A soft capsule formulation containing alfacalcidol for gradient release and a method for preparing the same

Abstract

The application belongs to the technical field of pharmaceutical preparations, and discloses a soft capsule preparation containing alfacalcidol and a preparation method thereof. The soft capsule preparation comprises a soft capsule shell and content filled in the soft capsule shell, and the content is composed of a drug-containing oil phase and alfacalcidol sustained-release pellets dispersed in the oil phase. The drug-containing oil phase comprises immediate-release alfacalcidol dissolved in an oily base. The sustained-release pellets comprise a blank pellet core, a drug-loaded layer and a separation layer, and the separation layer comprises a combined coating material of Eudragit RS30D and Eudragit RL30D. After oral administration, the alfacalcidol in the oil phase is rapidly released to achieve immediate effect, and the alfacalcidol in the sustained-release pellets is slowly released to maintain the steady state of blood drug concentration. The soft capsule preparation of the application realizes the dual-phase drug release behavior of immediate release and sustained release in the same soft capsule, so that the blood drug concentration is smooth and controllable within 24 hours, the steady state of blood drug concentration is maintained, the frequency of drug administration is reduced, and the risk of side effects such as hypercalcemia is reduced.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical formulation technology, specifically relating to a gradient-release soft capsule formulation containing alfacalcidol and its preparation method. Background Technology

[0002] Alfacalcidol (1α-hydroxyvitamin D3) is an analogue of the active metabolite of vitamin D3. It plays a crucial role in regulating calcium and phosphorus balance in the human body, increasing the absorption of calcium and phosphorus in the intestines, lowering plasma parathyroid hormone levels, and improving osteoporosis induced by menopause and the use of hormonal drugs in women. Alfacalcidol is primarily used to treat osteoporosis, renal osteodystrophy, hypoparathyroidism, vitamin D-resistant rickets, and osteomalacia.

[0003] Alfacalcidol is lipid-soluble with nearly 100% oral bioavailability. After absorption, it is rapidly converted in the liver to 1,25-dihydroxyvitamin D3, the active metabolite of vitamin D3, which regulates calcium and phosphorus balance in the body. The peak of 1,25-(OH)2D3 in the blood occurs 8-12 hours after administration, with a half-life of 17.6 hours. However, currently available commercially available alfacalcidol formulations (such as tablets, capsules, and soft capsules) are all single-phase immediate-release formulations. After oral administration, the drug is rapidly absorbed, and the blood concentration rises and falls rapidly, exhibiting a "peak-trough" fluctuation. This pulsatile release mode leads to large fluctuations in blood concentration, which can easily cause side effects such as hypercalcemia, nausea, and headache. Long-term use of high doses or combined use with calcium supplements may cause hypercalcemia and hypercalciuria.

[0004] To overcome the aforementioned problems, attempts have been made to develop extended-release formulations of alfacalcidol in the prior art. For example, CN103127020B discloses an extended-release tablet with an alfacalcidol matrix, using hydroxypropyl methylcellulose and polyoxyethylene as the extended-release matrix to achieve stable drug release; CN103142503B discloses an extended-release granule of alfacalcidol, consisting of an immediate-release granule core and an extended-release coating layer. During preparation, a extended-release coating layer is applied to the immediate-release granule core to achieve long-acting release. However, these prior technologies are all limited to a single release mechanism within a single dosage form and have not yet achieved a gradient drug release mode integrating two different release rates (immediate and extended release) within the same dosing unit.

[0005] In recent years, researchers have begun to explore technical solutions for combining components with different release rates in the same formulation. CN118252813B discloses an alfacalcidol soft capsule and its preparation method. By using a modified hydroxypropyl methylcellulose and starch shell to prevent alfacalcidol from contacting oxygen and moisture, and by using ultrasonic emulsification technology to encapsulate the drug within glyceryl monostearate, chemical stability and bioavailability are improved. However, the improvement of this technology focuses on the capsule shell material and anti-migration design, and does not involve a gradient release system that simultaneously achieves immediate and sustained release within the same soft capsule.

[0006] Furthermore, some studies have reported technical concepts for encapsulating solid microparticles and a liquid oil phase within the same soft capsule. CN109568287A describes a method for preparing alfacalcidol soft capsules, involving uniformly mixing alfacalcidol with an oily matrix, antioxidants, etc., to form soft capsules, but the contents are a single oil phase and do not contain sustained-release microparticle components. In the broader pharmaceutical field, US20030158154 discloses a scheme for the combined use of an immediate-release vitamin D derivative and a delayed-release bisphosphonate, which involves the combined use of two different drugs, and is technically quite different from the single-drug biphasic release design of this invention.

[0007] Therefore, there is currently a lack of alfacalcidol formulations that can achieve gradient release of the same drug at different release rates within the same dosing unit, thereby maintaining stable blood drug concentrations over a long period while ensuring rapid action. This requires solving the technical problems caused by traditional single-phase pulsed release, such as fluctuations in blood drug concentration, high safety risks, and high dosing frequency. Summary of the Invention

[0008] The present invention aims to overcome the above-mentioned defects in the prior art and provide a gradient-release soft capsule formulation containing alfacalcidol and its preparation method.

[0009] The core of this invention lies in simultaneously encapsulating a drug-containing oil phase (immediate-release component) and alfacalcidol sustained-release microspheres (sustained-release component) dispersed in the oil phase within the same soft capsule, thereby achieving gradient drug release: after oral administration, the free alfacalcidol dissolved in the oil phase is rapidly released, achieving rapid onset of action; at the same time, the sustained-release microspheres dispersed in the oil phase slowly release the drug under the protection of the oil phase medium, maintaining a stable blood drug concentration for 24 hours, thus achieving a synergistic unity of rapid and long-lasting effects.

[0010] To achieve the above objectives, the present invention adopts the following technical solution: A first aspect of the present invention provides a gradient-release soft capsule formulation containing alfacalcidol, the soft capsule formulation comprising a soft capsule shell and contents filled within the soft capsule shell; the contents comprising a drug-containing oil phase and alfacalcidol sustained-release microgranules dispersed in the drug-containing oil phase; The drug-containing oil phase comprises an oily matrix and alfacalcidol dissolved in the oily matrix; the sustained-release microcapsules comprise a blank capsule core, a drug-loaded layer coating the surface of the blank capsule core, and a sustained-release coating layer coating the surface of the drug-loaded layer. After oral administration, alfacalcidol in the drug-containing oil phase is rapidly released from the oil phase to achieve rapid effect, while alfacalcidol in the sustained-release microcapsules is slowly released through a sustained-release coating layer to achieve sustained release.

[0011] In some embodiments of the present invention, the sustained-release coating layer comprises a combination of Eutec RS30D and Eutec RL30D coating materials. Eutec RS30D is a low-permeability acrylic polymer, and Eutec RL30D is a high-permeability acrylic polymer. The combination of the two can synergistically regulate the drug release rate.

[0012] By adjusting the ratio of RS30D to RL30D, the permeability and mechanical strength of the release coating can be precisely controlled, thereby regulating the drug release rate of the sustained-release microcapsules. A higher proportion of RS30D results in a denser coating and slower drug release; a higher proportion of RL30D results in stronger coating permeability and faster drug release.

[0013] The preferred weight ratio of Yutchi RS30D to Yutchi RL30D is (10~20):1, and more preferably (14~16):1.

[0014] In some embodiments of the present invention, the sustained-release coating layer further comprises 20% to 30% of a plasticizer and 35% to 45% of an anti-sticking agent by the dry weight of the polymer.

[0015] The plasticizer is preferably triethyl citrate, which can improve the flexibility and crack resistance of the coating film and reduce the glass transition temperature of the coating film. The anti-adhesion agent is preferably talc, which can prevent the microcapsules from sticking together during the coating process and ensure the flowability of the microcapsules.

[0016] In some embodiments of the present invention, the weight ratio of alfacalcidol in the drug-containing oil phase to alfacalcidol in the sustained-release microcapsules is (0.1~1):(1~10), preferably 1:(4~7). Based on 500,000 capsules, the dosage of alfacalcidol in the drug-containing oil phase is 0.0375g, and the dosage of alfacalcidol in the sustained-release microcapsules is 0.2125g.

[0017] In some embodiments of the present invention, the blank pellet core is selected from microcrystalline cellulose pellet core, starch pellet core, or sucrose pellet core, with a particle size of 200-600 μm, preferably 300-500 μm; the oily matrix is ​​selected from one or more of soybean oil, sesame oil, and medium-chain triglycerides, preferably soybean oil. The drug-containing oil phase also contains an antioxidant, preferably 2,6-di-tert-butyl-4-methylphenol (BHT).

[0018] In some embodiments of the present invention, the drug-loaded layer comprises alfacalcidol, a film-forming agent, an antioxidant, and a solvent.

[0019] The film-forming agent is selected from one or more of hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone, and hydroxypropyl cellulose, preferably hydroxypropyl methylcellulose E5; The solvent is selected from anhydrous ethanol, purified water, and mixtures thereof.

[0020] A second aspect of the present invention provides a method for preparing the above-mentioned gradient-release soft capsule formulation containing alfacalcidol, comprising the following steps: (1) Preparation of alfacalcidol sustained-release microspheres: Alfacalcidol was dissolved in a solvent with a film-forming agent and an antioxidant to prepare a drug-loaded solution; the drug-loaded solution was sprayed onto the surface of a blank pellet core using fluidized bed coating technology, and the pellets were dried to obtain drug-loaded microspheres; Eutectic RS30D, Eutectic RL30D, plasticizer and anti-adhesion agent were dispersed in water to prepare a sustained-release coating solution; the sustained-release coating solution was sprayed onto the surface of the drug-loaded microspheres using fluidized bed coating technology, and the pellets were cured to obtain alfacalcidol sustained-release microspheres; (2) Preparation of drug-containing oil phase: Under nitrogen protection conditions, alfacalcidol and antioxidants are dissolved in an oily matrix and stirred evenly to obtain a drug-containing oil phase; (3) Preparation of soft capsule shell solution: After heating purified water to 80~90℃, add glycerin, polyethylene glycol 400, titanium dioxide, sorbitol and gelatin, stir and melt under vacuum, degas and keep warm for later use; (4) Pelletizing and drying: The drug-containing oil phase obtained in step (2) and the alfacalcidol sustained-release microspheres obtained in step (1) are mixed evenly and then simultaneously filled into soft capsule shells. After pressing and drying, the gradient release soft capsule formulation containing alfacalcidol is obtained.

[0021] In some embodiments of the present invention, the material temperature is controlled below 40°C during the fluidized bed coating process in step (1). After the slow-release coating liquid is sprayed, it continues to solidify at 40°C for 4 to 6 hours to ensure that the coating film is fully cross-linked and densified.

[0022] In some embodiments of the present invention, the melting process in step (3) is carried out under vacuum pressure of -0.085 to -0.070 MPa and temperature of 75 to 85°C; the degassing process is carried out at 60°C for 2 hours.

[0023] In some embodiments of the present invention, in step (4), the rubber is dried until the moisture content of the rubber is 2% to 5%.

[0024] The present invention adopts the above technical solution and has the following technical effects compared with the prior art: (1) By encapsulating the immediate-release component (free alfacalcidol in the drug-containing oil phase) and the sustained-release component (alfacalcidol in the Utec coated sustained-release microcapsules) in the same soft capsule, a gradient drug release mode after oral administration is achieved. After oral administration, the free alfacalcidol dissolved in the oil phase is rapidly released, quickly reaching the effective blood drug concentration and achieving rapid effect. Subsequently, the alfacalcidol in the sustained-release microcapsules is slowly and continuously released under the protection of the oil phase, maintaining a stable blood drug concentration for up to 24 hours, and significantly reducing the "peak and valley" fluctuation phenomenon of blood drug concentration.

[0025] (2) The oil inside the soft capsule shell simultaneously performs three important functions: first, as a solvent for immediate-release alfacalcidol; second, as a suspension medium for sustained-release microspheres to ensure their uniform dispersion within the soft capsule; and third, as a protective medium for oral delivery of microspheres, protecting the integrity of the microsphere coating layer in the gastrointestinal tract and ensuring the realization of the sustained-release function. This multi-functional integrated design embodies the unique creative concept of the present invention and produces a synergistic technical effect of "1+1>2". That is, neither a single immediate-release nor a single sustained-release formulation can simultaneously achieve the goals of rapid onset of action and sustained and stable blood drug concentration, while this solution achieves the organic unity of the two.

[0026] (3) By adjusting the ratio of Eucerin RS30D to RL30D in the sustained-release coating layer, the release rate of the drug can be precisely controlled. The higher the ratio of RS30D, the denser the coating and the slower the release. The higher the ratio of RL30D, the stronger the coating permeability and the faster the release. By adjusting the ratio of the two, the drug release rate requirements under different clinical needs can be met, which has good flexibility and universality.

[0027] (4) The preparation process of the present invention fully considers the sensitivity of alfacalcidol to light, air and humidity. Nitrogen protection and low temperature operation are used in key steps to ensure the stability of active ingredients. Fluidized bed coating technology and rotary molding are both mature pharmaceutical processes with good process reproducibility and are suitable for large-scale industrial production.

[0028] (5) Compared with the existing single-phase pulse release of ordinary alfacalcidol soft capsules, the gradient release design of the present invention makes the blood drug concentration more stable, maintains the steady state of blood drug concentration, and reduces the risk of side effects such as hypercalcemia, nausea, and headache; at the same time, since the dosing frequency can be reduced from multiple times a day to once a day, the patient's medication compliance is improved. Attached Figure Description

[0029] Figure 1 This is a schematic diagram of the structure of the gradient release soft capsule containing alfacalcidol prepared in Example 1 of the present invention.

[0030] Figure 2 This is a magnified structural diagram of the alfacalcidol sustained-release microspheres of the present invention.

[0031] Figure 3 This is a comparison of the release curves of the soft capsule formulation prepared in Example 1 of the present invention before and after being placed under accelerated test conditions (40℃±2℃, RH 75%±5%) for 6 months.

[0032] Figure 4 This is a comparison chart of the in vitro release curves of the soft capsule formulations prepared in Examples 1, 2, and 3 of the present invention, as well as Comparative Examples 1 and 2.

[0033] The figures are labeled as follows: 1-soft capsule shell, 2-drug-containing oil phase, 3-alfacalcidol sustained-release microspheres, 4-blank capsule core, 5-drug-loaded layer, 6-sustaining-release coating layer. Detailed Implementation

[0034] The present invention will be described in more detail below with reference to embodiments, but the scope of protection of the present invention is not limited to these specific embodiments. All technologies implemented based on the above content of the present invention fall within the scope of the present invention. Unless otherwise stated, the raw materials and reagents used in the embodiments are commercially available industrial products or chemically pure products.

[0035] The release rate determination method involved in the examples: The alfacalcidol content was determined according to Method II (slurry method) of General Chapter 0931, Part IV, Chinese Pharmacopoeia 2025 Edition. The dissolution medium was pH 6.8 phosphate buffer (containing 0.1% Tween 80), 900 mL in volume, at a rotation speed of 50 rpm and a temperature of 37℃ ± 0.5℃. Samples of 5 mL were taken at 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h, 16 h, 20 h, 24 h, 30 h, 36 h, 48 h, 60 h, 72 h, 84 h, and 92 h, and an equal volume of fresh dissolution medium was added immediately. After filtration through a 0.45 μm filter, the alfacalcidol content was determined by high-performance liquid chromatography (HPLC), and the cumulative release rate was calculated.

[0036] The content determination methods involved in the examples are as follows: The determination was performed using HPLC. The chromatographic column was C2000. 18 The column (150 mm × 4.6 mm, 5 μm) was used with acetonitrile-water (75:25, v / v) as the mobile phase, a flow rate of 1.0 mL / min, a detection wavelength of 265 nm, a column temperature of 40 °C, and an injection volume of 20 μL. Example 1

[0037] 1. Preparation of alfacalcidol sustained-release microcapsules (500,000 capsules) Prescription composition: Alfacalcidol 0.2125g BHT (antioxidant) 2.0g HPMC E5 (film-forming agent) 1.7kg Anhydrous ethanol 28.5L Purified water 28.5L Microcrystalline cellulose pellet core (300~500μm) Appropriate amount .

[0038] Preparation method: (1) Dissolve the prescribed amounts of alfacalcidol, BHT and HPMC E5 in a mixed solvent of anhydrous ethanol and purified water, and stir for 4 hours to completely dissolve them to obtain a drug-loaded solution.

[0039] (2) Place the blank microcrystalline cellulose pellet core into the fluidized bed coating machine, set the appropriate air inlet temperature, and adjust the fan frequency to make the pellet core fluidized in a fountain-like state.

[0040] (3) When the material temperature reaches 35℃, start spraying the drug-loaded solution and spray it evenly onto the surface of the pellet core using a peristaltic pump. Control the material temperature below 40℃ throughout the coating process until all the drug-loaded solution has been sprayed.

[0041] (4) After spraying, continue fluidized drying for 10-20 minutes to remove residual solvent, and then sieve to obtain drug-loaded microspheres.

[0042] Utachi RS30D 31.86kg Utachi RL30D 2.13kg Triethyl citrate (plasticizer) 3.06 kg (25% of the dry weight of the polymer) Talc (anti-sticking agent) 4.90 kg (40% of the dry weight of the polymer) Purified water 58L .

[0043] (6) After the slow-release coating liquid is stirred evenly, fluidized bed coating technology is used. When the material temperature in the fluidized bed coating machine reaches 35°C, the liquid is sprayed. The material temperature is controlled below 40°C throughout the coating process until all the coating liquid is sprayed.

[0044] (7) Place the coated microcapsules in a 40°C oven and continue to cure for 4-6 hours to obtain alfacalcidol sustained-release microcapsules.

[0045] 2. Preparation of the drug-containing oil phase (500,000 tablets) Prescription composition: Alfacalcidol 0.0375g BHT 3.272g soybean oil 13.635kg .

[0046] Preparation method: Under nitrogen purging, the prescribed amount of soybean oil was added to a mixing container, along with BHT and alfacalcidol. The mixture was stirred for 4 hours using a magnetic stirrer at 420-460 rpm to obtain a concentrated solution. The concentrated solution was transferred to a mixing tank, and the original container was thoroughly rinsed five times with soybean oil. All of the rinsing solution was then transferred to the mixing tank. The nitrogen valve was opened, and nitrogen was introduced to maintain positive pressure inside the tank. Stirring was continued for 2 hours at a stirring speed of 18Hz ± 1Hz to obtain a diluted solution. After the solution was prepared, it was protected with nitrogen and sealed for later use.

[0047] 3. Preparation of soft capsule shell gelatin solution (500,000 capsules) Prescription composition: gelatin 100kg glycerin 30kg PEG400 5kg Titanium dioxide 1.250kg Sorbitol 3kg Purified water 100kg .

[0048] Preparation method: Heat the prescribed amount of purified water to 85°C. While stirring, add the prescribed amounts of glycerin, polyethylene glycol 400, titanium dioxide, sorbitol, and gelatin. Melt under vacuum at -0.085 MPa and 85°C for 20 minutes. Reduce the temperature to 75°C and adjust the vacuum pressure to -0.075 MPa, continuing to melt for 5–30 minutes. Turn off the stirrer and melt under vacuum at -0.075 MPa and 75°C for 3 minutes. After melting, keep the solution at 60°C for 2 hours to remove bubbles, then set aside.

[0049] 4. Shot pressing and drying The pelleting process was performed using a rotary molding method. The drug-containing oil phase obtained in step 2 and the alfacalcidol sustained-release microgranules obtained in step 1 were mixed evenly in a predetermined ratio and then simultaneously filled into the soft capsule shells prepared by the gelatin solution in step 3, and then compressed. The compressed soft capsules were then rapidly dried until the moisture content of the outer shell was 2%~5%, thus obtaining the desired product. Figure 1 and Figure 2 The illustrated is a gradient-release soft capsule formulation containing alfacalcidol.

[0050] 5. Stability Study The soft capsule formulation prepared in Example 1 was subjected to accelerated testing for 6 months in a constant temperature and humidity chamber at 40℃±2℃ and 75%±5% relative humidity. Samples were taken at 0, 1, 2, 3, and 6 months to determine the content, related substances, and release rate. The results are as follows: Figure 3 As shown, all indicators meet the quality standard requirements, and the formulation has good stability. Example 2

[0051] The difference between this embodiment and Embodiment 1 is that the weight ratio of Euteco RS30D to Euteco RL30D in the sustained-release coating solution is adjusted.

[0052] Changes to the sustained-release coating solution formula: Utachi RS30D 29.75kg Utachi RL30D 4.25kg Triethyl citrate 3.06kg talcum powder 4.90kg Purified water 58L The weight ratio of RS30D to RL30D is 7:1.

[0053] The other components and preparation methods are the same as in Example 1. Example 3

[0054] The difference between this embodiment and Embodiment 1 is that the weight ratio of Euteco RS30D to Euteco RL30D in the sustained-release coating solution is adjusted.

[0055] Changes to the sustained-release coating solution formula: Utachi RS30D 33.40kg Utachi RL30D 0.60kg Triethyl citrate 3.06kg talcum powder 4.90kg Purified water 58L The weight ratio of RS30D to RL30D is 55.7:1 (approximately 56:1).

[0056] The other components and preparation methods are the same as in Example 1. Example 4

[0057] The difference between this embodiment and Example 1 is that the ratio of alfacalcidol in the drug-containing oil phase to alfacalcidol in the sustained-release microcapsules is adjusted.

[0058] The changes to the formulation of the medicated oil are as follows: Alfacalcidol 0.0625g (500,000 capsules), while the dosage of alfacalcidol in the sustained-release microcapsules remains unchanged at 0.2125g (500,000 capsules).

[0059] The other components and preparation methods are the same as in Example 1. Example 5

[0060] The difference between this embodiment and Example 1 is that the ratio of alfacalcidol in the drug-containing oil phase to alfacalcidol in the sustained-release microcapsules is adjusted.

[0061] The changes to the formulation of the medicated oil are as follows: Alfacalcidol 0.0250g (500,000 capsules), while the dosage of alfacalcidol in the sustained-release microcapsules remains unchanged at 0.2125g (500,000 capsules).

[0062] The other components and preparation methods are the same as in Example 1. Comparative Example 1

[0063] This comparative example provides a commercially available standard alfacalcidol soft capsule (0.5 μg / capsule, a commercially available brand), which does not contain sustained-release microcapsule components. After oral administration, the drug is rapidly released from the oil phase. Comparative Example 2

[0064] This comparative example was prepared according to the method of Example 1 in CN103127020B, with alfacalcidol matrix sustained-release tablets, which do not contain immediate-release components, and the drug is slowly released from the matrix. Performance testing and comparative analysis

[0065] 1. In vitro release rate determination The in vitro release rates of the alfacalcidol formulations prepared in Examples 1-5 and Comparative Examples 1-2 were determined. The release rate was measured using a slurry method at 50 rpm, pH 6.8 phosphate buffer (containing 0.1% Tween 80), and 37°C. Sampling time points covered 13 time points from 0.5 h to 92 h. The results are shown in the table below (expressed as cumulative release rate %).

[0066] 0.5 10.8 12.3 8.6 11.2 9.5 42.1 2.3 1 14.1 16.8 11.3 15.1 12.8 61.4 4.8 2 18.5 21.2 14.8 19.3 16.5 84.2 8.1 4 23.8 27.6 19.0 24.9 21.2 96.3 14.2 8 31.2 36.7 25.5 32.8 28.9 99.1 23.7 12 37.2 43.1 31.4 39.4 35.1 100.2 33.1 16 42.3 48.2 36.5 44.6 40.0 100.5 41.4 20 46.9 52.6 41.0 49.2 44.4 100.8 49.2 24 50.4 56.1 44.9 52.8 48.0 101.0 56.6 30 54.8 60.3 49.8 57.2 52.5 - 64.1 36 58.9 64.2 54.5 61.4 56.8 - 70.8 48 65.8 71.1 62.0 68.4 63.5 - 79.2 60 72.9 77.6 69.3 75.5 70.8 - 86.1 72 79.5 83.4 76.2 82.1 77.8 - 91.8 84 85.8 88.9 83.1 88.2 84.5 - 95.7 92 92.1 94.2 89.5 94.0 91.2 - 98.3 .

[0067] The measurement results are shown in the table above. Figure 4 The release curves show that: Comparative Example 1 (commercially available ordinary soft capsules) was almost completely released within 4 hours (release rate reached 96.3%), exhibiting typical pulsatile rapid release behavior, with large fluctuations in blood drug concentration and obvious peak-trough phenomena. Comparative Example 2 (maintenance-release tablets) had a more gradual drug release, with 56.5% released after 24 hours and 95.7% after 84 hours, but it lacked an immediate-release component, resulting in a slow onset of action and failing to meet the clinical need for rapid onset of action.

[0068] Examples 1-5 achieved a dual-phase drug release behavior of immediate and sustained release within the same soft capsule: a rapid release rate (cumulative release rate of approximately 10%-28%) within 0.5-4 hours, achieving rapid onset of action; thereafter, the release rate gradually slowed down, with stable and sustained release over 8-36 hours (cumulative release rate of approximately 25%-64%), maintaining steady-state blood drug concentration; and the residual drug was slowly released over 48-92 hours, achieving a long-lasting effect. Example 1 exhibited the most ideal release curve, with 10.8% release at 0.5 hours, 50.4% at 24 hours, 85.8% at 84 hours, and 92.1% at 92 hours, achieving a gradient release pattern of rapid initial release followed by sustained release.

[0069] Comparing Examples 1-3, it is evident that the ratio of RS30D to RL30D in Eute Chemical significantly affects the release rate: a higher RS30D ratio (Example 3) results in slower release (44.9% release in 24 hours); a higher RL30D ratio (Example 2) results in faster release (56.1% release in 24 hours). Example 1 (RS30D:RL30D ≈ 15:1) exhibits a moderate and most stable release rate, making it the preferred ratio.

[0070] Comparing Examples 1, 4, and 5 reveals that the ratio of immediate-release to sustained-release components also affects the release curve: a higher proportion of immediate-release component (Example 4) results in a faster release rate at 0.5 hours (11.2%), suitable for clinical scenarios requiring faster onset of action; a lower proportion of immediate-release component (Example 5) results in a lower overall release curve (9.5% release at 0.5 hours), suitable for scenarios emphasizing stable release. The ratio in Example 1 (immediate:sustained ≈ 1:5.7) achieves the best balance between onset of action and stable release.

[0071] 2. In vivo pharmacokinetic studies Twelve healthy Beagle dogs (weighing 8–12 kg) were randomly divided into two groups of six each. One group was orally administered the gradient-release soft capsules prepared in Example 1 of this invention (containing 0.25 μg / capsule of alfacalcidol), while the other group was orally administered a commercially available reference formulation of ordinary alfacalcidol soft capsules (0.25 μg / capsule). All dogs were fasted for 12 hours prior to administration but had free access to water. Blood samples were collected before administration and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 30, 36, 48, 60, and 72 hours after administration. Plasma was separated, and the concentration of 1,25-(OH)₂D₃ in the plasma was determined by LC-MS / MS. The main pharmacokinetic parameters were calculated.

[0072] The results are as follows: Cmax (pg / mL) 42.3 ± 5.6 61.6 ± 13.6 Tmax(h) 6.5 ± 1.2 8.0 ± 2.0 <![CDATA[AUC0→ 72 (pg·h / mL)]]> 1426.8 ± 135.2 895.4 ± 142.1 <![CDATA[Half-life t1 / 2 (h)]]> 18.3 ± 2.1 8.5 ± 1.8 Blood drug concentration fluctuation coefficient 0.58 ± 0.08 1.24 ± 0.15 .

[0073] The results above show that the Cmax (42.3 pg / mL) of the gradient release soft capsule of the present invention is significantly lower than that of commercially available ordinary soft capsules (61.6 pg / mL), indicating that the gradient release design effectively reduces the peak concentration of the drug in the blood.

[0074] The blood drug concentration fluctuation coefficient of the gradient release soft capsule of the present invention (0.58) is significantly better than that of commercially available ordinary soft capsules (1.24), which proves that gradient release makes the blood drug concentration more stable, reduces the "peak and valley" fluctuation phenomenon, and thus reduces the risk of side effects such as hypercalcemia.

[0075] The gradient-release soft capsules of this invention have a significantly longer half-life (18.3 h) than commercially available ordinary soft capsules (8.5 h), AUC0→ 72 The concentration of the drug in the sustained-release microcapsules (1426.8 pg·h / mL) was significantly higher than that in commercially available ordinary soft capsules (895.4 pg·h / mL), indicating that the drug in the sustained-release microcapsules can be continuously released and absorbed, resulting in improved bioavailability, while the dosing frequency can be reduced to once a day.

[0076] The Tmax (6.5h) of the gradient-release soft capsules of the present invention is slightly faster than that of commercially available ordinary soft capsules (8.0h), indicating that the immediate-release alfacalcidol in the oil phase plays a role in rapid onset of action, while the sustained-release drug in the microcapsules ensures long-term maintenance of effect.

[0077] 3. Long-term stability test Three batches of gradient-release soft capsules prepared in Example 1 of this invention were subjected to long-term stability tests at 25℃±2℃ and 60%±10% relative humidity. Samples were taken at 0, 3, 6, 9, 12, 18, and 24 months to determine the content, related substances, and in vitro release rate.

[0078] The results are as follows: (1) Content determination results: The content of alfacalcidol at each time point remained between 96% and 103% of the labeled amount, with no obvious degradation trend.

[0079] (2) Related substances: The total amount of related substances at each time point was less than 1.5%, and the largest single impurity was less than 0.5%, which met the quality standard requirements. Alfacalcidol is sensitive to light and air and is prone to oxidative degradation. The gradient release soft capsule of the present invention effectively inhibits degradation by adding BHT antioxidant to the oil phase and titanium dioxide light-blocking agent to the soft capsule shell.

[0080] (3) In vitro release rate: The in vitro release curves of the 24-month sample and the 0-month sample were basically the same, with no significant difference (similarity factor f2>70), indicating that the gradient release characteristics remained stable during long-term storage.

[0081] 4. Comparison of the effects of different coating ratios on release performance Using Examples 1 (RS30D:RL30D≈15:1), 2 (RS30D:RL30D≈7:1), and 3 (RS30D:RL30D≈56:1) as the research subjects, the effect of the eutectic ratio on the release rate was investigated. The measurement results are included in the in vitro release rate determination section. Figure 4 As can be seen from the release curves, the release rate of the sustained-release microparticles gradually decreases with the increase of the proportion of ULTEC RS30D; while the release rate gradually increases with the increase of the proportion of RL30D.

[0082] This indicates that by adjusting the ratio of RS30D to RL30D, the drug release rate can be precisely controlled to meet the release rate requirements of different clinical application scenarios. The release curve is most ideal when the ratio of RS30D to RL30D is (14~16):1.

[0083] 5. Comparison of the effects of different immediate-release / sustaining-release ratios on release behavior Using Examples 1 (immediate release: sustained release ≈ 1:5.7), 4 (immediate release: sustained release ≈ 1:3.4), and 5 (immediate release: sustained release ≈ 1:8.5) as research subjects, the effect of the ratio of immediate-release to sustained-release components on release behavior was investigated. In vitro release rate measurements showed that as the proportion of the immediate-release component increased, the release rates at 0.5 hours and 1 hour correspondingly increased. Example 4 showed a release rate of 11.2% at 0.5 hours, significantly higher than the 9.5% of Example 5. This indicates that different initial release rates can be controlled by adjusting the ratio of the immediate-release to sustained-release components. Considering both onset speed and release stability, the preferred weight ratio of the immediate-release to sustained-release components is 1:(4~7), with 1:5.7 being optimal.

[0084] In summary, the gradient-release soft capsule formulation containing alfacalcidol provided by this invention achieves both immediate and sustained-release drug release within the same soft capsule, ensuring stable and controllable blood drug concentrations over 24 hours. This significantly reduces the risk of side effects such as hypercalcemia, nausea, and headache caused by fluctuations in blood drug concentration, while also reducing dosing frequency and improving patient adherence. The formulation's preparation process is stable and controllable, with good reproducibility. The excipients are all commonly used pharmaceutical excipients, facilitating industrial production and widespread application, and offering broad economic and social benefits.

[0085] The specific embodiments of the present invention have been described in detail above, but they are merely examples, and the present invention is not limited to the specific embodiments described above. For those skilled in the art, any equivalent modifications and substitutions to the present invention are also within the scope of the present invention. Therefore, all equivalent transformations and modifications made without departing from the spirit and scope of the present invention should be covered within the scope of the present invention.

Claims

1. A gradient-release soft capsule formulation containing alfacalcidol, characterized in that, The soft capsule formulation comprises a soft capsule shell and contents filling the soft capsule shell; the contents comprise a drug-containing oil phase and alfacalcidol sustained-release microgranules dispersed in the drug-containing oil phase; wherein: The drug-containing oil phase comprises an oily matrix and alfacalcidol dissolved in the oily matrix; the sustained-release microcapsules comprise a blank core, a drug-loaded layer coated on the surface of the blank core, and a sustained-release coating layer coated on the surface of the drug-loaded layer. After oral administration, alfacalcidol in the drug-containing oil phase is rapidly released from the oil phase to achieve rapid effect; alfacalcidol in the sustained-release microcapsules is slowly released through the sustained-release coating layer to achieve sustained release.

2. The gradient-release soft capsule formulation containing alfacalcidol according to claim 1, characterized in that, The sustained-release coating layer comprises a combination of Eutec RS30D and Eutec RL30D coating materials; The weight ratio of the Yutchi RS30D to the Yutchi RL30D is (10~20):

1.

3. The gradient-release soft capsule formulation containing alfacalcidol according to claim 2, characterized in that, The sustained-release coating layer also contains 20% to 30% plasticizer and 35% to 45% anti-sticking agent by the dry weight of the polymer. The plasticizer is triethyl citrate, and the anti-sticking agent is talc.

4. The gradient-release soft capsule formulation containing alfacalcidol according to claim 1, characterized in that, The weight ratio of alfacalcidol in the drug-containing oil phase to alfacalcidol in the sustained-release microcapsules is (0.1~1):(1~10). Of these, per 500,000 pills, the amount of alfacalcidol in the medicated oil phase is 0.0375g, and the amount of alfacalcidol in the sustained-release microcapsules is 0.2125g.

5. The gradient-release soft capsule formulation containing alfacalcidol according to claim 1, characterized in that, The blank pellet core is selected from microcrystalline cellulose pellet core, starch pellet core or sucrose pellet core, and its particle size is 200~600μm; The oily matrix is ​​selected from one or more of soybean oil, sesame oil, and medium-chain triglycerides; the drug-containing oil phase also contains an antioxidant, which is 2,6-di-tert-butyl-4-methylphenol.

6. The gradient-release soft capsule formulation containing alfacalcidol according to claim 1, characterized in that, The drug-loaded layer comprises alfacalcidol, a film-forming agent, an antioxidant, and a solvent; The film-forming agent is selected from one or more of hydroxypropyl methylcellulose, polyvinylpyrrolidone, and hydroxypropyl cellulose; the solvent is selected from anhydrous ethanol, purified water, and mixtures thereof.

7. A method for preparing a gradient-release soft capsule formulation containing alfacalcidol according to any one of claims 1 to 6, characterized in that, Includes the following steps: (1) Preparation of alfacalcidol sustained-release microcapsules: Alfacalcidol, film-forming agent and antioxidant are dissolved in solvent to prepare drug-loaded solution; Fluidized bed coating technology was used to spray the drug-loaded solution onto the surface of blank pellet cores, and after drying, drug-loaded microparticles were obtained; Eutrich RS30D, Eutrich RL30D, plasticizer and anti-adhesion agent were dispersed in water to prepare a sustained-release coating solution; Fluidized bed coating technology was used to spray the sustained-release coating liquid onto the surface of drug-loaded microspheres, and after solidification, alfacalcidol sustained-release microspheres were obtained. (2) Preparation of drug-containing oil phase: Under nitrogen protection conditions, alfacalcidol and antioxidants are dissolved in an oily matrix and stirred evenly to obtain a drug-containing oil phase; (3) Preparation of soft capsule shell solution: After heating purified water, add glycerin, polyethylene glycol 400, titanium dioxide, sorbitol and gelatin, stir and melt under vacuum, degas and keep warm for later use; (4) Pelletizing and drying: The drug-containing oil phase obtained in step (2) and the alfacalcidol sustained-release microspheres obtained in step (1) are mixed evenly and then simultaneously filled into soft capsule shells. After pressing and drying, the gradient release soft capsule formulation containing alfacalcidol is obtained.

8. The preparation method according to claim 7, characterized in that, In step (1), the material temperature is controlled below 40°C during the fluidized bed coating process; after the slow-release coating liquid is sprayed, it continues to solidify at 40°C for 4 to 6 hours.

9. The preparation method according to claim 7, characterized in that, In step (3), the melting process is carried out under vacuum pressure of -0.085~-0.070MPa and temperature of 75~85℃; the degassing process is carried out at 60℃ for 2 hours.

10. The preparation method according to claim 7, characterized in that, In step (4), the rubber is dried until the moisture content is 2% to 5%.

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