CN110650730B

CN110650730B - Vitamin D analogue preparation and preparation method thereof

Info

Publication number: CN110650730B
Application number: CN201980002415.3A
Authority: CN
Inventors: 叶海; 陶莉; 马冲; 袁晓莉; 闵涛; 丁伯祥; 郑慧娟; 徐丽
Original assignee: Nanjing Heron Pharmaceutical Science and Technology Co Ltd
Current assignee: Nanjing Heron Pharmaceutical Science and Technology Co Ltd
Priority date: 2018-05-09
Filing date: 2019-04-30
Publication date: 2022-06-21
Anticipated expiration: 2039-04-30
Also published as: WO2019214512A1; CN110650730A; CN108420797B; JP2020534365A; CN108420797A; JP7062246B2

Abstract

A composition containing a vitamin D analogue, wherein the composition is a solid preparation, the vitamin D analogue is selected from one of vitamin D3, calcifediol, calcitriol, alfacalcidol, eldecalcitol, doxercalciferol, maxacalcitol, paricalcitol, tacalcitol and calcipotriol, and the amount of a precursor which generates the corresponding vitamin D analogue after being masked and stored at room temperature for 12 months is less than or equal to 7%.

Description

Vitamin D analogue preparation and preparation method thereof

Technical Field

The disclosure relates to a pharmaceutical composition containing vitamin D analogues, which is a solid preparation, and also relates to a method for preparing and obtaining the pharmaceutical composition by using a double-screw extrusion technology, belonging to the technical field of pharmaceutical preparation.

Background

The calciferol series of drugs are structural analogs of vitamin D. Vitamin D analogues are marketed worldwide for the treatment of osteoporosis, Secondary Hyperparathyroidism (SHPT) in renal dialysis patients and psoriasis. It is also clinically studied abroad as an anticancer drug. The medicines widely used in clinic comprise vitamin D2, vitamin D3, calcifediol, calcitriol, alfacalcidol, eldecalcitol, doxercalciferol, maxacalciferol, paricalcitol, tacalciferol, calcipotriol and the like.

Obtaining higher quality required content uniformity is one of the main difficulties in preparing the low-dose vitamin D analogue medicament solid preparation. For low dose solid formulations of the order of no more than 1mg, even micrograms, content uniformity is one of its key quality attributes. The change of content uniformity can directly influence the safety and effectiveness of the medicine; variations in both recipe and process can have an effect on content uniformity. It is therefore essential to evaluate the uniformity of content in product and process development.

The common preparation process of the solid preparation can not meet the requirement of content uniformity of the ultra-low dose products, and particularly, the parameter change has obvious influence on the physicochemical property of the low-dose medicament in the amplification production process. In the experimental exploration, the fact that when the trial production quantity is enlarged to more than 2 ten thousand pieces, the content uniformity of the pieces cannot meet the quality requirement easily is found. Even if a large amount of manpower and material resources are spent, and the content uniformity index can be just barely met after various parameters of equipment are strictly controlled, other quality attributes such as a calciferol precursor and a degradation product impurity can not meet the quality requirement at the same time.

The corresponding precursors, degradation products and other substances of the vitamin D analogue are similar in chemical structure, so that the vitamin D analogue has the same characteristics as the main drug, namely low dose and high activity. In view of the limitations of current pharmaceutical technology, it is also difficult to obtain large quantities of single conversion or degradation products for safety studies. For example, it is difficult to obtain a large amount of pure precursors of vitamin D analogues and to evaluate their safety in a targeted manner by the conventional methods. The corresponding precursor and the main drug are in a dynamic balance relationship, and the prior art is difficult to completely separate the two. At present, the precursors of the medicines can be controlled within the range of proven safety only by the preparation process. Therefore, studies on their conversion products or degradation products cannot be neglected, and their attention cannot be lost. In the prior art, in order to solve the problem of content uniformity, a micronization process, a fluidized bed granulation method, a spray drying method, a supercritical fluid method, a converted product or a degraded product and the like are generally adopted. However, due to the instability of the vitamin D analogues, the vitamin D analogues are easy to be converted or degraded under light, humidity and heat. Such drugs are highly susceptible to degradation and transformation, for example, during granulation, during baking, during tableting, and during later storage. Due to the long reaction time of the conventional preparation technology, the materials are more easily degraded and converted by long-time friction contact heating, precursors and degradation products of the vitamin D analogue are generated, and the content of the vitamin D analogue pharmaceutical preparation and the effective dose in clinical application are influenced.

The hot-melt extruder comprises a hot-melt extrusion (HME) module and a double-screw extrusion (TSG) module, and adopts single/double-screw extrusion equipment to make materials undergo three stages of solid conveying, melting and melt conveying, so that a high-mixing-dispersion formed product is obtained under the action of strong shearing force of a kneader and a screw element. The hot melting extrusion process can realize various unit operations of mixing, granulating and forming products on one device, and has the characteristics of less working procedures, low energy consumption, low cost, high yield, continuity, closed production and the like. The technology has breakthrough advantages in improving the dissolution rate of insoluble drugs, preparing sustained release preparations and local administration preparations, and has become a new hotspot in a drug delivery system of a preparation technology. The preparation process is also worthy of being realized in industrial scale-up production. In addition, the double-screw technical equipment can not only realize the preparation mode of the hot-melt extrusion technology, but also well realize the process of granulation by the double-screw technology; especially for the drug preparation with low drug content and sensitive to the environmental factors such as heat, air, water and the like, the quality indexes such as content uniformity, stability and the like can be better improved. The application of the twin-screw extrusion technology in the preparation of compositions of vitamin D analogues and formulations thereof has not been reported in the prior art.

Disclosure of Invention

Currently, the method for obtaining granules in the preparation of solid preparations is usually wet granulation and dry granulation, and more commonly, wet granulation is used. However, wet granulation has some disadvantages that are difficult to overcome:

1) inevitably contacting water, which may cause the drug with poor stability to degrade when meeting water, resulting in crystal form change; in the process of granulation, the dry powder releases heat when meeting water, so that the medicine is damaged by heat and the like. Even if a non-aqueous organic agent such as ethanol is selected for granulation, long-term stirring and shear dispersion are required to ensure content uniformity, which may result in excessive frictional heating of material particles to cause degradation.

2) In the preparation of solid preparations of vitamin D analogue drugs by wet granulation, the conventional stirring method is difficult to achieve highly uniform dispersion of the vitamin D analogue drug, so that the drug content uniformity is poor, and the requirements of the content uniformity inspection method, 0941 in the four-part general rule of chinese pharmacopoeia 2015 edition cannot be met.

3) The reproducibility of the process is poor, and the content data between batches is high and low, which is reflected by the instability of the preparation process and the product quality.

In view of the deficiencies of the prior art, namely, in view of the problems of the prior art that the preparation method of the vitamin D analogue drug cannot meet the requirement of content uniformity, the instability factors of the vitamin D analogue, and the easiness of the drug to be converted into a precursor and degraded into a degradation product during the granulation process, the present disclosure provides a composition containing a vitamin D analogue, which is a solid preparation, wherein the vitamin D analogue is selected from one of vitamin D3, calcifediol, calcitriol, alfacalcidol, eldercalciferol, doxercalciferol, maxacalcitol, paricalcitol, tacalcitol and calcipotriol, and can be selected from corresponding anhydrates, hydrates or solvates; the amount of precursor of corresponding vitamin D analogue generated after the solid preparation is shielded and stored at room temperature for 12 months is less than or equal to 7 percent; preferably, the amount of precursor is less than or equal to 5%; still more preferably, the amount of the precursor is 3% or less.

The pharmaceutical compositions of the present disclosure may be prepared using conventional granulation methods, including but not limited to: centrifugal granulation, high-speed shear mixing granulation, roller granulation, fluidized bed granulation, spray granulation, crystallization granulation in liquid phase, melt granulation, fluidized bed spray granulation; among them, fluidized bed spray granulation is preferable, and fluidized bed spray granulation can be further classified into fluidized bed low-spray granulation, fluidized bed side-spray granulation, or fluidized bed top-spray granulation, depending on the spray position.

The temperature and time at which drying occurs after wet granules are obtained are important parameters for controlling the final precursor content of the product. For example, the optimized parameter conditions are that the drying temperature of the obtained particles is 35-50 ℃, the drying time is 0.5-4 h, preferably, the drying temperature is 40-45 ℃, and the drying time is 0.5-2 h; and the drying mode of the particles is fluidized bed drying or oven drying.

Preferably, alfacalcidol tablets are prepared by preferably using a fluidized bed spray granulation method.

Preferably, the adicalciferol tablets are prepared by a fluidized bed spray granulation method.

Preferably, the calcitriol tablets are prepared by a fluidized bed spray granulation process.

The method has unique advantages in the process of preparing low-dose pharmaceutical preparation by using a double-screw extrusion granulation method. For example, more preferably, the composition, prepared using twin screw extrusion techniques, comprises the steps of:

a) dissolving vitamin D analogue in solvent, preferably absolute ethyl alcohol, to obtain solution; optionally adding a stabilizer into the solution and dissolving the stabilizer into the solution, or optionally adding no stabilizer;

b) uniformly mixing other solid auxiliary materials to form dry powder;

c) b, adding the dry powder obtained in the step b into a solid feeder, and connecting the solution obtained in the step a with an extruder through a peristaltic pump; simultaneously adjusting equipment parameters including dry powder feeding speed, peristaltic pump rotating speed, double-screw rotating speed and extrusion temperature; operating a double-screw extruder to granulate to obtain wet granules;

d) drying and granulating the wet granulate to obtain a dry granulate, i.e. a composition containing a highly uniform amount of vitamin D analogues;

wherein the solid form of the auxiliary material comprises one or more of a filler, a binder and an antioxidant; the stabilizer is a substance having a stabilizing effect on the vitamin D analogue and capable of inhibiting the degradation of the vitamin D analogue to the corresponding 1 β type impurity.

Preferably, the composition is a tablet, capsule, granule or dry suspension in a solid formulation; the components of the solid preparation also comprise a lubricant; the solid preparation is obtained by further preparing the dried granules prepared in claim 3 using conventional preparation techniques.

Preferably, the filler is selected from one or more of starch, pregelatinized starch, corn starch, lactose monohydrate, lactose anhydrous, mannitol, microcrystalline cellulose; the adhesive is one or more selected from polyvidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, and sodium carboxymethylcellulose; the antioxidant is selected from one or more of propyl gallate, DL-alpha-tocopherol, dibutyl hydroxy toluene (BHT), Butyl Hydroxy Anisole (BHA); the lubricant is one or more selected from pulvis Talci, magnesium stearate, calcium stearate, and sodium stearyl fumarate; if a stabilizer is required, the stabilizer is selected from one or more of tween, span, polyoxyethylene alkyl ether, poloxamer 188, sucrose stearate, polyoxyethylene (35) castor oil, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (20) octadecyl cetyl ether, polyoxyethylene lauryl ether, and polyoxyethylene stearate.

According to the technical scheme disclosed by the invention, the drying temperature and time of the wet granules prepared by adopting a double-screw extrusion granulation method need to be controlled so as to meet the quality requirement. For example, the drying temperature of the particles is 35 to 50 ℃, the drying time is 0.5 to 4 hours, preferably, the drying temperature is 40 to 45 ℃, and the drying time is 0.5 to 2 hours; and the drying mode of the particles is fluidized bed drying or oven drying.

With regard to parameter adjustment and setting in the twin-screw technology granulation process, we found through small test, middle test and scale-up production tests that reasonable adjustment and setting of relevant parameters are required according to the size of a medicine batch, and are not invariable. Particularly, the screening and the determination are carried out according to the quality index of the particles. The setting of the relevant parameters will be described below by taking the dry powder feeding speed of 1.0-3.0 kg/hr as an example.

The solid auxiliary materials are uniformly mixed in a mixing granulator for more than or equal to 5 minutes, so that uniform dry powder can be conveniently prepared; the dry powder feeding speed, the peristaltic pump rotating speed and the double-screw rotating speed need to be matched with each other, the dry powder feeding speed is 1.0-3.0 kg/hr, the peristaltic pump rotating speed is 2-8 rpm, the double-screw rotating speed is 100-400 rpm, and the weight ratio of the dry powder and the solution entering the double-screw extruder in unit time, namely the solid-liquid ratio, is 7: 1-11: 1, preferably 8.5: 1-9: 1; controlling the granulating temperature of the double-screw extruder to be 20-25 ℃; the drying temperature of the particles is 35-50 ℃, the drying time is 0.5-4 h, preferably, the drying temperature is 40-45 ℃, and the drying time is 0.5-2 h; and the drying mode of the particles is fluidized bed drying or oven drying.

In the formula disclosed by the disclosure, the mixing uniformity of the antioxidant needs to be considered due to the low weight ratio of the antioxidant. In the experiment, whether the auxiliary material carrier in a solid form can be uniformly mixed in a wet mixing granulator under the conditions of stirring speed of 5r/s and shearing speed of 5r/s and mixing time of 3 minutes, 5 minutes and 8 minutes is examined. When mixed for 3 minutes, the materials are not completely mixed; after the mixing time reaches 5 minutes, the antioxidant content of each sampling point in the mixed powder is uniform.

In the actual extrusion process research process, the fact that the dry powder feeding speed, the peristaltic pump rotating speed and the double-screw rotating speed need to be matched with each other is found, and then the proper wet particles can be prepared. The invention obtains the optimal process conditions through a large number of experiments as follows: the dry powder feeding speed is 1.0-3.0 kg/hr, the rotating speed of a peristaltic pump is 2-8 rpm, the rotating speed of a double screw is 100-400 rpm, and the rotating speeds are matched with each other so as to ensure that the retention time of the dry powder and the solution in the extruder is kept at 1-3 minutes, so that the optimal granulation effect is achieved.

According to the technical scheme of the disclosure, preferably, in the solid preparation, the dosage of the filler is 50-200 mg per tablet, preferably 81-83 mg per tablet; the dosage of the adhesive is 0.2-3 mg per tablet, preferably 1.0-2.0 mg per tablet; the dosage of the lubricant is 0.1-1 mg per tablet, preferably 0.4-0.5 mg per tablet; the dosage of the antioxidant is 0.02-2 mg per tablet, preferably 0.5-1.0 mg per tablet; the dosage of the stabilizer is 0.02-2 mg per tablet, preferably 0.1-0.5 mg per tablet. .

As one embodiment of a composition comprising a vitamin D analogue, the vitamin D analogue is alfacalcidol, i.e. a compound with the chemical name (5Z, 7E) -9, 10-secocholest-5, 7,10(19) -triene-1 α, 3 β -diol; the composition is a solid formulation, preferably a tablet; it comprises alfacalcidol, filler, binder, lubricant, antioxidant and stabilizer; wherein a stabilizer is added for inhibiting degradation of alfacalcidol to 1 β type impurities, i.e., chemical name (5Z, 7E) -9, 10-ring-opened cholest-5, 7,10(19) -triene-1 β, 3 β -diol, such that the amount of 1 β type impurities generated after the solid preparation is masked and stored at room temperature for 12 months is 0.3% or less, preferably 0.1% or less, or less.

Preferably, the solid preparation is a tablet, and the filler is selected from one or more of anhydrous lactose, lactose monohydrate, mannitol, microcrystalline cellulose and sucrose, preferably, anhydrous lactose; the binder is one or more selected from povidone, hydroxypropyl cellulose, hypromellose, and sodium carboxymethylcellulose, preferably povidone K30; the lubricant is one or more selected from talcum powder, magnesium stearate, calcium stearate and sodium stearyl fumarate, preferably magnesium stearate; the antioxidant is selected from one or more of propyl gallate, DL-alpha-tocopherol, dibutyl hydroxy toluene (BHT), and Butyl Hydroxy Anisole (BHA); the stabilizer is one or more selected from Tween, span, polyoxyethylene alkyl ether, poloxamer 188, sucrose stearate, polyoxyethylene (35) castor oil, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (20) octadecyl cetyl ether, polyoxyethylene lauryl ether, and polyoxyethylene stearate; preferably, one or more selected from tween, polyoxyethylene stearate, polyoxyethylene (40) hydrogenated castor oil; more preferably, tween is selected.

Preferably, the alfacalcidol solid preparation is a tablet, and the dosage of the filler is 50-200 mg per tablet, preferably 81-83 mg per tablet; the dosage of the adhesive is 0.2-3 mg per tablet, preferably 1.0-2.0 mg per tablet; the dosage of the lubricant is 0.1-1 mg per tablet, preferably 0.4-0.5 mg per tablet; the dosage of the antioxidant is 0.05-2 mg per tablet, preferably 0.5-1.0 mg per tablet; the dosage of the stabilizer is 0.02-2 mg per tablet, preferably 0.1-0.5 mg per tablet.

Preferably, the alfacalcidol solid preparation is prepared by adopting a double-screw extrusion technology, the drying temperature of the particles is 35-50 ℃, the drying time is 0.5-5 h, preferably, the drying temperature is 40-45 ℃, and the drying time is 0.5-2 h; and the drying mode of the particles is fluidized bed drying or oven drying.

More preferably, the composition is an alfacalcidol tablet comprising a filler that is anhydrous lactose, a binder that is povidone K30, a lubricant that is magnesium stearate, an antioxidant that is propyl gallate, or BHT, or a combination of BHT and BHA; the stabilizer is Tween 80, and the dosage of the Tween 80 is 0.02-2 mg per tablet, preferably 0.1-0.5 mg per tablet.

With respect to alfacalcidol, the present disclosure provides a method of inhibiting degradation of alfacalcidol contained in a solid formulation comprising a filler, a binder, a lubricant, an antioxidant, a stabilizer; the degradation of alfacalcidol to 1 beta type impurities, i.e. chemical name (5Z, 7E) -9, 10-ring-opened cholest-5, 7,10(19) -triene-1 beta, 3 beta-diol, is inhibited by adding a stabilizer, so that the amount of (5Z, 7E) -9, 10-ring-opened cholest-5, 7,10(19) -triene-1 beta, 3 beta-diol generated after the solid preparation is shielded and stored at room temperature for 12 months is less than or equal to 0.3%, preferably less than or equal to 0.1%, or less.

With respect to alfacalcidol, the present disclosure provides a method of preparing a tablet of alfacalcidol using twin screw extrusion techniques, the tablet formulation comprising alfacalcidol, tween 80, anhydrous lactose, propyl gallate, povidone K30, magnesium stearate; the method specifically comprises the following steps:

1) dissolving alfacalcidol in absolute ethyl alcohol, and then adding tween 80 for dissolving to obtain a solution;

2) weighing anhydrous lactose, propyl gallate and polyvidone K30 according to the prescription, adding into a wet mixing granulator, and mixing for 5 minutes or more to obtain dry powder;

3) adding the dry powder obtained in the step 2 into a solid feeder, connecting the solution obtained in the step 1 with an extruder through a low-pulse peristaltic pump, controlling the granulation temperature of the twin-screw extruder at 20-25 ℃, simultaneously adjusting the dry powder feeding speed, the peristaltic pump rotating speed and the twin-screw rotating speed, operating the twin-screw extruder to granulate, and starting material receiving after 5 minutes of materials before extrusion are discarded to obtain wet granules; the dry powder feeding speed, the peristaltic pump rotating speed and the double-screw rotating speed are set to be matched with each other, the dry powder feeding speed is 1.0-3.0 kg/hr, the peristaltic pump rotating speed is 2-8 rpm, the double-screw rotating speed is 100-400 rpm, and the weight ratio of the dry powder to the solution entering the double-screw extruder in unit time, namely the solid-liquid ratio, is 7: 1-11: 1, preferably 8.5: 1-9: 1;

4) drying the wet particles obtained in the step (3) to obtain dried particles, wherein the drying temperature is 35-50 ℃, the drying time is 0.5-4 h, preferably, the drying temperature is 40-45 ℃, and the drying time is 0.5-2 h; the drying mode of the particles is fluidized bed drying or oven drying;

5) and (3) sieving the dried granules with a 16-24-mesh sieve, preferably a 20-mesh sieve, granulating, adding magnesium stearate, uniformly mixing, and tabletting to obtain the magnesium stearate tablet.

As one of the embodiments of a composition comprising a vitamin D analog, the vitamin D analog is eldercalciferol, i.e., the chemical name (5Z, 7E) - (1R, 2R, 3R) -2- (3-hydroxypropoxy) -9, 10-secocholesta-5, 7,10(19) -triene-1, 3, 25-triol; the composition is a solid formulation, preferably a tablet; comprises digylcalciferol, a filler, a binder, a lubricant, an antioxidant; wherein, an antioxidant is added for inhibiting the conversion of the eldecalcitol into an eldecalcitol precursor, namely the chemical name 6Z- (1R, 2R, 3R) -2- (3-hydroxypropoxy) -9, 10-secocholest-5 (10), 6, 8(9) -triene-1, 3, 25-triol, so that the solid preparation generates the eldecalcitol precursor with the amount of less than or equal to 7 percent after being stored for 12 months at room temperature in a shielding way; preferably, the amount of the precursor is 5% or less, and more preferably, the amount of the precursor is 3% or less.

Preferably, the solid formulation is an eldecalcitol tablet comprising a filler selected from one or more of anhydrous lactose, lactose monohydrate, mannitol, microcrystalline cellulose, sucrose, preferably, anhydrous lactose; the binder is one or more selected from povidone, hydroxypropyl cellulose, hypromellose, and sodium carboxymethylcellulose, preferably povidone K30; the lubricant is selected from one or more of talcum powder, magnesium stearate, calcium stearate and sodium stearyl fumarate, preferably magnesium stearate; the antioxidant is selected from one or more of propyl gallate, DL-alpha-tocopherol, dibutyl hydroxy toluene (BHT), and Butyl Hydroxy Anisole (BHA).

More preferably, the solid formulation is an eldecalcitol tablet, the filler is anhydrous lactose, the binder is povidone K30, the lubricant is magnesium stearate, the antioxidant is propyl gallate, or BHT, or a combination of BHT and BHA.

Preferably, the dosage of the filler in the eldecalcitol tablet is 50-200 mg per tablet, preferably 80-84 mg per tablet; the dosage of the adhesive is 0.2-3 mg, preferably 0.4-0.5 mg per tablet; the dosage of the lubricant is 0.1-1 mg per tablet, preferably 0.4-0.5 mg per tablet; the amount of the antioxidant is 0.05-2 mg, preferably 0.5-1.0 mg per tablet.

In order to further improve the quality requirement, on the basis of the above formula, the solid preparation further comprises a stabilizer selected from one or more of tween, span, polyoxyethylene alkyl ether, poloxamer 188, sucrose stearate, polyoxyethylene (35) castor oil, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (20) octadecyl cetyl ether, polyoxyethylene lauryl ether and polyoxyethylene stearate; preferably, one or more selected from tween, polyoxyethylene stearate, polyoxyethylene (40) hydrogenated castor oil; more preferably, selected from tween; wherein a stabilizer is added for inhibiting degradation of the eldercalciferol into 1 beta type impurities, namely (5Z, 7E) - (1S, 2R, 3R) -2- (3-hydroxypropoxy) -9, 10-secocholest-5, 7,10(19) -triene-1, 3, 25-triol, so that the solid preparation generates less than or equal to 0.3%, preferably less than or equal to 0.1%, or less of 1 beta type impurities after being masked and stored at room temperature for 12 months.

More preferably, the solid formulation is an eldecalcitol tablet, the filler is anhydrous lactose, the binder is povidone K30, the lubricant is magnesium stearate, the antioxidant is propyl gallate, or BHT, or a combination of BHT and BHA; the stabilizer is Tween 80, and the dosage of the Tween 80 is 0.02-2 mg per tablet, preferably 0.1-0.5 mg per tablet.

Preferably, the eldecalcitol tablet is prepared by a twin-screw extrusion granulation method, the drying temperature of the granules is 35-50 ℃, the drying time is 0.5-5 h, preferably, the drying temperature is 40-45 ℃, the drying time is 0.5-2 h, and the drying mode of the granules is fluidized bed drying or oven drying.

With respect to eldecalcitol, the present disclosure provides a method of inhibiting the conversion of eldecalcitol contained in a solid formulation to an eldecalcitol precursor, said formulation comprising a filler, a binder, a lubricant, an antioxidant; the conversion of the eldercalciferol into an eldercalciferol precursor, namely 6Z- (1R, 2R, 3R) -2- (3-hydroxypropoxy) -9, 10-secocholest-5 (10), 6, 8(9) -triene-1, 3, 25-triol with the chemical name, is inhibited by adding an antioxidant, so that the solid preparation generates less than or equal to 3% of 6Z- (1R, 2R, 3R) -2- (3-hydroxypropoxy) -9, 10-secocholest-5 (10), 6, 8(9) -triene-1, 3, 25-triol after being stored for 12 months at a sheltered room temperature.

The present disclosure also provides a method of inhibiting degradation of eldercalciferol contained in a solid formulation to an eldercalciferol type 1 β impurity, the formulation comprising a filler, a binder, a lubricant, an antioxidant, a stabilizer; the degradation of the eldercalciferol into the 1 beta type impurity of the eldercalciferol, namely the chemical name (5Z, 7E) - (1S, 2R, 3R) -2- (3-hydroxypropoxy) -9, 10-secocholest-5, 7,10(19) -triene-1, 3, 25-triol, is inhibited by adding a stabilizer, so that the amount of the 1 beta type impurity generated after the solid preparation is shielded and stored at room temperature for 12 months is less than or equal to 0.3%, preferably less than or equal to 0.1%, or less.

With respect to eldecalcitol, the present disclosure provides a method for preparing an eldecalcitol tablet using twin screw extrusion technology, the tablet formulation comprising eldecalcitol, anhydrous lactose, povidone K30, magnesium stearate, an antioxidant; optionally adding stabilizer, preferably tween 80, or optionally adding no stabilizer; the preparation method specifically comprises the following steps:

1) dissolving eldecalcitol in absolute ethanol to obtain a solution: optionally, a stabilizer can be optionally added into the solution and dissolved in the solution, or the stabilizer can not be added;

2) weighing anhydrous lactose and polyvidone K30 according to the prescription, adding antioxidant into the wet granulator, mixing, adding into the wet mixing granulator, and mixing for 5 min or more to obtain dry powder; the antioxidant is propyl gallate, DL-alpha-tocopherol, BHT, or a combination of BHT and BHA;

3) adding the dry powder obtained in the step 2 into a solid feeder, connecting the solution obtained in the step 1 with an extruder through a low-pulse peristaltic pump, controlling the granulation temperature of the twin-screw extruder at 20-25 ℃, simultaneously adjusting the dry powder feeding speed, the peristaltic pump rotating speed and the twin-screw rotating speed, operating the twin-screw extruder to granulate, starting material receiving after 5 minutes of materials before extrusion are discarded, and obtaining wet granules; the dry powder feeding speed, the peristaltic pump rotating speed and the double-screw rotating speed are set to be matched with each other, the dry powder feeding speed is 1.0-3.0 kg/hr, the peristaltic pump rotating speed is 2-8 rpm, the double-screw rotating speed is 100-400 rpm, and the weight ratio of the dry powder and the solution entering the double-screw extruder in unit time is 7: 1-11: 1, preferably 8.5: 1-9: 1;

4) drying the obtained wet particles to obtain dried particles, wherein the drying temperature is 35-50 ℃, the drying time is 0.5-5 h, preferably, the drying temperature is 40-45 ℃, the drying time is 0.5-2 h, and the drying mode of the particles is fluidized bed drying or oven drying;

As one of the embodiments of a composition comprising a vitamin D analog, the vitamin D analog is calcitriol, i.e., cholesta-5, 7,10(19) -triene-1 α, 3 β, 25-triol having a chemical name of (5Z, 7E) -9, 10-ring opening; the composition is a solid formulation, preferably a tablet; comprises calcitriol, a filler, a binder, a lubricant, an antioxidant and a stabilizer; wherein a stabilizer is added for inhibiting the degradation of calcitriol to 1 β type impurities, i.e., cholesta-5, 7, 10-ring-opened cholesta-5, 7,10(19) -triene-1 β, 3 β, 25-triol having a chemical name of (5Z, 7E) -9, 10-ring, so that the amount of 1 β type impurities generated after the solid preparation is masked and stored at room temperature for 12 months is 0.3% or less, preferably 0.1% or less, or less.

Preferably, the filler is selected from one or more of anhydrous lactose, lactose monohydrate, mannitol, microcrystalline cellulose and sucrose, and is preferably anhydrous lactose; the binder is one or more selected from povidone, hydroxypropyl cellulose, hypromellose, and sodium carboxymethylcellulose, preferably povidone K30; the lubricant is one or more selected from talcum powder, magnesium stearate, calcium stearate and sodium stearyl fumarate, preferably magnesium stearate; the antioxidant is selected from one or more of propyl gallate, DL-alpha-tocopherol, dibutyl hydroxy toluene (BHT), Butyl Hydroxy Anisole (BHA); the stabilizer is one or more selected from Tween, span, polyoxyethylene alkyl ether, poloxamer 188, sucrose stearate, polyoxyethylene (35) castor oil, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (20) octadecyl cetyl ether, polyoxyethylene lauryl ether, and polyoxyethylene stearate; preferably, it is selected from one or more of tween, polyoxyethylene stearate, polyoxyethylene (40) hydrogenated castor oil, more preferably tween.

More preferably, the solid formulation is a calcitriol tablet comprising a filler which is anhydrous lactose, a binder which is povidone K30, an antioxidant which is propyl gallate, or dibutylhydroxytoluene (BHT), or a combination of dibutylhydroxytoluene (BHT) and Butylhydroxyanisole (BHA); the stabilizer is tween 80 or polyoxyethylene stearate; the lubricant is magnesium stearate, or sodium stearyl fumarate.

Preferably, the solid preparation is calcitriol tablets, and the dosage of the filler is 50-200 mg per tablet, preferably 81-83 mg per tablet; the dosage of the adhesive is 0.2-3 mg per tablet, preferably 1.0-2.0 mg per tablet; the dosage of the lubricant is 0.1-1 mg per tablet, preferably 0.4-0.5 mg per tablet, and the dosage of the antioxidant is 0.05-2 mg per tablet, preferably 0.5-1.0 mg per tablet; the dosage of the stabilizer is 0.02-2 mg per tablet, preferably 0.1-0.5 mg per tablet.

Preferably, the calcitriol tablet is prepared by a double-screw extrusion granulation method, the drying temperature of the granules is 35-50 ℃, the drying time is 0.5-5 h, preferably, the drying temperature is 40-45 ℃, the drying time is 0.5-2 h, and the drying mode of the granules is fluidized bed drying or oven drying.

The present disclosure provides a method of inhibiting the degradation of calcitriol contained in a solid formulation comprising a filler, a binder, a lubricant, an antioxidant, a stabilizer; the degradation of 1 beta type impurities, namely (5Z, 7E) -9, 10-ring-opening cholest-5, 7,10(19) -triene-1 beta, 3 beta, 25-triol, is inhibited by adding a stabilizing agent, so that the amount of (5Z, 7E) -9, 10-ring-opening cholest-5, 7,10(19) -triene-1 beta, 3 beta, 25-triol generated after the solid preparation is stored for 12 months at a sheltered room temperature is less than or equal to 0.3%, preferably less than or equal to 0.1%, or less.

The present disclosure provides a method for preparing calcitriol tablets using twin screw extrusion technology, characterized in that the tablet formulation comprises calcitriol, a stabilizer, a filler, an antioxidant, a binder, a lubricant; the method specifically comprises the following steps:

1) dissolving calcitriol in absolute ethyl alcohol, and adding a stabilizer for dissolving to obtain a solution:

2) weighing the filler, the antioxidant and the adhesive according to the prescription, adding the mixture into a wet mixing granulator, and mixing for more than or equal to 5 minutes to obtain dry powder;

3) adding the dry powder obtained in the step 2 into a solid feeder, connecting the solution obtained in the step 1 with an extruder through a low-pulse peristaltic pump, controlling the granulation temperature of the twin-screw extruder at 20-25 ℃, simultaneously adjusting the dry powder feeding speed, the peristaltic pump rotating speed and the twin-screw rotating speed, operating the twin-screw extruder to granulate, and starting material receiving after discarding materials 5 minutes before extrusion to obtain wet granules; the dry powder feeding speed, the peristaltic pump rotating speed and the double-screw rotating speed are matched with each other, the dry powder feeding speed is 1.0-3.0 kg/hr, the peristaltic pump rotating speed is 2-8 rpm, the double-screw rotating speed is 100-400 rpm, and the weight ratio of the dry powder to the solution entering the double-screw extruder in unit time, namely the solid-liquid ratio, is 7: 1-11: 1, preferably 8.5: 1-9: 1;

5) sieving the dried granules with a 16-24-mesh sieve for granulation, preferably a 20-mesh sieve for granulation, then adding magnesium stearate, uniformly mixing, and tabletting to obtain the magnesium stearate tablet;

wherein the filler is selected from one or more of anhydrous lactose, lactose monohydrate, mannitol, microcrystalline cellulose and sucrose, and is preferably anhydrous lactose; the binder is one or more selected from povidone, hydroxypropyl cellulose, hypromellose, and sodium carboxymethylcellulose, preferably povidone K30; the lubricant is one or more selected from talcum powder, magnesium stearate, calcium stearate and sodium stearyl fumarate, preferably magnesium stearate; the antioxidant is selected from one or more of propyl gallate, DL-alpha-tocopherol, dibutyl hydroxy toluene (BHT), and Butyl Hydroxy Anisole (BHA); the stabilizer is selected from one or more of tween, span, polyoxyethylene alkyl ether, poloxamer 188, sucrose stearate, polyoxyethylene (35) castor oil, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (20) octadecyl cetyl ether, polyoxyethylene lauryl ether and polyoxyethylene stearate, preferably selected from one or more of tween, polyoxyethylene stearate and polyoxyethylene (40) hydrogenated castor oil, and more preferably selected from tween.

The present disclosure achieves the following advantageous technical effects and improvements.

1) The solid preparation of the vitamin D analogue is prepared by adopting a double-screw extrusion technology for the first time, the medicines of the vitamin D analogue, in particular alfacalcidol, eldecalcitol and calcitriol, are deeply researched, and the tablets are prepared by adopting a double-screw extrusion granulation method. The content uniformity conforms to the pharmacopoeia regulations. However, the conventional wet granulation is poor in content uniformity when preparing a solid formulation of a low-dose drug because it is difficult to disperse the low-dose drug highly uniformly by conventional stirring means.

2) The preparation method disclosed by the invention is simple and feasible in process, low in energy consumption, free of other impurities introduced in the process, and capable of increasing the dissolution rate of each batch of hundreds of thousands of tablets in production attempt. The content of corresponding precursors and degradation products is reduced and effectively controlled. High process reproducibility and easy realization of continuous large-scale production.

3) Besides the auxiliary materials of the traditional solid preparation, the stabilizing agent is preferably Tween 80. When the bulk drug is dissolved in absolute ethyl alcohol, the tween 80 is added, so that the main drug can be stabilized in an ethanol solution environment, and the main drug can be effectively protected in a mixing stage in a double-screw technical machine and even in the drying of wet particles in subsequent stages, and a key effect is exerted on inhibiting the generation of degradation products. For example, it is presumed that tween 80 is sorbitan monooleate polyoxyethylene ether in chemical structure, belongs to a nonionic surfactant, and in an ethanol solution and in the processes of mixing granulation and subsequent drying, amphiphilic tween can effectively protect and wrap alfacalcidol with extremely low content and hydrophobicity in a micelle form, so that the alfacalcidol can be isolated from external factors such as light, heat, oxygen, moisture and the like, and plays a key role in inhibiting the generation of degradation products of alfacalcidol.

4) We studied carefully the effect of various factors on the formation of precursors and degradation products of alfacalcidol or calcitriol. It was found that in the formulation studies of alfacalcidol tablets and calcitriol tablets, the addition of an antioxidant such as propyl gallate or DL-alpha-tocopherol had no significant effect on the inhibition of the corresponding precursor formation and sometimes increased the production of degradation products in return. For example, we added 0.05mg, 0.1mg, 0.5mg, and 1.0mg of propyl gallate, respectively, while keeping the same tablet weight of 85mg in the alfacalcidol tablet formulation, and found that after propyl gallate was added to a certain amount, the alfacalcidol precursor content could not be further reduced with increasing dosage. However, the increase in degradation products such as 1 β type impurity was higher in the subsequent stability test after the corresponding tablets were made. The reduction of propyl gallate also reduces the formation of degradation products to some extent. We have found that, surprisingly, the addition of Tween 80 can effectively inhibit the generation of degradation products. In studying calcitriol tablets, we have also found that increased antioxidant usage has little effect on precursor control, but results in more degradation products. Some nonionic surfactants such as tween, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene stearate, etc. are effective in inhibiting the formation of degradation products, particularly 1 β type impurities. We speculate that the surfactant polymer material can be wrapped around main drug molecules in a micelle form to play a role in isolating external destructive factors.

While the commercial formulation of eldecalcitol is a soft capsule, we have surprisingly found an unexpected result different from alfacalcidol and calcitriol in the search for eldecalcitol tablets. Namely, the increase of the dosage of the antioxidant in the eldecalcitol tablet can obviously inhibit the generation of the eldecalcitol precursor. We speculate that it may be related to the chemical molecular structure that the 3-position in the idecalcitol molecule is hydroxypropoxy and that there is no substituent at the corresponding position on the alfacalcidol or calcitriol molecule. The precursors of eldecalcitol are clearly distinguished from alfacalcidol and calcitriol molecules in terms of molecular potential, and the conversion of boat and chair conformation in space. We speculate that this may be the reason why the antioxidant inhibits the eldecalcitol precursor more significantly.

5) In the experimental process, the mixing mode and mixing time of the auxiliary materials in a solid form are also considered, and the matching of the subsequent feeding speed and the liquid adding speed and the uniformity of the final material are further ensured.

6) We also examined the effect of extrusion temperature during the experiment. Due to the instability factor of the vitamin D analogue, the extrusion temperature is directly influenced on the content and the stability of the final preparation in experiments, and the factor is not required to be considered in the application of the double-screw extrusion technology in the prior art in the field of medicines. A large number of experiments prove that the granulating temperature of the double-screw extruder is controlled to be 20-25 ℃, the precursor content in the alfacalcidol tablet of the embodiment is obviously reduced compared with that of the commercially available alfacalcidol tablet, the drug degradation and conversion in the granulating process are effectively prevented, and the method has beneficial technical progress. However, this cannot be achieved by the conventional wet granulation, and the temperature of the system is relatively high during the stirring process and the solvent heating and volatilizing process, which results in the transformation and degradation of drug molecules. The temperature is therefore one of the key process parameters in the twin-screw extrusion granulation process.

7) The adjustment and setting of parameters during the twin-screw extrusion granulation process are also important in the technical solution of the present disclosure. For example, when the dry powder feeding speed is adjusted to be 1.0-3.0 kg/hr, the peristaltic pump rotating speed is 2-8 rpm, and the twin-screw rotating speed is 100-400 rpm, the obtained particles are observed to be uniform, the content of the measured extrudate is uniform, and the weight ratio of the dry powder and the solution entering the twin-screw extruder in unit time is 7: 1-11: 1, preferably 8.5: 1-9: 1.

8) The double-screw extrusion granulation technology is adopted in the method, the type of the used hot-melt extruder is the Saimeishefei PHARMA16, and the method has the characteristics of less processes, low energy consumption, safety, no pollution, no dead angle in mixing, good dispersion effect, high uniformity, less drug loss, integration of various unit operations, space saving, cost reduction and the like, and the technology becomes a new hot spot in a drug delivery system of the preparation technology. In addition, the preparation process is very convenient for realizing industrial scale-up production. The application of the twin-screw extrusion technology in the preparation of compositions of vitamin D analogues and formulations thereof has not been reported in the prior art.

Detailed Description

In order to make the aforementioned objects, features and advantages of the present disclosure more comprehensible, specific embodiments accompanied with specific examples are described in detail below.

In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present disclosure, but the present disclosure may be practiced in other ways than those described herein, and it will be apparent to those of ordinary skill in the art that the present disclosure may be practiced without departing from the spirit or scope of the present disclosure, and therefore the present disclosure is not limited to the specific embodiments disclosed below.

Example 1 preparation of alfacalcidol tablets

Single dose prescription:

alfacalcidol 0.5 μ g, lactose anhydrous 81.5mg, povidone K302 mg, propyl gallate 1mg,

magnesium stearate 0.4mg, Tween 800.1 mg, and appropriate amount of anhydrous ethanol

The preparation method comprises the following steps: 1) dissolving alfacalcidol in absolute ethyl alcohol, and adding tween 80 for dissolving to obtain a solution; 2) placing anhydrous lactose, polyvidone K30, and propyl gallate in a wet mixing granulator, and mixing for 5 min or more to obtain dry powder; 3) adding the dry powder obtained in the step (2) into a solid feeder, connecting the solution obtained in the step (1) with an extruder through a low-pulse peristaltic pump, controlling the granulation temperature of the twin-screw extruder at 20-25 ℃, adjusting the dry powder feeding speed to be 1.0-2.0 kg/hr, the peristaltic pump rotating speed to be 2-4 rpm, the twin-screw rotating speed to be 100-200 rpm, and controlling the weight ratio of the dry powder and the solution entering the twin-screw extruder in unit time, namely the solid-liquid ratio to be 8.5: 1-9: 1; after materials in 5 minutes before extrusion are discarded, material receiving is started to obtain wet particles; 4) putting the wet granules into an oven, and drying for 2 hours at 40-45 ℃ to obtain dried granules; 5) sieving the dried granules with 20 mesh sieve, grading, adding magnesium stearate, mixing, and tabletting.

Example 2 preparation of alfacalcidol tablets (without addition of surfactant)

Single dose prescription:

alfacalcidol 0.5 μ g, anhydrous lactose 82.6mg, polyvidone K302 mg, propyl gallate 1mg, magnesium stearate 0.4mg, and appropriate amount of anhydrous ethanol

The preparation method comprises the following steps: 1) dissolving alfacalcidol in absolute ethyl alcohol to obtain a solution; 2) placing anhydrous lactose, polyvidone K30, and propyl gallate in a wet mixing granulator, and mixing for 5 min or more to obtain dry powder; 3) adding the dry powder obtained in the step (2) into a solid feeder, connecting the solution obtained in the step (1) with an extruder through a low-pulse peristaltic pump, controlling the granulation temperature of the twin-screw extruder at 20-25 ℃, adjusting the dry powder feeding speed to be 2.0-3.0 kg/hr, the peristaltic pump rotating speed to be 4-8 rpm, the twin-screw rotating speed to be 300-400 rpm, and controlling the weight ratio of the dry powder and the solution entering the twin-screw extruder in unit time, namely the solid-liquid ratio to be 10: 1-9: 1; after materials in 5 minutes before extrusion are discarded, material receiving is started to obtain wet particles; 4) putting the wet granules into an oven, and drying for 2 hours at the temperature of 40-45 ℃ to obtain dried granules; 5) sieving the dried granules with 20 mesh sieve, grading, adding magnesium stearate, mixing, and tabletting.

EXAMPLE 3 preparation of alfacalcidol tablets

Single dose prescription:

alfacalcidol 1 μ g, anhydrous lactose 81.5mg, polyvidone K302 mg, propyl gallate 1mg, magnesium stearate 0.4mg, Tween 800.2 mg, and appropriate amount of anhydrous ethanol

The preparation method comprises the following steps: 1) dissolving alfacalcidol in absolute ethyl alcohol, and then adding tween 80 for dissolving to obtain a solution; 2) placing anhydrous lactose, polyvidone K30, and propyl gallate in a wet mixing granulator, and mixing for 5 min or more to obtain dry powder; 3) adding the dry powder obtained in the step (2) into a solid feeder, connecting the solution obtained in the step (1) with an extruder through a low-pulse peristaltic pump, controlling the granulation temperature of the twin-screw extruder at 20-25 ℃, adjusting the dry powder feeding speed to be 1.5-2.5 kg/hr, the peristaltic pump rotating speed to be 3-5 rpm, the twin-screw rotating speed to be 200-300 rpm, and controlling the weight ratio of the dry powder and the solution entering the twin-screw extruder in unit time, namely the solid-liquid ratio to be 10: 1-9: 1; after materials in 5 minutes before extrusion are discarded, material receiving is started to obtain wet particles; 4) putting the wet granules into an oven, and drying for 2 hours at the temperature of 40-45 ℃ to obtain dried granules; 5) sieving the dried granules with 20 mesh sieve, grading, adding magnesium stearate, mixing, and tabletting.

EXAMPLE 4 preparation of alfacalcidol tablets

Single dose prescription:

alfacalcidol 0.5 μ g, anhydrous lactose 81.5mg, polyvidone K302 mg, BHT 1mg, sodium stearyl fumarate 0.4mg, polyoxyethylene stearate 0.1mg, and appropriate amount of anhydrous ethanol

The preparation method comprises the following steps: 1) dissolving alfacalcidol in absolute ethyl alcohol, and then adding polyoxyethylene stearate for dissolving to obtain a solution; 2) mixing anhydrous lactose, polyvidone K30, and BHT in wet mixing granulator for 5 min or more to obtain dry powder; 3) adding the dry powder obtained in the step (2) into a solid feeder, connecting the solution obtained in the step (1) with an extruder through a low-pulse peristaltic pump, controlling the granulation temperature of the twin-screw extruder at 20-25 ℃, adjusting the dry powder feeding speed to be 1.5-2.0 kg/hr, the peristaltic pump rotating speed to be 3-5 rpm, the twin-screw rotating speed to be 250-300 rpm, and controlling the weight ratio of the dry powder and the solution entering the twin-screw extruder in unit time, namely the solid-liquid ratio to be 10: 1-9: 1; after materials in 5 minutes before extrusion are discarded, material receiving is started to obtain wet particles; 4) putting the wet granules into an oven, and drying for 2 hours at the temperature of 40-45 ℃ to obtain dried granules; 5) sieving the dried granules with 24 mesh sieve, grading, adding sodium stearyl fumarate, mixing, and tabletting.

EXAMPLE 5 preparation of alfacalcidol tablets

Single dose prescription:

alfacalcidol 0.5 μ g, anhydrous lactose 81.55mg, povidone K302 mg, DL-alpha-tocopherol 2mg, magnesium stearate 0.4mg, polyoxyethylene (40) hydrogenated castor oil 0.1mg, and appropriate amount of anhydrous ethanol

The preparation method comprises the following steps: 1) dissolving alfacalcidol in absolute ethyl alcohol, and then adding polyoxyethylene (40) hydrogenated castor oil for dissolving to obtain a solution; 2) placing anhydrous lactose, polyvidone K30 and DL-alpha-tocopherol into a wet mixing granulator, and mixing for more than or equal to 5 minutes to obtain dry powder; 3) adding the dry powder obtained in the step (2) into a solid feeder, connecting the solution obtained in the step (1) with an extruder through a low-pulse peristaltic pump, controlling the granulation temperature of the twin-screw extruder at 20-25 ℃, adjusting the dry powder feeding speed to be 2.0-2.5 kg/hr, the peristaltic pump rotating speed to be 4-6 rpm, the twin-screw rotating speed to be 100-150 rpm, and controlling the weight ratio of the dry powder and the solution entering the twin-screw extruder in unit time, namely the solid-liquid ratio to be 10: 1-9: 1; after materials in 5 minutes before extrusion are discarded, material receiving is started to obtain wet particles; 4) putting the wet granules into an oven, and drying for 2 hours at the temperature of 40-45 ℃ to obtain dried granules; 5) sieving the dried granules with 16 mesh sieve, grading, adding magnesium stearate, mixing, and tabletting.

Example 6 preparation of Adeladol tablets

Single dose prescription:

0.5 mu g of eldecalcitol, 83.6mg of anhydrous lactose, K300.5 mg of povidone, 0.5mg of propyl gallate, 0.4mg of magnesium stearate and a proper amount of anhydrous ethanol

The preparation method comprises the following steps: 1) dissolving the eldecalcitol in absolute ethyl alcohol to obtain a solution; 2) placing anhydrous lactose, polyvidone K30, and propyl gallate in a wet mixing granulator, and mixing for 5 min or more to obtain dry powder; 3) adding the dry powder obtained in the step (2) into a solid feeder, connecting the solution obtained in the step (1) with an extruder through a low-pulse peristaltic pump, controlling the granulation temperature of the twin-screw extruder at 20-25 ℃, adjusting the dry powder feeding speed to be 2.0-3.0 kg/hr, the peristaltic pump rotating speed to be 4-6 rpm, the twin-screw rotating speed to be 100-200 rpm, and controlling the weight ratio of the dry powder and the solution entering the twin-screw extruder in unit time, namely the solid-liquid ratio to be 10: 1-9: 1; after materials in 5 minutes before extrusion are discarded, material receiving is started to obtain wet particles; 4) putting the wet granules into an oven, and drying for 2 hours at the temperature of 40-45 ℃ to obtain dried granules; 5) sieving the dried granules with 20 mesh sieve, grading, adding magnesium stearate, mixing, and tabletting.

Example 7 preparation of Adeladol tablets

Single dose prescription:

0.75 mu g of eldecalcitol, 82.6mg of anhydrous lactose, povidone K301 mg, 1mg of propyl gallate, 0.4mg of magnesium stearate and a proper amount of anhydrous ethanol

The preparation method comprises the following steps: 1) dissolving the eldecalcitol in absolute ethyl alcohol to obtain a solution; 2) placing anhydrous lactose, polyvidone K30, and propyl gallate in a wet mixing granulator, and mixing for 5 min or more to obtain dry powder; 3) adding the dry powder obtained in the step (2) into a solid feeder, connecting the solution obtained in the step (1) with an extruder through a low-pulse peristaltic pump, controlling the granulation temperature of the twin-screw extruder at 20-25 ℃, adjusting the dry powder feeding speed to be 1.5-2.0 kg/hr, the peristaltic pump rotating speed to be 5-7 rpm, and the twin-screw rotating speed to be 200-300 rpm, and controlling the weight ratio of the dry powder and the solution entering the twin-screw extruder in unit time, namely the solid-liquid ratio to be 9: 1-8.5: 1; after materials in 5 minutes before extrusion are discarded, material receiving is started to obtain wet particles; 4) putting the wet granules into an oven, and drying for 2 hours at the temperature of 40-45 ℃ to obtain dried granules; 5) sieving the dried granules with 20 mesh sieve, grading, adding magnesium stearate, mixing, and tabletting.

Example 8 preparation of Adeladol tablets

Single dose formulations:

0.5 mu g of eldercalciferol, 83.1mg of anhydrous lactose, K300.5mg of povidone, 1mg of BHT, 0.4mg of sodium stearyl fumarate and a proper amount of anhydrous ethanol

The preparation method comprises the following steps: 1) dissolving the eldecalcitol in absolute ethyl alcohol to obtain a solution; 2) placing anhydrous lactose, polyvidone K30 and BHT in a wet mixing granulator, and mixing for 5 minutes or more to obtain dry powder; 3) adding the dry powder obtained in the step (2) into a solid feeder, connecting the solution obtained in the step (1) with an extruder through a low-pulse peristaltic pump, controlling the granulation temperature of the twin-screw extruder at 20-25 ℃, adjusting the dry powder feeding speed to be 2.0-2.5 kg/hr, the peristaltic pump rotating speed to be 6-7 rpm, and the twin-screw rotating speed to be 200-250 rpm, and controlling the weight ratio of the dry powder and the solution entering the twin-screw extruder in unit time, namely the solid-liquid ratio to be 9: 1-10: 1; after materials in 5 minutes before extrusion are discarded, material receiving is started to obtain wet particles; 4) putting the wet granules into an oven, and drying for 2 hours at the temperature of 40-45 ℃ to obtain dried granules; 5) sieving the dried granules with 20 mesh sieve, grading, adding sodium stearyl fumarate, mixing, and tabletting.

Example 9 preparation of Adeladol tablets

Single dose prescription:

0.75 mu g of eldecalcitol, 82.6mg of anhydrous lactose, povidone K301 mg, 1mg of DL-alpha-tocopherol, 0.4mg of magnesium stearate and a proper amount of anhydrous ethanol

The preparation method comprises the following steps: 1) dissolving the eldecalcitol in absolute ethyl alcohol to obtain a solution; 2) placing anhydrous lactose, polyvidone K30 and DL-alpha-tocopherol into a wet mixing granulator, and mixing for more than or equal to 5 minutes to obtain dry powder; 3) adding the dry powder obtained in the step (2) into a solid feeder, connecting the solution obtained in the step (1) with an extruder through a low-pulse peristaltic pump, controlling the granulation temperature of the twin-screw extruder at 20-25 ℃, adjusting the dry powder feeding speed to be 2.0-2.5 kg/hr, the peristaltic pump rotating speed to be 6-7 rpm, and the twin-screw rotating speed to be 200-250 rpm, and controlling the weight ratio of the dry powder and the solution entering the twin-screw extruder in unit time, namely the solid-liquid ratio to be 9: 1-10: 1; after materials in 5 minutes before extrusion are discarded, material receiving is started to obtain wet particles; 4) putting the wet granules into an oven, and drying for 2 hours at the temperature of 40-45 ℃ to obtain dried granules; 5) sieving the dried granules with 24 mesh sieve, grading, adding magnesium stearate, mixing, and tabletting.

Example 10 preparation of Adelalcidol tablets

Single dose prescription:

0.75 mu g of eldecalcitol, 83.0mg of anhydrous lactose, K300.5mg of polyvidone, 1mg of propyl gallate, 0.4mg of magnesium stearate, 800.1 mg of tween and a proper amount of anhydrous ethanol

The preparation method comprises the following steps: 1) dissolving the eldecalcitol in absolute ethyl alcohol, adding tween 80 for dissolving to obtain a solution; 2) placing anhydrous lactose, polyvidone K30, and propyl gallate in a wet mixing granulator, and mixing for 5 min or more to obtain dry powder; 3) adding the dry powder obtained in the step (2) into a solid feeder, connecting the solution obtained in the step (1) with an extruder through a low-pulse peristaltic pump, controlling the granulation temperature of the twin-screw extruder at 20-25 ℃, adjusting the dry powder feeding speed to be 2.0-2.5 kg/hr, the peristaltic pump rotating speed to be 3-4 rpm, the twin-screw rotating speed to be 200-250 rpm, and controlling the weight ratio of the dry powder and the solution entering the twin-screw extruder in unit time, namely the solid-liquid ratio to be 10: 1-11: 1; after materials in 5 minutes before extrusion are discarded, material receiving is started to obtain wet particles; 4) putting the wet granules into an oven, and drying for 2 hours at the temperature of 40-45 ℃ to obtain dried granules; 5) sieving the dried granules with 20 mesh sieve, grading, adding magnesium stearate, mixing, and tabletting.

Example 11 preparation of Adeladol tablets

Single dose prescription:

0.5 mu g of eldecalcitol, 82.4mg of anhydrous lactose, povidone K301 mg, 1mg of BHT, 0.4mg of magnesium stearate, 800.2 mg of Tween and a proper amount of anhydrous ethanol

The preparation method comprises the following steps: 1) dissolving the eldecalcitol in absolute ethyl alcohol, adding tween 80 for dissolving to obtain a solution; 2) placing anhydrous lactose, polyvidone K30 and BHT in a wet mixing granulator, and mixing for 5 minutes or more to obtain dry powder; 3) adding the dry powder obtained in the step (2) into a solid feeder, connecting the solution obtained in the step (1) with an extruder through a low-pulse peristaltic pump, controlling the granulation temperature of the twin-screw extruder at 20-25 ℃, adjusting the dry powder feeding speed to be 1.5-2.0 kg/hr, the peristaltic pump rotating speed to be 5-6 rpm, the twin-screw rotating speed to be 250-300 rpm, and controlling the weight ratio of the dry powder and the solution entering the twin-screw extruder in unit time, namely the solid-liquid ratio to be 10: 1-11: 1; after materials in 5 minutes before extrusion are discarded, material receiving is started to obtain wet particles; 4) putting the wet granules into an oven, and drying for 2 hours at the temperature of 40-45 ℃ to obtain dried granules; 5) sieving the dried granules with 20 mesh sieve, grading, adding magnesium stearate, mixing, and tabletting.

Example 12 preparation of Adelalcidol tablets

Single dose prescription:

0.75 mu g of eldercalciferol, 82.4mg of anhydrous lactose, 0.5mg of povidone K300.5, 0.5mg of BHT, 0.5mg of BHA, 0.4mg of sodium stearyl fumarate, 0.1mg of polyoxyethylene stearate and a proper amount of anhydrous ethanol

The preparation method comprises the following steps: 1) dissolving the eldecalcitol in absolute ethyl alcohol, adding polyoxyethylene stearate for dissolving to obtain a solution; 2) placing anhydrous lactose, polyvidone K30, BHT and BHA in a wet mixing granulator, and mixing for 5 min or more to obtain dry powder; 3) adding the dry powder obtained in the step (2) into a solid feeder, connecting the solution obtained in the step (1) with an extruder through a low-pulse peristaltic pump, controlling the granulation temperature of the twin-screw extruder at 20-25 ℃, adjusting the dry powder feeding speed to be 2.0-2.5 kg/hr, the peristaltic pump rotating speed to be 4-5 rpm, the twin-screw rotating speed to be 200-250 rpm, and controlling the weight ratio of the dry powder and the solution entering the twin-screw extruder in unit time, namely the solid-liquid ratio to be 10: 1-11: 1; after materials in 5 minutes before extrusion are discarded, material receiving is started to obtain wet particles; 4) putting the wet granules into an oven, and drying for 2 hours at the temperature of 40-45 ℃ to obtain dried granules; 5) sieving the dried granules with 20 mesh sieve, grading, adding sodium stearyl fumarate, mixing, and tabletting.

EXAMPLE 13 preparation of calcitriol tablets

Single dose prescription:

calcitriol 0.5 μ g, lactose monohydrate 70mg, mannitol 12.6mg, BHT 0.5mg, BHA0.5mg, magnesium stearate 0.4mg, polyoxyethylene stearate 0.2mg, polyoxyethylene (40) hydrogenated castor oil 0.2mg, polyvidone K301 mg, and appropriate amount of anhydrous ethanol

The preparation method comprises the following steps: 1) dissolving calcitriol in anhydrous ethanol, adding polyoxyethylene stearate and polyoxyethylene (40) hydrogenated castor oil, and dissolving to obtain solution; 2) putting lactose monohydrate, mannitol, BHT, BHA and povidone K30 into a wet mixing granulator, and mixing for more than or equal to 5 minutes to obtain dry powder; 3) adding the dry powder obtained in the step (2) into a solid feeder, connecting the solution obtained in the step (1) with an extruder through a low-pulse peristaltic pump, controlling the granulation temperature of the twin-screw extruder at 20-25 ℃, adjusting the dry powder feeding speed to be 2.0-2.5 kg/hr, the peristaltic pump rotating speed to be 4-5 rpm, the twin-screw rotating speed to be 200-250 rpm, and controlling the weight ratio of the dry powder and the solution entering the twin-screw extruder in unit time, namely the solid-liquid ratio to be 10: 1-11: 1; after materials in 5 minutes before extrusion are discarded, material receiving is started to obtain wet particles; 4) putting the wet granules into an oven, and drying for 2 hours at the temperature of 40-45 ℃ to obtain dried granules; 5) sieving the dried granules with 20 mesh sieve, grading, adding magnesium stearate, mixing, and tabletting.

EXAMPLE 14 preparation of calcitriol tablets

Single dose prescription:

1 microgram of calcitriol, 70mg of anhydrous lactose, 13.1mg of sorbitol, 1mg of propyl gallate, 0.4mg of magnesium stearate, 0.4mg of polyoxyethylene stearate, 0.5mg of hydroxypropyl cellulose and a proper amount of anhydrous ethanol

The preparation method comprises the following steps: 1) dissolving calcitriol in absolute ethyl alcohol, and adding polyoxyethylene stearate for dissolving to obtain a solution; 2) placing anhydrous lactose, sorbitol, propyl gallate and hydroxypropyl cellulose in a wet mixing granulator, and mixing for 5 minutes or longer to obtain dry powder; 3) adding the dry powder obtained in the step (2) into a solid feeder, connecting the solution obtained in the step (1) with an extruder through a low-pulse peristaltic pump, controlling the granulation temperature of the twin-screw extruder at 20-25 ℃, adjusting the dry powder feeding speed to be 2.0-2.5 kg/hr, the peristaltic pump rotating speed to be 4-5 rpm, the twin-screw rotating speed to be 200-250 rpm, and controlling the weight ratio of the dry powder and the solution entering the twin-screw extruder in unit time, namely the solid-liquid ratio to be 10: 1-11: 1; after materials in 5 minutes before extrusion are discarded, material receiving is started to obtain wet particles; 4) putting the wet granules into an oven, and drying for 2 hours at the temperature of 40-45 ℃ to obtain dried granules; 5) sieving the dried granules with 20 mesh sieve, grading, adding magnesium stearate, mixing, and tabletting.

EXAMPLE 15 preparation of calcitriol tablets

Single dose prescription:

calcitriol 3 μ g, anhydrous lactose 70mg, mannitol 13.4mg, DL-alpha-tocopherol 1mg,

magnesium stearate 0.4mg, Tween 800.4 mg, hypromellose 0.6mg, and appropriate amount of anhydrous alcohol

The preparation method comprises the following steps: 1) dissolving calcitriol in absolute ethyl alcohol, and adding tween 80 to dissolve to obtain a solution; 2) placing anhydrous lactose, mannitol, DL-alpha-tocopherol and hydroxypropyl methylcellulose into a wet mixing granulator to mix for more than or equal to 5 minutes to obtain dry powder; 3) adding the dry powder obtained in the step (2) into a solid feeder, connecting the solution obtained in the step (1) with an extruder through a low-pulse peristaltic pump, controlling the granulation temperature of the twin-screw extruder at 20-25 ℃, adjusting the dry powder feeding speed to be 2.0-2.5 kg/hr, the peristaltic pump rotating speed to be 4-5 rpm, the twin-screw rotating speed to be 200-250 rpm, and controlling the weight ratio of the dry powder and the solution entering the twin-screw extruder in unit time, namely the solid-liquid ratio to be 10: 1-11: 1; after materials in 5 minutes before extrusion are discarded, material receiving is started to obtain wet particles; 4) putting the wet granules into an oven, and drying for 2 hours at the temperature of 40-45 ℃ to obtain dried granules; 5) sieving the dried granules with 20 mesh sieve, grading, adding magnesium stearate, mixing, and tabletting.

EXAMPLE 16 preparation of calcitriol tablet (without addition of surfactant)

Single dose prescription:

calcitriol 0.5 μ g, lactose monohydrate 70mg, mannitol 13.1mg, BHT 0.5mg, BHA0.5mg, magnesium stearate 0.4mg, sodium carboxymethylcellulose 0.4mg, and appropriate amount of anhydrous ethanol

The preparation method comprises the following steps: 1) dissolving calcitriol in absolute ethyl alcohol to obtain a solution; 2) placing lactose monohydrate, mannitol, BHT, BHA and sodium carboxymethylcellulose into a wet mixing granulator, and mixing for more than or equal to 5 minutes to obtain dry powder; 3) adding the dry powder obtained in the step (2) into a solid feeder, connecting the solution obtained in the step (1) with an extruder through a low-pulse peristaltic pump, controlling the granulation temperature of the twin-screw extruder at 20-25 ℃, adjusting the dry powder feeding speed to be 2.0-2.5 kg/hr, the peristaltic pump rotating speed to be 4-5 rpm, and the twin-screw rotating speed to be 200-250 rpm, and controlling the weight ratio of the dry powder and the solution entering the twin-screw extruder in unit time, namely the solid-liquid ratio to be 10: 1-11: 1; after materials in 5 minutes before extrusion are discarded, material receiving is started to obtain wet particles; 4) putting the wet granules into an oven, and drying for 2 hours at the temperature of 40-45 ℃ to obtain dried granules; 5) sieving the dried granules with 20 mesh sieve, grading, adding magnesium stearate, mixing, and tabletting.

EXAMPLE 17 preparation of calcitriol tablets

Single dose prescription:

calcitriol 0.5 μ g, lactose monohydrate 70mg, sucrose 12.6mg, BHT 0.5mg, BHA0.5mg, magnesium stearate 0.4mg, Tween 800.4 mg, polyvidone K300.5mg, and appropriate amount of anhydrous ethanol

The preparation method comprises the following steps: 1) dissolving calcitriol in absolute ethyl alcohol, and adding tween 80 to dissolve to obtain a solution; 2) mixing lactose monohydrate, sucrose, BHT, BHA and polyvidone K30 in a wet mixing granulator for 5 min or more to obtain dry powder; 3) adding the dry powder obtained in the step (2) into a solid feeder, connecting the solution obtained in the step (1) with an extruder through a low-pulse peristaltic pump, controlling the granulation temperature of the twin-screw extruder at 20-25 ℃, adjusting the dry powder feeding speed to be 2.0-2.5 kg/hr, the peristaltic pump rotating speed to be 4-5 rpm, the twin-screw rotating speed to be 200-250 rpm, and controlling the weight ratio of the dry powder and the solution entering the twin-screw extruder in unit time, namely the solid-liquid ratio to be 10: 1-11: 1; after materials in 5 minutes before extrusion are discarded, material receiving is started to obtain wet particles; 4) putting the wet granules into an oven, and drying for 2 hours at the temperature of 40-45 ℃ to obtain dried granules; 5) sieving the dried granules with 20 mesh sieve, grading, adding magnesium stearate, mixing, and tabletting.

Example 18 comparative example 1CN104739793A discloses an alfacalcidol tablet and a method for preparing the same. Alfacalcidol tablets of comparative example 1 were obtained using the same formulation and process of the present disclosure using a conventional wet granulation method, according to the method of example 1 therein. The process is described as follows: weighing raw and auxiliary materials according to the prescription amount, and respectively sieving the raw and auxiliary materials by a 80-mesh sieve for later use; preparing a binder solution; uniformly mixing the sieved main drugs, auxiliary materials and the like according to an equivalent incremental method, and adding the adhesive solution to prepare a soft material; granulating with 40 mesh sieve, drying at 50 deg.C for 30 min, sieving with 20 mesh sieve, grading, adding magnesium stearate, mixing, and tabletting.

Example 19 comparative example 2CN1196677A discloses a method for preparing a very low dose pharmaceutical solid dosage form. Alfacalcidol tablets of comparative example 2 were obtained using the same formulation and process of the present disclosure using high shear mixing granulation technique according to the preparation method described therein. The process is generally described as follows: preparing a medicinal solution by adopting a proper amount of solvent, slowly adding the medicinal solution into the excipient and other auxiliary materials in a high-speed shearing mixing-granulating machine, violently mixing wet powder by using a stirring paddle at 1500rpm for 10-20 minutes, screening the obtained concentrate into a roller blender, uniformly mixing the concentrate with the rest materials, and tabletting to obtain the compound.

EXAMPLE 20 preparation of alfacalcidol tablets

Single dose formulations:

The preparation method comprises the following steps: 1) dissolving alfacalcidol in absolute ethyl alcohol, and adding tween 80 to dissolve to obtain a solution; 2) adding anhydrous lactose, polyvidone K30 and propyl gallate into a fluidized bed, spraying the solution obtained in the step (1) into a mixture of the anhydrous lactose, the polyvidone K30 and the propyl gallate through fluidized bed granulation, and uniformly mixing in the fluidized bed after the liquid spraying is finished to obtain wet granules; 3) putting the wet granules into an oven, and drying for 2 hours at the temperature of 40-45 ℃ to obtain dried granules; 4) sieving the dried granules with 20 mesh sieve, grading, adding magnesium stearate, mixing, and tabletting.

EXAMPLE 21 preparation of alfacalcidol tablets

Single dose prescription:

alfacalcidol 0.5 μ g, anhydrous lactose 81.5mg, Povidone K302 mg, BHT 1mg, sodium stearyl fumarate 0.4mg, polyoxyethylene stearate 0.1mg, and appropriate amount of anhydrous ethanol

The preparation method comprises the following steps: 1) dissolving alfacalcidol in absolute ethyl alcohol, adding polyoxyethylene stearate for dissolving, and adding povidone K30 and BHT to obtain a solution; 2) adding anhydrous lactose into a fluidized bed, spraying the solution obtained in the step (1) into the anhydrous lactose through fluidized bed granulation, and uniformly mixing in the fluidized bed after liquid spraying is finished to obtain wet granules; 3) directly drying the wet granules in a fluidized bed for 3 hours at 35-40 ℃ to obtain dry granules; 5) sieving the dried granules with 24 mesh sieve, grading, adding sodium stearyl fumarate, mixing, and tabletting.

EXAMPLE 22 preparation of alfacalcidol tablets

Single dose prescription:

The preparation method comprises the following steps: 1) dissolving alfacalcidol in anhydrous ethanol, adding polyoxyethylene (40) hydrogenated castor oil for dissolving, and adding povidone K30 and DL-alpha-tocopherol to obtain a solution; 2) adding anhydrous lactose into a fluidized bed, spraying the solution obtained in the step (1) into the anhydrous lactose through fluidized bed granulation, and uniformly mixing in the fluidized bed after liquid spraying is finished to obtain wet granules; 3) directly drying the wet granules in a fluidized bed for 3 hours at the temperature of 30-35 ℃ to obtain dried granules; 5) sieving the dried granules with 24 mesh sieve, grading, adding magnesium stearate, mixing, and tabletting.

Example 23 preparation of Adeladol tablets

Single dose formulations:

The preparation method comprises the following steps: 1) dissolving eldecalcitol in anhydrous ethanol, adding polyvidone K30 and propyl gallate for dissolving to obtain solution; 2) adding anhydrous lactose into a fluidized bed, spraying the solution obtained in the step (1) into the anhydrous lactose through fluidized bed granulation, and uniformly mixing in the fluidized bed after liquid spraying is finished to obtain wet granules; 3) drying the wet granules in an oven for 2 hours at the temperature of 40-45 ℃ to obtain dry granules; 5) sieving the dried granules with 20 mesh sieve, grading, adding magnesium stearate, mixing, and tabletting.

EXAMPLE 24 preparation of Adelacitol tablets

Single dose prescription:

0.5 mu g of eldercalciferol, 83.1mg of anhydrous lactose, 0.5mg of povidone K300, 1mg of BHT, 0.1mg of polyoxyethylene stearate, 0.4mg of sodium stearyl fumarate and a proper amount of anhydrous ethanol

The preparation method comprises the following steps: 1) dissolving the elderberry in absolute ethyl alcohol, adding polyoxyethylene stearate, povidone K30 and BHT for dissolving to obtain a solution; 2) adding anhydrous lactose into a fluidized bed, spraying the solution obtained in the step (1) into the anhydrous lactose through fluidized bed granulation, and uniformly mixing in the fluidized bed after liquid spraying is finished to obtain wet granules; 3) drying the wet granules in an oven for 3 hours at 35-40 ℃ to obtain dry granules; 5) sieving the dried granules with 20 mesh sieve, grading, adding sodium stearyl fumarate, mixing, and tabletting.

EXAMPLE 25 preparation of Elodicalciferol tablets

Single dose prescription:

The preparation method comprises the following steps: 1) dissolving eldercalciferol in absolute ethyl alcohol, adding tween 80, dissolving, and adding povidone K30 and BHT to obtain a solution; 2) adding anhydrous lactose into a fluidized bed, spraying the solution obtained in the step (1) into the anhydrous lactose through fluidized bed granulation, and uniformly mixing in the fluidized bed after liquid spraying is finished to obtain wet granules; 3) directly drying the wet granules in a fluidized bed for 2 hours at 35-40 ℃ to obtain dry granules; 5) sieving the dried granules with 20 mesh sieve, grading, adding magnesium stearate, mixing, and tabletting.

EXAMPLE 26 preparation of calcitriol tablets

Single dose prescription:

The preparation method comprises the following steps: 1) dissolving calcitriol in anhydrous ethanol, adding polyoxyethylene stearate and polyoxyethylene (40) hydrogenated castor oil, dissolving, and adding polyvidone K30, BHT and BHA to obtain solution; 2) adding lactose monohydrate and mannitol into a fluidized bed, spraying the solution obtained in the step 1 into anhydrous lactose through fluidized bed granulation, and uniformly mixing in the fluidized bed after spraying liquid to obtain wet granules; 3) directly drying the wet granules in a fluidized bed for 2 hours at 35-40 ℃ to obtain dried granules; 5) sieving the dried granules with 20 mesh sieve, grading, adding magnesium stearate, mixing, and tabletting.

EXAMPLE 27 preparation of calcitriol tablets

Single dose prescription:

calcitriol 1 μ g, anhydrous lactose 70mg, sorbitol 13.1mg, propyl gallate 1mg, magnesium stearate 0.4mg, polyoxyethylene stearate 0.4mg, hypromellose 0.5mg, and appropriate amount of anhydrous ethanol

The preparation method comprises the following steps: 1) dissolving calcitriol in absolute ethyl alcohol, adding polyoxyethylene stearate for dissolving, and adding hydroxypropyl methylcellulose and propyl gallate to obtain a solution; 2) adding anhydrous lactose and sorbitol into a fluidized bed, spraying the solution obtained in the step (1) into the anhydrous lactose through fluidized bed granulation, and uniformly mixing in the fluidized bed after spraying liquid to obtain wet granules; 3) directly drying the wet granules in a fluidized bed for 2 hours at 35-40 ℃ to obtain dry granules; 5) sieving the dried granules with 20 mesh sieve, grading, adding magnesium stearate, mixing, and tabletting.

EXAMPLE 28 preparation of calcitriol tablets

Single dose prescription:

calcitriol 3 μ g, anhydrous lactose 70mg, mannitol 13.4mg, DL-alpha-tocopherol 1mg, magnesium stearate 0.4mg, Tween 800.4 mg, polyvidone K300.6mg, and appropriate amount of anhydrous ethanol

The preparation method comprises the following steps: 1) dissolving calcitriol in absolute ethyl alcohol, adding tween 80 for dissolving, and adding povidone K30 and DL-alpha-tocopherol to obtain a solution; 2) adding anhydrous lactose and mannitol into a fluidized bed, spraying the solution obtained in the step 1 into the anhydrous lactose through fluidized bed granulation, and uniformly mixing in the fluidized bed after spraying liquid to obtain wet granules; 3) directly drying the wet granules in a fluidized bed for 2 hours at 35-40 ℃ to obtain dried granules; 5) sieving the dried granules with 20 mesh sieve, grading, adding magnesium stearate, mixing, and tabletting.

Test example 1 Effect of Tween 80 on stability of alfacalcidol in solution

Preparing alfa ossification alcohol solution containing tween and alfa ossification alcohol solution not containing tween, and sampling and detecting the precursor every 1h at the temperature of 40 ℃.

The above results show that the addition of tween 80 increases alfacalcidol stability for alfacalcidol solutions, maintains better stability during solution preparation and slow addition of the solution to the extruder, and inhibits the formation of degradation products.

Test example 2 Effect of surfactant addition on stability of alfacalcidol tablets

The bare chip of the alfacalcidol tablet prepared in the embodiment 1-5 is placed in an open state under the conditions of the temperature of 40 ℃ and the relative humidity of 75% RH, and is sampled at different days to detect the content of the degradation product. Wherein example 1 tablets contain tween 0.1mg, example 2 tablets contain no tween, example 3 tablets contain tween 0.2mg, example 4 tablets contain 0.1mg of polyoxyethylene stearate, and example 5 tablets contain 0.1mg of polyoxyethylene (40) hydrogenated castor oil. "n.d." means "not detected". The degradation products in this test example refer to 1 β type impurities of alfacalcidol, i.e. the chemical name (5Z, 7E) -9, 10-secocholest-5, 7,10(19) -triene-1 β, 3 β -diol.

The results show that the addition of the surfactant can inhibit the rate of degradation product 1 beta type impurity generation of the alfacalcidol tablet under the accelerated test condition, and improve the storage stability of the alfacalcidol tablet.

Test example 3 Effect of surfactant addition on the stability of calcitriol tablets

The bare chip of the calcitriol tablet prepared in the embodiment 13-17 is placed in an open state under the conditions of the temperature of 40 ℃ and the relative humidity of 75% RH, and is sampled at different days to detect the content of degradation products. In example 13, the tablet contains 0.4mg of polyoxyethylene stearate and polyoxyethylene (40) hydrogenated castor oil, the tablet contains 0.4mg of polyoxyethylene stearate, the tablets in example 15 and example 17 contain 0.4mg of tween, and the tablet in example 16 contains no surfactant. "n.d." means "not detected". The degradation product in this test example is 1 β type impurity of calcitriol, i.e., 1 β type impurity with chemical name (5Z, 7E) -9, 10-ring-opened cholesta-5, 7,10(19) -triene-1 β, 3 β, 25-triol.

The results show that the addition of the surfactant can inhibit the rate of the calcitriol tablet for generating degradation products under the accelerated test condition, and improve the storage stability of the calcitriol tablet.

Test example 4 comparative test of content uniformity of alfacalcidol tablet

In the experimental example, the preparation process of the alfacalcidol tablet is taken as a focus, and the influence of different preparation processes on the content uniformity of the main drug in the alfacalcidol tablet is mainly examined.

The above results show that example 18 is a conventional wet granulation process using an equivalent incremental process and example 19 is an improvement over example 18, namely, a high shear mixing granulation process. The content uniformity of the tablets obtained by the double-screw technical granulation method used in the embodiments 1 to 3 is very in line with the regulations of Chinese pharmacopoeia, and is obviously superior to the tablets obtained by the first two processes and equipment.

Test example 5 examination of mixing time

Avoid influencing the degree of consistency of final product, still need investigate auxiliary material mixing homogeneity. Prescribed amounts of fillers, binders, antioxidants, etc. are added to the mixer granulator and mixed, and additionally, the labeling agent is added. And (3) whether the materials can be uniformly mixed under the conditions of stirring speed of 5r/s and shearing speed of 5r/s and mixing time of 3 minutes, 5 minutes and 8 minutes is examined. Whether the materials can be uniformly mixed is judged by the content of the markers in the samples of 5 different sampling points in the pot body of the wet mixing granulator, and finally, the quantity of the markers at each sampling point in the mixed powder is uniform after the mixing time reaches 5 minutes.

Test example 6 Effect of extrusion temperature

The precursor content of the products on the market is higher due to the instability factor of the vitamin D analogue drugs. It was also found in the experiments of the present disclosure that the extrusion temperature has a direct influence on the content and stability of the final formulation. A large number of experiments prove that the granulating temperature of the double-screw extruder is controlled to be 20-25 ℃, and compared with the alfacalcidol tablets sold in the market, the content of the alfacalcidol tablets in the example 1 is remarkably reduced, so that the alfacalcidol tablets have a remarkable effect. At the same time, the samples were also tested for stability lofting, with the previous content still being below 3% within 0 to 6 months.

Test example 7 twin-screw extrusion granulation Process control

In the twin-screw extrusion granulation, the feeding speed of dry powder, the liquid adding speed of the wetting agent (namely the rotating speed of a peristaltic pump) and the rotating speed of the twin-screw need to be matched with each other to prepare proper wet granules. When the dry powder feeding speed is adjusted to be 1.0-3 kg/hr, the peristaltic pump rotating speed is 2-8 rpm, and the double screw rotating speed is 100-400 rpm, the solid-liquid ratio is adjusted to be 7: 1-11: 1, preferably 8.5: 1-9: 1, the prepared particles are observed to be uniform, and the content of the extrudate is measured to be uniform. The mutual matching of the rotating speeds is also to ensure that the residence time of the dry powder and the solution in the extruder is kept between 1 and 3 minutes so as to achieve the optimal granulation effect.

In addition, the material receiving time is considered, and the mixed material is added into the feeder. Meanwhile, after the wetting agent is connected with an extruder through a peristaltic pump, the preparation of an extrudate is carried out according to a feeding speed of 1.5kg/hr, a liquid adding speed of 4.0rpm and a twin-screw extrusion speed of 150rpm, the content of materials received 2-5 minutes after the start of extrusion is high, the quality control requirements are not met, and the reason for the phenomenon is mainly that the solid-liquid ratio in the extruder at the early stage is not adjusted to be in an equilibrium state. The material content after 5 minutes of extrusion is normal and meets the requirement of internal control. Therefore, in the actual operation, the material receiving process should be started after 5 minutes of extrusion.

Test example 8 Effect of antioxidant (propyl gallate or DL-alpha-tocopherol) amount on precursor content in Doiscalciferol tablets

The test method comprises the following steps: the test examples used in the test were obtained by changing the formulation examples and the preparation process of examples 6 to 8 of the present disclosure, wherein the amounts of lactose anhydrous, povidone K30 and magnesium stearate were kept consistent, and the respective eldecalcitol tablets containing no antioxidant, different amounts of propyl gallate and different amounts of DL- α -tocopherol were obtained in sequence. Under the conditions of 40 ℃ and 75% RH relative humidity, each bare chip is placed in an open state, and a sample is taken at the time point of 20 days to detect the content of the degradation products.

The above results show that when the antioxidant is propyl gallate or DL-alpha-tocopherol, the content of the eldecalcitol precursor is gradually reduced with the increase of the dosage, and the effect of inhibiting the precursor is more obvious. This is different from the cases of alfacalcidol and calcitriol tablets, in which an antioxidant such as propyl gallate has no significant effect on the respective precursor content at a given dose, and is at the equilibrium level of the corresponding precursor content, presumably related to the steric stabilization of the eldecalcitol precursor in the chemical molecular structure.

Test example 9 measurement of corresponding precursors and degradation products of alfacalcidol tablets, aldrich tablets and calcitriol tablets after masking and storage at room temperature for 12 months

In the above-mentioned tablets prepared using twin-screw extrusion granulation, the masked stability test conditions at room temperature for 12 months may be selected by sampling and examining the relevant data under a commercial product package, such as an aluminum-plastic blister package, stored at 25 ℃. + -. 2 ℃ and 60% RH. + -. 5% RH for 12 months.

Test example 10 measurement of the content of the corresponding precursor after masking alfacalcidol tablets, aldrich tablets and calcitriol tablets and storing at room temperature for 12 months

In the above-described tablets prepared using the fluidized bed spray granulation method, the masked stability test conditions at room temperature for 12 months may be selected to sample and examine relevant data under a commercial product package, such as an aluminum plastic blister package, stored at 25 ℃. + -. 2 ℃ and 60% RH. + -. 5% RH for 12 months.

Industrial applicability

The vitamin D analogue preparation is prepared by adopting a double-screw extrusion technology, so that the stability of the medicine is obviously improved, and the quality of the medicine is greatly improved.

Claims

1. A method for preparing a composition comprising a vitamin D analogue, wherein said composition comprising a vitamin D analogue selected from one of calcitriol, alfacalcidol, and eldercalciferol is a solid formulation, and wherein said vitamin D analogue is selected from the corresponding anhydrate, hydrate, or solvate; the solid preparation generates corresponding precursor of vitamin D analogue in an amount less than or equal to 7% after being shielded and stored at room temperature for 12 months;

the preparation method is a double-screw extrusion granulation method and comprises the following steps:

a) dissolving a vitamin D analogue in a solvent to obtain a solution; adding a stabilizer into the solution and dissolving the stabilizer into the solution;

b) uniformly mixing other solid auxiliary materials to form dry powder;

wherein the solid form of the auxiliary material comprises one or more of a filler, a binder and an antioxidant; the stabilizer is a substance which has a stabilizing effect on the vitamin D analogue and can inhibit the degradation of the vitamin D analogue into corresponding 1 beta type impurities;

the stabilizing agent is tween 80;

the granulating temperature of the double-screw extruder is controlled to be 20-25 ℃, the drying temperature is 35-50 ℃, the drying time is 0.5-4 h, the time for uniformly mixing the solid auxiliary materials is more than or equal to 5 minutes, the dry powder feeding speed is 1.0-3.0 kg/hr, the rotating speed of a peristaltic pump is 2-8 rpm, and the rotating speed of a double screw is 100-400 rpm.

2. The method according to claim 1, wherein the solvent is absolute ethanol.

3. The method of claim 1, wherein the amount of precursor of the corresponding vitamin D analog produced from the solid preparation after shielding and storing at room temperature for 12 months is 5% or less.

4. The method according to claim 3, wherein the amount of the precursor that produces the corresponding vitamin D analog after the solid preparation is masked and stored at room temperature for 12 months is 3% or less.

5. The method according to claim 1, wherein the obtained granules are dried at a temperature of 40 to 45 ℃ for 0.5 to 2 hours.

6. The method of claim 1, wherein the pharmaceutical composition is in the form of a tablet, capsule, granule or dry suspension in a solid formulation; the components of the solid preparation further comprise a lubricant.

7. The method according to claim 1, wherein the filler is selected from one or more of starch, pregelatinized starch, corn starch, lactose monohydrate, lactose anhydrous, mannitol, and microcrystalline cellulose; the adhesive is one or more selected from polyvidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, and sodium carboxymethylcellulose; the antioxidant is selected from one or more of propyl gallate, DL-alpha-tocopherol, dibutyl hydroxy toluene (BHT), Butyl Hydroxy Anisole (BHA); the lubricant is selected from one or more of pulvis Talci, magnesium stearate, calcium stearate, and sodium stearyl fumarate.

8. The method according to claim 1, wherein the amount of the filler in the solid preparation is 50 to 200mg per tablet; the dosage of the adhesive is 0.2-3 mg per tablet; the dosage of the lubricant is 0.1-1 mg per tablet; the dosage of the antioxidant is 0.02-2 mg per tablet; the dosage of the stabilizer is 0.02-2 mg per tablet.

9. The method according to claim 8, wherein the amount of the filler is 81 to 83mg per tablet.

10. The method according to claim 8, wherein the binder is used in an amount of 1.0 to 2.0mg per tablet.

11. The method according to claim 8, wherein the amount of the lubricant used in the solid preparation is 0.4 to 0.5mg per tablet.

12. The method according to claim 8, wherein the amount of the antioxidant is 0.5 to 1.0mg per tablet.

13. The method of claim 8, wherein the amount of the stabilizer used in the solid preparation is 0.1 to 0.5mg per tablet.

14. The process according to claim 1, wherein the vitamin D analogue is alfacalcidol, i.e. a compound having the chemical name (5Z, 7E) -9, 10-secocholest-5, 7,10(19) -triene-1 α, 3 β -diol; the composition is a solid preparation; it comprises alfacalcidol, filler, binder, lubricant, antioxidant and stabilizer; wherein, a stabilizer is added for inhibiting the degradation of alfacalcidol into 1 beta type impurities, namely (5Z, 7E) -9, 10-ring-opening cholest-5, 7,10(19) -triene-1 beta, 3 beta-diol, so that the amount of 1 beta type impurities generated after the solid preparation is shielded and stored at room temperature for 12 months is less than or equal to 0.3 percent.

15. The method of claim 14, wherein the composition is a tablet.

16. The method according to claim 14, wherein the solid preparation is masked and stored at room temperature for 12 months to produce 1 β type impurity in an amount of 0.1% or less.

17. The process according to claim 14, wherein the solid preparation is a tablet, and the filler is one or more selected from the group consisting of anhydrous lactose, lactose monohydrate, mannitol, microcrystalline cellulose, and sucrose; the adhesive is one or more selected from polyvidone, hydroxypropyl cellulose, hypromellose, and sodium carboxymethylcellulose; the lubricant is selected from one or more of talcum powder, magnesium stearate, calcium stearate and sodium stearyl fumarate; the antioxidant is one or more selected from propyl gallate, DL-alpha-tocopherol, dibutyl hydroxy toluene (BHT), and Butyl Hydroxy Anisole (BHA).

18. The process according to claim 17, wherein the filler is anhydrous lactose.

19. The method of claim 17, wherein the binder is povidone K30.

20. The method of claim 17, wherein the lubricant is magnesium stearate.

21. The method according to claim 14, wherein the solid preparation is a tablet, and the amount of the filler is 50 to 200mg per tablet; the dosage of the adhesive is 0.2-3 mg per tablet; the dosage of the lubricant is 0.1-1 mg per tablet; the dosage of the antioxidant is 0.05-2 mg per tablet; the dosage of the stabilizer is 0.02-2 mg per tablet.

22. The method of claim 21, wherein the filler is used in an amount of 81 to 83mg per tablet.

23. The method of claim 21, wherein the binder is used in an amount of 1.0 to 2.0mg per sheet.

24. The method of claim 21, wherein the lubricant is present in an amount of 0.4 to 0.5mg per tablet.

25. The method of claim 21, wherein the antioxidant is present in an amount of 0.5 to 1.0mg per tablet.

26. The method of claim 23, wherein the stabilizer is used in an amount of 0.1 to 0.5mg per tablet.

27. The method of claim 14, wherein the composition is an alfacalcidol tablet; wherein the filler is anhydrous lactose, the binder is povidone K30, the lubricant is magnesium stearate, and the antioxidant is propyl gallate, or BHT, or a combination of BHT and BHA; the stabilizer is Tween 80, and the dosage of the Tween 80 is 0.02-2 mg per tablet.

28. The method according to claim 27, wherein tween 80 is used in an amount of 0.1 to 0.5mg per tablet.

29. The process according to claim 1, wherein the vitamin D analogue is eldercalciferol, which is known by the chemical name (5Z, 7E) - (1R, 2R, 3R) -2- (3-hydroxypropoxy) -9, 10-secocholesta-5, 7,10(19) -triene-1, 3, 25-triol; the composition is a solid preparation; comprises the aldocalcitol, a filler, a binder, a lubricant, an antioxidant; wherein an antioxidant is added for inhibiting the conversion of the eldercalciferol into an eldercalciferol precursor, namely 6Z- (1R, 2R, 3R) -2- (3-hydroxypropoxy) -9, 10-secocholest-5 (10), 6, 8(9) -triene-1, 3, 25-triol, so that the solid preparation generates 7% or less of the eldercalciferol precursor after being stored at a sheltered room temperature for 12 months.

30. The method of claim 29, wherein the composition is a tablet.

31. The method of claim 29, wherein an antioxidant is added to inhibit the conversion of eldercalciferol into eldercalciferol precursor, i.e., 6Z- (1R, 2R, 3R) -2- (3-hydroxypropoxy) -9, 10-secocholest-5 (10), 6, 8(9) -triene-1, 3, 25-triol, which is masked and stored at room temperature for 12 months, and which generates an amount of eldercalciferol precursor of 5% or less.

32. The method of claim 31, wherein the amount of the eldecalcitol precursor produced after 12 months of masked room temperature storage is 3% or less.

33. The process according to claim 29, wherein the solid preparation is a tablet, and the filler is one or more selected from the group consisting of anhydrous lactose, lactose monohydrate, mannitol, microcrystalline cellulose, and sucrose; the adhesive is one or more selected from polyvidone, hydroxypropyl cellulose, hypromellose, and sodium carboxymethylcellulose; the lubricant is one or more selected from pulvis Talci, magnesium stearate, calcium stearate, and sodium stearyl fumarate; the antioxidant is selected from one or more of propyl gallate, DL-alpha-tocopherol, dibutyl hydroxy toluene (BHT), and Butyl Hydroxy Anisole (BHA).

34. The process according to claim 33, wherein the filler is anhydrous lactose.

35. The method of claim 33, wherein the binder is povidone K30.

36. The method of claim 33, wherein the lubricant is magnesium stearate.

37. The process of claim 29, wherein the solid dosage form is a tablet, the filler is anhydrous lactose, the binder is povidone K30, the lubricant is magnesium stearate, the antioxidant is propyl gallate, or BHT, or a combination of BHT and BHA.

38. The method of claim 29, wherein the amount of filler is 50 to 200mg per tablet; the dosage of the adhesive is 0.2-3 mg; the dosage of the lubricant is 0.1-1 mg per tablet; the dosage of the antioxidant is 0.05-2 mg.

39. The method of claim 38, wherein the amount of the filler is 80-84 mg per tablet.

40. The method of claim 38, wherein the binder is present in an amount of 0.4 to 0.5mg per tablet.

41. The method of claim 38, wherein the lubricant is present in an amount of 0.4 to 0.5mg per tablet.

42. The method of claim 38, wherein the antioxidant is present in an amount of 0.5 to 1.0mg per tablet.

43. The method of claim 29, wherein the solid formulation further comprises a stabilizer, wherein the stabilizer is added to inhibit the degradation of the eldercalciferol into its 1 β type impurity, i.e., its chemical name (5Z, 7E) - (1S, 2R, 3R) -2- (3-hydroxypropoxy) -9, 10-secocholesta-5, 7,10(19) -triene-1, 3, 25-triol, so that the amount of 1 β type impurity generated after the solid formulation is masked and stored at room temperature for 12 months is 0.3% or less.

44. The process according to claim 43, wherein the solid preparation is masked and stored at room temperature for 12 months to produce 1 β type impurity in an amount of 0.1% or less.

45. The method of claim 43, wherein the solid dosage form is a tablet, the filler is anhydrous lactose, the binder is povidone K30, the lubricant is magnesium stearate, the antioxidant is propyl gallate, or BHT, or a combination of BHT and BHA; the stabilizer is Tween 80, and the dosage of the Tween 80 is 0.02-2 mg per tablet.

46. The method of claim 45, wherein Tween 80 is used in an amount of 0.1-0.5 mg per tablet.

47. The method of claim 1, wherein the vitamin D analog is calcitriol, i.e., calcitriol having a chemical name of (5Z, 7E) -9, 10-secocholest-5, 7,10(19) -triene-1 α, 3 β, 25-triol; the composition is a solid preparation; comprises calcitriol, a filler, a binder, a lubricant, an antioxidant and a stabilizer; wherein, a stabilizer is added for inhibiting the degradation of calcitriol into 1 beta type impurities, namely (5Z, 7E) -9, 10-ring-opening cholest-5, 7,10(19) -triene-1 beta, 3 beta, 25-triol with the chemical name, so that the amount of 1 beta type impurities generated after the solid preparation is shielded and stored at room temperature for 12 months is less than or equal to 0.3 percent.

48. The method of claim 47, wherein the composition is a tablet.

49. The method according to claim 47, wherein the amount of 1 β type impurity generated from the masked solid preparation after 12 months of storage at room temperature is 0.1% or less.

50. The method for preparing the compound of claim 47, wherein the filler is selected from one or more of anhydrous lactose, lactose monohydrate, mannitol, microcrystalline cellulose and sucrose; the adhesive is one or more selected from polyvidone, hydroxypropyl cellulose, hypromellose, and sodium carboxymethylcellulose; the lubricant is selected from one or more of talcum powder, magnesium stearate, calcium stearate and sodium stearyl fumarate; the antioxidant is one or more selected from propyl gallate, DL-alpha-tocopherol, dibutyl hydroxy toluene (BHT), and Butyl Hydroxy Anisole (BHA).

51. The process according to claim 50, wherein the filler is anhydrous lactose.

52. The method of claim 50, wherein the binder is povidone K30.

53. The method of claim 50, wherein the lubricant is magnesium stearate.

54. The process of claim 47, wherein the solid dosage form is a tablet, the filler is anhydrous lactose, the binder is povidone K30, the antioxidant is propyl gallate, or dibutylhydroxytoluene (BHT), or a combination of dibutylhydroxytoluene (BHT) and Butylhydroxyanisole (BHA); the stabilizer is tween 80.

55. The method for preparing a pharmaceutical composition according to claim 47, wherein the solid preparation is a tablet, and the amount of the filler is 50 to 200mg per tablet; the dosage of the adhesive is 0.2-3 mg per tablet; the dosage of the lubricant is 0.1-1 mg per tablet, and the dosage of the antioxidant is 0.05-2 mg per tablet; the dosage of the stabilizer is 0.02-2 mg per tablet.

56. The method of claim 55, wherein the filler is present in an amount of 81-83 mg per tablet.

57. The method of claim 55, wherein the binder is present in an amount of 1.0 to 2.0mg per tablet.

58. The method of claim 55, wherein the lubricant is present in an amount of 0.4 to 0.5mg per tablet.

59. The method of claim 55, wherein the antioxidant is present in an amount of 0.5 to 1.0mg per tablet.

60. The method of claim 55, wherein the stabilizer is present in an amount of 0.1 to 0.5mg per tablet.