Pharmaceutical composition containing alfacalcidol and preparation method thereof

Abstract

The invention discloses a pharmaceutical composition containing alfacalcidol and a preparation method of the pharmaceutical composition. According to the alfacalcidol pharmaceutical composition, mannitol with a specific particle size is adopted as a filling agent, carboxymethyl starch sodium is adopted as an adhesive, poloxamer 188 is adopted as a stabilizer, and one-step granulation is performed in cooperation with a fluidized bed, so that the compliance, safety and effectiveness of medication of patients are improved, and the alfacalcidol pharmaceutical composition which is reliable and stable in quality and extremely small in specification is obtained. The preparation method is convenient, controllable, high in operability, good in reproducibility and suitable for industrialization.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition containing alfacalcidol and a preparation method thereof, and in particular to a pharmaceutical composition containing alfacalcidol with stable quality, safety and effectiveness and a preparation method thereof. Background Art

[0002] Alfacalcidol ((5Z,7E)-9,10-openedocholesterol-5,7,10(19)-triene-1α,3β-diol) is a calcitriol analogue that is sensitive to air or light. As a drug for the treatment of osteoporosis, it can increase the reabsorption of calcium by the small intestine and renal tubules, inhibit parathyroid hyperplasia, reduce the synthesis and release of parathyroid hormone, inhibit bone resorption, increase the synthesis of transforming growth factor-B (TGF-B) and insulin-like growth factor-1 (IGF-1), promote the synthesis of collagen and bone matrix protein, regulate muscle calcium metabolism, promote muscle cell differentiation, enhance muscle strength, increase neuromuscular coordination, and reduce the tendency to fall.

[0003]

[0004] CN110650730 discloses a pharmaceutical composition containing alfacalcidol, wherein the auxiliary materials include adhesive, lubricant, antioxidant, Tween 80 and anhydrous lactose, etc., and anhydrous lactose is also used in the alfacalcidol tablets produced by Teijin Pharma Co., Ltd. of Japan. Among them, people with intestinal lactase deficiency have poor lactose tolerance, which leads to frequent digestive system symptoms such as diarrhea, abdominal distension, abdominal pain, etc. after taking the drug; Tween 80 is relatively toxic, and excessive use may cause toxin accumulation in the body, causing nausea, vomiting, etc., increasing the risk of medication for children.

[0005] CN104739793 discloses an alfacalcidol tablet composition, the auxiliary material composition includes polyvinylpyrrolidone K30, hypromellose, sodium lauryl sulfate, filler (starch, lactose, dextrin, compressible starch, powdered sugar), disintegrant, appropriate amount of binder and lubricant. However, according to its prescription, sticking phenomenon is prone to occur during tablet compression, and the compressibility of the material is poor, which poses a quality risk for industrialization.

[0006] Therefore, it is very necessary to develop an alfacalcidol pharmaceutical composition with stable quality, lower toxicity, controllable process and conducive to industrialization. Summary of the invention

[0007] Objective of the invention: The first objective of the present invention is to provide a safe and effective pharmaceutical composition containing alfacalcidol, and the second objective is to provide a method for preparing the pharmaceutical composition with a stable and controllable preparation process.

[0008] Technical solution: The pharmaceutical composition containing alfacalcidol described in the present invention comprises, by weight, 0.0002-0.001 parts of alfacalcidol, 80-98 parts of mannitol, 0.1-0.5 parts of antioxidants, 0.05-0.25 parts of poloxamer 188, 0.5-3 parts of lubricants and 0.5-5 parts of sodium starch glycolate, wherein the average particle size of the mannitol is 50-400 μm.

[0009] The invention overcomes the adverse effects of lactose intolerance, reduces the toxic and side effects of stabilizers, improves the safety of medication for children through prescription optimization, and solves the problems of more fine powder in wet granulation, sticking during tableting, poor compressibility, larger particles, and overdue disintegration time.

[0010] The invention effectively solves the problems of sticking and poor compressibility in the tableting process by screening the types and proportions of auxiliary materials, using sodium carboxymethyl starch as a binder, and controlling the particle size of the filler mannitol. The preparation method is simple, safe, and economical. The product has uniform content, rapid dissolution, good compressibility, smooth surface, and stable quality. The product is suitable for large-scale industrial production, and the dissolution behavior is similar to that of the reference preparation alfacalcidol tablets. Since alfacalcidol is a highly active drug, the prescription design is further coordinated with a fluidized bed one-step granulation process to reduce cross contamination and safety problems caused by large dust.

[0011] Among them, mannitol is used as a filler. When its particle size is too high, the disintegration time becomes slower. Since the API accounts for a very small proportion in the pharmaceutical composition, the API is dissolved in an ethanol solution and evenly adhered to the surface of mannitol through fluidized bed bottom spraying. Mannitol is used as a drug carrier, and its particle size can be controlled to ensure uniform drug loading of the API. In addition, mannitol replaces lactose as a filler, reducing adverse reactions caused by lactose intolerance.

[0012] Low-viscosity sodium carboxymethyl starch is used as an adhesive, with a small amount and uniform particle size, fluffy particles, less fine powder, good content uniformity, stable subsequent tableting performance, no sticking, no tablet cracking, smooth and shiny tablet surface, and fast tablet disintegration. At the same time, sodium carboxymethyl starch is also used as a disintegrant, with a good disintegration effect, even when the prepared particles are large, it can also have a good disintegration effect, and has a synergistic promotion effect on granulation, tableting and disintegration time. The following problems that ordinary adhesives occur are avoided: (1) the cohesive force is large, resulting in a timeout of the disintegration time, (2) the small amount of particles resulting in more fine powder, poor particle fluidity, and alfacalcidol failing to fully adhere to the surface of mannitol during granulation, thereby drying and escaping, (3) sticking and poor compressibility still occur when a lubricant is added or the amount of lubricant is increased.

[0013] Poloxamer 188, as a stabilizer, can inhibit degradation products. Poloxamer 188 is a high molecular nonionic surfactant, a polyoxyethylene polyoxypropylene ether block copolymer, which is dissolved in an ethanol solution. Under the influence of lipophilic and hydrophilic groups, it forms micellar particles with hydrophobic alfacalcidol, thereby protecting alfacalcidol and isolating it from the influence of air. At the same time, the safety of poloxamer 188 is higher than that of Tween 80. Alfacalcidol tablets are suitable for children, and the use of poloxamer 188 helps to improve the safety of children's medication. In addition, poloxamer 188 has the effect of promoting absorption, which increases the retention time of the drug in the gastrointestinal tract and increases absorption, thereby improving bioavailability.

[0014] Sodium thiosulfate, as an antioxidant, can inhibit the formation of precursors.

[0015] Plant-derived magnesium stearate is used as a lubricant, which improves the fluidity of the particles, makes the surface of the compressed tablets smoother, and has better dissolution rate and disintegration time.

[0016] Preferably, the pharmaceutical composition comprises, by weight, 0.0002 to 0.0006 parts of alfacalcidol, 80 to 96.5 parts of mannitol, 0.1 to 0.375 parts of antioxidant, 0.05 to 0.125 parts of poloxamer 188, 0.5 to 3 parts of sodium starch glycolate and 0.5 to 2 parts of lubricant.

[0017] Preferably, the pharmaceutical composition comprises, by weight, 0.0006 parts of alfacalcidol, 96.5 parts of mannitol, 0.375 parts of antioxidant, 0.125 parts of poloxamer 188, 1 part of lubricant and 2 parts of sodium starch glycolate.

[0018] More preferably, in the pharmaceutical composition, the average particle size of the mannitol is 100 to 200 μm.

[0019] Preferably, in the pharmaceutical composition, the antioxidant is selected from one or more of sodium metabisulfite, sodium thiosulfate, and gallic acid.

[0020] More preferably, the antioxidant is selected from sodium thiosulfate.

[0021] Preferably, in the pharmaceutical composition, the lubricant is selected from magnesium stearate of plant origin or magnesium stearate of animal origin.

[0022] More preferably, the lubricant is selected from magnesium stearate of plant origin.

[0023] Preferably, the pharmaceutical composition comprises, by weight, 0.0006 parts of alfacalcidol, 96.5 parts of mannitol, 0.375 parts of sodium thiosulfate, 0.125 parts of poloxamer 188, 1 part of plant-derived magnesium stearate and 2 parts of sodium starch glycolate; wherein the average particle size of mannitol is 100 μm or 200 μm.

[0024] Preferably, the disintegration time of the pharmaceutical composition does not exceed 5 minutes.

[0025] Preferably, the dissolution rate of the pharmaceutical composition measured by the following method is not less than 90%;

[0026] Paddle method, dissolution medium: pH 1.2 sodium chloride-hydrochloric acid-0.05m% Tween 80 medium, dissolution medium volume: 100ml, rotation speed: 35 rpm, sampling time point: 15 minutes.

[0027] Preferably, in the dissolution curve of the pharmaceutical composition measured by the following method, the cumulative dissolution in 15 minutes is not less than 90%;

[0028] Paddle method, dissolution medium: pH 1.2 sodium chloride-hydrochloric acid-0.05% m / v Tween 80 medium, dissolution medium volume: 100 ml, rotation speed: 35 rpm, sampling time points: 5, 10, 15, 30, 45 and 60 minutes, sampling volume: 5 ml and add the same volume of dissolution medium at the same time.

[0029] The method for preparing the pharmaceutical composition containing alfacalcidol of the present invention comprises the following steps:

[0030] (1) Granulation: spray granulation, drying and granulation of mannitol and a binder solution, wherein the binder solution is an ethanol solution containing alfacalcidol, an antioxidant, poloxamer 188 and sodium starch glycolate;

[0031] (2) Total mixing: mixing the mixture obtained in step (1) with a lubricant;

[0032] (3) Tableting: The mixture obtained in step (2) is tableted to obtain the pharmaceutical composition.

[0033] The present invention adopts a one-step granulation method, reduces the operation links, and alfacalcidol is a highly active drug (low therapeutic dose, high pharmacological activity, high toxicity or high sensitization), and the fluidized bed one-step granulation can effectively prevent the harm to personnel and material cross contamination caused by large dust, and the granulation efficiency is high, saving production costs. At the same time, in the process of fluidized bed granulation, by selecting specific auxiliary materials and the ratio and dosage between the auxiliary materials, controlling the mannitol particle size, and parameter conditions in the granulation process, the small-scale raw material drugs in the formula are uniformly applied, and the obtained particles are uniform, have good fluidity, good compression formability, are non-sticky, and the tablets disintegrate quickly and have a fast dissolution rate.

[0034] Preferably, the order of adding alfacalcidol, antioxidant, sodium starch glycolate and poloxamer 188 in step (1) affects the stability of the API. Alfacalcidol is added after the antioxidant and poloxamer 188 are dissolved in ethanol, which results in the best stability.

[0035] Preferably, before step (1), the mannitol is passed through a 24-60 mesh sieve, more preferably a 30 mesh sieve, to eliminate agglomeration and caking caused by the mannitol during storage.

[0036] Preferably, step (1) is granulated in a fluidized bed, and the granulation parameters are as follows: the air volume during granulation is 30-100 Hz, the atomization pressure is 0.1-0.3 MPa, the ejector pressure is 0.2-0.4 MPa, when the material temperature is 35-45°C, the adhesive is sprayed into the bottom spray granulation, the liquid supply speed is 2-20 rpm, and the material temperature is controlled at 30-45°C during the granulation process.

[0037] Preferably, after the granulation in step (1), drying is performed at a temperature of 40 to 55° C., more preferably 45° C., and the loss on drying is controlled to be less than 0.5%, and then the granules are sieved through a 30-mesh screen.

[0038] Preferably, the hardness of the tablet during tableting in step (3) is 40 to 70N.

[0039] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages:

[0040] The present invention optimizes the types and proportions of auxiliary materials, uses mannitol with a specific particle size as a filler, sodium carboxymethyl starch as a binder, poloxamer 188 as a stabilizer, and cooperates with fluidized bed one-step granulation to improve the compliance, safety and effectiveness of patients' medication, and obtains an alfacalcidol pharmaceutical composition with extremely small specifications and reliable and stable quality. The preparation method is convenient and controllable, has strong operability, good reproducibility, and is suitable for industrialization. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] Figure 1 These are the dissolution curves of different alfacalcidol tablets. DETAILED DESCRIPTION

[0042] The technical solution of the present invention is further described below in conjunction with embodiments.

[0043] The amounts of raw and auxiliary materials used in the preparation of alfacalcidol tablets with different fillers and adhesives are shown in Tables 1 to 4.

[0044] Table 1 Summary of Alfacalcidol Tablet Prescriptions for Example 1 to Example 2 (Specifications: containing 0.5 μg of Alfacalcidol)

[0045] Raw materials Example 1 Example 2 Alfacalcidol 0.0006％ 0.0006％ Mannitol 96.5%(100μm) 96.5%(200μm) Compressible starch / / Microcrystalline Cellulose / / Polyvinyl alcohol / / Hydroxypropyl Cellulose / / Povidone K30 / / Sodium starch glycolate 2％ 2％ Poloxamer 188 0.125％ 0.125％ Sodium Thiosulfate 0.375％ 0.375％ Magnesium Stearate 1％ 1％

[0046] Example 1

[0047] According to the formula in Table 1, 4000 Alfacalcidol tablets were prepared. The specific preparation method is as follows:

[0048] (1) Pretreatment: Mannitol is passed through a 30-mesh sieve for later use; Poloxamer 188 and sodium thiosulfate are added to ethanol in sequence, and alfacalcidol is added after the solution is clear. After the solution is clear, sodium carboxymethyl starch is added and dispersed in the ethanol solution, and the mixture is stirred continuously to prepare a binder solution for later use.

[0049] (2) Granulation: The mannitol in (1) is placed in a fluidized bed and preheated for 3 minutes at an air volume of 50 Hz. Then, granulation is performed in the fluidized bed with the following parameters: granulation air volume of 70 Hz, atomization pressure of 0.2 MPa, ejector pressure of 0.3 MPa, when the material temperature is 35-45°C, the binder solution is sprayed into the bottom of the granulator for granulation, the liquid supply speed is 4-8 rpm, the granulation temperature is controlled at 30-45°C, when drying, the drying temperature is 45°C, and the moisture content is controlled to be less than 0.5%; after drying, the granules are sieved through a 30-mesh sieve.

[0050] (3) Mixing: Magnesium stearate and the dry granules obtained in step (2) were mixed in a hopper mixer at a speed of 10 rpm for 10 minutes.

[0051] (4) Tableting: Control the hardness to 40-70N.

[0052] Example 2

[0053] According to the formula in Table 1, 4000 Alfacalcidol tablets were prepared. The specific preparation method is as follows:

[0054] (1) Pretreatment: Mannitol is passed through a 30-mesh sieve for later use; Poloxamer 188 and sodium thiosulfate are added to ethanol in sequence, and alfacalcidol is added after the solution is clear. After the solution is clear, sodium carboxymethyl starch is added and dispersed in the ethanol solution, and the mixture is stirred continuously to prepare a binder solution for later use.

[0055] (2) Granulation: The mannitol in (1) is placed in a fluidized bed and preheated for 3 minutes at an air volume of 50 Hz. Then, granulation is performed in the fluidized bed with the following parameters: granulation air volume of 70 Hz, atomization pressure of 0.2 MPa, ejector pressure of 0.3 MPa, when the material temperature is 35-45°C, the binder solution is sprayed into the bottom of the granulator for granulation, the liquid supply speed is 4-8 rpm, the granulation temperature is controlled at 30-45°C, when drying, the drying temperature is 45°C, and the moisture content is controlled to be less than 0.5%; after drying, the granules are sieved through a 30-mesh sieve.

[0056] (3) Mixing: Magnesium stearate and the dry granules obtained in step (2) were mixed in a hopper mixer at a speed of 10 rpm for 10 minutes.

[0057] (4) Tableting: Control the hardness to 40-70N.

[0058] Table 2 Comparative Examples 1-2 Alfacalcidol Tablets Prescription Summary (Specification: containing 0.5 μg of Alfacalcidol)

[0059] Raw materials Comparative Example 1 Comparative Example 2 Alfacalcidol 0.0006％ 0.0006％ Mannitol / / Compressible starch 96.5％ / Microcrystalline Cellulose / 96.5％ Polyvinyl alcohol / / Hydroxypropyl Cellulose / / Povidone K30 / / Sodium starch glycolate 2％ 2％ Poloxamer 188 0.125％ 0.125％ Sodium Thiosulfate 0.375％ 0.375％ Magnesium Stearate 1％ 1％

[0060] Comparative Example 1

[0061] 4000 Alfacalcidol tablets were prepared according to the formula in Table 2. The specific preparation method is as follows:

[0062] (1) Pretreatment: compressible starch is passed through a 30-mesh sieve for later use; poloxamer 188 and sodium thiosulfate are added to ethanol in sequence, and alfacalcidol is added after the solution is clear, and sodium carboxymethyl starch is added after the solution is clear and dispersed in the ethanol solution, and the mixture is stirred continuously to prepare a binder solution for later use.

[0063] (2) Granulation: The mannitol in (1) is placed in a fluidized bed and preheated for 3 minutes at an air volume of 50 Hz. Then, granulation is performed in the fluidized bed with the following parameters: granulation air volume of 70 Hz, atomization pressure of 0.2 MPa, ejector pressure of 0.3 MPa, when the material temperature is 35-45°C, the binder solution is sprayed into the bottom of the granulator for granulation, the liquid supply speed is 4-8 rpm, the granulation temperature is controlled at 30-45°C, when drying, the drying temperature is 45°C, and the moisture content is controlled to be less than 0.5%; after drying, the granules are sieved through a 30-mesh sieve.

[0064] (3) Mixing: Magnesium stearate and the dry granules obtained in step (2) were mixed in a hopper mixer at a speed of 10 rpm for 10 minutes.

[0065] (4) Tableting: Control the hardness to 40-70N.

[0066] Comparative Example 2

[0067] 4000 Alfacalcidol tablets were prepared according to the formula in Table 2. The specific preparation method is as follows:

[0068] (1) Pretreatment: Microcrystalline cellulose is passed through a 30-mesh sieve for later use; Poloxamer 188 and sodium thiosulfate are added to ethanol in sequence, and alfacalcidol is added after the solution is clear. After the solution is clear, sodium starch glycolate is added and dispersed in the ethanol solution, and the mixture is stirred continuously to prepare a binder solution for later use.

[0069] (2) Granulation: The mannitol in (1) is placed in a fluidized bed and preheated for 3 minutes at an air volume of 50 Hz. Then, granulation is performed in the fluidized bed with the following parameters: granulation air volume of 70 Hz, atomization pressure of 0.2 MPa, ejector pressure of 0.3 MPa, when the material temperature is 35-45°C, the binder solution is sprayed into the bottom of the granulator for granulation, the liquid supply speed is 4-8 rpm, the granulation temperature is controlled at 30-45°C, when drying, the drying temperature is 45°C, and the moisture content is controlled to be less than 0.5%; after drying, the granules are sieved through a 30-mesh sieve.

[0070] (3) Mixing: Magnesium stearate and the dry granules obtained in step (2) were mixed in a hopper mixer at a speed of 10 rpm for 10 minutes.

[0071] (4) Tableting: Control the hardness to 40-70N.

[0072] Table 3 Summary of prescriptions for Alfacalcidol tablets in Comparative Examples 3 to 5 (Specifications: containing 0.5 μg of Alfacalcidol)

[0073] Raw materials Comparative Example 3 Comparative Example 4 Comparative Example 5 Alfacalcidol 0.0006％ 0.0006％ 0.0006 Mannitol 96.5％ 96.5％ 96.5％ Compressible starch / / / Microcrystalline Cellulose / / / Polyvinyl alcohol 2％ / / Hydroxypropyl Cellulose / 2％ / Povidone K30 / / 2％ Sodium starch glycolate / / / Poloxamer 188 0.125％ 0.125％ 0.125％ Sodium Thiosulfate 0.375％ 0.375％ 0.375％ Magnesium Stearate 1％ 1％ 1％

[0074] Comparative Example 3

[0075] According to the formula in Table 3, 4000 Alfacalcidol tablets were prepared. The specific preparation method is as follows:

[0076] (1) Pretreatment: Mannitol is passed through a 30-mesh sieve for later use; Poloxamer 188, polyvinyl alcohol, and sodium thiosulfate are added to ethanol in sequence, and after dissolving, alfacalcidol is added and stirred continuously to prepare the adhesive solution for later use.

[0077] (2) Granulation: The mannitol in (1) is placed in a fluidized bed and preheated for 3 minutes at an air volume of 50 Hz. Then, granulation is performed in the fluidized bed with the following parameters: granulation air volume of 70 Hz, atomization pressure of 0.2 MPa, ejector pressure of 0.3 MPa, when the material temperature is 35-45°C, the binder solution is sprayed into the bottom of the granulator for granulation, the liquid supply speed is 4-8 rpm, the granulation temperature is controlled at 30-45°C, when drying, the drying temperature is 45°C, and the moisture content is controlled to be less than 0.5%; after drying, the granules are sieved through a 30-mesh sieve.

[0078] (3) Mixing: Magnesium stearate and the dry granules obtained in step (2) were mixed in a hopper mixer at a speed of 10 rpm for 10 minutes.

[0079] (4) Tableting: Control the hardness to 40-70N.

[0080] Comparative Example 4

[0081] According to the formula in Table 3, 4000 Alfacalcidol tablets were prepared. The specific preparation method is as follows:

[0082] (1) Pretreatment: Mannitol is passed through a 30-mesh sieve for later use; poloxamer 188, hydroxypropyl cellulose, and sodium thiosulfate are added to ethanol in sequence, and after dissolving, alfacalcidol is added and stirred continuously to prepare the adhesive solution for later use.

[0083] (2) Granulation: The mannitol in (1) is placed in a fluidized bed and preheated for 3 minutes at an air volume of 50 Hz. Then, granulation is performed in the fluidized bed with the following parameters: granulation air volume of 70 Hz, atomization pressure of 0.2 MPa, ejector pressure of 0.3 MPa, when the material temperature is 35-45°C, the binder solution is sprayed into the bottom of the granulator for granulation, the liquid supply speed is 4-8 rpm, the granulation temperature is controlled at 30-45°C, when drying, the drying temperature is 45°C, and the moisture content is controlled to be less than 0.5%; after drying, the granules are sieved through a 30-mesh sieve.

[0084] (3) Mixing: Magnesium stearate and the dry granules obtained in step (2) were mixed in a hopper mixer at a speed of 10 rpm for 10 minutes.

[0085] (4) Tableting: Control the hardness to 40-70N.

[0086] Comparative Example 5

[0087] According to the formula in Table 3, 4000 Alfacalcidol tablets were prepared. The specific preparation method is as follows:

[0088] (1) Pretreatment: Mannitol is passed through a 30-mesh sieve for later use; Poloxamer 188, povidone K30, and sodium thiosulfate are added to ethanol in sequence, and after dissolving, alfacalcidol is added and stirred continuously to prepare the adhesive solution for later use.

[0089] (2) Granulation: The mannitol in (1) is placed in a fluidized bed and preheated for 3 minutes at an air volume of 50 Hz. Then, granulation is performed in the fluidized bed with the following parameters: granulation air volume of 70 Hz, atomization pressure of 0.2 MPa, ejector pressure of 0.3 MPa, when the material temperature is 35-45°C, the binder solution is sprayed into the bottom of the granulator for granulation, the liquid supply speed is 4-8 rpm, the granulation temperature is controlled at 30-45°C, when drying, the drying temperature is 45°C, and the moisture content is controlled to be less than 0.5%; after drying, the granules are sieved through a 30-mesh sieve.

[0090] (3) Mixing: Magnesium stearate and the dry granules obtained in step (2) were mixed in a hopper mixer at a speed of 10 rpm for 10 minutes.

[0091] (4) Tableting: Control the hardness to 40-70N.

[0092] Table 4 Summary of prescriptions for Alfacalcidol tablets in Comparative Examples 6 to 8 (Specifications: containing 0.5 μg of Alfacalcidol)

[0093]

[0094]

[0095] Comparative Example 6

[0096] According to the formula in Table 1, 4000 Alfacalcidol tablets were prepared. The specific preparation method is as follows:

[0097] (1) Pretreatment: Mannitol is passed through a 30-mesh sieve for later use; sodium thiosulfate is added to ethanol, and after the solution is clear, alfacalcidol is added, and after the solution is clear, sodium carboxymethyl starch is added and dispersed in the ethanol solution, and the mixture is stirred continuously to prepare a binder solution for later use.

[0098] (2) Granulation: The mannitol in (1) is placed in a fluidized bed and preheated for 3 minutes at an air volume of 50 Hz. Then, granulation is performed in the fluidized bed with the following parameters: granulation air volume of 70 Hz, atomization pressure of 0.2 MPa, ejector pressure of 0.3 MPa, when the material temperature is 35-45°C, the binder solution is sprayed into the bottom of the granulator for granulation, the liquid supply speed is 4-8 rpm, the granulation temperature is controlled at 30-45°C, when drying, the drying temperature is 45°C, and the moisture content is controlled to be less than 0.5%; after drying, the granules are sieved through a 30-mesh sieve.

[0099] (3) Mixing: Magnesium stearate and the dry granules obtained in step (2) were mixed in a hopper mixer at a speed of 10 rpm for 10 minutes.

[0100] (4) Tableting: Control the hardness to 40-70N.

[0101] Comparative Example 7

[0102] According to the formula in Table 1, 4000 Alfacalcidol tablets were prepared. The specific preparation method is as follows:

[0103] (1) Pretreatment: Mannitol is passed through a 30-mesh sieve for later use; Poloxamer 188 is added to ethanol, and after the solution is clear, alfacalcidol is added, and after the solution is clear, sodium starch glycolate is added and dispersed in the ethanol solution, and the mixture is stirred continuously to prepare the adhesive solution for later use.

[0104] (2) Granulation: The mannitol in (1) is placed in a fluidized bed and preheated for 3 minutes at an air volume of 50 Hz. Then, granulation is performed in the fluidized bed with the following parameters: granulation air volume of 70 Hz, atomization pressure of 0.2 MPa, ejector pressure of 0.3 MPa, when the material temperature is 35-45°C, the binder solution is sprayed into the bottom of the granulator for granulation, the liquid supply speed is 4-8 rpm, the granulation temperature is controlled at 30-45°C, when drying, the drying temperature is 45°C, and the moisture content is controlled to be less than 0.5%; after drying, the granules are sieved through a 30-mesh sieve.

[0105] (3) Mixing: Magnesium stearate and the dry granules obtained in step (2) were mixed in a hopper mixer at a speed of 10 rpm for 10 minutes.

[0106] (4) Tableting: Control the hardness to 40-70N.

[0107] Comparative Example 8

[0108] According to the formula in Table 1, 5000 Alfacalcidol tablets were prepared. The specific preparation method is as follows:

[0109] (1) Pretreatment: Mannitol is passed through a 30-mesh sieve for later use; Poloxamer 188 and sodium thiosulfate are added to ethanol in sequence, and alfacalcidol is added after the solution is clear. After the solution is clear, sodium carboxymethyl starch is added and dispersed in the ethanol solution, and the mixture is stirred continuously to prepare a binder solution for later use.

[0110] (2) Granulation: The mannitol in (1) is placed in a fluidized bed and preheated for 3 minutes at an air volume of 50 Hz. Then, granulation is performed in the fluidized bed with the following parameters: granulation air volume of 70 Hz, atomization pressure of 0.2 MPa, ejector pressure of 0.3 MPa, when the material temperature is 35-45°C, the binder solution is sprayed into the bottom of the granulator for granulation, the liquid supply speed is 4-8 rpm, the granulation temperature is controlled at 30-45°C, when drying, the drying temperature is 45°C, and the moisture content is controlled to be less than 0.5%; after drying, the granules are sieved through a 30-mesh sieve.

[0111] (3) Mixing: Magnesium stearate and the dry granules obtained in step (2) were mixed in a hopper mixer at a speed of 10 rpm for 10 minutes.

[0112] (4) Tableting: Control the hardness to 40-70N.

[0113] Comparative Example 9

[0114] Alfacalcidol tablets were prepared with reference to the formula and preparation method of Example 1 in CN104739793A.

[0115] Comparative Example 10

[0116] Alfacalcidol tablets were prepared with reference to the formula and preparation method of Example 2 in CN104739793A.

[0117] Comparative Example 11

[0118] Alfacalcidol tablets were prepared with reference to the formula and preparation method of Example 3 in CN104739793A.

[0119] Example 3: Quality and process evaluation

[0120] (1) Dissolution curve method

[0121] Method: paddle method, dissolution medium: pH 1.2 sodium chloride-hydrochloric acid (0.05% m / v Tween 80) medium, dissolution medium: 100 ml, rotation speed: 35 rpm, sampling time points: 5, 10, 15, 30, 45, 60 minutes sampling, take 5 ml of solution (add the same volume of solvent at the same time), filter through water membrane, and take the filtrate as the test solution.

[0122] Reference substance solution: Take an appropriate amount of alfacalcidol reference substance, weigh it accurately, add dissolution medium to dissolve it and quantitatively dilute it to make a solution containing approximately 0.1 μg of alfacalcidol per 1 ml.

[0123] (2) High performance liquid chromatography

[0124] The alfacalcidol tablets prepared in the examples and comparative examples were subjected to an investigation of the smoothness of the granulation process, the smoothness of the tableting process, the tablet core quality, the solubility, and the dissolution curve in a pH 1.2 sodium chloride-hydrochloric acid (0.05% m / v Tween 80) medium (including but not limited to the disintegration time and dissolution investigation).

[0125] Table 5 The smoothness of the granulation process of Alfacalcidol Tablets, the smoothness of the tableting process, the quality of the tablet core, and the dissolution results

[0126]

[0127] As can be seen from Table 5, by comparing the screening of different fillers, the samples prepared by fluidized bed granulation of mannitol as a filler (Example 1-Example 2) and the tablets obtained by fluidized bed granulation of compressible starch and microcrystalline cellulose (Comparative Example 1-Comparative Example 2) have excellent disintegration time, while the disintegration time of other filler groups exceeds the limit. In addition, the samples of different filler groups have uneven particles during granulation and sticking phenomenon during tablet compression. The present invention selects mannitol as a filler and controls its average particle size between 100-200 μm, and the tablets prepared do not have sticking phenomenon, the tablet surface is smooth, and there is excellent disintegration time, and the various indicators of the core meet the requirements. Among them, the tablets prepared by mannitol particle size not within the preferred range of the present invention (Comparative Example 8) are not sticky, the disintegration time barely meets the requirements and has a tendency to slow down, the particles have obvious unevenness during granulation, and the content uniformity of the sample exceeds the limit. The samples prepared by high shear granulation process showed sticking phenomenon during tableting and the disintegration time was slowed down.

[0128] Comparing the screening of different adhesives, the tablets obtained by fluidized bed granulation of sodium carboxymethyl starch (Example 1 to Example 2) and fluidized bed granulation of other adhesives polyvinyl alcohol, hydroxypropyl cellulose, and povidone K30 (Comparative Example 3 to Comparative Example 5) are compared. The sodium carboxymethyl starch has an excellent disintegration time as an adhesive sample, while the disintegration time of other adhesive groups is exceeded. In addition, the granulation process of different adhesive groups shows uneven particles and different degrees of sticking or large main pressure during tableting. The present invention uses sodium carboxymethyl starch as an adhesive to prepare samples, and no abnormalities occur in the tableting process of the granulator, and the quality of the core tablets meets the expected requirements.

[0129] Table 6 Dissolution curve of Alfacalcidol tablets (cumulative dissolution, %)

[0130]

[0131] As can be seen from Table 6, the samples prepared by selecting mannitol as a filler and sodium carboxymethyl starch as a binder (Example 1 to Example 2) have excellent dissolution rates, all of which belong to rapid dissolution, and the dissolution rate is faster than that of the high shear granulation method (Comparative Example 9 to Comparative Example 11). The particles prepared by the high shear process are relatively hard, which may be due to the high granulation intensity or the difference in auxiliary materials affecting the particle hardness and causing the dissolution to slow down. Therefore, the present invention selects mannitol as a filler and controls its average particle size to 50 to 400 μm, preferably 100 to 200 μm.

[0132] Without poloxamer 188 (Comparative Example 6) and sodium thiosulfate (Comparative Example 7) in the prescription, the dissolution rate showed a trend of slowing down and the end point dissolution value was relatively low. Combined with the decreasing trend of the content in Comparative Examples 6 to 7, it was preliminarily determined that poloxamer 188 as a stabilizer and sodium thiosulfate as an antioxidant could inhibit degradation to a certain extent.

[0133] Example 4: Stability Evaluation

[0134] The samples prepared in the embodiment and the comparative example were placed in an environment of 25±2° C. and RH60%±5% for 12 consecutive months, and the total impurity content of the alfacalcidol tablets at 0 day and 12 months was detected by high performance liquid chromatography.

[0135] Table 7 Related substances of Alfacalcidol Tablets

[0136]

[0137] As can be seen from Table 7, the alfacalcidol tablets designed by the present invention have no significant changes in disintegration time, related substances and content after a long period of 12 months, and the stability is optimal. Among them, the related substances and contents of the samples without poloxamer 188 (Comparative Example 6) and without sodium thiosulfate (Comparative Example 7) in the prescriptions all show obvious degradation trends, and the degradation trend of the prescription without poloxamer 188 is more obvious than that of the prescription without sodium thiosulfate, indicating that poloxamer 188 as a stabilizer is beneficial to inhibiting degradation products.

Claims

1. A pharmaceutical composition containing alfacalcidol, characterized in that: The invention comprises, by weight, 0.0002 to 0.001 parts of alfacalcidol, 80 to 98 parts of mannitol, 0.1 to 0.5 parts of antioxidant, 0.05 to 0.25 parts of poloxamer 188, 0.5 to 3 parts of lubricant and 0.5 to 5 parts of sodium starch glycolate, wherein the average particle size of the mannitol is 50 to 400 μm.

2. The pharmaceutical composition according to claim 1, characterized in that In parts by weight, it comprises 0.0002-0.0006 parts of alfacalcidol, 80-96.5 parts of mannitol, 0.1-0.375 parts of antioxidant, 0.05-0.125 parts of poloxamer 188, 0.5-2 parts of lubricant and 0.5-3 parts of sodium starch glycolate.

3. The pharmaceutical composition according to claim 1, characterized in that In parts by weight, it comprises 0.0006 parts of alfacalcidol, 96.5 parts of mannitol, 0.375 parts of antioxidant, 0.125 parts of poloxamer 188, 1 part of lubricant and 2 parts of sodium starch glycolate.

4. The pharmaceutical composition according to claim 1, characterized in that The average particle size of the mannitol is 100-200 μm.

5. The pharmaceutical composition according to claim 1, characterized in that The antioxidant is selected from one or more of sodium pyrosulfite, sodium thiosulfate and gallic acid.

6. The pharmaceutical composition according to claim 1, characterized in that The lubricant is selected from magnesium stearate of plant origin or magnesium stearate of animal origin.

7. The pharmaceutical composition according to claim 1, characterized in that In parts by weight, it comprises 0.0006 parts of alfacalcidol, 96.5 parts of mannitol, 0.375 parts of sodium thiosulfate, 0.125 parts of poloxamer 188, 1 part of plant-derived magnesium stearate and 2 parts of sodium starch glycolate; wherein the average particle size of mannitol is 100 μm or 200 μm.

8. The pharmaceutical composition according to claim 1, characterized in that The disintegration time limit does not exceed 5 minutes.

9. The pharmaceutical composition according to claim 1, characterized in that In the dissolution curve determined by the following method, the cumulative dissolution in 15 minutes is not less than 90%; Paddle method, dissolution medium: pH 1.2 sodium chloride-hydrochloric acid-0.05% m / v Tween 80 medium, dissolution medium volume: 100 ml, rotation speed: 35 rpm, sampling time points: 5, 10, 15, 30, 45, 60 minutes, sampling volume: 5 ml and add the same volume of dissolution medium at the same time.

10. The method for preparing the pharmaceutical composition containing alfacalcidol according to claim 1, characterized in that: The following steps are involved: (1) Granulation: spray granulation, drying and granulation of mannitol and a binder solution, wherein the binder solution is an ethanol solution containing alfacalcidol, an antioxidant, poloxamer 188 and sodium starch glycolate; (2) Total mixing: mixing the mixture obtained in step (1) with a lubricant; (3) Tableting: The mixture obtained in step (2) is tableted to obtain the pharmaceutical composition.

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