CN114948878B - Parcalcitol solid composition and preparation method and application thereof - Google Patents

Parcalcitol solid composition and preparation method and application thereof Download PDF

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CN114948878B
CN114948878B CN202110187994.2A CN202110187994A CN114948878B CN 114948878 B CN114948878 B CN 114948878B CN 202110187994 A CN202110187994 A CN 202110187994A CN 114948878 B CN114948878 B CN 114948878B
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paricalcitol
parts
solid composition
preparation
polymer
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CN114948878A (en
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满艳哲
赵京华
程思奇
孔华
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Corbeille Park Beijing Medical Technology Co ltd
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Corbeille Park Beijing Medical Technology Co ltd
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    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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    • 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
    • A61K31/592—9,10-Secoergostane derivatives, e.g. ergocalciferol, i.e. vitamin D2
    • 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
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A61P5/16—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4 for decreasing, blocking or antagonising the activity of the thyroid hormones

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Abstract

The invention discloses a paricalcitol solid composition, and a preparation method and application thereof. Mixing the mixture of paricalcitol and the polymer with other pharmaceutical excipients to prepare the solid composition; wherein the mixture of paricalcitol and the polymer is prepared by hot melt extrusion. In the solid composition, paricalcitol exists in an amorphous state, and the medicine is dissolved rapidly and has good stability. The invention also provides an oral preparation containing the solid composition, which has simple preparation process, no use of any organic solvent, very rapid dissolution and good stability under proper packaging conditions.

Description

Parcalcitol solid composition and preparation method and application thereof
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a paricalcitol solid composition, and a preparation method and application thereof.
Background
Parycalcitol formula C 27 H 44 O 3 The molecular weight is 416.636, and the structural formula is shown as follows:
paricalcitol is a white powder, insoluble in water, soluble in most polar solvents, such as: diethyl ether, methanol, ethanol, and the like. Parcalcitol is relatively sensitive to pH, oxygen, but not to temperature.
Parcalcitol was originally developed by ABBVEE (Atban), and its injectable formulation was marketed in the United states at 4 months 17 of 1998, and FDA approved Parcalcitol Soft Capsule was marketed in 2005 under the trade name Zemplar in 1 μg, 2 μg and 4 μg specifications. Currently, paricalcitol soft capsules are marketed in the uk, swiss and other countries. Parcalcitol is an artificially synthesized vitamin D analogue with biological activity, and calcitriol side chain (D2) and A ring (19-nor) are modified. Preclinical studies and in vitro experimental studies have shown that paricalcitol needs to elicit a biological effect through selective activation of the vitamin D response pathway by binding to Vitamin D Receptor (VDR). Vitamin D and paricalcitol can reduce parathyroid hormone (PTH) levels by inhibiting synthesis and secretion of PTH.
The soft capsule and injection of paricalcitol on the market at present contain a large amount of organic solvents and/or antioxidants, the prescription and the process are complex, the stability of the preparation is poor, for example, the capsule shell has high requirements on the environment in the storage process of the soft capsule, and the capsule shell is dehydrated and aged under the drying condition to influence the disintegration time; when the humidity is high, the capsule shell absorbs water and adheres to the skin, so that the integrity of the preparation is affected when the medicine is taken. The injection is inconvenient to administer and needs to be administered under the nursing of medical staff. In addition, the organic solvent in the preparation can bring side effects such as vascular irritation and the like. Because of the unstable nature of paricalcitol itself and its hygroscopicity, it is difficult to obtain an oral formulation using conventional methods.
Patent document CN110974797a discloses a preparation method of a paricalcitol enteric capsule, in which the preparation method indicates that the paricalcitol bulk drug and the filler are uniformly mixed, but the proportion of the bulk drug and the filler in the prescription is 0.00002% (55-65)%, the dosage of the bulk drug and the filler is greatly different, even if an equal progressive method is adopted, the mixing uniformity of the bulk drug is still difficult to control, and the preparation process is complex. Patent document CN104162168B discloses a method for preparing a pharmaceutical composition of paricalcitol by adopting cyclodextrin inclusion and freeze drying, wherein the method comprises the steps of adding the paricalcitol serving as a raw material into cyclodextrin aqueous solution, stirring until the solution is clear and transparent, forming a paricalcitol cyclodextrin inclusion compound, adding a stabilizer (framework material), then placing the mixture into a freeze dryer for freeze drying, crushing the freeze-dried mixture, adding other auxiliary materials for dry granulation, and placing the mixture into a vacuum dryer for tabletting and packaging. Although the method overcomes the defects that the main medicine paricalcitol is very easy to absorb moisture, has very poor stability and is difficult to prepare into an oral preparation, the preparation process needs freeze drying, the time consumption is long, dry granulation is also needed after freeze drying, and the whole preparation process is complex.
Disclosure of Invention
In order to solve the above-mentioned problems occurring in the prior art, the present invention provides a solid composition of paricalcitol, comprising: the active ingredients are paricalcitol and pharmaceutic adjuvant, and the pharmaceutic adjuvant at least contains a polymer.
According to an embodiment of the invention, the polymer is selected from one, two or a mixture of three of polyvinyl alcohol, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and hydroxypropyl cellulose (HPC); preferably polyvinyl alcohol.
For example, the polymer is a polyvinyl alcohol having a weight average molecular weight of less than 50000, exemplary being selected from the following types of polyvinyl alcohols: PVA 4-88 and/or PVA 5-88.
For another example, the polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer may be
According to an embodiment of the invention, the weight ratio of paricalcitol to polymer in the solid composition is 1 (500-25000), such as 1 (1000-20000), preferably 1 (1200-10000), more preferably 1 (1500-5000); exemplary are 1:1000, 1:2000, 1:3000, 1:4000, 1:5000, 1:7500, 1:10000, 1:15000.
According to an embodiment of the present invention, the solid composition may be in the form of a block, a tablet, a bar, a powder, or the like.
According to an embodiment of the invention, in the solid composition, paricalcitol is present in amorphous form, not in crystalline form.
According to an embodiment of the invention, in the solid composition, paricalcitol is present in solid form, not in liquid form.
Preferably, in the solid composition, paricalcitol is present in a solid amorphous form.
According to an embodiment of the present invention, the pharmaceutical excipients may further include one, two or more of a filler, a disintegrant, a lubricant, a flavoring agent, and the like.
According to an embodiment of the present invention, the filler may be selected from one, two or more of microcrystalline cellulose, lactose, mannitol, starch and dextrin; preferably, one, two or more of microcrystalline cellulose, lactose and mannitol, more preferably microcrystalline cellulose and/or mannitol, and most preferably microcrystalline cellulose.
According to an embodiment of the present invention, the disintegrant may be selected from one, two or more of sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low substituted hydroxypropylcellulose (L-HPC) and corn starch; preferably one, two or three of sodium carboxymethyl starch, croscarmellose sodium and low substituted hydroxypropyl cellulose, more preferably sodium carboxymethyl starch and/or croscarmellose sodium, and most preferably sodium croscarmellose.
According to an embodiment of the present invention, the lubricant is selected from one, two or more of talc, magnesium stearate, stearic acid, polyethylene glycol and sodium stearyl fumarate, exemplified by magnesium stearate.
According to an embodiment of the present invention, the flavoring agent may be selected from one, two or more selected from the group consisting of sweeteners and flavoring agents known in the art, and the like.
According to an embodiment of the present invention, the pharmaceutical excipients in the solid composition include the above-mentioned polymer, filler, disintegrant and lubricant.
According to an embodiment of the present invention, the solid composition contains, in parts by weight, 0.0004 to 0.01 parts, for example, 0.001 to 0.008 parts, illustratively 0.001 parts, 0.002 parts, 0.003 parts, 0.004 parts, 0.005 parts, 0.006 parts, 0.007 parts, 0.008 parts, 0.009 parts, 0.01 parts of paricalcitol.
According to an embodiment of the present invention, the solid composition contains 1 to 50 parts, for example 5 to 40 parts, and for example 7 to 25 parts, and exemplified by 1 part, 3 parts, 5 parts, 7 parts, 10 parts, 15 parts, 20 parts, 25 parts, 30 parts, 35 parts, 40 parts, 45 parts, 50 parts of the polymer in parts by weight.
According to an embodiment of the present invention, the solid composition contains 0 to 1 part, for example, 0.01 to 0.8 part, and further, for example, 0.1 to 0.6 part, and exemplified by 0.01 part, 0.05 part, 0.1 part, 0.2 part, 0.5 part, 0.7 part, and 0.9 part of the lubricant in parts by weight.
According to an embodiment of the present invention, the solid composition contains 1 to 10 parts, for example 2 to 8 parts, exemplified by 1 part, 2 parts, 3 parts, 4 parts, 5 parts, 6 parts, 7 parts, 8 parts, 9 parts, 10 parts of the disintegrant in parts by weight.
According to an embodiment of the present invention, the solid composition contains 15 to 90 parts, for example 30 to 88 parts, exemplified by 15 parts, 20 parts, 25 parts, 30 parts, 40 parts, 50 parts, 60 parts, 70 parts, 80 parts, 85 parts, 86 parts, 90 parts of filler in parts by weight.
According to a preferred embodiment of the present invention, the solid composition contains, in parts by weight, 0.002 to 0.01 part of paricalcitol, 0.1 to 50 parts of a polymer, 0.1 to 0.6 part of a lubricant, 1 to 10 parts of a disintegrant and 30 to 90 parts of a filler.
According to an embodiment of the present invention, the solid composition contains, in parts by weight, 0.002 to 0.01 part of paricalcitol, 1 to 20 parts of a polymer, 0.1 to 0.5 part of a lubricant, 2 to 8 parts of a disintegrant, and 40 to 90 parts of a filler.
According to an exemplary embodiment of the present invention, the solid composition contains, in parts by weight, 0.002 to 0.01 part of paricalcitol, 0.1 to 50 parts of polyvinyl alcohol, 0.1 to 0.6 part of magnesium stearate, 1 to 10 parts of croscarmellose sodium and 30 to 90 parts of microcrystalline cellulose.
According to an exemplary embodiment of the present invention, the solid composition contains, in parts by weight, 0.002 to 0.01 part of paricalcitol, 1 to 20 parts of polyvinyl alcohol, 0.1 to 0.5 part of magnesium stearate, 2 to 8 parts of croscarmellose sodium and 40 to 90 parts of microcrystalline cellulose.
According to an exemplary embodiment of the present invention, the solid composition contains, in parts by weight, 0.002 to 0.005 part of paricalcitol, 3 to 10 parts of polyvinyl alcohol, 0.1 to 0.5 part of magnesium stearate, 3 to 8 parts of croscarmellose sodium and 60 to 90 parts of microcrystalline cellulose.
According to an exemplary embodiment of the present invention, the solid composition contains, in parts by weight, 0.002 parts of paricalcitol, 7 parts of polyvinyl alcohol, 0.5 parts of magnesium stearate, 6 parts of croscarmellose sodium and 86.5 parts of microcrystalline cellulose.
The invention also provides a preparation method of the solid composition, which comprises the following steps: mixing the mixture of paricalcitol and the polymer with other pharmaceutical excipients to prepare the solid composition; wherein the mixture of paricalcitol and the polymer is prepared by hot melt extrusion.
According to an embodiment of the present invention, the heating temperature of the hot melt extrusion may be 100 to 300 ℃, preferably 120 to 250 ℃, more preferably 150 to 200 ℃, and exemplified by 100 ℃, 150 ℃, 170 ℃,200 ℃, 220 ℃, 280 ℃.
According to an embodiment of the present invention, the hot melt extrusion may be performed in an extruder. For example, the extruder is selected from a single screw extruder, a intermeshing screw extruder or other multi-screw extruder, preferably a twin screw extruder, which can be co-or counter-rotating and (optionally) equipped with kneading units to maximize the extrusion of the extruded material. An example is a twin screw extruder from Thermo Scientific.
According to an embodiment of the invention, the rotational speed of the hot melt extrusion is 100-300rpm, for example 120-250rpm, and exemplary 150rpm.
According to an embodiment of the present invention, the process for preparing the mixture of paricalcitol and polymer comprises: dissolving paricalcitol in a solvent, uniformly mixing the obtained paricalcitol solution with a polymer, drying to remove the solvent, and carrying out hot melt extrusion on the dried mixture to obtain the mixture of the paricalcitol and the polymer.
Preferably, the solvent is selected from one, two or more of water, ethanol, glycerol, acetone, and the like.
Preferably, the mixing process of the paricalcitol solution and the polymer comprises: the solution of paricalcitol is sprayed into the polymer and then mixed with high shear. For example, conditions of high shear mixing include: the rotating speed of the horizontal paddle is 250-500rpm, and the rotating speed of the shearing blade is 1200-1800rpm; preferably, the rotation speed of the horizontal paddles is 300rpm and the rotation speed of the shearing blades is 1500rpm.
According to an embodiment of the present invention, the other pharmaceutical excipients may be selected from one, two or more of a filler, a disintegrant, a lubricant, a flavoring agent, and the like.
According to an embodiment of the invention, the polymer and other pharmaceutical excipients have the options and amounts as described above.
According to an embodiment of the present invention, the mixture of paricalcitol and polymer is preferably pulverized and then sieved before being mixed with other pharmaceutical excipients.
According to an embodiment of the present invention, the method for preparing a solid composition further comprises: mixing the mixture of paricalcitol and polymer with other pharmaceutical excipients, and granulating, tabletting, briquetting, layering or pulverizing to obtain solid composition in the form of granule, tablet, block, strip, powder, etc.
According to an exemplary embodiment of the present invention, the method for preparing the paricalcitol solid composition comprises the following steps:
(1) Dissolving paricalcitol in a solvent to obtain a solution of paricalcitol, spraying the solution into a polymer, shearing and mixing at a high speed, and drying to remove the solvent; hot-melt extrusion is carried out on the dried mixture, the heating temperature of the hot-melt extrusion is 100-300 ℃, and the mixture of paricalcitol and polymer is obtained;
(2) And mixing the paricalcitol and polymer mixture with other pharmaceutical excipients to prepare the solid composition.
Wherein the polymer and other pharmaceutical excipients have the above selections and amounts; the paricalcitol has the amounts as indicated above.
The invention also provides a solid composition of paricalcitol prepared by the method.
The invention also provides application of the solid composition in preparation of paricalcitol preparation, preferably in preparation of paricalcitol solid preparation.
The invention also provides a paricalcitol preparation which comprises the solid composition.
According to an embodiment of the invention, the paricalcitol formulation is an oral formulation, such as a tablet, capsule, granule, powder, lozenge or the like, preferably a tablet.
According to an embodiment of the invention, the paricalcitol formulation has the following in vitro dissolution profile: the cumulative dissolution of paricalcitol reaches more than 70% in 30 minutes; preferably, the cumulative dissolution of paricalcitol reaches more than 80% at 30 minutes; more preferably, the cumulative dissolution of paricalcitol reaches more than 90% at 30 minutes.
The invention also provides application of the solid composition and/or the preparation in preparing medicines for preventing and/or treating Secondary Hyperparathyroidism (SHPT).
Advantageous effects
In order to improve the physical and chemical stability and the solubility of the paricalcitol and combine the characteristic that the paricalcitol is insensitive to temperature, the invention adopts a hot-melt extrusion method to prepare the mixture of the paricalcitol and the polymer carrier, and then the mixture is mixed with other auxiliary materials to prepare the paricalcitol solid preparation. The paricalcitol raw material medicine is sprayed on a polymer carrier after being dissolved, and the mixing uniformity of the raw material medicine in the preparation is improved to a great extent through high-shear mixing, so that the preparation is very suitable for the preparation with extremely low specification of active ingredients.
The paricalcitol in the solid composition and the preparation exists in an amorphous state, the dissolution speed is high, and the solubility of the active ingredient is improved, so that the oral bioavailability of the paricalcitol is improved; the preparation is preferably tablet, so that the stability of the preparation is improved, and the administration of patients is convenient.
In addition, in the solid composition and the preparation, the raw material medicines can be uniformly mixed, and the process is simple and easy for mass production.
Drawings
Fig. 1 shows the powder diffraction pattern of the paricalcitol drug substance.
Fig. 2 shows a powder diffraction pattern of the solid dispersion of example 1.
Fig. 3 shows a powder diffraction pattern of polyvinyl alcohol.
Detailed Description
The technical scheme of the invention will be further described in detail below with reference to specific embodiments. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the invention. All techniques implemented based on the above description of the invention are intended to be included within the scope of the invention.
Unless otherwise indicated, the starting materials and reagents used in the following examples were either commercially available or may be prepared by known methods.
Example 1
The prescription is as follows:
the preparation process comprises the following steps:
parycalciferol is dissolved in 5ml of ethanol and sprayed into a carrier polymer polyvinyl alcohol MXP, in order to improve the mixing uniformity, the materials are placed in a high-shear mixer, the rotating speed of a horizontal paddle is set at 300rpm, the rotating speed of a cutter is set at 1500rpm, the high-speed shearing is carried out for 5min, and the ethanol is removed after mixing and drying (60 ℃ for 0.5 h). And (3) placing the dried mixture of the medicine and the carrier polyvinyl alcohol MXP in a hot-melt extruder, setting the heating temperature to 200 ℃ and the rotating speed to 150rpm, and extruding to obtain yellowish transparent solid dispersion. And (3) after the solid dispersion is cooled, putting the solid dispersion into a pulverizer, pulverizing, sieving with a 60-mesh sieve, taking a sample below the sieve, adding the microcrystalline cellulose, the croscarmellose sodium and the magnesium stearate with the prescribed amount, mixing, and tabletting to obtain the paricalcitol-containing composition tablet. Meanwhile, double aluminum packages are selected, and paricalcitol tablets are packaged.
And detecting and researching stability of the obtained paricalcitol tablet.
(1) Content uniformity detection:
samples were obtained according to the recipe and preparation method of example 1, 10 samples from the batch were selected for testing, and the uniformity of the active ingredient content of the samples from the batch was examined.
HPLC detection method:
chromatographic column: c18 250mm 4.6mm 5 μm;
mobile phase: water-acetonitrile (volume ratio 45:55);
flow rate: 1.0ml/min;
wavelength: 252nm.
Table 1 example 1 results of measuring uniformity of content of active ingredient in the formulation
The content uniformity detection result shows that: by adopting the method of the embodiment, the raw material medicine and the auxiliary materials can be uniformly mixed, and the content uniformity of the raw material medicine in the obtained sample is good.
(2) Related substance detection
The detection of substances on the paricalcitol tablet and the paricalcitol bulk drug prepared in example 1 is carried out by HPLC detection method:
chromatographic column: c18 250mm 4.6mm 5 μm;
mobile phase: water-acetonitrile (volume ratio 45:55);
flow rate: 1.0ml/min;
wavelength: 252nm.
TABLE 2 comparison of the test results of substances related to the prescription of example 1 with crude drugs
Sample name Maximum mono-hetero (%) Total impurity (%)
Bulk drug 0.078 0.078
EXAMPLE 1 Parcalcitol tablet 0.048 0.048
The detection results of related substances show that compared with the bulk drug, the paricalcitol tablet prepared by the process has no increase of related substances, which indicates that the bulk drug has no degradation in the preparation process by the process.
(3) Dissolution profile
The dissolution method comprises the following steps: basket method (first method of measuring dissolution and release of the four general rules 0931 of the year 2020 edition of Chinese pharmacopoeia), 100rpm, dissolution medium: 500ml of a 0.4% solution of dodecyldimethylamine oxide. Sampling points: 10min,20min,30min,45min,60min.
TABLE 3 comparison of the dissolution profile of the prescription of example 1 and the dissolution profile of the commercially available soft capsules
Note [ 1 ]: the data are derived from patent US2011/0033529A1Is a dissolution rate of (4. Mu.g capsule).
The dissolution results show that the paricalcitol tablet prepared in example 1 has a dissolution profile substantially identical to that of the paricalcitol soft capsule under the same dissolution conditions.
(4) Stability study
Parycalciferol tablets are placed under acceleration conditions (40 ℃ C., RH 75%) and the drug dissolution and related substance changes during stability are examined.
TABLE 4 example 1 prescription stability test results
The stability result of the paricalcitol tablet shows that the tablet has better drug stability within 3 months, and the relative substances and dissolution curves have no change basically with the zero day ratio.
(5) Crystal form detection
The solid dispersion powder of paricalcitol, the crude drug of paricalcitol and the polymer polyvinyl alcohol prepared in the example 1 are subjected to crystal form inspection, and the results are shown in figures 1-3. The crystal form detection result shows that the paricalcitol bulk drug is crystal form powder, and the prepared paricalcitol solid dispersion powder is in an amorphous state after hot-melt extrusion, so that the solubility of the drug can be improved, and the bioavailability of the drug can be improved. Compared with the original ground paricalcitol soft capsule, the paricalcitol tablet prepared by adopting the hot-melt extrusion technology is more convenient to store and transport.
The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiment. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims (24)

1. A process for the preparation of a solid composition of paricalcitol, characterized in that it comprises the steps of:
dissolving paricalcitol in a solvent, spraying the solution of paricalcitol into a polymer, then shearing and mixing at a high speed, and drying to remove the solvent; the dried mixture of the paricalcitol and the polymer is subjected to hot-melt extrusion, and the heating temperature of the hot-melt extrusion is 100-300 ℃ to obtain a mixture of the paricalcitol and the polymer;
crushing and sieving the mixture of paricalcitol and polymer, and then mixing with other pharmaceutical excipients to prepare the solid composition;
the polymer is selected from polyvinyl alcohol;
the weight ratio of the paricalcitol to the polymer is 1 (500-25000);
in the solid composition, paricalcitol is present in an amorphous form;
the other pharmaceutical excipients are selected from fillers, disintegrants and lubricants.
2. The preparation method of claim 1, wherein the weight ratio of paricalcitol to polymer is 1 (1000-20000).
3. The preparation method of claim 1, wherein the weight ratio of paricalcitol to polymer is 1 (1200-10000).
4. The preparation method of claim 1, wherein the weight ratio of paricalcitol to polymer is 1 (1500-5000).
5. The method of claim 1, wherein the filler is selected from one, two or more of microcrystalline cellulose, lactose, mannitol, starch, and dextrin;
the disintegrating agent is selected from one, two or more of sodium carboxymethyl starch, crosslinked sodium carboxymethyl cellulose, crosslinked povidone, low-substituted hydroxypropyl cellulose and corn starch;
the lubricant is selected from one, two or more of talcum powder, magnesium stearate, stearic acid, polyethylene glycol and sodium stearyl fumarate.
6. The method of claim 1, wherein the additional pharmaceutical excipients further comprise a flavoring agent selected from one or both of a sweetener and a flavoring agent.
7. The method according to any one of claims 1 to 6, wherein the solid composition contains 0.0004 to 0.01 parts by weight of paricalcitol.
8. The method of any one of claims 1 to 6, wherein the solid composition comprises 1 to 50 parts by weight of the polymer.
9. The method of any one of claims 1 to 6, wherein the solid composition contains 0 to 1 part by weight of a lubricant.
10. The method of any one of claims 1 to 6, wherein the solid composition contains 1 to 10 parts by weight of the disintegrant.
11. The method of any one of claims 1 to 6, wherein the solid composition contains 15 to 90 parts by weight of filler.
12. The preparation method according to any one of claims 1 to 6, wherein the solid composition contains, in parts by weight, 0.002 to 0.01 part of paricalcitol, 0.1 to 50 parts of a polymer, 0.1 to 0.6 part of a lubricant, 1 to 10 parts of a disintegrant and 30 to 90 parts of a filler.
13. The preparation method according to claim 12, wherein the solid composition contains, in parts by weight, 0.002-0.01 parts of paricalcitol, 1-20 parts of a polymer, 0.1-0.5 parts of a lubricant, 2-8 parts of a disintegrant and 40-90 parts of a filler.
14. The preparation method according to claim 12, wherein the solid composition contains, in parts by weight, 0.002-0.01 part of paricalcitol, 0.1-50 parts of polyvinyl alcohol, 0.1-0.6 part of magnesium stearate, 1-10 parts of croscarmellose sodium and 30-90 parts of microcrystalline cellulose.
15. The preparation method according to claim 14, wherein the solid composition contains, in parts by weight, 0.002-0.01 part of paricalcitol, 1-20 parts of polyvinyl alcohol, 0.1-0.5 part of magnesium stearate, 2-8 parts of croscarmellose sodium and 40-90 parts of microcrystalline cellulose.
16. The preparation method according to claim 14, wherein the solid composition contains, in parts by weight, 0.002-0.005 parts of paricalcitol, 3-10 parts of polyvinyl alcohol, 0.1-0.5 parts of magnesium stearate, 3-8 parts of croscarmellose sodium and 60-90 parts of microcrystalline cellulose.
17. The method according to any one of claims 1 to 6, wherein the solvent is one, two or more selected from the group consisting of water, ethanol, glycerol, and acetone.
18. The method of any one of claims 1-6, wherein the method of preparing the solid composition further comprises: mixing the paricalcitol and polymer mixture with other pharmaceutical adjuvants, granulating, tabletting, briquetting, layering or pulverizing to obtain granular, tablet, block, strip, or powder solid composition.
19. Use of the solid composition obtained by the preparation method according to any one of claims 1 to 18 for the preparation of a solid preparation of paricalcitol.
20. A paricalcitol formulation, characterized in that it is prepared from the solid composition of the preparation process according to any of claims 1-18;
the paricalcitol formulation has the following in vitro dissolution characteristics: the cumulative dissolution of paricalcitol reaches more than 70% at 30 minutes.
21. The paricalcitol formulation according to claim 20 characterized in that the cumulative dissolution of paricalcitol is over 80% at 30 minutes.
22. The paricalcitol formulation according to claim 20 characterized in that the cumulative dissolution of paricalcitol is over 90% at 30 minutes.
23. The paricalcitol formulation according to claim 20, characterized in that it is a tablet, capsule, granule, powder or lozenge.
24. The paricalcitol formulation according to any of claims 20-23 for use in the prevention and/or treatment of secondary hyperparathyroidism.
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WO2009118167A1 (en) * 2008-03-25 2009-10-01 Ratiopharm Gmbh Pharmaceutical formulation comprising a solid dispersion and method for the production thereof
CN104162168A (en) * 2014-08-07 2014-11-26 北京泰德制药股份有限公司 Stable paricalcitol pharmaceutical composition and preparation method thereof
CN108524454A (en) * 2018-05-09 2018-09-14 南京海融制药有限公司 Composition of low-dose drugs of high degree of dispersion and preparation method thereof

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WO2009118167A1 (en) * 2008-03-25 2009-10-01 Ratiopharm Gmbh Pharmaceutical formulation comprising a solid dispersion and method for the production thereof
CN104162168A (en) * 2014-08-07 2014-11-26 北京泰德制药股份有限公司 Stable paricalcitol pharmaceutical composition and preparation method thereof
CN108524454A (en) * 2018-05-09 2018-09-14 南京海融制药有限公司 Composition of low-dose drugs of high degree of dispersion and preparation method thereof

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