A solid preparation containing alfacalcidol complex and preparation method thereof

Abstract

The invention belongs to the technical field of preparation of alfacalcidol preparations, and specifically relates to a solid preparation containing an alfacalcidol complex and a preparation method thereof. The solid preparation comprises a tablet or a hard capsule containing the alfacalcidol complex; the alfacalcidol complex comprises alfacalcidol, a sunscreen, a solubility aid and an adhesive; compared with the prior art, the invention has the following beneficial effects: the alfacalcidol complex has high light stability, high temperature stability and water solubility, so it can be applied to a conventional preparation method to produce alfacalcidol drugs, and is suitable for the production of a variety of alfacalcidol oral solid preparations; the sunscreen is selected from nano calcium carbonate or nano titanium dioxide, which can have a better sunscreen effect on alfacalcidol, thereby further improving the light stability of the alfacalcidol complex; the auxiliary materials selected for preparing the solid preparation containing the alfacalcidol complex are common, the preparation process is simple, the obtained product has stable quality, and is suitable for large-scale production.

Description

Technical Field

[0001] The invention belongs to the technical field of preparation of alfacalcidol preparations, and specifically relates to a solid preparation containing an alfacalcidol complex and a preparation method thereof. Background Art

[0002] Alfacalcidol regulates the balance of calcium and phosphorus in the human body, increases the absorption of calcium and phosphorus in the intestine, reduces the level of parathyroid hormone in plasma, and improves osteoporosis caused by menopause and the use of hormone drugs in women. It is suitable for osteoporosis and rickets and osteomalacia caused by various reasons. Alfacalcidol is extremely sensitive to light and heat, resulting in poor light stability and high temperature stability, which leads to the risk of reduced drug activity during the transportation of alfacalcidol raw materials and the preparation of alfacalcidol preparations; and alfacalcidol has low solubility in water, resulting in low active ingredients of alfacalcidol in alfacalcidol preparations, making the production of the most widely used oral solid preparations in clinical practice difficult.

[0003] The dosage form characteristics of alfacalcidol capsules determine that the drug contained in the capsule shell is isolated from the outside world. At the same time, the capsule has plasticity and elasticity, can be moisture-proof, anti-oxidation, and light-proof, thereby improving the stability of the drug. However, alfacalcidol has poor stability. Although its stability can be improved to a certain extent after being prepared into capsules, the stability of existing alfacalcidol capsules is still not ideal, and there are still defects such as poor stability and low bioavailability. In addition, the capsule process is complicated to implement and the production cycle is long. Summary of the invention

[0004] The purpose of the present invention is to solve the above-mentioned problems of poor photostability and low water solubility of alfacalcidol, and to provide a solid preparation containing an alfacalcidol complex and a preparation method thereof.

[0005] A solid preparation containing an alfacalcidol complex, the solid preparation comprising tablets or hard capsules; the alfacalcidol complex comprises alfacalcidol, a sunscreen, a solubility aid and a binder.

[0006] Preferably, the alfacalcidol complex is in granular form with a particle size D 90 The value is 10~30μm.

[0007] Preferably, the sunscreen comprises nano calcium carbonate or nano titanium dioxide.

[0008] Preferably, the particle size D of the sunscreen agent is 90 The value is between 200 and 500nm.

[0009] Preferably, the co-solvent is a sugar alcohol, and the sugar alcohol includes one or more of mannitol, xylitol, sucrose, and lactose.

[0010] Preferably, the adhesive comprises one or more of hydroxypropyl methylcellulose, polyvinyl pyrrolidone, highly substituted hydroxypropyl cellulose, and sodium carboxymethyl cellulose; and the viscosity of the adhesive is between 100 and 5000 cps.

[0011] A method for preparing a solid preparation containing an alfacalcidol complex, wherein the preparation comprises spray drying to prepare the alfacalcidol complex, wherein the steps of spray drying to prepare the alfacalcidol complex are as follows:

[0012] The binder and the cosolvent are dissolved in a solvent, stirred until clarified, and then the alfacalcidol and the sunscreen are added to obtain a suspension in which the weight ratio of the alfacalcidol, the sunscreen, the binder and the cosolvent is 1:(1-5):(5-8):(10-100); the suspension is added to a spray dryer, and sprayed into tiny droplets in a material bin at a spray speed of 50-90 rpm and a nozzle diameter of 0.1-0.5 μm, and then dried at a drying temperature of 40-80°C and a ventilation efficiency of 100-300 m 3 / min, and dried into tiny particles, wherein the tiny particles are the alfacalcidol complex; after the spray drying is completed, the alfacalcidol complex is collected and sealed for storage.

[0013] Preferably, the solvent is one of an aqueous solution, an ethanol aqueous solution, and an ethanol solution.

[0014] Preferably, the tablet is prepared by adding an excipient, a disintegrant and a lubricant to the alfacalcidol complex; or the hard capsule is prepared by adding an encapsulating material and an excipient, a disintegrant and a lubricant to the alfacalcidol complex.

[0015] Preferably, the excipient includes one or more of starch, anhydrous lactose, and microcrystalline cellulose; the disintegrant includes one or more of dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, alginic acid, and sodium alginate; the lubricant includes one or more of magnesium stearate, calcium stearate, polyethylene glycol, magnesium dodecyl sulfate, and micropowdered silica gel; the encapsulating material includes one or more of gelatin, gum arabic, cellulose, polyvinyl alcohol, and polylactic acid.

[0016] Compared with the prior art, the advantages and positive effects of the present invention are:

[0017] Compared with the prior art, the solid preparation containing the alfacalcidol complex and the preparation method of the present invention are

[0018] (1) When preparing the alfacalcidol complex, a sunscreen and a sugar alcohol are added to protect the light and heat stability of alfacalcidol. Compared with the conventional method for preparing capsules, the alfacalcidol complex is used to prepare capsules. This prevents the destruction of the activity of alfacalcidol by light and high temperature during the production process before filling the capsule shell;

[0019] (2) When preparing the alfacalcidol complex, sugar alcohol is added as a solubility aid to solve the problem of poor water solubility of alfacalcidol. In addition, sugar alcohol is heat-resistant and is coated on the surface of alfacalcidol to prevent alfacalcidol from deteriorating when exposed to heat and losing its drug activity. Sugar alcohol can form a sugar alcohol complex with free calcium ions in the body, thereby preventing calcium from being lost in the human body and promoting calcium absorption. Adding sugar alcohol to the alfacalcidol complex further increases calcium absorption in the intestine.

[0020] (3) When preparing the alfacalcidol complex, alfacalcidol is added to form a suspension, and the suspension is sprayed into tiny droplets using a spray dryer, and then converted into tiny particles. The alfacalcidol particles in the formed tiny particles are smaller than the alfacalcidol particles before dissolution, which increases the surface area of ​​alfacalcidol and improves the water solubility of alfacalcidol; the problem of low alfacalcidol content in the alfacalcidol drug is solved, thereby improving the efficacy of the drug;

[0021] (4) The alfacalcidol complex has high light stability, high temperature stability and water solubility, so the alfacalcidol complex can be used in conventional preparation methods to produce alfacalcidol drugs, and is suitable for the production of a variety of alfacalcidol oral solid preparations; the alfacalcidol raw material is made into the alfacalcidol complex, which avoids the reduction of drug activity caused by light and heat during the preparation, packaging and transportation of solid preparations containing the alfacalcidol complex;

[0022] (5) When preparing the alfacalcidol complex, the sunscreen is selected from nano calcium carbonate or nano titanium dioxide. The nano calcium carbonate or nano titanium dioxide is coated around the alfacalcidol. Since the particle size of the nano calcium carbonate or nano titanium dioxide is small, the gap between adjacent particles is small, so the nano calcium carbonate or nano titanium dioxide can play a better sunscreening role for the alfacalcidol, thereby further improving the photostability of the alfacalcidol complex;

[0023] (6) The excipients selected for preparing the solid preparation containing the alfacalcidol complex are common, the preparation process is simple, the quality of the obtained product is stable, and it is suitable for large-scale production. DETAILED DESCRIPTION

[0024] In order to more clearly understand the above-mentioned objects, features and advantages of the present invention, the present invention is further described below in conjunction with embodiments.

[0025] In the following description, many specific details are set forth to facilitate a full understanding of the present invention. However, the present invention may also be implemented in other ways than those described herein. Therefore, the present invention is not limited to the specific embodiments of the following disclosure.

[0026] Example 1

[0027] 1) Preparation of Alfacalcidol Complex

[0028] prescription:

[0029] materials Dosage Alfacalcidol 1mg Nano Calcium Carbonate 1mg Mannitol 10mg Hydroxypropyl methylcellulose (K100M) 5mg

[0030] Preparation steps:

[0031] The method comprises dissolving hydroxypropyl methylcellulose and mannitol in a 50% ethanol aqueous solution, stirring until clarified, adding alfacalcidol and nano-calcium carbonate to obtain a suspension of alfacalcidol, hydroxypropyl methylcellulose, nano-calcium carbonate and mannitol; adding the suspension to a spray dryer, spraying into tiny droplets in a material bin at a spray speed of 55 rpm and a nozzle diameter of 0.2 μm, and then drying at a drying temperature of 60° C. and a ventilation efficiency of 200 m / s. 3 / min, dried into tiny particles, which are alfacalcidol complexes; after the spray drying is completed, the alfacalcidol complexes are collected and sealed for storage.

[0032] 2) Preparation of tablets containing alfacalcidol complex

[0033] prescription:

[0034] materials Dosage Alfacalcidol Complex 30mg Microcrystalline Cellulose 120mg Sodium carboxymethyl starch 15mg Magnesium Stearate 5mg

[0035] Preparation steps:

[0036] The alfacalcidol complex, microcrystalline cellulose and carboxymethyl cellulose are mixed at a speed of 25 rpm for 30 minutes using a hopper mixer; magnesium stearate is added and the mixture is continued to be mixed at a speed of 25 rpm for 5 minutes to obtain a preparation intermediate; after the preparation intermediate is tested and qualified, tableting is performed to obtain tablets containing the alfacalcidol complex.

[0037] Example 2

[0038] 1) Preparation of Alfacalcidol Complex

[0039] prescription:

[0040] materials Dosage Alfacalcidol 1mg Nano Silica 3mg Xylitol 50mg Polyvinyl pyrrolidone (viscosity: 3000cps) 8mg

[0041] Preparation steps:

[0042] The polyvinyl pyrrolidone and xylitol are dissolved in an aqueous solution, stirred until clarified, and then alfacalcidol and nano-silicon dioxide are added to obtain a suspension of alfacalcidol, polyvinyl pyrrolidone, nano-silicon dioxide and xylitol; the suspension is added to a spray dryer, sprayed into tiny droplets in a material bin at a spray speed of 80 rpm and a nozzle diameter of 0.5 μm, and then dried at a drying temperature of 50° C. and a ventilation efficiency of 150 m 3 / min, dried into tiny particles, which are alfacalcidol complexes; after the spray drying is completed, the alfacalcidol complexes are collected and sealed for storage.

[0043] 2) Preparation of hard capsules containing alfacalcidol complex

[0044] prescription:

[0045]

[0046]

[0047] Preparation steps:

[0048] The alfacalcidol complex, anhydrous lactose and cross-linked polyvinylpyrrolidone are mixed at a speed of 25 rpm for 30 minutes using a hopper mixer; polyethylene glycol is added and the mixture is continued to be mixed at a speed of 25 rpm for 5 minutes to obtain a preparation intermediate; gelatin is dissolved in an ethanol solvent to prepare a gelatin solution, which is then co-molded into a capsule shape, and then dried and cooled to form a hard capsule shell; after the preparation intermediate is tested and qualified, it is filled into a hard capsule shell to obtain a hard capsule containing the alfacalcidol complex.

[0049] Example 3

[0050] 1) Preparation of ordinary alfacalcidol tablets

[0051] prescription:

[0052] materials Dosage Alfacalcidol 4mg Anhydrous lactose 815mg Povidone K30 25mg Pegfilgrastim 5mg Magnesium Stearate 5mg Ethanol solution 95mg

[0053] Preparation steps:

[0054] The raw material drug alfacalcidol is dissolved in anhydrous ethanol to prepare an alfacalcidol solution; the prescribed amount of anhydrous lactose, povidone, and propyl gallate are weighed and placed in a wet mixing granulator for 5 minutes to prepare a dry powder; the obtained dry powder is added to a solid feeder, and the obtained alfacalcidol solution enters a twin-screw extruder through a low-pulse peristaltic pump, the granulation temperature of the twin-screw extruder is controlled at 25°C, the dry powder feeder speed is adjusted to 1.5kg / hr, the peristaltic pump speed is 4rpm, and the twin-screw speed is 150rpm, and the ratio of the weight of the above-mentioned alfacalcidol solution and the dry powder entering the twin-screw extruder per unit time, that is, the liquid-solid ratio is controlled within a range of 1:10, and the material before 5 minutes of extrusion is discarded and then the material is started to be connected to obtain wet granules with uniform drug content; the obtained wet granules are dried in a constant temperature blast drying oven at 40°C; the dried granules are sieved through a 20-mesh sieve, mixed with magnesium stearate, and tableted to obtain ordinary alfacalcidol tablets.

[0055] 2) The above-mentioned ordinary alfacalcidol tablets and the tablets containing the alfacalcidol complex in Example 1 were placed under strong light (4500lx±500) to investigate the influence of light. The properties were observed and related substances were detected on day 0, day 7 and day 14 of light exposure. The test results are shown in the following table.

[0056]

[0057] It can be seen from the table that after 14 days of illumination, the tablets containing the alfacalcidol complex are still white tablets, while the properties of ordinary alfacalcidol tablets change from white tablets to slightly yellow tablets; when the illumination time is the same, the maximum single impurity and total impurities in the related substances of the tablets containing the alfacalcidol complex are smaller than those of the ordinary alfacalcidol tablets; this proves that the photostability of the tablets containing the alfacalcidol complex is higher than that of the ordinary alfacalcidol tablets.

[0058] 3) The above-mentioned ordinary alfacalcidol tablets and the tablets containing the alfacalcidol complex in Example 1 were placed under accelerated test conditions (high temperature 40°C ± 2, relative humidity 65% ​​± 5%), and the changes in properties were observed after 0 month, 1 month, 2 months, 3 months, and 6 months, and the dissolution, content and related substances were tested. The test results are shown in the following table.

[0059]

[0060] It can be seen from the table that when the storage time is 0 month, the solubility of the tablets containing the alfacalcidol complex is higher than that of the ordinary alfacalcidol tablets, which proves that the preparation of the alfacalcidol complex can improve the solubility of alfacalcidol; the test results of the tablets containing the alfacalcidol complex and the ordinary alfacalcidol tablets after storage for 0 month, 1 month, 2 months, 3 months and 6 months are compared respectively. When the storage time is the same, the solubility and content of the tablets containing the alfacalcidol complex are higher than those of the ordinary alfacalcidol tablets, and the maximum single impurity and total impurities in the related substances of the tablets containing the alfacalcidol complex are smaller than those of the ordinary alfacalcidol tablets. When the tablets containing the alfacalcidol complex are stored for 6 months, their properties change from white tablets to slightly yellow tablets, and when the ordinary alfacalcidol tablets are stored for 3 months, their properties have changed from white tablets to slightly yellow tablets, which proves that the tablets containing the alfacalcidol complex are more stable than the ordinary alfacalcidol tablets.

[0061] The above description is only a preferred embodiment of the present invention and does not limit the present invention in other forms. Any technician familiar with the profession may use the technical content disclosed above to change or modify it into an equivalent embodiment with equivalent changes for application in other fields. However, any simple modification or equivalent change made to the above embodiment based on the technical essence of the present invention without departing from the content of the technical solution of the present invention still falls within the protection scope of the technical solution of the present invention.

Claims

1. A solid preparation containing an alfacalcidol complex, characterized in that: The solid preparation includes tablets or hard capsules; the alfacalcidol complex includes alfacalcidol, a sunscreen, a solubilizing agent and a binder; the alfacalcidol complex is granular, and the particle size D 90 value is 10 to 30 μm; the sunscreen is nano calcium carbonate or nano titanium dioxide; the solubilizing agent is a sugar alcohol, and the sugar alcohol is coated on the surface of the alfacalcidol; The preparation of the solid preparation containing the alfacalcidol complex comprises spray drying to prepare the alfacalcidol complex, and the steps of spray drying to prepare the alfacalcidol complex are as follows: The binder and the cosolvent are dissolved in a solvent, stirred until clarified, and then the alfacalcidol and the sunscreen are added to obtain a suspension in which the weight ratio of the alfacalcidol, the sunscreen, the binder and the cosolvent is 1:(1-5):(5-8):(10-100); the suspension is added to a spray dryer, and sprayed into tiny droplets in a material bin at a spray speed of 50-90rpm and a nozzle diameter of 0.1-0.5μm; then dried into tiny particles at a drying temperature of 40-80°C and a wind exchange efficiency of 100-300 m³ / min, wherein the tiny particles are the alfacalcidol complex; after spray drying is completed, the alfacalcidol complex is collected and sealed for storage.

2. The solid preparation containing the alfacalcidol complex according to claim 1, characterized in that: The particle size D 90 of the sunscreen agent is between 200 and 500 nm.

3. The solid preparation containing the alfacalcidol complex according to claim 1, characterized in that: The sugar alcohol is one or a combination of mannitol and xylitol.

4. The solid preparation containing the alfacalcidol complex according to claim 1, characterized in that: The adhesive comprises one or more of hydroxypropyl methylcellulose, polyvinyl pyrrolidone, highly substituted hydroxypropyl cellulose and sodium carboxymethyl cellulose; the viscosity of the adhesive is between 100 and 5000 cps.

5. The solid preparation containing the alfacalcidol complex according to claim 1, characterized in that: The solvent is one of an aqueous solution, an ethanol aqueous solution, and an ethanol solution.

6. The solid preparation containing the alfacalcidol complex according to claim 1, characterized in that: The tablet is prepared by adding excipients, disintegrants and lubricants to the alfacalcidol complex; or the hard capsule is prepared by adding encapsulation materials and excipients, disintegrants and lubricants to the alfacalcidol complex.

7. The solid preparation containing the alfacalcidol complex according to claim 6, characterized in that: The excipients include one or more of starch, anhydrous lactose, and microcrystalline cellulose; the disintegrants include one or more of dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, alginic acid, and sodium alginate; the lubricants include one or more of magnesium stearate, calcium stearate, polyethylene glycol, magnesium dodecyl sulfate, and micropowdered silica gel; and the encapsulating materials include one or more of gelatin, gum arabic, celluloses, and polyvinyl alcohol.

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