WO2019214512A1 - 维生素d类似物制剂及其制备方法 - Google Patents

维生素d类似物制剂及其制备方法 Download PDF

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Publication number
WO2019214512A1
WO2019214512A1 PCT/CN2019/085213 CN2019085213W WO2019214512A1 WO 2019214512 A1 WO2019214512 A1 WO 2019214512A1 CN 2019085213 W CN2019085213 W CN 2019085213W WO 2019214512 A1 WO2019214512 A1 WO 2019214512A1
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per tablet
polyoxyethylene
amount
drying
solid preparation
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PCT/CN2019/085213
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English (en)
French (fr)
Inventor
叶海
陶莉
马冲
袁晓莉
闵涛
丁伯祥
郑慧娟
徐丽
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南京海融医药科技股份有限公司
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Priority to JP2020537836A priority Critical patent/JP7062246B2/ja
Priority to CN201980002415.3A priority patent/CN110650730B/zh
Publication of WO2019214512A1 publication Critical patent/WO2019214512A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A61K31/593—9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease

Definitions

  • the present disclosure relates to a pharmaceutical composition comprising a vitamin D analog, which is a solid preparation, and to a method for preparing and obtaining the above pharmaceutical composition by a twin-screw extrusion technique, and belongs to the technical field of pharmaceutical preparation.
  • Vitamin D analogues are marketed worldwide for the treatment of osteoporosis, secondary hyperparathyroidism (SHPT) and psoriasis in renal dialysis patients. Foreign countries also have clinical research as anticancer drugs.
  • Such drugs widely used in clinical practice include vitamin D2, vitamin D3, calcifediol, calcitriol, alfacalcidol, edecalcitol, calciferol, maxacalcitol, parical bone Alcohol, tacalcitol, calcipotriol, etc.
  • the corresponding precursors, degradation products and the like of the vitamin D analog are likely to have the same characteristics as the main drug due to their similar chemical structures, that is, low dose and high activity.
  • precursors of vitamin D analogs under current means, are indeed difficult to obtain a large number of pure products for targeted safety evaluation.
  • the precursor can only be controlled within the proven safety range by the formulation process. Therefore, the research on their conversion products or degradation products can not be ignored, and their attention can not be lost.
  • a micronization process 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 conversion product or a degradation product, and the like are generally employed.
  • a micronization process due to the instability characteristics of the vitamin D analog itself, it is easy to transform or degrade under light, wet and heat conditions.
  • the drugs are easily degraded and converted.
  • the hot melt extruder includes a hot melt extrusion (HME) module and a twin screw extrusion (TSG) module.
  • HME hot melt extrusion
  • TSG twin screw extrusion
  • the single/double screw extrusion equipment is used to make the material undergo three stages of solid transportation, melting and melt transportation. Under the strong shearing action of the kneader and the screw element, a highly mixed and dispersed molded product is obtained.
  • the hot melt extrusion process can realize various unit operations of mixing, granulating and molding products on one equipment, and has the characteristics of less process, low energy consumption, low cost, high yield, continuous, and closable production.
  • the technology has a breakthrough advantage in improving the dissolution of poorly soluble drugs, preparing sustained release preparations and topical preparations, and has become a new hot spot in the drug delivery system of preparation technology. It is also worth noting that its preparation process is easy to achieve industrial scale-up production.
  • the application of twin-screw technology equipment can not only realize the preparation mode of hot melt extrusion technology, but also achieve the process of granulation by twin-screw technology; especially for low-drug content, environmental factors such as heat, air and water.
  • Sensitive pharmaceutical preparations can better improve the quality index such as content uniformity and stability.
  • the use of twin-screw extrusion techniques in the preparation of compositions for vitamin D analogs and their formulations has not been reported in the prior art.
  • wet granulation has some disadvantages that are difficult to overcome:
  • the preparation method of the existing vitamin D analog drug cannot satisfy the content uniformity requirement, and the instability factor of the vitamin D analog itself, the drug is easily converted into a precursor during the granulation process.
  • a composition comprising a vitamin D analog, which is a solid preparation selected from the group consisting of vitamin D3, calcifediol, calcitriol, Alpha bone One of an alcohol, an osteocalcin, a calciferol, a maxacalcitol, a paricalcitol, tacalcitol, or calcipotriol, the vitamin D analog being selected from the corresponding An anhydrate, a hydrate or a solvate; the amount of the precursor of the corresponding vitamin D analog produced by the solid preparation after being blocked for 12 months at room temperature is 7% or less; preferably, the amount of the precursor is less than Equal to 5%; still more preferably, the amount of the precursor is 3% or less, or
  • the present disclosure is the pharmaceutical composition, which can be prepared by a conventional granulation method, including but not limited to: centrifugal granulation, high-speed shear mixing granulation, rolling granulation, fluidized bed granulation, spraying Granulation method, crystallization granulation method in liquid phase, melt granulation method, fluidized bed spray granulation method; among them, fluidized bed spray granulation method is preferred, wherein fluidized bed spray granulation method is according to spray position
  • the difference can be subdivided into fluidized bed low-spray granulation method, fluidized bed side spray granulation method or fluidized bed top spray granulation method.
  • the temperature and time of drying are important parameters for controlling the final precursor content of the product.
  • the optimized parameter condition is that the obtained pellet has a drying temperature of 35 to 50 ° C, a drying time of 0.5 to 4 h, preferably, a drying temperature of 40 to 45 ° C, a drying time of 0.5 to 2 h, and a drying method of the pellet. It is fluidized bed drying or oven drying.
  • the alfacalcidol tablet is preferably prepared by fluidized bed spray granulation.
  • the fluidized bed spray granulation method is preferably used to prepare the edodes.
  • the calcitriol tablet is preferably prepared by fluidized bed spray granulation.
  • the twin-screw extrusion granulation method has unique advantages in the process of preparing low-dose pharmaceutical preparations.
  • the composition is prepared by a twin-screw extrusion technique and comprises the following steps:
  • the solvent is preferably anhydrous ethanol
  • the solution may optionally be added with a stabilizer and dissolved in the solution, or may be selected without adding a stabilizer
  • the solid form of the excipient comprises one or more of a filler, a binder, and an antioxidant; the stabilizer has a stabilizing effect on the vitamin D analog and is capable of inhibiting degradation of the vitamin D analog to Corresponding substance of the 1 ⁇ type impurity.
  • the composition is a tablet, a capsule, a granule or a dry suspension in a solid preparation; the component of the solid preparation further comprises a lubricant; the solid preparation is obtained by the method of claim 3.
  • the dried granules are further prepared by conventional formulation techniques.
  • the filler is selected from one or more of starch, pregelatinized starch, corn starch, lactose monohydrate, anhydrous lactose, mannitol, microcrystalline cellulose;
  • the binder is selected from the group consisting of povidone One or more of hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose;
  • the antioxidant is selected from the group consisting of propyl propyl ester, DL- ⁇ -tocopherol, and dibutyl hydroxytoluene (BHT) One or more of butyl hydroxyanisole (BHA);
  • the lubricant is selected from one or more of talc, magnesium stearate, calcium stearate, sodium stearyl fumarate;
  • the stabilizer is selected from the group consisting of Tween, Span, polyoxyethylene alkyl ether, poloxamer 188, sucrose stearate, polyoxyethylene (35) castor oil, polyoxyethylene (40).
  • the wet granules produced by the twin-screw extrusion granulation method are required to control the drying temperature and time in order to meet the quality requirements.
  • the drying temperature of the granules is 35 to 50 ° C
  • the drying time is 0.5 to 4 h, preferably, the drying temperature is 40 to 45 ° C, the drying time is 0.5 to 2 h
  • the drying method of the granules is fluidized bed drying, or oven drying. .
  • the solid form of the auxiliary material is uniformly mixed in the mixing granulator for 5 minutes or more to facilitate the formation of a uniform dry powder; the three parameters of the dry powder feeding speed, the peristaltic pump speed, and the twin screw speed need to be matched.
  • the dry powder feeding rate is 1.0 to 3.0 kg/hr
  • the peristaltic pump rotation speed is 2 rpm to 8 rpm
  • the twin screw rotation speed is 100 rpm to 400 rpm
  • the ratio of the dry powder to the weight of the solution entering the twin screw extruder per unit time is
  • the "solid-liquid ratio" is 7:1 to 11:1, preferably 8.5:1 to 9:1
  • the granulation temperature of the twin-screw extruder is controlled at 20 to 25 ° C
  • the drying temperature of the particles is 35 to 50 ° C.
  • the drying time is 0.5 to 4 h, preferably, the drying temperature is 40 to 45 ° C, and the drying time is 0.5 to 2 h
  • the drying method of the particles is fluidized bed drying or oven drying.
  • the mixing uniformity needs to be examined.
  • the auxiliary carrier of the solid form was investigated in the wet mixing granulator, and the mixing time was 5r/s, the shearing speed was 5r/s, and the mixing time was 3 minutes, 5 minutes and 8 minutes. Evenly. When mixing for 3 minutes, the material is not completely mixed; after the mixing time reaches 5 minutes, the antioxidant content of each sampling point in the mixed powder can be made uniform.
  • the filler is used in an amount of 50 to 200 mg per tablet, preferably 81 to 83 mg per tablet; and the binder is used in an amount of 0.2 to 3 mg per tablet, preferably, per tablet.
  • the tablet is 1.0 to 2.0 mg; the amount of the lubricant is 0.1 to 1 mg per tablet, preferably 0.4 to 0.5 mg per tablet; the amount of the antioxidant is 0.02 to 2 mg per tablet, preferably 0.5 to 1.0 mg per tablet; and a stabilizer The amount used is 0.02 to 2 mg per tablet, preferably 0.1 to 0.5 mg per tablet. .
  • the vitamin D analog is alfacalcidol, the chemical name (5Z,7E)-9,10-open-loop cholester-5,7, 10(19)-triene-1 ⁇ , 3 ⁇ -diol;
  • the composition is a solid preparation, preferably a tablet; it comprises alfacalcidol, a filler, a binder, a lubricant, an antioxidant, and a stabilizer; Among them, a stabilizer is added for inhibiting the degradation of alfacalcidol into a 1 ⁇ -type impurity, that is, a chemical name (5Z, 7E)-9,10-open-loop cholester-5,7,10(19)-triene-1 ⁇
  • the 3 ⁇ -diol is such that the amount of the 1 ⁇ -type impurity produced by the solid preparation after being blocked for 12 months at room temperature is 0.3% or less, preferably 0.1% or less, or less.
  • the solid preparation is a tablet
  • the filler is selected from one or more of anhydrous lactose, lactose monohydrate, mannitol, microcrystalline cellulose, sucrose, preferably anhydrous lactose
  • binder One or more selected from the group consisting of povidone, hydroxypropylcellulose, hypromellose, sodium carboxymethylcellulose, preferably povidone K30
  • the lubricant is selected from the group consisting of talc, stearic acid One or more of magnesium, calcium stearate, sodium stearyl fumarate, preferably magnesium stearate
  • antioxidant selected from the group consisting of propyl propyl ester, DL- ⁇ -tocopherol, dibutyl
  • BHT hydroxytoluene
  • BHA butylated hydroxyanisole
  • stabilizer selected from the group consisting of Tween, Span, polyoxyethylene alkyl ether, poloxamer 188, sucrose stearic acid Ester
  • the solid preparation of alfacalcidol is a tablet
  • the filler is used in an amount of 50 to 200 mg per tablet, preferably 81 to 83 mg per tablet; and the amount of the binder is 0.2 to 3 mg per tablet, preferably, 1.0 to 2.0 mg per tablet;
  • the amount of lubricant is 0.1 to 1 mg per tablet, preferably 0.4 to 0.5 mg per tablet;
  • the amount of antioxidant is 0.05 to 2 mg per tablet, preferably 0.5 to 1.0 mg per tablet;
  • the amount of the agent is 0.02 to 2 mg per tablet, preferably 0.1 to 0.5 mg per tablet.
  • the above solid solution of alfacalcidol is prepared by a twin-screw extrusion technique, and the drying temperature of the particles is 35 to 50 ° C, the drying time is 0.5 to 5 h, and preferably, the drying temperature is 40 to 45 ° C. The drying time is 0.5 to 2 h; and the drying method of the particles is fluidized bed drying or oven drying.
  • the composition is an alfacalcidol tablet comprising a filler which is anhydrous lactose, the binder is povidone K30, the lubricant is magnesium stearate, and the antioxidant is propyl propyl ester.
  • BHT or a combination of BHT and BHA; the stabilizer is Tween 80, and Tween 80 is used in an amount of 0.02 to 2 mg per tablet, preferably 0.1 to 0.5 mg per tablet.
  • the present disclosure provides a method of inhibiting degradation of alfacalcidol contained in a solid preparation, the preparation comprising a filler, a binder, a lubricant, an antioxidant, a stabilizer; Stabilizer is added to inhibit the degradation of Alfacalcidol into 1 ⁇ -type impurities, namely chemical name (5Z,7E)-9,10-open-loop cholester-5,7,10(19)-triene-1 ⁇ ,3 ⁇ - a diol, which is (5Z,7E)-9,10-open-ring cholester-5,7,10(19)-triene-1 ⁇ ,3 ⁇ -di which is produced after being blocked for 12 months at room temperature.
  • the amount of the alcohol is 0.3% or less, preferably 0.1% or less, or less.
  • the present disclosure provides a method for preparing a fare calcitonol tablet by a twin-screw extrusion technique, the tablet formulation comprising Alfacalcidol, Tween 80, anhydrous lactose, and cyanide Ester, povidone K30, magnesium stearate; the following steps are specifically used:
  • the dry powder obtained in the above step 2 is added to the solid feeder, and the solution obtained in the above step 1 is connected to the extruder through a low-pulsation peristaltic pump, and the granulation temperature of the twin-screw extruder is controlled at 20 to 25 ° C.
  • the dry powder feeding speed, the peristaltic pump rotation speed, the twin screw rotation speed are adjusted, the twin-screw extruder is operated for granulation, and the material is started after the material 5 minutes before the extrusion is discarded, and the wet granule is obtained; wherein the dry powder is fed.
  • the setting between the material speed, the peristaltic pump speed and the twin-screw speed must be matched.
  • the dry powder feeding speed is 1.0-3.0 kg/hr
  • the peristaltic pump speed is 2 rpm-8 rpm
  • the twin-screw speed is 100 rpm-400 rpm.
  • the ratio of the weight of the dry powder and the solution entering the twin-screw extruder per unit time, that is, the "solid-liquid ratio" is 7:1 to 11:1, preferably 8.5:1 to 9:1;
  • step 3 The wet granules obtained in step 3 are dried to obtain dry granules, the drying temperature is 35 to 50 ° C, the drying time is 0.5 h to 4 h, preferably, the drying temperature is 40 to 45 ° C, and the drying time is 0.5 to 2 h; And the drying method of the particles is fluidized bed drying, or oven drying;
  • the dried granules are sieved through 16 to 24 mesh sieves, preferably 20 mesh sieve granules, then added with magnesium stearate, uniformly mixed, and tableted.
  • the vitamin D analog is a decalcified alcohol, ie, the chemical name (5Z, 7E)-(1R, 2R, 3R)-2-(3- Hydroxypropoxy)-9,10-broken guanidine-5,7,10(19)-triene-1,3,25-triol;
  • the composition is a solid preparation, preferably a tablet; Alcohols, fillers, binders, lubricants, antioxidants; among them, the addition of antioxidants for inhibiting the conversion of edecalcitol to the edematite precursor, ie chemical name 6Z-(1R, 2R, 3R )-2-(3-hydroxypropoxy)-9,10-broken guanidine-5(10),6,8(9)-triene-1,3,25-triol, which makes the solid preparation
  • the amount of the edetyl alcohol precursor produced after shading and storage at room temperature for 12 months is 7% or less; preferably, the amount of
  • the solid preparation is an edevic acid alcohol tablet comprising a filler selected from one or more of anhydrous lactose, lactose monohydrate, mannitol, microcrystalline cellulose, and sucrose, preferably, Is anhydrous lactose;
  • the binder is selected from one or more of povidone, hydroxypropyl cellulose, hypromellose, sodium carboxymethyl cellulose, preferably povidone K30;
  • lubricant One or more selected from the group consisting of talc, magnesium stearate, calcium stearate, and sodium stearyl fumarate, preferably magnesium stearate; antioxidant selected from the group consisting of propyl propyl ester, DL- ⁇ - One or more of tocopherol, dibutylhydroxytoluene (BHT), and butylhydroxyanisole (BHA).
  • the solid preparation is an edecalcitol tablet
  • the filler is anhydrous lactose
  • the binder is povidone K30
  • the lubricant is magnesium stearate
  • the antioxidant is propyl propyl ester, or BHT , or a combination of BHT and BHA.
  • the amount of the filler in the edecalcitol tablet is 50 to 200 mg per tablet, preferably 80 to 84 mg per tablet; the amount of the binder is 0.2 to 3 mg, preferably 0.4 to 0.5 per tablet.
  • the amount of the lubricant is from 0.1 to 1 mg per tablet, preferably from 0.4 to 0.5 mg per tablet; the amount of the antioxidant is from 0.05 to 2 mg, preferably from 0.5 to 1.0 mg per tablet.
  • the solid preparation further comprises a stabilizer selected from the group consisting of Tween, Span, polyoxyethylene alkyl ether, poloxamer 188, sucrose stearate.
  • a stabilizer selected from the group consisting of Tween, Span, polyoxyethylene alkyl ether, poloxamer 188, sucrose stearate.
  • Stabilizers are used to inhibit the degradation of edeofol to 1 ⁇ -type impurities, ie, the chemical name (5Z,7E)-(1S,2R,3R)
  • the solid preparation is an edecalcitol tablet
  • the filler is anhydrous lactose
  • the binder is povidone K30
  • the lubricant is magnesium stearate
  • the antioxidant is propyl propyl ester, or BHT Or a combination of BHT and BHA
  • the stabilizer is Tween 80
  • the amount of Tween 80 is 0.02 to 2 mg per tablet, preferably 0.1 to 0.5 mg per tablet.
  • the edoderolol tablet is prepared by a twin-screw extrusion granulation method, and the drying temperature of the granule is 35 to 50 ° C, the drying time is 0.5 to 5 h, and preferably, the drying temperature is 40 to 45. °C, drying time is 0.5 ⁇ 2h, and the particles are dried by fluidized bed drying or oven drying.
  • the present disclosure provides a method of inhibiting the conversion of edecalcitol to an edecalcitol precursor contained in a solid preparation, the preparation comprising a filler, a binder, a lubricant , antioxidants; by adding antioxidants to inhibit the conversion of edecalcitol to the ede oxidized alcohol precursor, the chemical name 6Z-(1R, 2R, 3R)-2-(3-hydroxypropoxy)-9 , 10-broken guanidine-5(10),6,8(9)-triene-1,3,25-triol, 6Z-(1R) produced by the solid preparation after being stored for 12 months at room temperature ,2R,3R)-2-(3-hydroxypropoxy)-9,10-broken cholesta-5(10),6,8(9)-triene-1,3,25-triol It is 3% or less, or less.
  • the present disclosure also provides a method of inhibiting degradation of edetolic alcohol contained in a solid preparation into an edecalcitol 1 ⁇ type impurity, which comprises a filler, a binder, a lubricant, an antioxidant, and a stable Reducing the degradation of edevicol to the 1 ⁇ -type impurity of edecalcitol by adding a stabilizer, namely the chemical name (5Z,7E)-(1S,2R,3R)-2-(3-hydroxypropoxy -9,10-broken guanidine-5,7,10(19)-triene-1,3,25-triol, the solid preparation is blocked and stored at room temperature for 12 months to produce 1 ⁇ -type impurities.
  • the amount is 0.3% or less, preferably 0.1% or less, or less.
  • the present disclosure provides a method for preparing an edoderolol tablet using a twin-screw extrusion technique, the tablet formulation comprising edecalcitol, anhydrous lactose, povidone K30, hard Magnesium citrate, antioxidant; a stabilizer may be optionally added to the solution, the stabilizer is preferably Tween 80, or no stabilizer is added; the preparation method specifically adopts the following steps:
  • the solution may optionally be added with a stabilizer and dissolved in the solution, or no stabilizer;
  • the antioxidant is propyl propyl ester, DL- ⁇ -tocopherol, BHT, or a combination of BHT and BHA;
  • the dry powder obtained in the above step 2 is added to the solid feeder, and the solution obtained in the above step 1 is connected to the extruder through a low-pulsation peristaltic pump, and the granulation temperature of the twin-screw extruder is controlled at 20 to 25 ° C.
  • the dry powder feeding speed, the peristaltic pump speed and the twin-screw speed are adjusted, and the twin-screw extruder is used for granulation.
  • the material is removed 5 minutes before the extrusion, the material is collected to obtain wet granules; the dry powder feeding speed is obtained.
  • the setting between the peristaltic pump speed and the twin-screw speed should be matched with each other.
  • the dry powder feeding speed is 1.0 to 3.0 kg/hr
  • the peristaltic pump rotation speed is 2 rpm to 8 rpm
  • the twin screw rotation speed is 100 rpm to 400 rpm.
  • the ratio of the dry powder to the weight of the solution entering the twin-screw extruder per unit time, that is, the solid-liquid ratio is 7:1 to 11:1, preferably 8.5:1 to 9:1;
  • the drying temperature is 35 to 50 ° C
  • the drying time is 0.5 to 5 h, preferably, the drying temperature is 40 to 45 ° C
  • the drying time is 0.5 to 2 h
  • the granules are Drying method is fluidized bed drying, or oven drying;
  • the dried granules are sieved through 16 to 24 mesh sieves, preferably 20 mesh sieve granules, then added with magnesium stearate, uniformly mixed, and tableted.
  • the vitamin D analog is calcitriol, ie, the chemical name (5Z, 7E)-9, 10-open ring cholester-5, 7, 10 (19)-Triene-1 ⁇ , 3 ⁇ , 25-triol;
  • the composition is a solid preparation, preferably a tablet; comprising calcitriol, a filler, a binder, a lubricant, an antioxidant, a stabilizer; Stabilizer is added to inhibit the degradation of calcitriol to 1 ⁇ -type impurity, namely chemical name (5Z,7E)-9,10-open-ring cholester-5,7,10(19)-triene-1 ⁇ ,3 ⁇ And 25-triol, the amount of the 1 ⁇ -type impurity produced by the solid preparation after being blocked for 12 months at room temperature is 0.3% or less, preferably 0.1% or less, or less.
  • the filler is selected from one or more of anhydrous lactose, lactose monohydrate, mannitol, microcrystalline cellulose, sucrose, preferably anhydrous lactose;
  • the binder is selected from the group consisting of povidone Or one or more of hydroxypropylcellulose, hypromellose, sodium carboxymethylcellulose, preferably povidone K30;
  • the lubricant is selected from the group consisting of talc, magnesium stearate, stearic acid One or more of calcium, stearyl fumarate, preferably magnesium stearate; antioxidant selected from the group consisting of propyl propyl ester, DL- ⁇ -tocopherol, dibutyl hydroxytoluene (BHT) One or more of butyl hydroxyanisole (BHA);
  • the stabilizer is selected from the group consisting of Tween, Span, polyoxyethylene alkyl ether, poloxamer 188, sucrose stearate, polyoxyethylene (35)
  • the solid preparation is a calcitriol tablet comprising a filler which is anhydrous lactose, the binder is povidone K30, the antioxidant is propyl propyl ester, or dibutyl hydroxytoluene (BHT) , or a combination of dibutylhydroxytoluene (BHT) and butyl hydroxyanisole (BHA); the stabilizer is Tween 80, or polyoxyethylene stearate; the lubricant is magnesium stearate, or stearic acid Sodium fumarate.
  • the solid preparation is a calcitriol tablet
  • the filler is used in an amount of 50 to 200 mg per tablet, preferably 81 to 83 mg per tablet
  • the binder is used in an amount of 0.2 to 3 mg per tablet, preferably, per tablet.
  • the tablet is 1.0 to 2.0 mg
  • the amount of the lubricant is 0.1 to 1 mg per tablet, preferably 0.4 to 0.5 mg per tablet
  • the antioxidant is used in an amount of 0.05 to 2 mg per tablet, preferably 0.5 to 1.0 mg per tablet
  • a stabilizer The amount used is 0.02 to 2 mg per tablet, preferably 0.1 to 0.5 mg per tablet.
  • the calcitriol tablet is prepared by a twin-screw extrusion granulation method, and the drying temperature of the granule is 35 to 50 ° C, the drying time is 0.5 to 5 h, and preferably, the drying temperature is 40 to 45. °C, drying time is 0.5 ⁇ 2h, and the particles are dried by fluidized bed drying or oven drying.
  • the present disclosure provides a method of inhibiting degradation of calcitriol contained in a solid preparation, the preparation comprising a filler, a binder, a lubricant, an antioxidant, a stabilizer; and the inhibition of ossification by adding a stabilizer
  • the alcohol degrades the 1 ⁇ -type impurity, ie, the chemical name (5Z, 7E)-9, 10-open-ring cholester-5,7,10(19)-triene-1 ⁇ , 3 ⁇ ,25-triol, so that the solid preparation is
  • the amount of (5Z,7E)-9,10-open-ring cholester-5,7,10(19)-triene-1 ⁇ ,3 ⁇ ,25-triol produced after shading and storage at room temperature for 12 months is less than or equal to 0.3%, preferably, 0.1% or less, or less.
  • the present disclosure provides a method for preparing a calcitriol tablet using a twin-screw extrusion technique, characterized in that the tablet formulation comprises calcitriol, a stabilizer, a filler, an antioxidant, a binder, a lubricant Specifically includes the following steps:
  • the dry powder obtained in the above step 2 is added to the solid feeder, and the solution obtained in the above step 1 is connected to the extruder through a low-pulsation peristaltic pump, and the granulation temperature of the twin-screw extruder is controlled at 20 to 25 ° C.
  • the dry powder feeding speed, the peristaltic pump speed and the twin-screw speed are adjusted, the twin-screw extruder is operated for granulation, and the material is started after the material is removed 5 minutes before the extrusion, and the wet granules are obtained; the dry powder feeding speed is obtained.
  • the setting between the peristaltic pump speed and the twin-screw speed should be matched with each other.
  • the dry powder feeding speed is 1.0-3.0 kg/hr
  • the peristaltic pump speed is 2 rpm-8 rpm
  • the twin-screw rotational speed is 100 rpm-400 rpm
  • the above dry powder The ratio of the weight of the solution entering the twin-screw extruder per unit time, that is, the "solid-liquid ratio" is 7:1 to 11:1, preferably 8.5:1 to 9:1;
  • the drying temperature is 35 to 50 ° C
  • the drying time is 0.5 h to 5 h, preferably, the drying temperature is 40 to 45 ° C, the drying time is 0.5 to 2 h
  • the granules Drying method is fluidized bed drying, or oven drying;
  • the dried granules are sieved through 16 to 24 mesh sieves, preferably 20 mesh sieve granules, then added with magnesium stearate, uniformly mixed, and tableted;
  • the filler is selected from one or more of anhydrous lactose, lactose monohydrate, mannitol, microcrystalline cellulose, sucrose, preferably anhydrous lactose;
  • the binder is selected from the group consisting of povidone, One or more of hydroxypropylcellulose, hypromellose, sodium carboxymethylcellulose, preferably povidone K30;
  • the lubricant is selected from the group consisting of talc, magnesium stearate, calcium stearate One or more of sodium stearyl fumarate, preferably magnesium stearate;
  • the antioxidant is selected from the group consisting of isopropyl propyl ester, DL- ⁇ -tocopherol, dibutyl hydroxytoluene (BHT), One or more of butyl hydroxyanisole (BHA);
  • the stabilizer is selected from the group consisting of Tween, Span, polyoxyethylene alkyl ether, poloxamer 188, sucrose stearate,
  • the present disclosure achieves the following beneficial technical effects and advancements.
  • the present disclosure adopts a twin-screw extrusion technique to prepare a solid preparation for obtaining a vitamin D analog, and intensively studies vitamin D analog drugs, especially alfacalcidol, edecalcitol and calcitriol. Tablets were prepared by twin screw extrusion granulation.
  • the content uniformity complies with the Pharmacopoeia regulations.
  • conventional wet granulation in the preparation of a solid preparation of a low-dose drug is difficult to uniformly disperse a low-dose drug due to a conventional agitation method, so that the content of the drug is poor.
  • the preparation method of the present disclosure is simple and easy to operate, has low energy consumption, does not introduce other impurities in the process, and enlarges the production attempt by 100,000 pieces per batch, and the dissolution rate is improved.
  • the content of the corresponding precursors and degradation products is reduced and effectively controlled. High process reproducibility, easy to achieve continuous large production.
  • the stabilizer is preferably added to Tween 80.
  • Tween 80 When the drug substance is dissolved in absolute ethanol, the addition of Tween 80 not only stabilizes the main drug in the ethanol solution environment, but also can be used in the mixing stage after entering the twin-screw technology machine, and even when the wet particles are dried in the subsequent stage. To effective protection, it plays a key role in inhibiting the formation of degradation products.
  • Tween 80 is chemically structurally sorbitan monooleate polyoxyethylene ether, which is a nonionic surfactant, in ethanol solution and in mixed granulation and subsequent drying processes.
  • the affinity of Tween to the hydrophobic and extremely low content of Alfacalcidol can be effectively protected and encapsulated in the form of micelles, so as to isolate external light, heat, oxygen, moisture and other factors,
  • the formation of osalylated alcohol degradation products plays a key role.
  • edecalcitol is a soft capsule.
  • ede sulphate tablets we were surprised to find an unexpected result different from alfacalcidol and calcitriol. That is, the increase in the amount of antioxidants in the diatomized alcohol tablets can significantly inhibit the formation of the edevic precursor. We speculate that it may be related to the chemical molecular structure.
  • the 3rd position in the ossified molecule is hydroxypropoxy, and the alpha-calciferol or calcitriol molecule has no substituent at its corresponding position.
  • the precursors of edecalcitol have significant differences in molecular potential energy, as well as in ship-and-chair transformations in spatial conformation, with alpha-calciferol and calcitriol molecules. We speculate that this may be the reason for the more significant inhibition of the antioxidants on the edeofostamin precursor.
  • Parameter adjustment and setting in the twin-screw extrusion granulation process are also noteable in the technical solution of the present disclosure.
  • the dry powder feeding speed is adjusted to 1.0 to 3.0 kg/hr
  • the peristaltic pump rotation speed is 2 rpm to 8 rpm
  • the twin screw rotation speed is 100 rpm to 400 rpm
  • the obtained particles are observed to be relatively uniform, and the extrudate content is determined to be uniform.
  • the ratio of the dry powder to the weight of the solution entering the twin-screw extruder per unit time that is, the solid-liquid ratio is 7:1 to 11:1, preferably 8.5:1 to 9:1.
  • the present disclosure adopts twin-screw extrusion granulation technology, and the model of the hot melt extruder used is Thermo Scientific PHARMA16, which has fewer processes, low energy consumption, safety and pollution-free, no dead angle of mixing, good dispersion effect, uniformity High, low drug loss, integrated multi-unit operation, space saving and cost reduction, this technology has become a new hot spot in the drug delivery system of preparation technology.
  • the preparation process is very convenient for industrialized scale production.
  • twin-screw extrusion techniques in the preparation of compositions for vitamin D analogs and their formulations has not been reported in the prior art.
  • Preparation method 1) Dissolve Alfacalcidol in absolute ethanol, add Tween 80 to dissolve, and obtain a solution; 2) Place anhydrous lactose, povidone K30, propyl propyl ester in wet mixing granulator Mixing, mixing time is greater than or equal to 5 minutes, to obtain dry powder; 3) adding the dry powder obtained in step 2 to the solid feeder, and connecting the solution obtained in step 1 to the extruder through a low-pulsation peristaltic pump, the twin-screw extruder
  • the granulation temperature is controlled at 20 to 25 ° C, the dry powder feeding speed is adjusted to 1.0 to 2.0 kg / hr, the peristaltic pump rotation speed is 2 rpm to 4 rpm, the twin screw rotation speed is 100 rpm to 200 rpm, and the above dry powder and solution enters per unit time.
  • the ratio of the weight to the twin-screw extruder is controlled at 8.5:1 to 9:1; after the material is discarded 5 minutes before the extrusion, the material is started to obtain wet particles; 4) The wet granules are placed in an oven and dried at 40 to 45 ° C for 2 hours to obtain dry granules; 5) the dried granules are passed through a 20 mesh sieve granule, and magnesium stearate is added, uniformly mixed, and tableted.
  • the preparation method comprises the following steps: 1) dissolving alfacalcidol in absolute ethanol to obtain a solution; 2) mixing anhydrous lactose, povidone K30 and propyl propyl ester in a wet mixing granulator, and mixing time is greater than Equivalent to 5 minutes, dry powder; 3) Add the dry powder obtained in step 2 to the solid feeder, connect the solution obtained in step 1 to the extruder through a low-pulse peristaltic pump, and control the granulation temperature of the twin-screw extruder 20 ⁇ 25 ° C, adjust the dry powder feeding speed of 2.0 ⁇ 3.0kg / hr, peristaltic pump speed of 4rpm ⁇ 8rpm, twin screw speed of 300rpm ⁇ 400rpm, and the above dry powder and solution into the twin-screw extruder per unit time
  • the ratio of the weight in the medium that is, the "solid-liquid ratio" is controlled at 10:1 to 9:1; the material is started after the material 5 minutes before
  • Preparation method 1) Dissolve Alfacalcidol in absolute ethanol, and then add Tween 80 to dissolve, to obtain a solution; 2) Dissolve anhydrous lactose, povidone K30, propyl propyl ester in wet mixing granulation Mixing in the machine, mixing time is greater than or equal to 5 minutes, to obtain dry powder; 3) adding the dry powder obtained in step 2 to the solid feeder, connecting the solution obtained in step 1 to the extruder through a low pulse peristaltic pump, and extruding the twin screw
  • the granulation temperature of the machine is controlled at 20 to 25 ° C, the dry powder feeding speed is 1.5 to 2.5 kg / hr, the peristaltic pump rotation speed is 3 rpm to 5 rpm, the twin screw rotation speed is 200 rpm to 300 rpm, and the above dry powder and solution are in unit time.
  • the ratio of the weight entering the twin-screw extruder is controlled at 10:1 to 9:1; the material is started after discarding the material 5 minutes before extrusion to obtain wet particles; 4) The wet granules are placed in an oven and dried at 40 to 45 ° C for 2 hours to obtain dried granules; 5) the dried granules are sieved through a 20 mesh sieve, and magnesium stearate is added, uniformly mixed, and tableted.
  • the preparation method comprises the following steps: 1) dissolving Alphacalciferol in absolute ethanol, and then adding polyoxyethylene stearate to dissolve to obtain a solution; 2) placing anhydrous lactose, povidone K30 and BHT in wet mixing Mixing in the granulator, mixing time is greater than or equal to 5 minutes to obtain dry powder; 3) adding the dry powder obtained in step 2 to the solid feeder, and connecting the solution obtained in step 1 to the extruder through a low pulse peristaltic pump, the twin screw
  • the granulation temperature of the extruder is controlled at 20 to 25 ° C, the dry powder feeding speed is adjusted to 1.5 to 2.0 kg / hr, the peristaltic pump rotation speed is 3 rpm to 5 rpm, the twin screw rotation speed is 250 rpm to 300 rpm, and the above dry powder and solution are in units.
  • the ratio of the weight entering the twin-screw extruder during the time is controlled at 10:1 to 9:1; the material is started after the material 5 minutes before the extrusion is discarded, and wet particles are obtained; 4) The wet granules are placed in an oven, dried at 40-45 ° C for 2 h to obtain dry granules; 5) The dried granules are passed through a 24-mesh sieve, and the stearyl fumarate is added, uniformly mixed, and tableted.
  • Alfacalcidol 0.5 ⁇ g, anhydrous lactose 81.55mg, povidone K30 2mg, DL- ⁇ -tocopherol 2mg, magnesium stearate 0.4mg, polyoxyethylene (40) hydrogenated castor oil 0.1mg, absolute ethanol Moderate amount
  • Preparation method 1) Alphacalciferol is dissolved in absolute ethanol, and then polyoxyethylene (40) hydrogenated castor oil is added to dissolve to obtain a solution; 2) anhydrous lactose, povidone K30, DL- ⁇ - The tocopherol is mixed in a wet mixing granulator for a mixing time of 5 minutes or more to obtain a dry powder; 3) the dry powder obtained in the step 2 is added to the solid feeder, and the solution obtained in the step 1 is passed through a low pulse peristaltic pump and squeezed.
  • the granulation temperature of the twin-screw extruder is controlled at 20 to 25 ° C, the dry powder feeding speed is adjusted to 2.0 to 2.5 kg / hr, the peristaltic pump rotation speed is 4 rpm to 6 rpm, and the twin screw rotation speed is 100 rpm to 150 rpm.
  • the ratio of the above dry powder to the weight of the solution entering the twin-screw extruder per unit time that is, the "solid-liquid ratio" is controlled at 10:1 to 9:1; after the material 5 minutes before the extrusion is discarded Picking up, obtaining wet granules; 4) placing the wet granules in an oven, drying at 40-45 ° C for 2 h to obtain dry granules; 5) drying the granules through a 16 mesh sieve, adding magnesium stearate, mixing uniformly, and compressing That's it.
  • the preparation method comprises the following steps: 1) dissolving the edecalcitol in anhydrous ethanol to obtain a solution; 2) mixing anhydrous lactose, povidone K30 and propyl propyl ester in a wet mixing granulator, and mixing time is greater than Equivalent to 5 minutes, dry powder; 3) Add the dry powder obtained in step 2 to the solid feeder, connect the solution obtained in step 1 to the extruder through a low-pulse peristaltic pump, and control the granulation temperature of the twin-screw extruder 20 ⁇ 25 ° C, adjust the dry powder feeding speed of 2.0 ⁇ 3.0kg / hr, peristaltic pump speed of 4 rpm ⁇ 6rpm, twin screw speed of 100rpm ⁇ 200rpm, and the above dry powder and solution into the twin-screw extruder per unit time
  • the ratio of the weight in the medium that is, the "solid-liquid ratio" is controlled at 10:1 to 9:1; the material is started after the
  • the preparation method comprises the following steps: 1) dissolving edecalcitol in absolute ethanol to obtain a solution; 2) mixing anhydrous lactose, povidone K30 and isopropyl ketone in a wet mixing granulator, and mixing time is greater than Equivalent to 5 minutes, dry powder; 3) Add the dry powder obtained in step 2 to the solid feeder, connect the solution obtained in step 1 to the extruder through a low-pulse peristaltic pump, and control the granulation temperature of the twin-screw extruder 20 ⁇ 25 ° C, adjust the dry powder feeding speed of 1.5 ⁇ 2.0kg / hr, peristaltic pump speed of 5rpm ⁇ 7rpm, twin screw speed of 200rpm ⁇ 300rpm, and the above dry powder and solution into the twin-screw extruder per unit time
  • the ratio of the weight in the medium that is, the "solid-liquid ratio" is controlled at 9:1 to 8.5:1; the material is started after the material is discarded
  • the preparation method comprises the following steps: 1) dissolving edecalcitol in absolute ethanol to obtain a solution; 2) mixing anhydrous lactose, povidone K30 and BHT in a wet mixing granulator, and mixing time is greater than or equal to 5 Minute, dry powder; 3) Add the dry powder obtained in step 2 to the solid feeder, connect the solution obtained in step 1 to the extruder through a low-pulse peristaltic pump, and control the granulation temperature of the twin-screw extruder to 20 ⁇
  • the dry powder feed rate is adjusted to 2.0 to 2.5 kg / hr
  • the peristaltic pump rotation speed is 6 rpm to 7 rpm
  • the twin screw rotation speed is 200 rpm to 250 rpm
  • the above dry powder and solution enter the twin screw extruder in a unit time.
  • the ratio of the weight that is, the "solid-liquid ratio” is controlled at 9:1 to 10:1; the material is started after the material is discarded 5 minutes before the extrusion, and the wet granules are obtained; 4) the wet granules are placed in an oven, 40 Dry at ⁇ 45 °C for 2h to obtain dry granules; 5) Dry granules through 20 mesh sieve granules, add stearyl fumarate, mix well, and compress.
  • the preparation method comprises the following steps: 1) dissolving edecalcitol in absolute ethanol to obtain a solution; 2) mixing anhydrous lactose, povidone K30 and DL- ⁇ -tocopherol in a wet mixing granulator, The mixing time is greater than or equal to 5 minutes to obtain a dry powder; 3) the dry powder obtained in the step 2 is added to the solid feeder, and the solution obtained in the step 1 is connected to the extruder through a low pulse peristaltic pump to granulate the twin screw extruder.
  • the temperature is controlled at 20 to 25 ° C, the dry powder feeding speed is 2.0 to 2.5 kg / hr, the peristaltic pump rotation speed is 6 rpm to 7 rpm, the twin screw rotation speed is 200 rpm to 250 rpm, and the dry powder and the solution enter the twin screw per unit time.
  • the ratio of the weight in the extruder that is, the "solid-liquid ratio” is controlled at 9:1 to 10:1; the material is started after the material is discarded 5 minutes before extrusion, and wet particles are obtained; 4) the wet particles are placed Dry in the oven at 40-45 ° C for 2 h to obtain dry granules; 5) Dry the granules through a 24-mesh sieve, add magnesium stearate, mix well, and compress.
  • Preparation method 1) Dissolving edecalcitol in absolute ethanol, adding Tween 80 to dissolve, to obtain a solution; 2) placing anhydrous lactose, povidone K30, propyl propyl ester in a wet mixing granulator Mixing, mixing time is greater than or equal to 5 minutes, to obtain dry powder; 3) adding the dry powder obtained in step 2 to the solid feeder, and connecting the solution obtained in step 1 to the extruder through a low-pulsation peristaltic pump, the twin-screw extruder
  • the granulation temperature is controlled at 20 to 25 ° C, the dry powder feeding speed is adjusted to 2.0 to 2.5 kg / hr, the peristaltic pump rotation speed is 3 rpm to 4 rpm, the twin screw rotation speed is 200 rpm to 250 rpm, and the above dry powder and solution enters per unit time.
  • the ratio of the weight to the twin-screw extruder is controlled at 10:1 to 11:1; the material is collected after the material is discarded 5 minutes before extrusion, and wet particles are obtained; 4) The wet granules are placed in an oven and dried at 40 to 45 ° C for 2 hours to obtain dry granules; 5) the dried granules are passed through a 20 mesh sieve granule, and magnesium stearate is added, uniformly mixed, and tableted.
  • Preparation method 1) Dissolving edecalcitol in absolute ethanol, adding Tween 80 to dissolve, to obtain a solution; 2) mixing anhydrous lactose, povidone K30, BHT in a wet mixing granulator The mixing time is greater than or equal to 5 minutes to obtain a dry powder; 3) the dry powder obtained in the step 2 is added to the solid feeder, and the solution obtained in the step 1 is connected to the extruder through a low pulse peristaltic pump, and the twin screw extruder is manufactured.
  • the pellet temperature is controlled at 20 to 25 ° C, the dry powder feeding speed is 1.5 to 2.0 kg / hr, the peristaltic pump rotation speed is 5 rpm to 6 rpm, the twin screw rotation speed is 250 rpm to 300 rpm, and the above dry powder and solution enter the double in unit time.
  • the ratio of the weight in the screw extruder that is, the "solid-liquid ratio" is controlled at 10:1 to 11:1; the material is started after the material 5 minutes before the extrusion is discarded, and the wet particles are obtained; 4) the wet particles are obtained. It is placed in an oven and dried at 40-45 ° C for 2 h to obtain dry granules. 5) The dried granules are sieved through a 20-mesh sieve, and magnesium stearate is added, uniformly mixed, and tableted.
  • the preparation method comprises the following steps: 1) dissolving edecalcitol in anhydrous ethanol, adding polyoxyethylene stearate to dissolve, and obtaining a solution; 2) placing anhydrous lactose, povidone K30, BHT, BHA in wet method Mixing in a mixing granulator, mixing time is greater than or equal to 5 minutes to obtain a dry powder; 3) adding the dry powder obtained in the step 2 to the solid feeder, and connecting the solution obtained in the step 1 to the extruder through a low pulse peristaltic pump,
  • the granulation temperature of the screw extruder is controlled at 20 to 25 ° C, the dry powder feeding speed is adjusted to 2.0 to 2.5 kg / hr, the peristaltic pump rotation speed is 4 rpm to 5 rpm, the twin screw rotation speed is 200 rpm to 250 rpm, and the above dry powder and solution are
  • the ratio of the weight entering the twin-screw extruder per unit time that is, the "solid-liquid ratio" is controlled
  • Calcitriol 0.5 ⁇ g, lactose 70 mg, mannitol 12.6 mg, BHT 0.5 mg, BHA 0.5 mg, magnesium stearate 0.4 mg, polyoxyethylene stearate 0.2 mg, polyoxyethylene (40) hydrogenated hydrazine Sesame oil 0.2mg, povidone K30 1mg, absolute ethanol
  • Preparation method 1) dissolving calcitriol in absolute ethanol, adding polyoxyethylene stearate, polyoxyethylene (40) hydrogenated castor oil to dissolve, to obtain a solution; 2) lactose monohydrate, mannitol, BHT, BHA, povidone K30 are mixed in a wet mixing granulator, mixing time is greater than or equal to 5 minutes to obtain a dry powder; 3) the dry powder obtained in step 2 is added to the solid feeder, and the solution obtained in step 1 is passed.
  • the low-pulsation peristaltic pump is connected to the extruder, the granulation temperature of the twin-screw extruder is controlled at 20 to 25 ° C, the dry powder feeding speed is adjusted to 2.0 to 2.5 kg / hr, the peristaltic pump rotation speed is 4 rpm to 5 rpm, and the twin screw The rotation speed is from 200 rpm to 250 rpm, and the ratio of the above dry powder to the weight of the solution entering the twin-screw extruder per unit time, that is, the "solid-liquid ratio" is controlled at 10:1 to 11:1; before the extrusion is discarded After 5 minutes of material, the material is started to obtain wet granules; 4) the wet granules are placed in an oven, dried at 40 to 45 ° C for 2 hours to obtain dry granules; 5) the dried granules are passed through a 20 mesh sieve, and magnesium stearate is added. , evenly mixed, compressed, that is.
  • Preparation method 1) Dissolving calcitriol in absolute ethanol, adding polyoxyethylene stearate to dissolve, obtaining a solution; 2) dissolving anhydrous lactose, sorbitol, propyl propyl ester, hydroxypropyl cellulose Mixing in a wet mixing granulator, mixing time is greater than or equal to 5 minutes to obtain a dry powder; 3) adding the dry powder obtained in the step 2 to the solid feeder, and connecting the solution obtained in the step 1 to the extruder through a low pulse peristaltic pump , the granulation temperature of the twin-screw extruder is controlled at 20 to 25 ° C, the dry powder feeding speed is adjusted to 2.0 to 2.5 kg / hr, the peristaltic pump rotation speed is 4 rpm to 5 rpm, the twin screw rotation speed is 200 rpm to 250 rpm, and the above dry powder
  • the ratio of the weight of the solution entering the twin-screw extruder per unit time that is, the "solid-liquid
  • Preparation method 1) Dissolving calcitriol in absolute ethanol, adding Tween 80 to dissolve, to obtain a solution; 2) placing anhydrous lactose, mannitol, DL- ⁇ -tocopherol, hypromellose Mixing in a wet mixing granulator, mixing time is greater than or equal to 5 minutes to obtain a dry powder; 3) adding the dry powder obtained in the step 2 to the solid feeder, and connecting the solution obtained in the step 1 to the extruder through a low pulse peristaltic pump,
  • the granulation temperature of the twin-screw extruder is controlled at 20 to 25 ° C, the dry powder feeding speed is adjusted to 2.0 to 2.5 kg / hr, the peristaltic pump rotation speed is 4 rpm to 5 rpm, the twin screw rotation speed is 200 rpm to 250 rpm, and the above dry powder and
  • the ratio of the weight of the solution entering the twin-screw extruder per unit time, that is, the "solid-liquid ratio" is
  • wet granules 4) The wet granules are placed in an oven, dried at 40-45 ° C for 2 h to obtain dry granules; 5) The dried granules are sieved through a 20 mesh sieve, and magnesium stearate is added, uniformly mixed, and tableted.
  • Calcitriol 0.5 ⁇ g, lactose 70mg, mannitol 13.1mg, BHT 0.5mg, BHA0.5mg, magnesium stearate 0.4mg, sodium carboxymethylcellulose 0.4mg, absolute ethanol
  • Preparation method 1) dissolving calcitriol in absolute ethanol to obtain a solution; 2) mixing lactose monohydrate, mannitol, BHT, BHA, sodium carboxymethylcellulose in a wet mixing granulator The mixing time is greater than or equal to 5 minutes to obtain a dry powder; 3) the dry powder obtained in the step 2 is added to the solid feeder, and the solution obtained in the step 1 is connected to the extruder through a low pulse peristaltic pump, and the twin screw extruder is manufactured.
  • the pellet temperature is controlled at 20 to 25 ° C, the dry powder feeding speed is adjusted to 2.0 to 2.5 kg / hr, the peristaltic pump rotation speed is 4 rpm to 5 rpm, the twin screw rotation speed is 200 rpm to 250 rpm, and the above dry powder and solution enter the double in unit time.
  • the ratio of the weight in the screw extruder that is, the "solid-liquid ratio" is controlled at 10:1 to 11:1; the material is started after the material 5 minutes before the extrusion is discarded, and the wet particles are obtained; 4) the wet particles are obtained. It is placed in an oven and dried at 40-45 ° C for 2 h to obtain dry granules. 5) The dried granules are sieved through a 20-mesh sieve, and magnesium stearate is added, uniformly mixed, and tableted.
  • Calcitriol 0.5 ⁇ g, lactose 70mg, sucrose 12.6mg, BHT 0.5mg, BHA 0.5mg, magnesium stearate 0.4mg, Tween 80 0.4mg, povidone K30 0.5mg, absolute ethanol
  • Preparation method 1) Dissolving calcitriol in absolute ethanol, adding Tween 80 to dissolve, to obtain a solution; 2) placing lactose monosaccharide, sucrose, BHT, BHA, povidone K30 in wet mixing granulation Mixing in the machine, mixing time is greater than or equal to 5 minutes, to obtain dry powder; 3) adding the dry powder obtained in step 2 to the solid feeder, connecting the solution obtained in step 1 to the extruder through a low pulse peristaltic pump, and extruding the twin screw
  • the granulation temperature of the machine is controlled at 20 to 25 ° C, the dry powder feeding speed is adjusted to 2.0 to 2.5 kg / hr, the peristaltic pump rotation speed is 4 rpm to 5 rpm, the twin screw rotation speed is 200 rpm to 250 rpm, and the above dry powder and solution are in unit time.
  • the ratio of the weight entering the twin-screw extruder is controlled at 10:1 to 11:1; the material is started after the material 5 minutes before the extrusion is discarded, and the wet particles are obtained; 4) The wet granules are placed in an oven and dried at 40 to 45 ° C for 2 hours to obtain dried granules; 5) the dried granules are sieved through a 20 mesh sieve, and magnesium stearate is added, uniformly mixed, and tableted.
  • Example 18 Comparative Example 1 CN104739793A discloses an alfacalcidol sheet and a process for the preparation thereof.
  • the Alfacalcidol sheet of Comparative Example 1 was obtained by the conventional wet granulation method according to the method of Example 1, using the same formulation and process of the present disclosure.
  • the process description is as follows: the raw materials of the prescription amount are weighed and passed through a sieve for 80 mesh respectively; the binder solution is prepared; the main drug and the auxiliary materials after sieving are uniformly mixed according to the equal increment method, and the above binder solution is added. It is made of soft material; after granulation with 40 mesh sieve, it is dried at 50 ° C for 30 minutes, sieved through 20 mesh sieves, mixed with magnesium stearate and then compressed.
  • Example 19 Comparative Example 2 CN1196677A discloses a process for the preparation of a very low dose pharmaceutical solid dosage form.
  • the alfacalcidol sheet of Comparative Example 2 was obtained by the high speed shear mixing granulation technique according to the preparation method described therein using the same formulation and process of the present disclosure.
  • the process is roughly described as follows: a proper amount of solvent is used to prepare a drug solution, which is slowly added to excipients and other excipients in a high-speed shear mixing-granulator, and vigorously mixed with a stirring paddle of 1500 rpm, and the total mixing time is 10 to 20 minutes, the obtained concentrate is sieved into a drum blender, and evenly mixed with the remaining materials, and the tablet is obtained.
  • Preparation method 1) Dissolve Alfacalcidol in absolute ethanol, add Tween 80 to dissolve, and obtain a solution; 2) Add anhydrous lactose, povidone K30, propyl propyl ester to the fluidized bed, and pass through the flow. Chemical bed granulation The solution obtained in step 1 is sprayed into a mixture of anhydrous lactose, povidone K30 and isopropyl ketone.
  • the spray After the spray is completed, it is uniformly mixed in a fluidized bed to obtain wet granules; 3) the wet granules are placed In the oven, drying at 40-45 ° C for 2 h to obtain dry granules; 4) drying the granules through 20 mesh sieve granules, adding magnesium stearate, mixing well, tableting, that is.
  • Preparation method 1) Dissolve Alfacalcidol in absolute ethanol, add polyoxyethylene stearate to dissolve, then add povidone K30, BHT to obtain a solution; 2) Add anhydrous lactose to the fluidized bed The solution obtained in the first step is sprayed into the anhydrous lactose by fluidized bed granulation. After the spraying is completed, the mixture is uniformly mixed in the fluidized bed to obtain wet granules; 3) the wet granules are directly dried in a fluidized bed. Drying at 35-40 ° C for 3 h to obtain dry granules; 5) Drying the granules through a 24-mesh sieve, adding stearyl fumarate, mixing well, and pressing, and obtaining.
  • Alfacalcidol 0.5 ⁇ g, anhydrous lactose 81.55mg, povidone K30 2mg, DL- ⁇ -tocopherol 2mg, magnesium stearate 0.4mg, polyoxyethylene (40) hydrogenated castor oil 0.1mg, absolute ethanol Moderate amount
  • Preparation method 1) Dissolve Alfacalcidol in absolute ethanol, add polyoxyethylene (40) hydrogenated castor oil to dissolve, then add povidone K30, DL- ⁇ -tocopherol to obtain a solution; 2) The anhydrous lactose is added to the fluidized bed, and the solution obtained in the step 1 is sprayed into the anhydrous lactose by fluidized bed granulation.
  • the mixture is uniformly mixed in the fluidized bed to obtain wet granules; 3) the wet granules are directly Drying in a fluidized bed, drying at 30-35 ° C for 3 h to obtain dry granules; 5) drying the granules through a 24-mesh sieve, adding magnesium stearate, mixing uniformly, and tableting.
  • Preparation method 1) Dissolving edecalcitol in absolute ethanol, adding povidone K30 and propyl propyl ester to dissolve to obtain a solution; 2) adding anhydrous lactose to the fluidized bed and granulating through a fluidized bed The solution obtained in the step 1 is sprayed into the anhydrous lactose, and after the spraying is completed, the mixture is uniformly mixed in the fluidized bed to obtain wet granules; 3) the wet granules are dried in an oven, dried at 40 to 45 ° C for 2 hours to obtain dry granules; The dried granules are sieved through a 20 mesh sieve, and magnesium stearate is added, uniformly mixed, and tableted.
  • the preparation method comprises the following steps: 1) dissolving the edecalcitol in anhydrous ethanol, adding polyoxyethylene stearate, povidone K30 and BHT to dissolve to obtain a solution; 2) adding anhydrous lactose to the fluidized bed, The solution obtained in the first step is sprayed into the anhydrous lactose by fluidized bed granulation. After the spraying is completed, the mixture is uniformly mixed in the fluidized bed to obtain wet granules; 3) the wet granules are dried in an oven and dried at 35 to 40 ° C for 3 hours. , dry particles; 5) dry granules through 20 mesh sieve granules, add stearyl fumarate, mix well, tablet, that is.
  • Preparation method 1) Dissolving edecalcitol in absolute ethanol, adding Tween 80 to dissolve, then adding povidone K30, BHT to obtain a solution; 2) adding anhydrous lactose into the fluidized bed, passing through the flow Chemical bed granulation The solution obtained in step 1 is sprayed into anhydrous lactose. After the spraying is completed, it is uniformly mixed in the fluidized bed to obtain wet granules; 3) the wet granules are directly dried in a fluidized bed, 35-40 ° C Dry for 2h to obtain dry granules; 5) Dry the granules through 20 mesh sieve granules, add magnesium stearate, mix well, and compress.
  • Calcitriol 0.5 ⁇ g, lactose 70 mg, mannitol 12.6 mg, BHT 0.5 mg, BHA 0.5 mg, magnesium stearate 0.4 mg, polyoxyethylene stearate 0.2 mg, polyoxyethylene (40) hydrogenated hydrazine Sesame oil 0.2mg, povidone K30 1mg, absolute ethanol
  • Preparation method 1) Dissolving calcitriol in absolute ethanol, adding polyoxyethylene stearate, polyoxyethylene (40) hydrogenated castor oil, and then adding povidone K30, BHT, BHA to obtain a solution 2) adding lactose monohydrate and mannitol to the fluidized bed, spraying the solution obtained in step 1 into anhydrous lactose by fluidized bed granulation, and uniformly mixing in the fluidized bed after the spraying is completed to obtain wet granules; 3) The wet granules are directly dried in a fluidized bed, dried at 35-40 ° C for 2 h to obtain dry granules; 5) dried granules are passed through a 20 mesh sieve, and magnesium stearate is added, uniformly mixed, and tableted. .
  • Preparation method 1) Dissolving calcitriol in absolute ethanol, adding polyoxyethylene stearate to dissolve, adding hypromellose, propyl propyl ester to obtain a solution; 2) anhydrous lactose, sorbus The sugar alcohol is added into the fluidized bed, and the solution obtained in the step 1 is sprayed into the anhydrous lactose by fluidized bed granulation.
  • the mixture is uniformly mixed in the fluidized bed to obtain wet granules; 3) the wet granules are directly flowed Drying in a chemical bed, drying at 35-40 ° C for 2 h, to obtain dry granules; 5) drying the granules through a 20 mesh sieve granules, adding magnesium stearate, mixing uniformly, and tableting, that is, obtained.
  • Preparation method 1) Dissolving calcitriol in absolute ethanol, adding Tween 80 to dissolve, adding povidone K30, DL- ⁇ -tocopherol to obtain a solution; 2) adding anhydrous lactose and mannitol In the fluidized bed, the solution obtained in the step 1 is sprayed into the anhydrous lactose by fluidized bed granulation, and after the spraying is completed, the mixture is uniformly mixed in the fluidized bed to obtain wet granules; 3) the wet granules are directly in the fluidized bed. Drying, drying at 35-40 ° C for 2 h, to obtain dry granules; 5) drying granules through 20 mesh sieve granules, adding magnesium stearate, mixing evenly, tableting, that is.
  • the Alfacalcidol solution containing Tween and Tween-free was prepared separately, and the precursor was sampled every 1 h at 40 °C.
  • Tween 80 can increase the stability of Alfacalcidol for Alfacalcitol solution, and maintain better stability during solution preparation and slow addition of solution to the extruder. Inhibition of the formation of degradation products.
  • the dies of the Alfacalcidol tablets prepared in Examples 1 to 5 were placed in a bare film at a temperature of 40 ° C and a relative humidity of 75% RH, and samples were taken at different time points to detect degradation products. content.
  • the first embodiment contained Tween 0.1 mg
  • the second sample did not contain Tween
  • the third sample contained Tween 0.2 mg
  • the fourth sample contained 0.1 mg of polyoxyethylene stearate.
  • Example 5 Contains 0.1 mg of polyoxyethylene (40) hydrogenated castor oil.
  • N.D means "not detected.”
  • the degradation product in this test example refers to the 1 ⁇ -type impurity of Alfacalcidol, that is, the chemical name (5Z, 7E)-9,10-open-loop cholester-5,7,10(19)-triene-1 ⁇ , 3 ⁇ -diol.
  • Example 13 contained a total of 0.4 mg of a combination of polyoxyethylene stearate and polyoxyethylene (40) hydrogenated castor oil, and Example 14 contained 0.4 mg of polyoxyethylene stearate, Example 15 Twenty-four mg of Tween was contained in the film of Example 17, and no surfactant was added to the film of Example 16.
  • N.D means "not detected.”
  • the degradation product in this test case is a 1 ⁇ -type impurity of calcitriol, that is, the chemical name (5Z, 7E)-9,10-open-loop cholester-5,7,10(19)-triene-1 ⁇ , 3 ⁇ , 25-triol.
  • Test Example 4 Comparative test of content uniformity of Alfacalcitol tablets
  • Example 18 is a conventional wet granulation process using an equal-increasing method, and Example 19 is modified by the use of Example 18, i.e., high-speed shear mixing granulation.
  • the content uniformity of the tablets obtained by the twin-screw granulation method used in Examples 1 to 3 was in conformity with the regulations of the Chinese Pharmacopoeia, and was significantly superior to the tablets obtained by the first two processes and equipment.
  • a prescribed amount of a filler, a binder, an antioxidant, and the like are added to a mixing granulator for mixing, and a marker is additionally added.
  • the stirring speed was 5r/s and the shearing speed was 5r/s
  • the mixing time was 3 minutes, 5 minutes and 8 minutes.
  • Investigating whether the material can be uniformly mixed is judged by the content of the marker in the samples of five different sampling points in the pot of the wet mixing granulator.
  • the final measurement of the mixing time is 5 minutes, and the amount of each sampling point in the mixed powder is measured. Evenly.
  • the content of the precursor in the marketed product is relatively high. It has also been found in the experiments of the present disclosure that the extrusion temperature has a direct effect on the content and stability of the final formulation.
  • the present disclosure has confirmed through a large number of experiments that the granulation temperature of the twin-screw extruder is controlled at 20-25 ° C, and the content of the pre-formation of the Alfacalcitol tablet of Example 1 is significantly lower than that of the commercially available Alfacalcitol tablet. Has a prominent effect.
  • the sample was tested for stability stakeout, and the content before it was still less than 3% within 0 to 6 months.
  • twin-screw extrusion granulation the setting between the feeding speed of the dry powder, the filling speed of the wetting agent (ie, the peristaltic pump rotation speed) and the rotation speed of the twin-screw needs to be matched to each other in order to obtain a suitable wetness. Particles, the present disclosure examines the effect of different screw speeds and different wetting agent dosing rates on product quality.
  • the dry powder feeding speed is adjusted to 1.0 to 3 kg/hr
  • the peristaltic pump rotation speed is 2 rpm to 8 rpm
  • the twin screw rotation speed is 100 rpm to 400 rpm
  • the solid-liquid ratio is adjusted from 7:1 to 11:1, preferably from 8.5:1 to 9:1.
  • the content of the extrudate was determined to be uniform.
  • the above-mentioned rotational speeds are also coordinated to maintain the residence time of the dry powder and the solution in the extruder for 1 to 3 minutes to achieve an optimum granulation effect.
  • the picking time was also examined and the mixed material was added to the feeder.
  • the extrudate was prepared at a feeding speed of 1.5 kg/hr, a filling speed of 4.0 rpm and a twin-screw extrusion speed of 150 rpm.
  • the material content received in 2 to 5 minutes is too high and does not meet the quality control requirements.
  • the main reason for this phenomenon is that the ratio of solid to liquid in the previous extruder has not been adjusted to equilibrium. After 5 minutes of extrusion, the material content is normal and meets the internal control requirements. Therefore, in the actual operation, the material should be received after 5 minutes of extrusion.
  • Test Example 8 Effect of the Amount of Antioxidant (Methyl Propionate or DL- ⁇ -Tocopherol) on the Content of Precursor in Ai Decalcified Alcohol Tablets
  • Test method Based on the prescription examples and preparation processes of Examples 6 to 8 of the present disclosure, the test pieces used in the test were obtained, wherein the amount of anhydrous lactose, povidone K30, and magnesium stearate was maintained. Consistently, each of the tablets of edetene containing no antioxidant, containing different amounts of isopropyl propyl ester, and containing different amounts of DL- ⁇ -tocopherol was obtained in sequence. At a temperature of 40 ° C and a relative humidity of 75% RH, each of the dies was placed open, and samples were taken at the time of the 20th day to detect the content of the degradation products.
  • Test Example 9 Determination of Corresponding Precursors and Degradation Products of Alfacalcitol Tablets, Eitracalcitol Tablets and Calcitriol Tablets After Shading and Storage at Room Temperature for 12 Months
  • the stability test conditions of the masked, room-temperature storage for 12 months may be selected, in the case of commercially available product packaging, such as aluminum-plastic blister packaging, at 25 Store in an environment of °C ⁇ 2 ° C and 60% RH ⁇ 5% RH for 12 months, and sample the relevant data.
  • Example 15 0.10 2.2
  • Example 17 0.08 1.8
  • Test Example 10 Determination of the content of the corresponding precursors after the 12-month incubation of Alfacalcitol tablets, Adienol tablets and calcitriol tablets after storage at room temperature for 12 months
  • the stability test conditions of the masked, room temperature storage for 12 months may be selected, in the case of a commercially available product package, such as an aluminum-plastic blister package, Store in an environment of 25 ° C ⁇ 2 ° C and 60% RH ⁇ 5% RH for 12 months, sampling and testing related data.
  • the present disclosure provides a vitamin D analog preparation and a preparation method thereof, which are prepared by using a twin-screw extrusion technique to prepare a vitamin D analog preparation, so that the stability of the medicine is remarkably improved, and the quality of the medicine is greatly improved.

Abstract

一种包含维生素D类似物的组合物，其特征在于，是固体制剂，所述维生素D类似物选自维生素D3、骨化二醇、骨化三醇、阿法骨化醇、艾地骨化醇、度骨化醇、马沙骨化醇、帕立骨化醇、他卡西醇、卡泊三醇中的一种，该固体制剂经遮蔽、室温保存12个月后产生相应的维生素D类似物的前体的量为小于等于7％。

Description

维生素D类似物制剂及其制备方法 技术领域
本公开涉及一种包含维生素D类似物的药物组合物，该组合物是固体制剂，还涉及利用双螺杆挤出技术制备和获得以上药物组合物的方法，属于药物制备技术领域。
背景技术
骨化醇系列药物是维生素D的结构类似物。世界范围内已上市的维生素D类似物主要用于骨质疏松、肾透析患者继发性甲状旁腺功能亢进(SHPT)和银屑病的治疗。国外也有作为抗癌药物进行临床研究的。临床广泛应用的该类药物包括维生素D2、维生素D3、骨化二醇、骨化三醇、阿法骨化醇、艾地骨化醇、度骨化醇、马沙骨化醇、帕立骨化醇、他卡西醇、卡泊三醇等。
获得较高质量要求的含量均匀度，是制备该低剂量维生素D类似物药物固体制剂的主要难点之一。对于规格不大于1mg，甚至微克级别的低剂量固体制剂而言，含量均匀度是其关键质量属性之一。含量均匀度的变化会直接影响药物安全性和有效性；处方和工艺的变动均会对含量均匀度产生影响。因此在产品和工艺开发中对含量均匀度进行评估是十分必要的。
常用的固体制剂制备工艺并不能满足该类超低剂量产品的含量均匀度要求，尤其在放大生产过程中，参数变化对低剂量药物理化性质的影响甚为显著。我们在试验探索中发现当试制量放大至2万片以上时，片子含量均匀度就难以符合质量要求。即使花费大量人力物力，以及严格控制设备各项参数之后，才能勉强满足含量均匀度指标，但同时其他质量属性，比例如骨化醇前体、降解产物杂质等就无法满足质量要求了。
维生素D类似物的相应前体、降解产物等物质，由于化学结构上类似，极有可能具备与主药相同的特性，即低剂量同时高活性。鉴于目前药学技术的局限性，还难以获得大量的单一转化产物或降解产物进行安全性研究。例如，维生素D类似物的前体，在目前手段下，确实难以获得大量纯品而进行针对性的安全性评价。相应前体与主药之间是一种动态平衡的关系，现有技术难以将两 者完全分离。现阶段只能通过制剂工艺将其前体控制在经过验证的安全性范围之内。因此对其转化产物或降解产物的研究不能忽视，对它们的关注不能缺失。现有技术中为了解决含量均匀度问题通常采用微粉化工艺、流化床造粒法、喷雾干燥法、超临界流体法、转化产物或降解产物等。但由于维生素D类似物本身的不稳定性特点，即在光、湿、热情况下容易进行转化或者降解。例如在制粒过程中、烘干过程中、压片过程中、以及后期存储过程中，该类药物极易降解和转化。采用通常制备技术由于反应时间较长，物料长时间摩擦接触生热更加容易发生降解和转化，生成维生素D类似物的前体和降解产物，这影响了维生素D类似物药物制剂的含量和临床应用的有效剂量。
热熔挤出机包含有热熔挤出(HME)模块和双螺杆挤出(TSG)模块，是应用单/双螺杆挤出设备，使得物料经历固体输送、熔融、熔体输送三阶段，在捏制器和螺杆元件的强力剪切作用下，获得高度混合分散的成型产品。热熔挤出过程可在一台设备上实现混合、造粒和成型制品多种单元操作，具有工序少、能耗低、成本低、产率高、连续化、可封闭式生产等特点。该技术在提高难溶性药物溶出度、制备缓释制剂以及局部给药制剂方面具有突破性优势，已成为制剂技术药物传递系统中的一个新热点。值得注意的还包含其制备工艺易于实现工业化放大生产。此外，应用双螺杆技术设备不仅可以实现热熔挤出技术的制备模式，还能够很好地实现双螺杆技术制粒的工序；尤其对于药物含量低的，对热、空气、水等环境因素较敏感的药物制剂，可更好地提高含量均匀度、稳定性等质量指标。现有技术中尚未报道双螺杆挤出技术在制备维生素D类似物的组合物及其制剂的应用。
发明内容
目前，制备固体制剂中得到颗粒的方法，通常是湿法制粒和干法制粒，更加常用的是湿法制粒。但湿法制粒具有一些难以克服的如下缺点：
1)不可避免地接触水，可能导致稳定性较差的药物遇水降解，致使晶型变化；制粒过程中干粉遇水放热，导致药物遇热破坏等。即使选择不含水的有机试剂例如乙醇进行制粒，为保证含量均匀性，需长时间搅拌和剪切分散，会导致物料颗粒过度摩擦生热而产生降解。
2)湿法制粒在制备维生素D类似物药物的固体制剂时，由于常规搅拌方式 难以使得维生素D类似物药物高度的均匀分散，故药物含量均匀度较差，通常不能满足中国药典2015年版四部通则0941号即含量均匀度检查法的规定。
3)工艺的重现性很差，批次间的含量数据忽高忽低，体现为制备工艺和产品质量的不稳定性。
针对现有技术的不足，即针对现有维生素D类似物药物的制备方法不能满足其含量均匀度要求，以及维生素D类似物本身的不稳定性因素，制粒过程中药物容易转变为前体和降解为降解产物的缺陷，本公开提供了一种包含维生素D类似物的组合物，是固体制剂，所述维生素D类似物选自维生素D3、骨化二醇、骨化三醇、阿法骨化醇、艾地骨化醇、度骨化醇、马沙骨化醇、帕立骨化醇、他卡西醇、卡泊三醇中的一种，所述维生素D类似物可选自相应的无水物、水合物或溶剂合物；该固体制剂经遮蔽、室温保存12个月后产生的相应维生素D类似物的前体的量为小于等于7％；优选地，前体的量小于等于5％；更进一步优选地，前体的量小于等于3％，或者更少。
本公开是所述药物组合物，可以采用常规的制粒法进行制备，包括但不限于：离心制粒法、高速剪切混合制粒法、滚压制粒法、流化床制粒法、喷雾制粒法、液相中晶析制粒法、熔融制粒法、流化床喷雾制粒法；其中，优选为流化床喷雾制粒法，其中流化床喷雾制粒法按照喷液位置的不同，又可细分为流化床低喷制粒法、流化床侧喷制粒法或流化床顶喷制粒法。
获得湿颗粒之后，干燥时的温度和时间是控制产品最终前体含量的重要参数。例如，优化的参数条件是将所获得的颗粒的干燥温度是35～50℃，干燥时间0.5～4h，优选地，干燥温度是40～45℃，干燥时间是0.5～2h；并且颗粒的干燥方式是流化床干燥，或烘箱干燥。
优选地，优先选用流化床喷雾制粒法制备阿法骨化醇片。
优选地，优先选用流化床喷雾制粒法制备艾地骨化醇片。
优选地，优先选用流化床喷雾制粒法制备骨化三醇片。
运用双螺杆挤出制粒法，在制备低剂量药物制剂的工艺中具有独特优势。例如，更加优选地，所述组合物，是采用双螺杆挤出技术制备获得的，包含如下步骤：
a)将维生素D类似物溶解于溶剂中，得到溶液，溶剂优选为无水乙醇；该溶液中还可以选择性地加入稳定剂并溶解于该溶液中，或者选择不加入稳定剂；
b)将其他固体形式的辅料混合均匀，形成干粉；
c)将上述步骤b所得干粉加入固体喂料器中，将上述步骤a所得溶液通过蠕动泵与挤出机相连；同时调节的设备参数包括干粉喂料速度、蠕动泵转速、双螺杆转速、挤出温度；运行双螺杆挤出机进行制粒，获得湿颗粒；
d)将湿颗粒干燥，整粒，获得干燥颗粒，即含量高度均匀的维生素D类似物的组合物；
其中，所述固体形式的辅料包括填充剂、粘合剂、抗氧化剂中的一种或多种；所述稳定剂是对维生素D类似物具有稳定作用，并且能够抑制该维生素D类似物降解为相应的1β型杂质的物质。
优选地，所述组合物是固体制剂中的片剂、胶囊剂、颗粒剂或干混悬剂；该固体制剂的组分还包含润滑剂；该固体制剂是通过将权利要求3所制得的干燥颗粒进一步使用常规制剂技术制备获得的。
优选地，所述填充剂选自淀粉、预胶化淀粉、玉米淀粉、一水乳糖、无水乳糖、甘露醇、微晶纤维素中的一种或多种；粘合剂选自聚维酮、羟丙甲基纤维素、羟丙基纤维素、羧甲基纤维素钠中的一种或多种；抗氧化剂选自棓丙酯、DL-α-生育酚、二丁基羟基甲苯(BHT)、丁基羟基茴香醚(BHA)中的一种或多种；润滑剂选自滑石粉、硬脂酸镁、硬脂酸钙、硬脂富马酸钠中的一种或多种；如果需要加入稳定剂时，稳定剂选自吐温、司盘、聚氧乙烯烷基醚、泊洛沙姆188、蔗糖酸硬脂酸酯、聚氧乙烯(35)蓖麻油、聚氧乙烯(40)氢化蓖麻油、聚氧乙烯(20)十八十六烷基醚、聚氧乙烯月桂醚、聚氧乙烯硬脂酸酯中的一种或多种。
根据本公开技术方案，采用双螺杆挤出制粒法制得的湿颗粒，需控制干燥温度和时间，以便满足质量要求。例如，颗粒的干燥温度是35～50℃，干燥时间0.5～4h，优选地，干燥温度是40～45℃，干燥时间是0.5～2h；并且颗粒的干燥方式是流化床干燥，或烘箱干燥。
关于在双螺杆技术制粒过程中的参数调节和设置，我们经过小试、中试和 放大生产试验发现，需要根据药品批量的大小进行相关参数的合理调节和设定，并非一成不变。具体是根据颗粒的质量指标进行筛选和确定的。以下我们仅以干粉喂料速度为1.0～3.0kg/hr为举例，说明相关参数的设定。
固体形式的辅料在混合制粒机中进行混合均匀的时间大于等于5分钟，才能便于制成均匀干粉；干粉喂料速度、蠕动泵转速、双螺杆转速这三个参数的设定需相互配合，干粉喂料速度为1.0～3.0kg/hr、蠕动泵转速为2rpm～8rpm、双螺杆转速为100rpm～400rpm，且上述干粉与溶液在单位时间内进入双螺杆挤出机中的重量的比值，即“固液比”是7:1～11:1，优选8.5:1～9:1；双螺杆挤出机的制粒温度控制在20～25℃；且颗粒的干燥温度是35～50℃，干燥时间0.5～4h，优选地，干燥温度是40～45℃，干燥时间是0.5～2h；并且颗粒的干燥方式是流化床干燥，或烘箱干燥。
本公开配方中，由于抗氧化剂的重量占比较低，需对其混合均匀性进行考察。实验中考察了固体形式的辅料载体在湿法混合制粒机中，在搅拌转速5r/s、剪切速度5r/s时，混合时间3分钟、5分钟和8分钟条件下，物料能否混合均匀。当混合3分钟时，物料未完全混匀；混合时长达到5分钟后，可使得混粉中各取样点抗氧剂含量均匀。
在实际挤出工艺研究过程中发现干粉的喂料速度、蠕动泵转速和双螺杆转速三者之间的设定需要相互配合，才能制得合适的湿颗粒。本明经过大量实验得出最佳工艺条件为：干粉喂料速度为1.0～3.0kg/hr、蠕动泵转速为2rpm～8rpm、双螺杆转速为100rpm～400rpm，上述转速的相互配合也是为了满足干粉和溶液在挤出机中的停留时间保持在1～3分钟，以达到最佳的制粒效果。
根据本公开技术方案，优选地，上述固体制剂中，填充剂用量为每片50～200mg，优选地，为每片81～83mg；粘合剂用量为每片0.2～3mg，优选地，为每片1.0～2.0mg；润滑剂用量为每片0.1～1mg，优选地，为每片0.4～0.5mg；抗氧化剂用量为每片0.02～2mg，优选地，为每片0.5～1.0mg；稳定剂用量为每片0.02～2mg，优选地，为每片0.1～0.5mg。。
作为一种包含维生素D类似物的组合物的实施方案之一，维生素D类似物是阿法骨化醇，即化学名(5Z，7E)-9，10-开环胆甾-5，7，10(19)-三烯-1α，3β-二醇；该组合物是固体制剂，优选片剂；其包含阿法骨化醇、填充剂、 粘合剂、润滑剂、抗氧化剂和稳定剂；其中，加入稳定剂用于抑制阿法骨化醇降解为1β型杂质，即化学名(5Z，7E)-9，10-开环胆甾-5，7，10(19)-三烯-1β，3β-二醇，使得该固体制剂经遮蔽、室温保存12个月后产生的1β型杂质的量为小于等于0.3％，优选地，小于等于0.1％，或更少。
优选地，该固体制剂是片剂，填充剂选自无水乳糖、一水乳糖、甘露醇、微晶纤维素、蔗糖中的一种或多种，优选地，为无水乳糖；粘合剂选自聚维酮、羟丙纤维素、羟丙甲纤维素、羧甲基纤维素钠中的一种或多种，优选地，为聚维酮K30；润滑剂选自滑石粉、硬脂酸镁、硬脂酸钙、硬脂富马酸钠中的一种或几种，优选地，为硬脂酸镁；抗氧化剂选自选自棓丙酯、DL-α-生育酚、二丁基羟基甲苯(BHT)、丁基羟基茴香醚(BHA)中的一种或多种；稳定剂选自吐温、司盘、聚氧乙烯烷基醚、泊洛沙姆188、蔗糖酸硬脂酸酯、聚氧乙烯(35)蓖麻油、聚氧乙烯(40)氢化蓖麻油、聚氧乙烯(20)十八十六烷基醚、聚氧乙烯月桂醚、聚氧乙烯硬脂酸酯中的一种或多种；优选地，选自吐温、聚氧乙烯硬脂酸酯、聚氧乙烯(40)氢化蓖麻油中的一种或多种；更优选地，选自吐温。
优选地，上述阿法骨化醇固体制剂是片剂，填充剂用量为每片50～200mg，优选地，为每片81～83mg；粘合剂用量为每片0.2～3mg，优选地，为每片1.0～2.0mg；润滑剂用量为每片0.1～1mg，优选地，为每片0.4～0.5mg；抗氧化剂用量为每片0.05～2mg，优选地，为每片0.5～1.0mg；稳定剂用量为每片0.02～2mg，优选地，为每片0.1～0.5mg。
优选地，上述阿法骨化醇固体制剂，是采用双螺杆挤出技术制备获得的，且颗粒的干燥温度是35～50℃，干燥时间0.5～5h，优选地，干燥温度是40～45℃，干燥时间是0.5～2h；并且颗粒的干燥方式是流化床干燥，或烘箱干燥。
更加优选地，所述组合物是阿法骨化醇片剂，其包含填充剂是无水乳糖，粘合剂是聚维酮K30，润滑剂是硬脂酸镁，抗氧化剂是棓丙酯，或是BHT，或是BHT与BHA的组合；稳定剂是吐温80，且吐温80的用量为每片0.02～2mg，优选地，为每片0.1～0.5mg。
关于阿法骨化醇，本公开提供了一种抑制在固体制剂中包含的阿法骨化醇降解的方法，所述制剂包含填充剂、粘合剂、润滑剂、抗氧化剂、稳定剂；通 过加入稳定剂来抑制阿法骨化醇降解为1β型杂质，即化学名(5Z，7E)-9，10-开环胆甾-5，7，10(19)-三烯-1β，3β-二醇，使得该固体制剂经遮蔽、室温保存12个月后产生的(5Z，7E)-9，10-开环胆甾-5，7，10(19)-三烯-1β，3β-二醇的量为小于等于0.3％，优选地，小于等于0.1％，或更少。
关于阿法骨化醇，本公开提供了一种利用双螺杆挤出技术制备阿法骨化醇片剂的方法，片剂处方包含阿法骨化醇、吐温80、无水乳糖、棓丙酯、聚维酮K30、硬脂酸镁；具体采用如下步骤：
1)将阿法骨化醇溶解于无水乙醇中，再加入吐温80溶解，得到溶液；
2)按处方称取无水乳糖、棓丙酯、聚维酮K30，加入湿法混合制粒机中混合，混合时间大于等于5分钟，得到干粉；
3)将上述步骤2所得干粉加入至固体喂料器中，将上述步骤1所得溶液通过低脉冲蠕动泵与挤出机相连，将双螺杆挤出机的制粒温度控制在20～25℃，同时调节干粉喂料速度、蠕动泵转速、双螺杆的转速，运行双螺杆挤出机进行制粒，在弃去挤出前5分钟的物料后开始接料，获得湿颗粒；其中所述干粉喂料速度、蠕动泵转速、双螺杆的转速三者之间的设定需相互配合，干粉喂料速度为1.0～3.0kg/hr、蠕动泵转速为2rpm～8rpm、双螺杆转速为100rpm～400rpm，且上述干粉与溶液在单位时间内进入到双螺杆挤出机中的重量的比值，即“固液比”是7:1～11:1，优选8.5:1～9:1；
4)将步骤3所得湿颗粒进行干燥，得干燥颗粒，所述干燥温度是35～50℃，干燥时间0.5h～4h，优选地，干燥温度是40～45℃，干燥时间是0.5～2h；并且颗粒的干燥方式是流化床干燥，或烘箱干燥；
5)干燥颗粒过16～24目筛整粒，优选20目筛整粒，然后加入硬脂酸镁，混合均匀，压片，即得。
作为一种包含维生素D类似物的组合物的实施方案之一，维生素D类似物是艾地骨化醇，即化学名(5Z，7E)-(1R，2R，3R)-2-(3-羟基丙氧基)-9,10-断胆甾-5,7,10(19)-三烯-1，3,25-三醇；该组合物是固体制剂，优选片剂；包含艾地骨化醇、填充剂、粘合剂、润滑剂、抗氧化剂；其中，加入抗氧化剂用于抑制艾地骨化醇转变为艾地骨化醇前体，即化学名6Z-(1R，2R，3R)-2-(3-羟基丙氧基)-9，10-断胆甾-5(10)，6，8(9)-三烯-1，3，25-三醇，使得该固体制剂 经遮蔽、室温保存12个月后产生的艾地骨化醇前体的量为小于等于7％；优选地，前体的量小于等于5％，进一步优选地，前体的量小于等于3％，或更少。
优选地，该固体制剂是艾地骨化醇片剂，其包含的填充剂选自无水乳糖、一水乳糖、甘露醇、微晶纤维素、蔗糖中的一种或多种，优选地，为无水乳糖；粘合剂选自聚维酮、羟丙纤维素、羟丙甲纤维素、羧甲基纤维素钠中的一种或多种，优选地，为聚维酮K30；润滑剂选自滑石粉、硬脂酸镁、硬脂酸钙、硬脂富马酸钠中的一种或多种，优选地，为硬脂酸镁；抗氧化剂选自棓丙酯、DL-α-生育酚、二丁基羟基甲苯(BHT)、丁基羟基茴香醚(BHA)中的一种或多种。
更加优选地，该固体制剂是艾地骨化醇片剂，填充剂是无水乳糖，粘合剂是聚维酮K30，润滑剂是硬脂酸镁，抗氧化剂是棓丙酯，或是BHT，或是BHT与BHA的组合。
优选地，艾地骨化醇片剂中，填充剂用量为每片50～200mg，优选地，为每片80～84mg；粘合剂用量为0.2～3mg，优选地，为每片0.4～0.5mg；润滑剂用量为每片0.1～1mg，优选地，为每片0.4～0.5mg；抗氧化剂用量为0.05～2mg，优选地，选自每片0.5～1.0mg。
为了质量要求进一步提高，在上述处方基础上，该固体制剂中还包含稳定剂，稳定剂选自吐温、司盘、聚氧乙烯烷基醚、泊洛沙姆188、蔗糖酸硬脂酸酯、聚氧乙烯(35)蓖麻油、聚氧乙烯(40)氢化蓖麻油、聚氧乙烯(20)十八十六烷基醚、聚氧乙烯月桂醚、聚氧乙烯硬脂酸酯中的一种或多种；优选地，选自吐温、聚氧乙烯硬脂酸酯、聚氧乙烯(40)氢化蓖麻油中的一种或多种；更优选地，选自吐温；其中，加入稳定剂用于抑制艾地骨化醇降解为1β型杂质，即化学名(5Z，7E)-(1S，2R，3R)-2-(3-羟基丙氧基)-9,10-断胆甾-5,7,10(19)-三烯-1，3,25-三醇，使得该固体制剂经遮蔽、室温保存12个月后产生的1β型杂质的量为小于等于0.3％，优选地，小于等于0.1％，或更少。
更加优选地，该固体制剂是艾地骨化醇片剂，填充剂是无水乳糖，粘合剂是聚维酮K30，润滑剂是硬脂酸镁，抗氧化剂是棓丙酯，或是BHT，或是BHT与BHA的组合；稳定剂是吐温80，且吐温80的用量为每片0.02～2mg，优选地，为每片0.1～0.5mg。
优选地，该艾地骨化醇片剂是采用双螺杆挤出制粒法制备获得的，且颗粒的干燥温度是35～50℃，干燥时间0.5～5h，优选地，干燥温度是40～45℃，干燥时间是0.5～2h，且颗粒的干燥方式是流化床干燥，或烘箱干燥。
关于艾地骨化醇，本公开提供了一种抑制在固体制剂中包含的艾地骨化醇转变为艾地骨化醇前体的方法，所述制剂包含填充剂、粘合剂、润滑剂、抗氧化剂；通过加入抗氧化剂来抑制艾地骨化醇转变为艾地骨化醇前体，即化学名6Z-(1R，2R，3R)-2-(3-羟基丙氧基)-9，10-断胆甾-5(10)，6，8(9)-三烯-1，3，25-三醇，使得该固体制剂在遮蔽、室温保存12个月后产生的6Z-(1R，2R，3R)-2-(3-羟基丙氧基)-9，10-断胆甾-5(10)，6，8(9)-三烯-1，3，25-三醇的量为小于等于3％，或更少。
本公开还提供了一种抑制在固体制剂中包含的艾地骨化醇降解为艾地骨化醇1β型杂质的方法，所述制剂包含填充剂、粘合剂、润滑剂、抗氧化剂、稳定剂；通过加入稳定剂来抑制艾地骨化醇降解为艾地骨化醇1β型杂质，即化学名(5Z，7E)-(1S，2R，3R)-2-(3-羟基丙氧基)-9,10-断胆甾-5,7,10(19)-三烯-1，3,25-三醇，使得该固体制剂经遮蔽、室温保存12个月后产生的1β型杂质的量为小于等于0.3％，优选地，小于等于0.1％，或更少。
关于艾地骨化醇，本公开提供了一种利用双螺杆挤出技术制备艾地骨化醇片剂的方法，片剂处方包含艾地骨化醇、无水乳糖、聚维酮K30、硬脂酸镁、抗氧化剂；该溶液中还可以选择性地加入稳定剂，稳定剂优选为吐温80，或者选择不加入稳定剂；该制备方法具体采用如下步骤：
1)将艾地骨化醇溶解于无水乙醇中，得到溶液：可选地，该溶液中还可选择性地加入稳定剂并溶解在溶液中，也可不加稳定剂；
2)按处方称取无水乳糖、聚维酮K30，在湿法制粒机中加入再加入抗氧化剂，混合均匀，加入湿法混合制粒机中混合，混合时间时间大于等于5分钟，得到干粉；抗氧化剂是棓丙酯、DL-α-生育酚、BHT，或是BHT与BHA的组合；
3)将上述步骤2所得干粉加入至固体喂料器中，将上述步骤1所得溶液通过低脉冲蠕动泵与挤出机相连，将双螺杆挤出机的制粒温度控制在20～25℃，同时调节干粉喂料速度、蠕动泵转速及双螺杆转速，运行双螺杆挤出机进行制 粒，在弃去挤出前5分钟的物料后开始接料，，获得湿颗粒；上述干粉喂料速度、蠕动泵转速、双螺杆的转速三者之间的设定需相互配合，干粉喂料速度为1.0～3.0kg/hr、蠕动泵转速为2rpm～8rpm、双螺杆转速为100rpm～400rpm，且上述干粉与溶液在单位时间内进入到双螺杆挤出机中的重量的比例，即固液比是7:1～11:1，优选8.5:1～9:1；
4)将所得湿颗粒进行干燥，得干燥颗粒，所述干燥温度是35～50℃，干燥时间0.5～5h，优选地，干燥温度是40～45℃，干燥时间是0.5～2h，且颗粒的干燥方式是流化床干燥，或者烘箱干燥；
5)干燥颗粒过16～24目筛整粒，优选20目筛整粒，然后加入硬脂酸镁，混合均匀，压片，即得。
作为一种包含维生素D类似物的组合物的实施方案之一，维生素D类似物是骨化三醇，即化学名(5Z，7E)-9，10-开环胆甾-5，7，10(19)-三烯-1α，3β，25-三醇；该组合物是固体制剂，优选片剂；包含骨化三醇、填充剂、粘合剂、润滑剂、抗氧化剂、稳定剂；其中，加入稳定剂用于抑制骨化三醇降解为1β型杂质，即化学名(5Z，7E)-9，10-开环胆甾-5，7，10(19)-三烯-1β，3β，25-三醇，使得该固体制剂经遮蔽、室温保存12个月后产生的1β型杂质的量为小于等于0.3％，优选地，小于等于0.1％，或更少。
优选地，所述填充剂选自无水乳糖、一水乳糖、甘露醇、微晶纤维素、蔗糖中的一种或多种，优选地，为无水乳糖；粘合剂选自聚维酮、羟丙纤维素、羟丙甲纤维素、羧甲基纤维素钠中的一种或多种，优选地，为聚维酮K30；润滑剂选自滑石粉、硬脂酸镁、硬脂酸钙、硬脂富马酸钠中的一种或几种，优选地，为硬脂酸镁；抗氧化剂选自选自棓丙酯、DL-α-生育酚、二丁基羟基甲苯(BHT)、丁基羟基茴香醚(BHA)中的一种或多种；稳定剂选自吐温、司盘、聚氧乙烯烷基醚、泊洛沙姆188、蔗糖酸硬脂酸酯、聚氧乙烯(35)蓖麻油、聚氧乙烯(40)氢化蓖麻油、聚氧乙烯(20)十八十六烷基醚、聚氧乙烯月桂醚、聚氧乙烯硬脂酸酯中的一种或多种；优选地，选自吐温、聚氧乙烯硬脂酸酯、聚氧乙烯(40)氢化蓖麻油中的一种或多种，更优选地，选自吐温。
更加优选地，该固体制剂是骨化三醇片剂，其包含的填充剂是无水乳糖，粘合剂是聚维酮K30，抗氧化剂是棓丙酯，或二丁基羟基甲苯(BHT)，或二丁 基羟基甲苯(BHT)与丁基羟基苯甲醚(BHA)的组合；稳定剂是吐温80，或聚氧乙烯硬脂酸酯；润滑剂是硬脂酸镁，或硬脂富马酸钠。
优选地，该固体制剂是骨化三醇片剂，填充剂用量为每片50～200mg，优选地，为每片81～83mg；粘合剂用量为每片0.2～3mg，优选地，为每片1.0～2.0mg；润滑剂用量为每片0.1～1mg，优选地，为每片0.4～0.5mg，抗氧化剂用量为每片0.05～2mg，优选地，为每片0.5～1.0mg；稳定剂用量为每片0.02～2mg，优选地，为每片0.1～0.5mg。
优选地，所述骨化三醇片剂是采用双螺杆挤出制粒法制备获得的，且颗粒的干燥温度是35～50℃，干燥时间0.5～5h，优选地，干燥温度是40～45℃，干燥时间是0.5～2h，且颗粒的干燥方式是流化床干燥，或烘箱干燥。
本公开提供了一种抑制在固体制剂中包含的骨化三醇降解的方法，所述制剂包含填充剂、粘合剂、润滑剂、抗氧化剂、稳定剂；通过加稳定剂来抑制骨化三醇降解1β型杂质，即化学名(5Z，7E)-9，10-开环胆甾-5，7，10(19)-三烯-1β，3β，25-三醇，使得该固体制剂在遮蔽、室温保存12个月后产生的(5Z，7E)-9，10-开环胆甾-5，7，10(19)-三烯-1β，3β，25-三醇的量为小于等于0.3％，优选地，小于等于0.1％，或更少。
本公开提供了一种利用双螺杆挤出技术制备骨化三醇片剂的方法，其特征在于，片剂处方包括骨化三醇、稳定剂、填充剂、抗氧化剂、粘合剂、润滑剂；具体包含如下步骤：
1)将骨化三醇溶解于无水乙醇中，再加入稳定剂溶解，得到溶液：
2)按处方称取填充剂、抗氧化剂、粘合剂，加入湿法混合制粒机中混合，混合时间大于等于5分钟，得到干粉；
3)将上述步骤2所得干粉加入至固体喂料器中，将上述步骤1所得溶液通过低脉冲蠕动泵与挤出机相连，将双螺杆挤出机的制粒温度控制在20～25℃，同时调节干粉喂料速度、蠕动泵转速及双螺杆的转速，运行双螺杆挤出机进行制粒，在弃去挤出前5分钟的物料后开始接料，获得湿颗粒；上述干粉喂料速度、蠕动泵转速、双螺杆转速三者之间的设定需相互配合，干粉喂料速度为1.0～3.0kg/hr、蠕动泵转速为2rpm～8rpm、双螺杆转速为100rpm～400rpm，且上述干粉与溶液在单位时间内进入到双螺杆挤出机中的重量的比值，即“固液比” 是7:1～11:1，优选8.5:1～9:1；
4)将所得湿颗粒进行干燥，得干燥颗粒，所述干燥温度是35～50℃，干燥时间0.5h～5h，优选地，干燥温度是40～45℃，干燥时间是0.5～2h，且颗粒的干燥方式是流化床干燥，或烘箱干燥；
5)干燥颗粒过16～24目筛整粒，优选20目筛整粒，然后加入硬脂酸镁，混合均匀，压片，即得；
其中，所述填充剂选自无水乳糖、一水乳糖、甘露醇、微晶纤维素、蔗糖中的一种或多种，优选地，为无水乳糖；粘合剂选自聚维酮、羟丙纤维素、羟丙甲纤维素、羧甲基纤维素钠中的一种或多种，优选地，为聚维酮K30；润滑剂选自滑石粉、硬脂酸镁、硬脂酸钙、硬脂富马酸钠中的一种或几种，优选地，为硬脂酸镁；抗氧化剂选自选自棓丙酯、DL-α-生育酚、二丁基羟基甲苯(BHT)、丁基羟基茴香醚(BHA)中的一种或多种；稳定剂选自吐温、司盘、聚氧乙烯烷基醚、泊洛沙姆188、蔗糖酸硬脂酸酯、聚氧乙烯(35)蓖麻油、聚氧乙烯(40)氢化蓖麻油、聚氧乙烯(20)十八十六烷基醚、聚氧乙烯月桂醚、聚氧乙烯硬脂酸酯中的一种或多种，优选地，选自吐温、聚氧乙烯硬脂酸酯、聚氧乙烯(40)氢化蓖麻油中的一种或多种，更优选地，选自吐温。
本公开取得了如下有益的技术效果和进步。
1)本公开首次采用双螺杆挤出技术制备获得维生素D类似物的固体制剂，深入研究了维生素D类似物药物，尤其是阿法骨化醇、艾地骨化醇及骨化三醇，经过双螺杆挤出制粒法制备片剂。含量均匀度符合药典规定。然而，传统湿法制粒在制备低剂量药物的固体制剂时，由于常规搅拌方式难以使得低剂量的药物高度均匀的分散，所以药物的含量均匀度较差。
2)本公开制备方法工艺简单易行，能耗小，过程中不会引入其他杂质，且放大生产尝试每批次十万片，溶出度均有所提高。相应的前体和降解产物的含量有所降低，得到有效控制。工艺重现性高，易于实现连续化大生产。
3)配方中除了传统固体制剂的辅料，还加入稳定剂优选为吐温80。在将原料药溶解在无水乙醇中时，加入吐温80不仅能够在乙醇溶液环境中稳定主药，而且在进入双螺杆技术机器内部的混合阶段，乃至后续阶段湿颗粒干燥时，均能够起到有效的保护作用，对于抑制其降解产物生成发挥了关键的作用。举例 说明，我们推测，吐温80在化学结构上是脱水山梨醇单油酸酯聚氧乙烯醚，属于非离子型表面活性剂，在乙醇溶液中以及在混合制粒和后续干燥过程中，两亲性的吐温对疏水性且含量极低的阿法骨化醇能够高效地以胶束的形式进行保护、包裹，使其隔绝外界的光、热、氧、水分等因素，对于抑制阿法骨化醇降解产物的生成发挥了关键作用。
4)我们细致地研究了各种因素对阿法骨化醇或骨化三醇的前体和降解产物生成的影响。发现在阿法骨化醇片和骨化三醇片的处方研究中，抗氧化剂如棓丙酯或DL-α-生育酚的加入对抑制相应的前体生成并没有显著影响，有时反而增加了降解产物的产生。例如，我们在阿法骨化醇片处方中，保持相同片重85mg，分别添加了0.05mg、0.1mg、0.5mg、1.0mg棓丙酯，发现在棓丙酯加至一定的量之后，再随着用量增加，不能进一步降低阿法骨化醇前体含量。但是制成相应片剂后，其后续稳定性试验中降解产物如1β型杂质却增加较高。棓丙酯用量减少在一定程度上也能减少降解产物的生成。我们在处方中意外的发现，加入吐温80，能够有效抑制降解产物生成。在研究骨化三醇片剂中，我们也发现了抗氧化剂用量增加对前体控制影响不大，但却导致了更多降解产物。一些非离子型的表面活性剂例如吐温、聚氧乙烯(40)氢化蓖麻油、聚氧乙烯硬脂酸酯等，能有效抑制降解产物，特别是抑制1β型杂质生成。我们推测上述表面活性剂高分子材料能够通过胶束形式，包裹在主药分子周围，起到隔绝外界破坏因素的作用。
艾地骨化醇上市制剂是软胶囊，我们在探索艾地骨化醇片过程中，惊奇地发现一个与阿法骨化醇和骨化三醇不一样的意外结果。即艾地骨化醇片中抗氧化剂用量增加能够显著抑制艾地骨化醇前体的生成。我们推测可能与化学分子结构有关，艾地骨化分子中3位是羟基丙氧基，阿法骨化醇或骨化三醇分子相应位置没有取代基。艾地骨化醇的前体在分子势能、以及空间构象上的船式与椅式的转化上，与阿法骨化醇和骨化三醇分子具有明显的区别。我们推测这可能是导致抗氧化剂对艾地骨化醇前体的抑制更为显著的原因。
5)我们在实验过程中还考察了固体形式的辅料混合方式及混合时间，进一步确保后续喂料速度与加液速度的匹配及最终物料的均匀性。
6)我们在实验过程中还考察了挤出温度的影响。由于维生素D类似物本身 不稳定性因素，实验中发现挤出温度对最终制剂的含量和稳定性有直接影响，而现有技术中双螺杆挤出技术药物领域应用中，无需考虑这一因素。本公开经过大量实验证实双螺杆挤出机的制粒温度控制在20～25℃，实施例的阿法骨化醇片剂中前体含量相较于市售阿法骨化醇片有显著降低，有效防止了制粒过程药物降解和转化，具有有益的技术进步。然而普通湿法制粒无法做到这一点，在搅拌过程中、溶剂加热挥发过程中体系的温度偏高，导致药物分子遭到转变和降解。因此温度是双螺杆挤出制粒过程中的关键工艺参数之一。
7)双螺杆挤出制粒过程中的参数调节和设定也是本公开技术方案中须注意的。举例来说，当调节干粉喂料速度为1.0～3.0kg/hr、蠕动泵转速为2rpm～8rpm、双螺杆转速为100rpm～400rpm时，观察制得的颗粒较为均匀、测定挤出物含量均匀，且干粉与溶液在单位时间内进入到双螺杆挤出机中的重量的比例，即固液比是7:1～11:1，优选8.5:1～9:1。
8)本公开采用双螺杆挤出制粒技术，使用的热熔挤出机型号是赛默飞PHARMA16，具有工序少，能耗低，安全无污染，混合无死角，分散效果好，均匀度高，药物损失少，集多种单元操作于一体，节省空间和降低成本等特点，该技术现已成为制剂技术药物传递系统中的一个新热点。此外其制备工艺十分便于实现工业化放大生产。现有技术中尚未报道双螺杆挤出技术在制备维生素D类似物的组合物及其制剂方面的应用。
具体实施方式
为了使本公开的上述目的、特征和优点能够更加明显易懂，下面结合具体实施例对本公开的具体实施方式做详细的说明。
在下面的描述中阐述了很多具体细节以便于充分理解本公开，但是本公开还可以采用其他不同于在此描述的其它方式来实施，本领域技术人员可以在不违背本公开内涵的情况下做类似推广，因此本公开不受下面公开的具体实施例的限制。
实施例1阿法骨化醇片的制备
单剂量处方：
阿法骨化醇0.5μg，无水乳糖81.5mg，聚维酮K30 2mg，棓丙酯1mg， 硬脂酸镁0.4mg，吐温80 0.1mg，无水乙醇 适量
制备方法：1)将阿法骨化醇溶解于无水乙醇中，加入吐温80溶解，得溶液；2)将无水乳糖、聚维酮K30、棓丙酯置于湿法混合制粒机中混合，混合时间大于等于5分钟，得干粉；3)将步骤2所得干粉加入至固体喂料器中，将步骤1所得溶液通过低脉冲蠕动泵与挤出机相连，将双螺杆挤出机的制粒温度控制在20～25℃，调节干粉喂料速度为1.0～2.0kg/hr、蠕动泵转速为2rpm～4rpm、双螺杆转速为100rpm～200rpm，且上述干粉与溶液在单位时间内进入到双螺杆挤出机中的重量的比值，即“固液比”控制在8.5:1～9:1；在弃去挤出前5分钟的物料后开始接料，获得湿颗粒；4)将湿颗粒置于烘箱中，40～45℃干燥2h，得干燥颗粒；5)干燥颗粒过20目筛整粒，加入硬脂酸镁，混合均匀，压片，即得。
实施例2阿法骨化醇片剂的制备(不添加表面活性剂)
单剂量处方：
阿法骨化醇0.5μg，无水乳糖82.6mg，聚维酮K30 2mg，棓丙酯1mg，硬脂酸镁0.4mg，无水乙醇 适量
制备方法：1)将阿法骨化醇溶解于无水乙醇中，得溶液；2)将无水乳糖、聚维酮K30、棓丙酯置于湿法混合制粒机中混合，混合时间大于等于5分钟，得干粉；3)将步骤2所得干粉加入至固体喂料器中，将步骤1所得溶液通过低脉冲蠕动泵与挤出机相连，将双螺杆挤出机的制粒温度控制在20～25℃，调节干粉喂料速度为2.0～3.0kg/hr、蠕动泵转速为4rpm～8rpm、双螺杆转速为300rpm～400rpm，且上述干粉与溶液在单位时间内进入到双螺杆挤出机中的重量的比值，即“固液比”控制在10:1～9:1；在弃去挤出前5分钟的物料后开始接料，获得湿颗粒；4)将湿颗粒置于烘箱中，40～45℃干燥2h，得干燥颗粒；5)干燥颗粒过20目筛整粒，加入硬脂酸镁，混合均匀，压片，即得。
实施例3阿法骨化醇片剂的制备
单剂量处方：
阿法骨化醇1μg，无水乳糖81.5mg，聚维酮K30 2mg，棓丙酯1mg，硬脂酸镁0.4mg，吐温80 0.2mg，无水乙醇 适量
制备方法：1)将阿法骨化醇溶解于无水乙醇中，再加入吐温80溶解，得溶液；2)将无水乳糖、聚维酮K30、棓丙酯置于湿法混合制粒机中混合，混合时间大于等于5分钟，得干粉；3)将步骤2所得干粉加入至固体喂料器中，将步骤1所得溶液通过低脉冲蠕动泵与挤出机相连，将双螺杆挤出机的制粒温度控制在20～25℃，调节干粉喂料速度为1.5～2.5kg/hr、蠕动泵转速为3rpm～5rpm、双螺杆转速为200rpm～300rpm，且上述干粉与溶液在单位时间内进入到双螺杆挤出机中的重量的比值，即“固液比”控制在10:1～9:1；在弃去挤出前5分钟的物料后开始接料，获得湿颗粒；4)将湿颗粒置于烘箱中，40～45℃干燥2h，得干燥颗粒；5)干燥颗粒过20目筛整粒，加入硬脂酸镁，混合均匀，压片，即得。
实施例4阿法骨化醇片剂的制备
单剂量处方：
阿法骨化醇0.5μg，无水乳糖81.5mg，聚维酮K30 2mg，BHT 1mg，硬脂富马酸钠0.4mg，聚氧乙烯硬脂酸酯0.1mg，无水乙醇 适量
制备方法：1)将阿法骨化醇溶解于无水乙醇中，再加入聚氧乙烯硬脂酸酯溶解，得溶液；2)将无水乳糖、聚维酮K30、BHT置于湿法混合制粒机中混合，混合时间大于等于5分钟，得干粉；3)将步骤2所得干粉加入至固体喂料器中，将步骤1所得溶液通过低脉冲蠕动泵与挤出机相连，将双螺杆挤出机的制粒温度控制在20～25℃，调节干粉喂料速度为1.5～2.0kg/hr、蠕动泵转速为3rpm～5rpm、双螺杆转速为250rpm～300rpm，且上述干粉与溶液在单位时间内进入到双螺杆挤出机中的重量的比值，即“固液比”控制在10:1～9:1；在弃去挤出前5分钟的物料后开始接料，获得湿颗粒；4)将湿颗粒置于烘箱中，40～45℃干燥2h，得干燥颗粒；5)干燥颗粒过24目筛整粒，加入硬脂富马酸钠，混合均匀，压片，即得。
实施例5阿法骨化醇片剂的制备
单剂量处方：
阿法骨化醇0.5μg，无水乳糖81.55mg，聚维酮K30 2mg，DL-α-生育酚2mg，硬脂酸镁0.4mg，聚氧乙烯(40)氢化蓖麻油0.1mg，无水乙醇 适量
制备方法：1)将阿法骨化醇溶解于无水乙醇中，再加入聚氧乙烯(40)氢化蓖麻油溶解，得溶液；2)将无水乳糖、聚维酮K30、DL-α-生育酚置于湿法混合制粒机中混合，混合时间大于等于5分钟，得干粉；3)将步骤2所得干粉加入至固体喂料器中，将步骤1所得溶液通过低脉冲蠕动泵与挤出机相连，将双螺杆挤出机的制粒温度控制在20～25℃，调节干粉喂料速度为2.0～2.5kg/hr、蠕动泵转速为4rpm～6rpm、双螺杆转速为100rpm～150rpm，且上述干粉与溶液在单位时间内进入到双螺杆挤出机中的重量的比值，即“固液比”控制在10:1～9:1；在弃去挤出前5分钟的物料后开始接料，获得湿颗粒；4)将湿颗粒置于烘箱中，40～45℃干燥2h，得干燥颗粒；5)干燥颗粒过16目筛整粒，加入硬脂酸镁，混合均匀，压片，即得。
实施例6艾地骨化醇片的制备
单剂量处方：
艾地骨化醇0.5μg，无水乳糖83.6mg，聚维酮K30 0.5mg，棓丙酯0.5mg，硬脂酸镁0.4mg，无水乙醇 适量
制备方法：1)将艾地骨化醇溶解于无水乙醇中，得溶液；2)将无水乳糖、聚维酮K30、棓丙酯置于湿法混合制粒机中混合，混合时间大于等于5分钟，得干粉；3)将步骤2所得干粉加入至固体喂料器中，将步骤1所得溶液通过低脉冲蠕动泵与挤出机相连，将双螺杆挤出机的制粒温度控制在20～25℃，调节干粉喂料速度为2.0～3.0kg/hr、蠕动泵转速为4rpm～6rpm、双螺杆转速为100rpm～200rpm，且上述干粉与溶液在单位时间内进入到双螺杆挤出机中的重量的比值，即“固液比”控制在10:1～9:1；在弃去挤出前5分钟的物料后开始接料，获得湿颗粒；4)将湿颗粒置于烘箱中，40～45℃干燥2h，得干燥颗粒；5)干燥颗粒过20目筛整粒，加入硬脂酸镁，混合均匀，压片，即得。
实施例7艾地骨化醇片的制备
单剂量处方：
艾地骨化醇0.75μg，无水乳糖82.6mg，聚维酮K30 1mg，棓丙酯1mg，硬脂酸镁0.4mg，无水乙醇 适量
制备方法：1)将艾地骨化醇溶解于无水乙醇中，得溶液；2)将无水乳糖、 聚维酮K30、棓丙酯置于湿法混合制粒机中混合，混合时间大于等于5分钟，得干粉；3)将步骤2所得干粉加入至固体喂料器中，将步骤1所得溶液通过低脉冲蠕动泵与挤出机相连，将双螺杆挤出机的制粒温度控制在20～25℃，调节干粉喂料速度为1.5～2.0kg/hr、蠕动泵转速为5rpm～7rpm、双螺杆转速为200rpm～300rpm，且上述干粉与溶液在单位时间内进入到双螺杆挤出机中的重量的比值，即“固液比”控制在9:1～8.5:1；在弃去挤出前5分钟的物料后开始接料，获得湿颗粒；4)将湿颗粒置于烘箱中，40～45℃干燥2h，得干燥颗粒；5)干燥颗粒过20目筛整粒，加入硬脂酸镁，混合均匀，压片，即得。
实施例8艾地骨化醇片的制备
单剂量处方：
艾地骨化醇0.5μg，无水乳糖83.1mg，聚维酮K30 0.5mg，BHT 1mg，硬脂富马酸钠0.4mg，无水乙醇 适量
制备方法：1)将艾地骨化醇溶解于无水乙醇中，得溶液；2)将无水乳糖、聚维酮K30、BHT置于湿法混合制粒机中混合，混合时间大于等于5分钟，得干粉；3)将步骤2所得干粉加入至固体喂料器中，将步骤1所得溶液通过低脉冲蠕动泵与挤出机相连，将双螺杆挤出机的制粒温度控制在20～25℃，调节干粉喂料速度为2.0～2.5kg/hr、蠕动泵转速为6rpm～7rpm、双螺杆转速为200rpm～250rpm，且上述干粉与溶液在单位时间内进入到双螺杆挤出机中的重量的比值，即“固液比”控制在9:1～10:1；在弃去挤出前5分钟的物料后开始接料，获得湿颗粒；4)将湿颗粒置于烘箱中，40～45℃干燥2h，得干燥颗粒；5)干燥颗粒过20目筛整粒，加入硬脂富马酸钠，混合均匀，压片，即得。
实施例9艾地骨化醇片的制备
单剂量处方：
艾地骨化醇0.75μg，无水乳糖82.6mg，聚维酮K30 1mg，DL-α-生育酚1mg，硬脂酸镁0.4mg，无水乙醇 适量
制备方法：1)将艾地骨化醇溶解于无水乙醇中，得溶液；2)将无水乳糖、聚维酮K30、DL-α-生育酚置于湿法混合制粒机中混合，混合时间大于等于5分钟，得干粉；3)将步骤2所得干粉加入至固体喂料器中，将步骤1所得溶液 通过低脉冲蠕动泵与挤出机相连，将双螺杆挤出机的制粒温度控制在20～25℃，调节干粉喂料速度为2.0～2.5kg/hr、蠕动泵转速为6rpm～7rpm、双螺杆转速为200rpm～250rpm，且上述干粉与溶液在单位时间内进入到双螺杆挤出机中的重量的比值，即“固液比”控制在9:1～10:1；在弃去挤出前5分钟的物料后开始接料，获得湿颗粒；4)将湿颗粒置于烘箱中，40～45℃干燥2h，得干燥颗粒；5)干燥颗粒过24目筛整粒，加入硬脂酸镁，混合均匀，压片，即得。
实施例10艾地骨化醇片的制备
单剂量处方：
艾地骨化醇0.75μg，无水乳糖83.0mg，聚维酮K30 0.5mg，棓丙酯1mg，硬脂酸镁0.4mg，吐温80 0.1mg，无水乙醇 适量
制备方法：1)将艾地骨化醇溶解于无水乙醇中，加入吐温80溶解，得溶液；2)将无水乳糖、聚维酮K30、棓丙酯置于湿法混合制粒机中混合，混合时间大于等于5分钟，得干粉；3)将步骤2所得干粉加入至固体喂料器中，将步骤1所得溶液通过低脉冲蠕动泵与挤出机相连，将双螺杆挤出机的制粒温度控制在20～25℃，调节干粉喂料速度为2.0～2.5kg/hr、蠕动泵转速为3rpm～4rpm、双螺杆转速为200rpm～250rpm，且上述干粉与溶液在单位时间内进入到双螺杆挤出机中的重量的比值，即“固液比”控制在10:1～11:1；在弃去挤出前5分钟的物料后开始接料，获得湿颗粒；4)将湿颗粒置于烘箱中，40～45℃干燥2h，得干燥颗粒；5)干燥颗粒过20目筛整粒，加入硬脂酸镁，混合均匀，压片，即得。
实施例11艾地骨化醇片的制备
单剂量处方：
艾地骨化醇0.5μg，无水乳糖82.4mg，聚维酮K30 1mg，BHT 1mg，硬脂酸镁0.4mg，吐温80 0.2mg，无水乙醇 适量
制备方法：1)将艾地骨化醇溶解于无水乙醇中，加入吐温80溶解，得溶液；2)将无水乳糖、聚维酮K30、BHT置于湿法混合制粒机中混合，混合时间大于等于5分钟，得干粉；3)将步骤2所得干粉加入至固体喂料器中，将步骤1所得溶液通过低脉冲蠕动泵与挤出机相连，将双螺杆挤出机的制粒温度控制在 20～25℃，调节干粉喂料速度为1.5～2.0kg/hr、蠕动泵转速为5rpm～6rpm、双螺杆转速为250rpm～300rpm，且上述干粉与溶液在单位时间内进入到双螺杆挤出机中的重量的比值，即“固液比”控制在10:1～11:1；在弃去挤出前5分钟的物料后开始接料，获得湿颗粒；4)将湿颗粒置于烘箱中，40～45℃干燥2h，得干燥颗粒；5)干燥颗粒过20目筛整粒，加入硬脂酸镁，混合均匀，压片，即得。
实施例12艾地骨化醇片的制备
单剂量处方：
艾地骨化醇0.75μg，无水乳糖82.4mg，聚维酮K30 0.5mg，BHT 0.5mg，BHA 0.5mg，硬脂富马酸钠0.4mg，聚氧乙烯硬脂酸酯0.1mg，无水乙醇 适量
制备方法：1)将艾地骨化醇溶解于无水乙醇中，加入聚氧乙烯硬脂酸酯溶解，得溶液；2)将无水乳糖、聚维酮K30、BHT、BHA置于湿法混合制粒机中混合，混合时间大于等于5分钟，得干粉；3)将步骤2所得干粉加入至固体喂料器中，将步骤1所得溶液通过低脉冲蠕动泵与挤出机相连，将双螺杆挤出机的制粒温度控制在20～25℃，调节干粉喂料速度为2.0～2.5kg/hr、蠕动泵转速为4rpm～5rpm、双螺杆转速为200rpm～250rpm，且上述干粉与溶液在单位时间内进入到双螺杆挤出机中的重量的比值，即“固液比”控制在10:1～11:1；在弃去挤出前5分钟的物料后开始接料，获得湿颗粒；4)将湿颗粒置于烘箱中，40～45℃干燥2h，得干燥颗粒；5)干燥颗粒过20目筛整粒，加入硬脂富马酸钠，混合均匀，压片，即得。
实施例13骨化三醇片的制备
单剂量处方：
骨化三醇0.5μg，一水乳糖70mg，甘露醇12.6mg，BHT 0.5mg，BHA0.5mg，硬脂酸镁0.4mg，聚氧乙烯硬脂酸酯0.2mg，聚氧乙烯(40)氢化蓖麻油0.2mg，聚维酮K30 1mg，无水乙醇 适量
制备方法：1)将骨化三醇溶解于无水乙醇中，加入聚氧乙烯硬脂酸酯、聚氧乙烯(40)氢化蓖麻油溶解，得溶液；2)将一水乳糖、甘露醇、BHT、BHA、聚维酮K30置于湿法混合制粒机中混合，混合时间大于等于5分钟，得干粉；3) 将步骤2所得干粉加入至固体喂料器中，将步骤1所得溶液通过低脉冲蠕动泵与挤出机相连，将双螺杆挤出机的制粒温度控制在20～25℃，调节干粉喂料速度为2.0～2.5kg/hr、蠕动泵转速为4rpm～5rpm、双螺杆转速为200rpm～250rpm，且上述干粉与溶液在单位时间内进入到双螺杆挤出机中的重量的比值，即“固液比”控制在10:1～11:1；在弃去挤出前5分钟的物料后开始接料，获得湿颗粒；4)将湿颗粒置于烘箱中，40～45℃干燥2h，得干燥颗粒；5)干燥颗粒过20目筛整粒，加入硬脂酸镁，混合均匀，压片，即得。
实施例14骨化三醇片的制备
单剂量处方：
骨化三醇1μg，无水乳糖70mg，山梨糖醇13.1mg，棓丙酯1mg，硬脂酸镁0.4mg，聚氧乙烯硬脂酸酯0.4mg，羟丙纤维素0.5mg，无水乙醇适量
制备方法：1)将骨化三醇溶解于无水乙醇中，加入聚氧乙烯硬脂酸酯溶解，得溶液；2)将无水乳糖、山梨糖醇、棓丙酯、羟丙纤维素置于湿法混合制粒机中混合，混合时间大于等于5分钟，得干粉；3)将步骤2所得干粉加入至固体喂料器中，将步骤1所得溶液通过低脉冲蠕动泵与挤出机相连，将双螺杆挤出机的制粒温度控制在20～25℃，调节干粉喂料速度为2.0～2.5kg/hr、蠕动泵转速为4rpm～5rpm、双螺杆转速为200rpm～250rpm，且上述干粉与溶液在单位时间内进入到双螺杆挤出机中的重量的比值，即“固液比”控制在10:1～11:1；在弃去挤出前5分钟的物料后开始接料，获得湿颗粒；4)将湿颗粒置于烘箱中，40～45℃干燥2h，得干燥颗粒；5)干燥颗粒过20目筛整粒，加入硬脂酸镁，混合均匀，压片，即得。
实施例15骨化三醇片的制备
单剂量处方：
骨化三醇3μg，无水乳糖70mg，甘露醇13.4mg，DL-α-生育酚1mg，硬脂酸镁0.4mg，吐温80 0.4mg，羟丙甲纤维素0.6mg，无水乙醇 适量
制备方法：1)将骨化三醇溶解于无水乙醇中，加入吐温80溶解，得溶液；2)将无水乳糖、甘露醇、DL-α-生育酚、羟丙甲纤维素置于湿法混合制粒机中混合，混合时间大于等于5分钟，得干粉；3)将步骤2所得干粉加入至固体喂 料器中，将步骤1所得溶液通过低脉冲蠕动泵与挤出机相连，将双螺杆挤出机的制粒温度控制在20～25℃，调节干粉喂料速度为2.0～2.5kg/hr、蠕动泵转速为4rpm～5rpm、双螺杆转速为200rpm～250rpm，且上述干粉与溶液在单位时间内进入到双螺杆挤出机中的重量的比值，即“固液比”控制在10:1～11:1；在弃去挤出前5分钟的物料后开始接料，获得湿颗粒；4)将湿颗粒置于烘箱中，40～45℃干燥2h，得干燥颗粒；5)干燥颗粒过20目筛整粒，加入硬脂酸镁，混合均匀，压片，即得。
实施例16骨化三醇片的制备(不添加表面活性剂)
单剂量处方：
骨化三醇0.5μg，一水乳糖70mg，甘露醇13.1mg，BHT 0.5mg，BHA0.5mg，硬脂酸镁0.4mg，羧甲基纤维素钠0.4mg，无水乙醇 适量
制备方法：1)将骨化三醇溶解于无水乙醇中，得溶液；2)将一水乳糖、甘露醇、BHT、BHA、羧甲基纤维素钠置于湿法混合制粒机中混合，混合时间大于等于5分钟，得干粉；3)将步骤2所得干粉加入至固体喂料器中，将步骤1所得溶液通过低脉冲蠕动泵与挤出机相连，将双螺杆挤出机的制粒温度控制在20～25℃，调节干粉喂料速度为2.0～2.5kg/hr、蠕动泵转速为4rpm～5rpm、双螺杆转速为200rpm～250rpm，且上述干粉与溶液在单位时间内进入到双螺杆挤出机中的重量的比值，即“固液比”控制在10:1～11:1；在弃去挤出前5分钟的物料后开始接料，获得湿颗粒；4)将湿颗粒置于烘箱中，40～45℃干燥2h，得干燥颗粒；5)干燥颗粒过20目筛整粒，加入硬脂酸镁，混合均匀，压片，即得。
实施例17骨化三醇片的制备
单剂量处方：
骨化三醇0.5μg，一水乳糖70mg，蔗糖12.6mg，BHT 0.5mg，BHA 0.5mg，硬脂酸镁0.4mg，吐温80 0.4mg，聚维酮K30 0.5mg，无水乙醇 适量
制备方法：1)将骨化三醇溶解于无水乙醇中，加入吐温80溶解，得溶液；2)将一水乳糖、蔗糖、BHT、BHA、聚维酮K30置于湿法混合制粒机中混合，混合时间大于等于5分钟，得干粉；3)将步骤2所得干粉加入至固体喂料器中， 将步骤1所得溶液通过低脉冲蠕动泵与挤出机相连，将双螺杆挤出机的制粒温度控制在20～25℃，调节干粉喂料速度为2.0～2.5kg/hr、蠕动泵转速为4rpm～5rpm、双螺杆转速为200rpm～250rpm，且上述干粉与溶液在单位时间内进入到双螺杆挤出机中的重量的比值，即“固液比”控制在10:1～11:1；在弃去挤出前5分钟的物料后开始接料，获得湿颗粒；4)将湿颗粒置于烘箱中，40～45℃干燥2h，得干燥颗粒；5)干燥颗粒过20目筛整粒，加入硬脂酸镁，混合均匀，压片，即得。
实施例18对比实施例1CN104739793A公开了一种阿法骨化醇片及其制备方法。是采用传统湿法制粒方法，按照其中实施例1方法，使用本公开相同处方和工艺，得到对比实施例1的阿法骨化醇片。工艺描述如下：称取处方量的原辅料，分别过80目筛备用；配制粘合剂溶液；将过筛后的主药、辅料等按照等量递增法混合均匀，加入上述粘合剂溶液制成软材；用40目筛制粒后，50℃下干燥30分钟，过20目筛整粒，加入硬脂酸镁混匀后压片即得。
实施例19对比实施例2CN1196677A公开了一种很低剂量药物固体剂型的制备方法。是采用高速剪切混合造粒技术，按照其中描述的制备方法，运用本公开相同处方和工艺，得到对比实施例2的阿法骨化醇片。工艺大致描述如下：采用适量溶剂配制成药物溶液，缓慢加入到在高速剪切混合-造粒机中的赋形剂和其他辅料中，以1500rpm的搅拌桨湿粉剧烈的混合，总混合时间在10～20分钟，再将所得浓缩物筛入滚筒掺混机中，与剩余物料混合均匀，压片即得。
实施例20阿法骨化醇片的制备
单剂量处方：
阿法骨化醇0.5μg，无水乳糖81.5mg，聚维酮K30 2mg，棓丙酯1mg，硬脂酸镁0.4mg，吐温80 0.1mg，无水乙醇 适量
制备方法：1)将阿法骨化醇溶解于无水乙醇中，加入吐温80溶解，得溶液；2)将无水乳糖、聚维酮K30、棓丙酯加入流化床内，通过流化床制粒将步骤1所得溶液喷雾至无水乳糖、聚维酮K30和棓丙酯的混合物中，喷液完成后在流化床内混合均匀，获得湿颗粒；3)将湿颗粒置于烘箱中，40～45℃干燥2h，得干燥颗粒；4)干燥颗粒过20目筛整粒，加入硬脂酸镁，混合均匀，压片，即得。
实施例21阿法骨化醇片的制备
单剂量处方：
阿法骨化醇0.5μg，无水乳糖81.5mg，聚维酮K30 2mg，BHT 1mg，硬脂富马酸钠0.4mg，聚氧乙烯硬脂酸酯0.1mg，无水乙醇 适量
制备方法：1)将阿法骨化醇溶解于无水乙醇中，加入聚氧乙烯硬脂酸酯溶解，再加入聚维酮K30、BHT，得到溶液；2)将无水乳糖加入流化床内，通过流化床制粒将步骤1所得溶液喷雾至无水乳糖中，喷液完成后在流化床内混合均匀，获得湿颗粒；3)将湿颗粒直接在流化床中进行干燥，35～40℃干燥3h，得干燥颗粒；5)干燥颗粒过24目筛整粒，加入硬脂富马酸钠，混合均匀，压片，即得。
实施例22阿法骨化醇片的制备
单剂量处方：
阿法骨化醇0.5μg，无水乳糖81.55mg，聚维酮K30 2mg，DL-α-生育酚2mg，硬脂酸镁0.4mg，聚氧乙烯(40)氢化蓖麻油0.1mg，无水乙醇 适量
制备方法：1)将阿法骨化醇溶解于无水乙醇中，加入聚氧乙烯(40)氢化蓖麻油溶解，再加入聚维酮K30、DL-α-生育酚，得到溶液；2)将无水乳糖加入流化床内，通过流化床制粒将步骤1所得溶液喷雾至无水乳糖中，喷液完成后在流化床内混合均匀，获得湿颗粒；3)将湿颗粒直接在流化床中进行干燥，30～35℃干燥3h，得干燥颗粒；5)干燥颗粒过24目筛整粒，加入硬脂酸镁，混合均匀，压片，即得。
实施例23艾地骨化醇片的制备
单剂量处方：
艾地骨化醇0.75μg，无水乳糖82.6mg，聚维酮K30 1mg，棓丙酯1mg，硬脂酸镁0.4mg，无水乙醇 适量
制备方法：1)将艾地骨化醇溶解于无水乙醇中，加入聚维酮K30、棓丙酯溶解，得到溶液；2)将无水乳糖加入流化床内，通过流化床制粒将步骤1所得溶液喷雾至无水乳糖中，喷液完成后在流化床内混合均匀，获得湿颗粒；3)将 湿颗粒烘箱中进行干燥，40～45℃干燥2h，得干燥颗粒；5)干燥颗粒过20目筛整粒，加入硬脂酸镁，混合均匀，压片，即得。
实施例24艾地骨化醇片的制备
单剂量处方：
艾地骨化醇0.5μg，无水乳糖83.1mg，聚维酮K30 0.5mg，BHT 1mg，聚氧乙烯硬脂酸酯0.1mg，硬脂富马酸钠0.4mg，无水乙醇 适量
制备方法：1)将艾地骨化醇溶解于无水乙醇中，加入聚氧乙烯硬脂酸酯、聚维酮K30、BHT溶解，得到溶液；2)将无水乳糖加入流化床内，通过流化床制粒将步骤1所得溶液喷雾至无水乳糖中，喷液完成后在流化床内混合均匀，获得湿颗粒；3)将湿颗粒烘箱中进行干燥，35～40℃干燥3h，得干燥颗粒；5)干燥颗粒过20目筛整粒，加入硬脂富马酸钠，混合均匀，压片，即得。
实施例25艾地骨化醇片的制备
单剂量处方：
艾地骨化醇0.5μg，无水乳糖82.4mg，聚维酮K30 1mg，BHT 1mg，硬脂酸镁0.4mg，吐温80 0.2mg，无水乙醇 适量
制备方法：1)将艾地骨化醇溶解于无水乙醇中，加入吐温80溶解，再加入聚维酮K30、BHT，得到溶液；2)将无水乳糖加入流化床内，通过流化床制粒将步骤1所得溶液喷雾至无水乳糖中，喷液完成后在流化床内混合均匀，获得湿颗粒；3)将湿颗粒直接在流化床中进行干燥，35～40℃干燥2h，得干燥颗粒；5)干燥颗粒过20目筛整粒，加入硬脂酸镁，混合均匀，压片，即得。
实施例26骨化三醇片的制备
单剂量处方：
骨化三醇0.5μg，一水乳糖70mg，甘露醇12.6mg，BHT 0.5mg，BHA0.5mg，硬脂酸镁0.4mg，聚氧乙烯硬脂酸酯0.2mg，聚氧乙烯(40)氢化蓖麻油0.2mg，聚维酮K30 1mg，无水乙醇 适量
制备方法：1)将骨化三醇溶解于无水乙醇中，加入聚氧乙烯硬脂酸酯、聚氧乙烯(40)氢化蓖麻油溶解，再加入聚维酮K30、BHT、BHA，得到溶液；2) 将一水乳糖、甘露醇加入流化床内，通过流化床制粒将步骤1所得溶液喷雾至无水乳糖中，喷液完成后在流化床内混合均匀，获得湿颗粒；3)将湿颗粒直接在流化床中进行干燥，35～40℃干燥2h，得干燥颗粒；5)干燥颗粒过20目筛整粒，加入硬脂酸镁，混合均匀，压片，即得。
实施例27骨化三醇片的制备
单剂量处方：
骨化三醇1μg，无水乳糖70mg，山梨糖醇13.1mg，棓丙酯1mg，硬脂酸镁0.4mg，聚氧乙烯硬脂酸酯0.4mg，羟丙甲纤维素0.5mg，无水乙醇 适量
制备方法：1)将骨化三醇溶解于无水乙醇中，加入聚氧乙烯硬脂酸酯溶解，再加入羟丙甲纤维素、棓丙酯，得到溶液；2)将无水乳糖、山梨糖醇加入流化床内，通过流化床制粒将步骤1所得溶液喷雾至无水乳糖中，喷液完成后在流化床内混合均匀，获得湿颗粒；3)将湿颗粒直接在流化床中进行干燥，35～40℃干燥2h，得干燥颗粒；5)干燥颗粒过20目筛整粒，加入硬脂酸镁，混合均匀，压片，即得。
实施例28骨化三醇片的制备
单剂量处方：
骨化三醇3μg，无水乳糖70mg，甘露醇13.4mg，DL-α-生育酚1mg，硬脂酸镁0.4mg，吐温80 0.4mg，聚维酮K30 0.6mg，无水乙醇 适量
制备方法：1)将骨化三醇溶解于无水乙醇中，加入吐温80溶解，再加入聚维酮K30、DL-α-生育酚，得到溶液；2)将无水乳糖、甘露醇加入流化床内，通过流化床制粒将步骤1所得溶液喷雾至无水乳糖中，喷液完成后在流化床内混合均匀，获得湿颗粒；3)将湿颗粒直接在流化床中进行干燥，35～40℃干燥2h，得干燥颗粒；5)干燥颗粒过20目筛整粒，加入硬脂酸镁，混合均匀，压片，即得。
试验例1吐温80对阿法骨化醇的在溶液中稳定性作用
分别配制含吐温和不含吐温的阿法骨化醇溶液，至于40℃条件下，每隔1h取样检测其前体物。
Figure PCTCN2019085213-appb-000001
以上结果表明，吐温80的加入对于阿法骨化醇溶液，可增加阿法骨化醇稳定性，在溶液配制和溶液缓慢加至挤出机中的过程中可保持更好的稳定性，抑制降解产物的生成。
试验例2表面活性剂的加入对阿法骨化醇片的稳定性影响
将实施例1～5所制得的阿法骨化醇片的裸片在温度40℃、相对湿度75％RH条件下裸片敞口放置，于不同天数的时间点取样，检测其降解产物的含量。其中实施例1片含有吐温0.1mg，实施例2片不添加吐温，实施例3片中含有吐温0.2mg，实施例4片含有0.1mg聚氧乙烯硬脂酸酯，实施例5片含有0.1mg聚氧乙烯(40)氢化蓖麻油。“N.D.”是指“未检测到”。本试验例中降解产物是指阿法骨化醇的1β型杂质，即化学名(5Z，7E)-9，10-开环胆甾-5，7，10(19)-三烯-1β，3β-二醇。
Figure PCTCN2019085213-appb-000002
以上结果表明，表面活性剂的加入能够抑制阿法骨化醇片在加速试验条件下产生降解产物1β型杂质的速率，提高阿法骨化醇片的存储稳定性。
试验例3表面活性剂的加入对骨化三醇片的稳定性影响
将实施例13～17所制得的骨化三醇片的裸片在温度40℃、相对湿度75％RH条件下裸片敞口放置，于不同天数的时间点取样，检测降解产物的含量。其中实施例13片含有总量0.4mg的聚氧乙烯硬脂酸酯与聚氧乙烯(40)氢化蓖麻油的组合，实施例14片含有0.4mg的聚氧乙烯硬脂酸酯，实施例15和实施例17片中含有吐温0.4mg，实施例16片中不添加表面活性剂。“N.D.”是指“未检测到”。本试验例中降解产物是骨化三醇的1β型杂质，即化学名(5Z，7E)-9，10-开环胆甾-5，7，10(19)-三烯-1β，3β，25-三醇。
Figure PCTCN2019085213-appb-000003
以上结果表明，表面活性剂的加入能够抑制骨化三醇片在加速试验条件下产生降解产物的速率，提高骨化三醇片存储稳定性。
试验例4阿法骨化醇片的含量均匀度的对比试验
本试验例以阿法骨化醇片的制备工艺为关注点，着重考察不同制备工艺对阿法骨化醇片中主药的含量均匀度的影响。
Figure PCTCN2019085213-appb-000004
以上结果表明，实施例18是采用等量递增法的传统湿法制粒工艺，实施 例19是运用比实施例18改进过的，即高速剪切混合造粒法。实施例1～3使用的双螺杆技术制粒法所得片的含量均匀度十分符合中国药典的规定，且明显优于前两种工艺和设备所得片剂。
试验例5混合时间的考察
避免影响最终产品的均匀度，还需对辅料混合均匀性进行考察。将处方量的填充剂、粘合剂、抗氧化剂等加入至混合制粒机进行混合，另外加入标记物。考察在搅拌转速5r/s、剪切速度5r/s时，混合时间3分钟、5分钟和8分钟条件下，物料能否混合均匀。考察物料能否混合均匀是通过在湿法混合制粒机锅体中5个不同取样点的样品中标记物含量来判断，最终测得混合时长达到5分钟后，混粉中各取样点标记物量均匀。
试验例6挤出温度的影响
由于维生素D类似物药物本身的不稳定性因素，已上市产品中前体物含量较高。本公开实验中也发现挤出温度对最终制剂的含量和稳定性有着直接的影响。本公开经过大量实验证实双螺杆挤出机的制粒温度控制在20～25℃，实施例1阿法骨化醇片中前的含量相比于市售阿法骨化醇片有显著降低，具有突出效果。同时，还对样品进行了稳定性放样测试，0至6个月内，其前的含量仍然低于3％。
Figure PCTCN2019085213-appb-000005
试验例7双螺杆挤出制粒过程控制
在双螺杆挤出制粒中，干粉的喂料速度、润湿剂的加液速度(即蠕动泵转 速)和双螺杆的转速三者之间的设定需要相互配合，才能制得合适的湿颗粒，本公开考察了不同的螺杆转速及不同的润湿剂加液速度下，对产品质量的影响。当调节干粉喂料速度为1.0～3kg/hr、蠕动泵转速为2rpm～8rpm、双螺杆转速为100rpm～400rpm时，调节固液比7:1～11:1，优选8.5:1～9:1时，观察制得的颗粒较为均匀、测定挤出物含量均匀。上述转速的相互配合也是为了满足干粉和溶液在挤出机中的停留时间保持在1～3分钟，以达到最佳的制粒效果。
此外，还考察了接料时间，将混合后的物料加入至喂料器中。同时，润湿剂通过蠕动泵与挤出机相连后，按照1.5kg/hr的喂料速度，4.0rpm的加液速度及150rpm的双螺杆挤出速度进行挤出物的制备，挤出开始后2～5分钟接到的物料含量偏高，不符合质量控制要求，造成这种现象的原因主要是前期挤出机中固液比例未调整至平衡态。挤出5分钟后的物料含量正常，符合内控要求。因而在实际操作过程中，应在挤出5分钟后再开始接收物料。
试验例8艾地骨化醇片中抗氧化剂(棓丙酯或DL-α-生育酚)用量对前体含量的影响
试验方法：以本公开实施例6～8的处方举例和制备工艺为基础进行变化，得到用于本试验中的试验例片，其中保持无水乳糖、聚维酮K30、硬脂酸镁的用量保持一致，依次得到不含抗氧化剂、含有不同用量的棓丙酯、含有不同用量的DL-α-生育酚的各个艾地骨化醇片。在温度40℃、相对湿度75％RH条件下，各个裸片敞口放置，于第20天的时间点取样，检测降解产物的含量。
Figure PCTCN2019085213-appb-000006
以上结果表明，当抗氧化剂为棓丙酯或者DL-α-生育酚时，随着其用量增加，艾地骨化醇前体的含量逐渐降低，抑制前体的效果更加明显。这一点跟阿法骨化醇、骨化三醇片的情况有所不同，后两者中抗氧化剂如棓丙酯在一定用量后即对各自前体含量无显著作用，处于相应的前体含量的平衡水平，经推测可能与艾地骨化醇前体在化学分子结构的空间构象上的稳定情况有关。
试验例9阿法骨化醇片、艾地骨化醇片以及骨化三醇片经遮蔽、室温保存12个月后的相应前体和降解产物的测定
在上述使用双螺杆挤出制粒法制备的片剂，所述经遮蔽、室温保存12个月的稳定性试验条件可以选择为，在市售产品包装，例如铝塑泡罩包装下，在25℃±2℃和60％RH±5％RH的环境下保存12个月，取样检测相关数据。
样品 相应的1β型杂质降解产物含量(％) 相应的前体含量(％)
实施例1 0.12 2.8
实施例3 0.07 2.0
实施例4 0.18 3.4
实施例5 0.16 3.0
实施例6 2.2 2.2
实施例7 0.09 1.1
实施例8 0.13 1.2
实施例9 0.19 1.5
实施例10 0.08 1.0
实施例11 0.20 1.2
实施例12 0.23 1.4
实施例13 0.18 2.9
实施例14 0.14 2.5
实施例15 0.10 2.2
实施例17 0.08 1.8
试验例10阿法骨化醇片、艾地骨化醇片以及骨化三醇片经遮蔽、室温保存12个月后的相应前体含量的测定
在上述使用流化床喷雾制粒法制备的片剂中，所述经遮蔽、室温保存12个月的稳定性试验条件可以选择为，在市售产品包装，例如铝塑泡罩包装下，在25℃±2℃和60％RH±5％RH的环境下保存12个月，取样检测相关数据。
Figure PCTCN2019085213-appb-000007
工业实用性
本公开提供了一种维生素D类似物制剂及其制备方法，通过采用双螺杆挤出技术来制备维生素D类似物制剂，使得药物的稳定性显著提高，药品质量大幅改善。

Claims (35)

  1. 一种包含维生素D类似物的组合物，其特征在于，是固体制剂，所述维生素D类似物选自维生素D3、骨化二醇、骨化三醇、阿法骨化醇、艾地骨化醇、度骨化醇、马沙骨化醇、帕立骨化醇、他卡西醇、卡泊三醇中的一种，所述维生素D类似物可选自相应的无水物、水合物或溶剂合物；该固体制剂经遮蔽、室温保存12个月后产生相应的维生素D类似物的前体的量为小于等于7％。
  2. 根据权利要求1所述的组合物，其特征在于，所述固体制剂经遮蔽、室温保存12个月后产生相应的维生素D类似物的前体的量为小于等于5％，优选地，小于等于3％，或更少。
  3. 根据权利要求1或2所述的组合物，其特征在于，所述组合物，是采用如下制粒方法中的一种，进行制备获得的：离心制粒法、高速剪切混合制粒法、滚压制粒法、流化床制粒法、喷雾制粒法、液相中晶析制粒法、熔融制粒法、流化床喷雾制粒法；优选为流化床喷雾制粒法；其中，流化床制粒法按照喷液位置的不同，又可细分为流化床低喷制粒法、流化床侧喷制粒法或流化床顶喷制粒法。
  4. 根据权利要求3所述的组合物，其特征在于，所获得的颗粒的干燥温度是35～50℃，干燥时间0.5～4h，优选地，干燥温度是40～45℃，干燥时间是0.5～2h；并且颗粒的干燥方式是流化床干燥，或烘箱干燥。
  5. 根据权利要求4所述的组合物，其特征在于，所述维生素D类似物是阿法骨化醇；其是采用流化床喷雾制粒法制备获得的。
  6. 根据权利要求4所述的组合物，其特征在于，所述维生素D类似物是艾地骨化醇；其是采用流化床喷雾制粒法制备获得的。
  7. 根据权利要求4所述的组合物，其特征在于，所述维生素D类似物是骨 化三醇；其是采用流化床喷雾制粒法制备获得的。
  8. 根据权利要求1或2所述的组合物，其特征在于，所述组合物，是采用双螺杆挤出制粒法制备获得的，包含如下步骤：
    a)将维生素D类似物溶解于溶剂中，得到溶液，溶剂优选为无水乙醇；该溶液中还可以选择性地加入稳定剂并溶解于该溶液中，或者选择不加入稳定剂；
    b)将其他固体形式的辅料混合均匀，形成干粉；
    c)将上述步骤b所得干粉加入固体喂料器中，将上述步骤a所得溶液通过蠕动泵与挤出机相连；同时调节的设备参数包括干粉喂料速度、蠕动泵转速、双螺杆转速、挤出温度；运行双螺杆挤出机进行制粒，获得湿颗粒；
    d)将湿颗粒干燥，整粒，获得干燥颗粒，即含量高度均匀的维生素D类似物的组合物；
    其中，所述固体形式的辅料包括填充剂、粘合剂、抗氧化剂中的一种或多种；所述稳定剂是对维生素D类似物具有稳定作用，并且能够抑制该维生素D类似物降解为相应的1β型杂质的物质。
  9. 根据权利要求1或2所述的组合物，其特征在于，是固体制剂中的片剂、胶囊剂、颗粒剂或干混悬剂；该固体制剂的组分还包含润滑剂。
  10. 根据权利要求8所述的组合物，其特征在于，该固体制剂是通过将权利要求8所制得的干燥颗粒进一步使用常规制剂技术制备获得的。
  11. 根据权利要求8所述的组合物，其特征在于，其中所述填充剂选自淀粉、预胶化淀粉、玉米淀粉、一水乳糖、无水乳糖、甘露醇、微晶纤维素中的一种或多种；粘合剂选自聚维酮、羟丙甲基纤维素、羟丙基纤维素、羧甲基纤维素钠中的一种或多种；抗氧化剂选自棓丙酯、DL-α-生育酚、二丁基羟基甲 苯(BHT)、丁基羟基茴香醚(BHA)中的一种或多种；润滑剂选自滑石粉、硬脂酸镁、硬脂酸钙、硬脂富马酸钠中的一种或多种；如果需要加入稳定剂时，稳定剂选自吐温、司盘、聚氧乙烯烷基醚、泊洛沙姆188、蔗糖酸硬脂酸酯、聚氧乙烯(35)蓖麻油、聚氧乙烯(40)氢化蓖麻油、聚氧乙烯(20)十八十六烷基醚、聚氧乙烯月桂醚、聚氧乙烯硬脂酸酯中的一种或多种。
  12. 根据权利要求8所述的组合物，其特征在于，颗粒的干燥温度是35～50℃，干燥时间0.5～4h，优选地，干燥温度是40～45℃，干燥时间是0.5～2h；并且颗粒的干燥方式是流化床干燥，或烘箱干燥。
  13. 根据权利要求8所述的组合物，其特征在于，该固体制剂中，填充剂用量为每片50～200mg，优选地，为每片81～83mg；粘合剂用量为每片0.2～3mg，优选地，为每片1.0～2.0mg；润滑剂用量为每片0.1～1mg，优选地，为每片0.4～0.5mg；抗氧化剂用量为每片0.02～2mg，优选地，为每片0.5～1.0mg；稳定剂用量为每片0.02～2mg，优选地，为每片0.1～0.5mg。
  14. 一种包含维生素D类似物的组合物，其特征在于，维生素D类似物是阿法骨化醇，即化学名(5Z，7E)-9，10-开环胆甾-5，7，10(19)-三烯-1α，3β-二醇；该组合物是固体制剂，优选片剂；其包含阿法骨化醇、填充剂、粘合剂、润滑剂、抗氧化剂和稳定剂；其中，加入稳定剂用于抑制阿法骨化醇降解为1β型杂质，即化学名(5Z，7E)-9，10-开环胆甾-5，7，10(19)-三烯-1β，3β-二醇，使得该固体制剂经遮蔽、室温保存12个月后产生的1β型杂质的量为小于等于0.3％，优选地，小于等于0.1％，或更少。
  15. 根据权利要求14所述的组合物，其特征在于，固体制剂是片剂，填充剂选自无水乳糖、一水乳糖、甘露醇、微晶纤维素、蔗糖中的一种或多种，优 选地，为无水乳糖；粘合剂选自聚维酮、羟丙纤维素、羟丙甲纤维素、羧甲基纤维素钠中的一种或多种，优选地，为聚维酮K30；润滑剂选自滑石粉、硬脂酸镁、硬脂酸钙、硬脂富马酸钠中的一种或几种，优选地，为硬脂酸镁；抗氧化剂选自选自棓丙酯、DL-α-生育酚、二丁基羟基甲苯(BHT)、丁基羟基茴香醚(BHA)中的一种或多种；稳定剂选自吐温、司盘、聚氧乙烯烷基醚、泊洛沙姆188、蔗糖酸硬脂酸酯、聚氧乙烯(35)蓖麻油、聚氧乙烯(40)氢化蓖麻油、聚氧乙烯(20)十八十六烷基醚、聚氧乙烯月桂醚、聚氧乙烯硬脂酸酯中的一种或多种；优选地，选自吐温、聚氧乙烯硬脂酸酯、聚氧乙烯(40)氢化蓖麻油中的一种或多种；更优选地，选自吐温。
  16. 根据权利要求14所述的组合物，其特征在于，固体制剂是片剂，填充剂用量为每片50～200mg，优选地，为每片81～83mg；粘合剂用量为每片0.2～3mg，优选地，为每片1.0～2.0mg；润滑剂用量为每片0.1～1mg，优选地，为每片0.4～0.5mg；抗氧化剂用量为每片0.05～2mg，优选地，为每片0.5～1.0mg；稳定剂用量为每片0.02～2mg，优选地，为每片0.1～0.5mg。
  17. 根据权利要求14所述的组合物，其特征在于，是采用双螺杆挤出制粒法制备获得的，且颗粒的干燥温度是35～50℃，干燥时间0.5～5h，优选地，干燥温度是40～45℃，干燥时间是0.5～2h；并且颗粒的干燥方式是流化床干燥，或烘箱干燥。
  18. 根据权利要求14所述的组合物，其特征在于，是阿法骨化醇片剂；其中，填充剂是无水乳糖，粘合剂是聚维酮K30，润滑剂是硬脂酸镁，抗氧化剂是棓丙酯，或是BHT，或是BHT与BHA的组合；稳定剂是吐温80，且吐温80的用量为每片0.02～2mg，优选地，为每片0.1～0.5mg。
  19. 一种抑制在固体制剂中包含的阿法骨化醇降解的方法，所述制剂包含填充剂、粘合剂、润滑剂、抗氧化剂、稳定剂；通过加入稳定剂来抑制阿法骨化醇降解为1β型杂质，即化学名(5Z，7E)-9，10-开环胆甾-5，7，10(19)-三烯-1β，3β-二醇，使得该固体制剂经遮蔽、室温保存12个月后产生的(5Z，7E)-9，10-开环胆甾-5，7，10(19)-三烯-1β，3β-二醇的量为小于等于0.3％，优选地，小于等于0.1％，或更少。
  20. 一种包含维生素D类似物的组合物，其特征在于，维生素D类似物是艾地骨化醇，即化学名(5Z，7E)-(1R，2R，3R)-2-(3-羟基丙氧基)-9,10-断胆甾-5,7,10(19)-三烯-1，3,25-三醇；该组合物是固体制剂，优选片剂；包含艾地骨化醇、填充剂、粘合剂、润滑剂、抗氧化剂；其中，加入抗氧化剂用于抑制艾地骨化醇转变为艾地骨化醇前体，即化学名6Z-(1R，2R，3R)-2-(3-羟基丙氧基)-9，10-断胆甾-5(10)，6，8(9)-三烯-1，3，25-三醇，使得该固体制剂经遮蔽、室温保存12个月后产生的艾地骨化醇前体的量为小于等于7％。
  21. 根据权利要求20所述的组合物，其特征在于，加入抗氧化剂用于抑制艾地骨化醇转变为艾地骨化醇前体，即化学名6Z-(1R，2R，3R)-2-(3-羟基丙氧基)-9，10-断胆甾-5(10)，6，8(9)-三烯-1，3，25-三醇，经遮蔽、室温保存12个月后产生的艾地骨化醇前体的量为小于等于5％，优选地，为小于等于3％，或更少。
  22. 根据权要求20所述的组合物，其特征在于，该固体制剂是片剂，填充剂选自无水乳糖、一水乳糖、甘露醇、微晶纤维素、蔗糖中的一种或多种，优选地，为无水乳糖；粘合剂选自聚维酮、羟丙纤维素、羟丙甲纤维素、羧甲基纤维素钠中的一种或多种，优选地，为聚维酮K30；润滑剂选自滑石粉、硬脂 酸镁、硬脂酸钙、硬脂富马酸钠中的一种或多种，优选地，为硬脂酸镁；抗氧化剂选自棓丙酯、DL-α-生育酚、二丁基羟基甲苯(BHT)、丁基羟基茴香醚(BHA)中的一种或多种。
  23. 根据权利要求22所述的组合物，其特征在于，固体制剂是片剂，填充剂是无水乳糖，粘合剂是聚维酮K30，润滑剂是硬脂酸镁，抗氧化剂是棓丙酯，或是BHT，或是BHT与BHA的组合。
  24. 根据权利要求20所述的组合物，其特征在于，填充剂用量为每片50～200mg，优选地，为每片80～84mg；粘合剂用量为0.2～3mg，优选地，为每片0.4～0.5mg；润滑剂用量为每片0.1～1mg，优选地，为每片0.4～0.5mg；抗氧化剂用量为0.05～2mg，优选地，选自每片0.5～1.0mg。
  25. 根据权利要求20所述的组合物，其特征在于，该固体制剂中还包含稳定剂，稳定剂选自吐温、司盘、聚氧乙烯烷基醚、泊洛沙姆188、蔗糖酸硬脂酸酯、聚氧乙烯(35)蓖麻油、聚氧乙烯(40)氢化蓖麻油、聚氧乙烯(20)十八十六烷基醚、聚氧乙烯月桂醚、聚氧乙烯硬脂酸酯中的一种或多种；优选地，选自吐温、聚氧乙烯硬脂酸酯、聚氧乙烯(40)氢化蓖麻油中的一种或多种；更优选地，选自吐温；其中，加入稳定剂用于抑制艾地骨化醇降解为其1β型杂质，即化学名(5Z，7E)-(1S，2R，3R)-2-(3-羟基丙氧基)-9,10-断胆甾-5,7,10(19)-三烯-1，3,25-三醇，使得该固体制剂经遮蔽、室温保存12个月后产生的1β型杂质的量为小于等于0.3％，优选地，小于等于0.1％，或更少。
  26. 根据权利要求24或25所述的组合物，其特征在于，该固体制剂是片剂，填充剂是无水乳糖，粘合剂是聚维酮K30，润滑剂是硬脂酸镁，抗氧化剂是棓丙酯，或是BHT，或是BHT与BHA的组合；稳定剂是吐温80，且吐温80 的用量为每片0.02～2mg，优选地，为每片0.1～0.5mg。
  27. 根据权利要求20所述的组合物，其特征在于，该固体制剂是采用双螺杆挤出制粒法制备获得的，且颗粒的干燥温度是35～50℃，干燥时间0.5～5h，优选地，干燥温度是40～45℃，干燥时间是0.5～2h，且颗粒的干燥方式是流化床干燥，或烘箱干燥。
  28. 一种抑制在固体制剂中包含的艾地骨化醇转变为艾地骨化醇前体的方法，所述制剂包含填充剂、粘合剂、润滑剂、抗氧化剂；通过加入抗氧化剂来抑制艾地骨化醇转变为艾地骨化醇前体，即化学名6Z-(1R，2R，3R)-2-(3-羟基丙氧基)-9，10-断胆甾-5(10)，6，8(9)-三烯-1，3，25-三醇，使得该固体制剂在遮蔽、室温保存12个月后产生的6Z-(1R，2R，3R)-2-(3-羟基丙氧基)-9，10-断胆甾-5(10)，6，8(9)-三烯-1，3，25-三醇的量为小于等于3％，或更少。
  29. 一种抑制在固体制剂中包含的艾地骨化醇降解为艾地骨化醇1β型杂质的方法，所述制剂包含填充剂、粘合剂、润滑剂、抗氧化剂、稳定剂；通过加入稳定剂来抑制艾地骨化醇降解为艾地骨化醇1β型杂质，即化学名(5Z，7E)-(1S，2R，3R)-2-(3-羟基丙氧基)-9,10-断胆甾-5,7,10(19)-三烯-1，3,25-三醇，使得该固体制剂经遮蔽、室温保存12个月后产生的1β型杂质的量为小于等于0.3％，优选地，小于等于0.1％，或更少。
  30. 一种包含维生素D类似物的组合物，其特征在于，维生素D类似物是骨化三醇，即化学名(5Z，7E)-9，10-开环胆甾-5，7，10(19)-三烯-1α，3β，25-三醇；该组合物是固体制剂，优选片剂；包含骨化三醇、填充剂、粘合剂、润滑剂、抗氧化剂、稳定剂；其中，加入稳定剂用于抑制骨化三醇降解为1β型杂质，即化学名(5Z，7E)-9，10-开环胆甾-5，7，10(19)-三烯-1β，3 β，25-三醇，使得该固体制剂经遮蔽、室温保存12个月后产生的1β型杂质的量为小于等于0.3％，优选地，小于等于0.1％，或更少。
  31. 根据权利要求30所述的组合物，其特征在于，所述填充剂选自无水乳糖、一水乳糖、甘露醇、微晶纤维素、蔗糖中的一种或多种，优选地，为无水乳糖；粘合剂选自聚维酮、羟丙纤维素、羟丙甲纤维素、羧甲基纤维素钠中的一种或多种，优选地，为聚维酮K30；润滑剂选自滑石粉、硬脂酸镁、硬脂酸钙、硬脂富马酸钠中的一种或几种，优选地，为硬脂酸镁；抗氧化剂选自选自棓丙酯、DL-α-生育酚、二丁基羟基甲苯(BHT)、丁基羟基茴香醚(BHA)中的一种或多种；稳定剂选自吐温、司盘、聚氧乙烯烷基醚、泊洛沙姆188、蔗糖酸硬脂酸酯、聚氧乙烯(35)蓖麻油、聚氧乙烯(40)氢化蓖麻油、聚氧乙烯(20)十八十六烷基醚、聚氧乙烯月桂醚、聚氧乙烯硬脂酸酯中的一种或多种；优选地，选自吐温、聚氧乙烯硬脂酸酯、聚氧乙烯(40)氢化蓖麻油中的一种或多种，更优选地，选自吐温。
  32. 根据权利要求31所述的组合物，其特征在于，固体制剂是片剂，填充剂是无水乳糖，粘合剂是聚维酮K30，抗氧化剂是棓丙酯，或二丁基羟基甲苯(BHT)，或二丁基羟基甲苯(BHT)与丁基羟基苯甲醚(BHA)的组合；稳定剂是吐温80，或聚氧乙烯硬脂酸酯；润滑剂是硬脂酸镁，或硬脂富马酸钠。
  33. 根据权利要求30所述的组合物，其特征在于，固体制剂是片剂，填充剂用量为每片50～200mg，优选地，为每片81～83mg；粘合剂用量为每片0.2～3mg，优选地，为每片1.0～2.0mg；润滑剂用量为每片0.1～1mg，优选地，为每片0.4～0.5mg，抗氧化剂用量为每片0.05～2mg，优选地，为每片0.5～1.0mg；稳定剂用量为每片0.02～2mg，优选地，为每片0.1～0.5mg。
  34. 根据权利要求30所述的组合物，其特征在于，是采用双螺杆挤出制粒法制备获得的，且颗粒的干燥温度是35～50℃，干燥时间0.5～5h，优选地，干燥温度是40～45℃，干燥时间是0.5～2h，且颗粒的干燥方式是流化床干燥，或烘箱干燥。
  35. 一种抑制在固体制剂中包含的骨化三醇降解的方法，所述制剂包含填充剂、粘合剂、润滑剂、抗氧化剂、稳定剂；通过加稳定剂来抑制骨化三醇降解为1β型杂质，即化学名(5Z，7E)-9，10-开环胆甾-5，7，10(19)-三烯-1β，3β，25-三醇，使得该固体制剂在遮蔽、室温保存12个月后产生的(5Z，7E)-9，10-开环胆甾-5，7，10(19)-三烯-1β，3β，25-三醇的量为小于等于0.3％，优选地，小于等于0.1％，或更少。
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