerol, completely dissolved, then add the suspension of titanium dioxide, stirring, dispersion, water bath heating 60℃; add gelatin, heating to 70℃, vacuum, vacuum degree ≤-0.08 Mpa, the weight of the gelatin in the gelatin tank decreased 3~10%, stop vacuum, filtration, 55℃, get soft capsule shell.

[0060] ②Pressing: adjust the temperature in the preparation room to be lower than 25℃, humidity lower than 45%; the temperature of the gelatin box is 55℃, the temperature of the spray body is 39℃; adjust the thickness of the gelatin to be 0.7~0.8mm, fill the alfacalcidol solution into the hopper, press the soft capsules, and then shape at 21~24℃ and dry at 25~30℃, get the alfacalcidol soft capsules. Each soft capsule contains 100mg of the content, and contains 1.0μg of alfacalcidol pure substance.

[0061] Comparative Example 2: A kind of alfacalcidol soft capsule composition and its preparation method (1) Preparation of alfacalcidol-nicotinamide co-crystal Take 1mmol (400mg) of alfacalcidol powder (purity: 100.30%) and 1mmol (122mg) of nicotinamide, put them in a beaker, add 5.06mL of ethanol to the beaker, completely dissolved to get a clear solution. Slowly add 2.3mL of purified water drop by drop during stirring at room temperature, and then cool the obtained milky white suspension at 2-8℃ for 24 hours to get white crystals, and then dry at 30℃ under vacuum until the moisture content is less than 1.0%, get the alfacalcidol-nicotinamide co-crystal.

[0062] (2) Preparation of alfacalcidol content drug solution Table 11: Composition of soft capsule content drug solution Ingredients Amount Alfacalcidol pure substance 2.5 mg Medium chain triglycerides 1.0 kg Add the prescribed amount of alfacalcidol-nicotinamide co-crystal to the medium-chain triglyceride, stir at a speed of 1200rpm for 35min, get the colorless to slightly yellow oil of alfacalcidol content drug solution.

[0063] (3) Preparation of alfacalcidol soft capsules Table 12: Composition of soft capsule shell Ingredients Amount Gelatin 12.5 kg Glycerin 6.0 kg Erythritol 2.83 kg Purified water 12.5 kg Titanium dioxide 0.2 kg ①The prescription amount of titanium dioxide is dispersed uniformly with 1.25 kg purified water and then is ready for use. The purified water is placed in a gelatinizing tank, glycerol and erythritol are dissolved, and then the titanium dioxide suspension is added. After stirring and dispersing uniformly, water bath heating is performed at 60°C. After adding gelatin and heating to 70°C, vacuum is applied with a vacuum degree of ≤-0.08 MPa. When the weight of the gelatin solution in the gelatinizing tank decreases by 3-10%, the vacuum is stopped. Filtration is performed at 55°C, and a soft capsule shell is obtained.

[0064] ②Pill pressing: the temperature and humidity in the preparation room are controlled below 25°C and 45%, respectively. The temperature of the gelatin box is 55°C, and the temperature of the spraying body is 40°C. The thickness of the gelatin is controlled to be 0.7-0.8 mm. The alfacalcidol solution is filled into a hopper, and soft capsules are pressed. After shaping at 21-24°C and drying at 25-30°C, alfacalcidol soft capsules are obtained. The content of each soft capsule is 100 mg, and the content of alfacalcidol is 0.25 μg.

[0065] Example 3: An alfacalcidol soft capsule composition and a preparation method thereof (1) Preparation of an alfacalcidol content solution Table 13: Composition of the soft capsule content solution Ingredients Amount Alfacalcidol 5 mg Sesame oil 1.0 kg The prescription amount of alfacalcidol is added to sesame oil, and stirring is performed at a speed of 1000 rpm at 25°C or below in the dark until complete dissolution, and a colorless to light yellow oily alfacalcidol content solution is obtained.

[0066] (2) Preparation of alfacalcidol soft capsules Table 14: Composition of the soft capsule shell Ingredients Amount Gelatin 12.5 kg Glycerin 5.529 kg Glycine 0.56 kg Purified water 12.02 kg Titanium dioxide 0.15 kg ①The prescription amount of titanium dioxide is dispersed uniformly with 1.25 kg purified water and then is ready for use. The purified water is placed in a gelatinizing tank, glycerol and erythritol are dissolved, and then the titanium dioxide suspension is added. After stirring and dispersing uniformly, water bath heating is performed at 60°C. After adding gelatin and heating to 70°C, vacuum is applied with a vacuum degree of ≤-0.08 MPa. When the weight of the gelatin solution in the gelatinizing tank decreases by 3-10%, the vacuum is stopped. Filtration is performed at 55°C, and a soft capsule shell is obtained.

[0067] ②Pill pressing: the temperature and humidity in the preparation room are controlled below 25°C and 45%, respectively. The temperature of the gelatin box is 55°C, and the temperature of the spraying body is 40°C. The thickness of the gelatin is controlled to be 0.7-0.8 mm. The alfacalcidol solution is filled into a hopper, and soft capsules are pressed. After shaping at 21-24°C and drying at 25-30°C, alfacalcidol soft capsules are obtained. The content of each soft capsule is 100 mg, and the content of alfacalcidol is 0.25 μg.

[0068] Comparative Example 4: An Alfacalcidol Soft Capsule Composition and Its Preparation Method (1) Preparation of alfacalcidol contents solution Table 15 Components of the Soft Capsule Contents Ingredients Amount Alfacalcidol 2.5 mg Medium chain triglycerides 1.0 kg 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.

[0069] (3) Preparation of alfacalcidol soft capsules Table 16 Components of Soft Capsule Shells Ingredients Amount Gelatin 12.5 kg Glycerin 5.8 kg Purified water 12.5 kg Titanium dioxide 0.25 kg 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.

[0070] 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.

[0071] The inventors compared the embodiments and comparative examples, and the specific results are as follows: (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.

[0072] (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.

[0073] (3) Comparative Example 3, the raw material drug was not treated in any way, and there were problems of instability of the raw material drug, long dissolution time, uneven dissolution, etc.; the capsule shell was similar to that of Comparative Example 2, the difference was that a small amount of glycine was added to the soft capsule shell, and erythritol was not added, and the disadvantage was that slight adhesion occurred during the drying process of the soft capsule, the drying time was long, which was not conducive to the stability of the alfacalcidol raw material drug; and slight cross-linking aging phenomenon might also occur during long-term storage.

[0074] (4) Comparative Example 4, the raw material drug was not treated in any way, similar to Comparative Example 3, and there were problems of long dissolution time, uneven dissolution, content degradation, etc. of the raw material drug; in addition, the capsule shell used a conventional ordinary plasticizer-glycerol, and there were problems of adhesion of the capsule during the drying process, long drying time, which might cause degradation of the raw material drug during the drying process, instability of the soft capsule during long-term storage, cross-linking aging of the capsule shell, and influence on drug release, etc.

[0075] Specifically, the following experimental examples are used for further verification: Experimental Example 1 Stability of Alfacalcidol Co-crystal The alfacalcidol co-crystal products prepared in Examples 1-3 of the present application, and the alfacalcidol raw material drug, were placed under high temperature, high humidity, and strong light for 10 days. The influence factor test referred to the “9001 Raw Material Drug and Preparation Stability Test Guiding Principles” in the Chinese Pharmacopoeia 2020 Edition, 4th Volume, 100 mg samples were placed under high temperature (60±2℃), high humidity (95%±5% RH), and strong light (4500 lx±500 lx), and samples were taken at 0 days, 5 days, and 10 days for observation of appearance, purity, etc., and the results are shown in Table 17.

[0076] Table 17 Summary of Stability Test Results of Alfacalcidol Co-crystal The results show that the co-crystal formed by alfacalcidol and the co-crystal ligand can effectively reduce the degradation rate of the alfacalcidol raw material drug, and improve the stability of the product in high temperature, high humidity, and strong light irradiation environments.

[0077] Experimental Example 2 Determination of the Equilibrium Swelling Amount S of Gelatin eq Gelatin is a macromolecular hydrophilic colloidal compound, and when the swelling of gelatin reaches the limit, the equilibrium swelling amount of gelatin is related to the degree of cross-linking, and the greater the degree of cross-linking, the smaller the equilibrium swelling amount, so the equilibrium swelling amount can be used to indirectly evaluate the degree of cross-linking of gelatin. The limited swelling process of gelatin conforms to the second-order kinetic equation: ds / dt=k(S eq -S) 2 , where: ds / dt is the swelling rate at a certain time, k is the swelling rate constant, S eq ​To balance the swelling amount, S is the expansion rate. Wherein, S = (W s -W i ) / W i , in the formula: W s is the weight at time t, W i is the initial dry weight of the film. The formula ① is integrated and simplified to formula ②: t / s = A + Bt, wherein A = 1 / (k × S eq 2 ), B = 1 / S eq . It can be seen that the value of S eq can be determined by the slope B of the straight line t / s→t.

[0078] Take the same size and weight of the film prepared in Examples 1-3 and Comparative Examples 1-4 (thickness of 0.8 mm, diameter of 1.5 cm film), respectively, in a 100 mL beaker, add distilled water, take out at 0, 1, 2, 2.5, 3, 3.5 and 4 h under the condition of 20℃, wipe clean with filter paper, accurately weigh. Another 3 pieces of film are dried at 105℃ to constant weight, the initial dry weight of the film is measured, the expansion rate of the film at different time points is calculated respectively, and the equilibrium swelling amount is calculated according to formula ②.

[0079] The greater the crosslinking degree, the smaller the equilibrium swelling amount; the smaller the crosslinking degree, the greater the equilibrium swelling amount. From the equilibrium swelling amount S eq of Examples 1-3 and Comparative Examples 1-4 recorded in Table 18, the test results show that the conventional gelatin soft capsule shell with only glycerol as a plasticizer has a relatively small S eq , indicating that the crosslinking degree of the shell is relatively large; the S eq slightly increases when erythritol or glycine is added alone, indicating that the crosslinking degree of the shell is relatively reduced; however, when erythritol and glycine are added together in the soft capsule shell, the S eq increases, the crosslinking degree of the shell decreases, indicating that the compound plasticizer of glycerol, erythritol and glycine can significantly reduce the crosslinking aging of the gelatin soft capsule shell to a certain extent, and improve the product stability.

[0080] Table 18 S eq measurement results of gelatin soft capsules with different prescription compositions .

[0081] Experimental Example 3 Determination of Peroxide Value of Soft Capsule Oxidation of oil and fat is the main cause of rancidity. In order to verify the antioxidant performance of the alfacalcidol soft capsules of the application, the peroxide values of the soft capsules prepared in Examples 1-3 and Comparative Examples 1-4 of the application were determined. The soft capsules prepared in Examples 1-3 and Comparative Examples 1-4 were placed in a constant temperature box at a temperature of 30℃±2℃ and a relative humidity of 65%±5% RH for 1 month, and then the contents of the soft capsules of Examples 1-3 and Comparative Examples 1-4 were determined for peroxide value according to GB 5009.227-2023 "National Food Safety Standard Determination of Peroxide Value in Food" first method titration method. The determination method is as follows: under light-proof conditions, the contents of the samples were squeezed out after the soft capsules were cut longitudinally, and then mixed thoroughly, 3g of the content of each sample was weighed into a 250mL iodometric flask, 30mL of a mixture of chloroform-ice acetic acid was added, the sample was dissolved completely by gentle shaking, 1mL of saturated potassium iodide solution was accurately added, the flask was tightly capped, and shaken gently for 30s, then placed in the dark for 3min, 100mL of deionized water was added, shaken well, and then titrated with sodium thiosulfate immediately after the solution turned yellow, 1mL of starch indicator was added, and the titration was continued and the solution was shaken vigorously until the blue color disappeared; at the same time, a blank test was performed, and the peroxide value was determined by colorimetry. The test results are shown in Table 19.

[0082] Table 19 Peroxide value determination results of soft capsules 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 The lower the peroxide value, the stronger the antioxidant performance, and the better the stability of the product; the higher the peroxide value, the weaker the antioxidant performance, and the worse the stability of the product. From the comparison of the peroxide values of Examples 1-3 and Comparative Examples 1-4, it can be seen that the prepared alfacalcidol co-crystals and the new type of compound plasticizer of glycerol, erythritol and glycine added in the soft capsule shell significantly improve the antioxidant property of the oil in the soft capsule, and further improve the product stability problem after long-term storage of the soft capsule.

[0083] Experimental Example 4 Accelerated stability experiment The alfacalcidol soft capsules prepared in Examples 1-3 and Comparative Examples 1-4 of the application were investigated for 6 months under accelerated test conditions. The samples were placed at a temperature of 40℃±2℃ and a relative humidity of 75%±5% RH for 6 months according to the "Guidelines for Stability Testing of Raw Pharmaceutical Materials and Preparations" in the fourth volume of "Chinese Pharmacopoeia" 2020 edition, and the samples were taken at 0, 1, 2, 3 and 6 months for detection of properties, content and disintegration time limit.

[0084] The results of Examples 1-3 and Comparative Examples 1-4 (see Table 20) show that the content of the product of Comparative Example 1-4 decreases significantly and the disintegration time limit is prolonged with the increase of the accelerated time; while the properties, content and disintegration time limit of the product prepared in Examples 1-3 of the application have no significant change, indicating that the addition of the new type of compound plasticizer can increase the stability of the product.

[0085] Table 20 Product accelerated stability comparison .

[0086] Experimental Example 5 Light stability experiment The alfacalcidol soft capsules prepared in Examples 1-2 and the reference preparation Eliane ® (LEO Pharma A / S) were sealed in transparent bottles and the sample stability was investigated. The light stability experiment was performed according to the “Guidelines for Stability Testing of Raw Materials and Preparations” in the fourth volume of the Chinese Pharmacopoeia 2020 edition. The samples were placed under strong light with an illumination of 5000±500 Lux, and the total light source illumination should not be less than 1.2x10 6 Lux·hr for 20 days. Samples were taken at 0, 10, and 20 days, and the properties, content, disintegration, and rupture time were detected.

[0087] Results of alfacalcidol-containing Examples 1-2 and the reference preparation Eliane ® (LEO Pharma A / S) (see Table 21) showed that with the extension of light time, the product properties and content of Examples 1-3 and the reference preparation Eliane ® (LEO Pharma A / S) did not change significantly; the disintegration and rupture time were both correspondingly extended. Compared with Examples 1-2, the reference preparation Eliane ® (LEO Pharma A / S) product had a swollen, thin, tough and elastic water-insoluble film on the surface of the soft capsule, which could extend the disintegration and rupture time of the soft capsule in the disintegration and rupture test. Examples 1-2 with the new compound plasticizer did not have this phenomenon, indicating that the new compound plasticizer can delay the aging of the capsule shell, thereby improving the disintegration, rupture, and dissolution delay of the soft capsule after long-term storage.

[0088] Figure 3 Disintegration test of alfacalcidol soft capsule samples under strong light irradiation for 20 days, wherein A is the disintegration test of the reference preparation Eliane ® (LEO Pharma A / S) under strong light irradiation for 20 days, 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.

[0089] The results show that the soft capsules of Example 1 are wetted on the surface after being irradiated by strong light for 20 days and float on the surface of the medium, then the capsule shell is gradually softened, the capsule shell is partially broken, the content is slowly exuded, and finally the capsule shell is completely dissolved or disintegrated, and the residual capsule shell fragments completely pass through the screen of the disintegration tester. The reference preparation is cross-linked after being irradiated by strong light, a layer of wrinkled water-insoluble gelatin film appears on the surface of the capsule shell, and the capsule shell is difficult to disintegrate or disintegrate.

[0090] Figure 4 The sample rupture test phenomenon of alfacalcidol soft capsules under the condition of strong light irradiation for 20 days, wherein A is the reference preparation of Elan ® (LEO Pharma A / S) under the condition of strong light irradiation for 20 days, the surface of the soft capsule appears a dense water-insoluble film, indicating that the soft capsule shell is seriously cross-linked; B is the sample rupture test phenomenon of Example 1 under the condition of strong light irradiation for 20 days.

[0091] The results show that the soft capsules of Example 1 are wetted on the surface after being irradiated by strong light for 20 days and float on the surface of the medium, then the capsule shell is gradually softened, the capsule shell is partially broken, the content is slowly exuded, and finally the capsule shell is completely dissolved or disintegrated, and the residual capsule shell fragments completely pass through the screen of the disintegration tester. The reference preparation is cross-linked after being irradiated by strong light, a layer of wrinkled water-insoluble gelatin film appears on the surface of the capsule shell, and the capsule shell is difficult to disintegrate or disintegrate.

[0092] Compared with the reference preparation, the technical scheme of the present application further reduces the risk of soft capsule light instability and capsule shell cross-linking by adding a compounded plasticizer, improves the storage stability of the product, and makes the product fully play the drug efficacy. Figure 3 4 The comparison of the above

[0093] Table 21 Comparison of product strong light stability results In the table, “—” indicates that the capsule shell is aged, a layer of water-insoluble film is formed on the surface, and the complete dissolution time of the capsule shell is not observed.

[0094] The above describes specific embodiments of the present application, and it should be understood that the present application is not limited to the above specific embodiments, and those skilled in the art can make various modifications or modifications within the scope of the claims, which does not affect the essential content of the present application.​

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, oily base, wherein the weight percentage of alfacalcidol pure substance in the content medicine liquid is 0.0001-0.1%.

2. The high stability alfacalcidol softgel capsule composition according to claim 1, wherein, The co-crystal ligand in the alfacalcidol co-crystal is selected from nicotinamide, proline, tyrosine, arginine and L-alanine; The oily base is one or several 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 high stability alfacalcidol softgel capsule composition according to claim 2, wherein, The co-crystal ligand in the alfacalcidol co-crystal is nicotinamide; the oily base is medium-chain triglyceride and / or sesame oil; and the weight ratio of the gelatin, plasticizer, purified water and light shielding agent is 1:0.46:1:0.

015.

4. The high stability 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 glycerol, erythritol and glycine is (0.05-5):(0.02-3):(0.001-1.5); and the light shielding agent is one or several of titanium dioxide, red iron oxide and yellow iron oxide.

5. The high stability alfacalcidol softgel capsule composition according to claim 4, wherein, The weight ratio of glycerol, erythritol and glycine is 1.875:1:0.2; and 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: the powders of alfacalcidol and co-crystal ligand are weighed respectively; then the powders are dissolved in a reaction solvent to form a clear solution of alfacalcidol and co-crystal ligand; during stirring, 0.1-15 times of purified water of the reaction solvent is added dropwise to crystallize; after the dropwise addition is completed, the mixed suspension is placed in low temperature or room temperature to crystallize, filtered, and dried to obtain white crystalline solid, which is alfacalcidol co-crystal; wherein the molar ratio of alfacalcidol to co-crystal ligand is 1:(0.5-2.5); (2) Preparation of alfacalcidol content medicine liquid: the alfacalcidol co-crystal obtained in step (1) is added to the oily base, and stirred to obtain alfacalcidol content medicine liquid; (3) Preparation of alfacalcidol soft capsule: ①The light shielding agent is dispersed in water in a prescription amount of 10-15% to be used, the plasticizer is dissolved in water and placed in a gelatinizing pot, the suspension of the light shielding agent is added, stirred and dispersed uniformly, and heated to 55-60°C in a water bath; after the gelatin is added and heated to 65-72°C, vacuum is applied, the vacuum degree is ≤-0.08 Mpa, the weight of the gelatin in the gelatinizing pot is reduced by 3-10% after the vacuum degree is reached, and then the gelatin is filtered and kept at 50-60°C to obtain the soft capsule shell; ②The alfacalcidol content medicine liquid and the soft capsule shell 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 process for preparing high stability alfacalcidol soft capsule composition according to claim 6, characterized in that, The specification of the alfacalcidol soft capsule is that each soft capsule contains 0.25 μg, or 0.5 μg, or 1.0 μg of alfacalcidol pure substance.

8. The process for preparing high stability alfacalcidol soft capsule composition according to claim 6, characterized in that, The molar ratio of alfacalcidol and co-crystal ligand in step (1) is 1:1, and the reaction solvent is one or any two of ethanol, methanol, isopropanol and acetonitrile.

9. The process for preparing high stability alfacalcidol soft capsule composition as claimed in claim 6, wherein, The volume / mass ratio of the reaction solvent to alfacalcidol in step (1) is 0.1-100 mL / g; the cooling 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 moisture content is less than 1.0% after drying.

10. The process for preparing high stability alfacalcidol soft capsule composition as claimed in 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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