CN113876715A - Sofantinib solid dispersion, tablet thereof and preparation method thereof - Google Patents

Sofantinib solid dispersion, tablet thereof and preparation method thereof Download PDF

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CN113876715A
CN113876715A CN202111267079.0A CN202111267079A CN113876715A CN 113876715 A CN113876715 A CN 113876715A CN 202111267079 A CN202111267079 A CN 202111267079A CN 113876715 A CN113876715 A CN 113876715A
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solid dispersion
tablet
solitinib
hpmcas
carrier material
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CN113876715B (en
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傅崇东
施斌
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Hutchison Medipharma Suzhou Co Ltd
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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
    • A61K9/141—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
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • 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
    • 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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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

Abstract

The invention discloses a sovitinib solid dispersion, a tablet thereof and a preparation method thereof. The tablet is prepared by mixing the solid dispersion and common auxiliary materials (such as a filler, a disintegrating agent, a lubricant and the like) and tabletting. The tablet prepared from the solid dispersion can not only greatly improve the dissolution rate of the solitinib, but also reduce the influence on the dissolution rate due to the change of pH value, and has the potential of improving the bioavailability of the solitinib and reducing the dissolution and absorption difference of the medicine due to the change of the pH condition of the gastrointestinal tract. And the solid dispersion and the tablet thereof have better stability.

Description

Sofantinib solid dispersion, tablet thereof and preparation method thereof
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a sovitinib solid dispersion, a sovitinib tablet and a preparation method of the sovitinib solid dispersion and the sovitinib tablet.
Background
The sufantinib is named as Surufatinib, and the chemical name is N- [2- (dimethylamino) ethyl ] -1- [3- ({4- [ (2-methyl-1H-indol-5-yl) oxy ] pyrimidin-2-yl } amino) phenyl ] methanesulfonamide, and the structural formula is as follows:
Figure BDA0003325761890000011
solitinib is a small molecule inhibitor of Vascular Endothelial Growth Factor Receptor (VEGFR), fibroblast growth factor receptor 1(FGFR1) and cytokine receptor CSF-1R. Solitinib was developed by and yellow medicine, inc, and was approved in china for the treatment of surgically unresectable neuroendocrine tumors of locally advanced or metastatic, advanced non-functional, well differentiated (G1, G2) pancreatic or non-pancreatic origin in 12 months of 2020. The preparation form is capsule, the process is wet granulation, and the preparation process needs a plurality of unit operations and is relatively complex.
Sofantinib is almost insoluble in water, has pH-dependent solubility, and has good solubility in acidic environment, but has the characteristics of rapid decrease of solubility with increase of pH, high solubility in stomach, and possibility of precipitation due to increase of pH in intestinal tract. The solubility and the dissolution rate of the solitinib are improved, the influence on the dissolution of the medicine caused by the change of the environmental pH value is reduced, and the method has important significance for improving the bioavailability of the solitinib.
Disclosure of Invention
The invention mainly aims to provide a solid dispersion containing solitinib, a tablet thereof and preparation methods thereof, so as to greatly improve the dissolution rate of the solitinib in an intestinal pH medium, reduce the influence of pH value change on drug dissolution, further improve the bioavailability of the solitinib, and simultaneously ensure the stability of the solid dispersion and the tablet thereof.
In one aspect, the present invention provides a solid dispersion comprising solitinib and a polymeric carrier material.
In some embodiments, the solid dispersion provided herein comprises solitinib and the polymeric carrier material in a mass ratio of from about 1:2 to about 1:8, for example from 1:3 to about 1:4, such as about 1:2, about 1:3, about 1:4, about 1: 5, about 1: 6, about 1: 7 or about 1:8, preferably about 1:3 or about 1: 4.
In some embodiments, the solid dispersion provided herein comprises a polymeric carrier material selected from copolymers of vinylpyrrolidone and vinyl acetate (e.g., a copolymer of vinylpyrrolidone and vinyl acetate
Figure BDA0003325761890000021
VA64), hydroxypropyl methylcellulose acetate succinate (e.g., HPMCAS-MG, HPMCAS-LG), hydroxypropyl methylcellulose phthalate (e.g., HPMCP-HP55), butyl methacrylate/dimethylaminoethyl methacrylate (e.g., HPMCAS-HP 55)
Figure BDA0003325761890000022
EPO) or polyethylene glycol/vinylcaprolactam (e.g. polyethylene glycol/vinylcaprolactam
Figure BDA0003325761890000023
) One or more of (a). In some embodiments, the solid dispersion provided herein comprises a polymeric carrier material selected from one or more of a copolymer of vinylpyrrolidone and vinyl acetate, hydroxypropyl methylcellulose acetate succinate, and hydroxypropyl methylcellulose phthalate. In some embodiments, the solid dispersion provided herein comprises a polymeric carrier material selected from the group consisting of
Figure BDA0003325761890000024
One or more of VA64, HPMCAS-MG, HPMCAS-LG and HPMCP-HP 55. In some embodiments, the solid dispersion provided herein comprises a polymeric carrier material of
Figure BDA0003325761890000025
VA64 or HPMCAS-MG.
In some embodiments, the solid dispersion provided herein comprises solitinib and a copolymer of vinylpyrrolidone and vinyl acetate in a mass ratio of about 1: 3. In some embodiments, the solid dispersion provided herein comprises solitinib and fulvestrant in a mass ratio of about 1:3
Figure BDA0003325761890000026
VA64。
In some embodiments, the solid dispersion provided herein comprises solitinib and hydroxypropyl methylcellulose acetate succinate in a mass ratio of about 1: 4. In some embodiments, the solid dispersion provided herein comprises solitinib and HPMCAS-MG in a mass ratio of about 1: 4.
In some embodiments, the solid dispersion provided herein further comprises a plasticizer. Preferably, the plasticizer is selected from polyethylene glycol, water soluble tocopheryl polyethylene glycol succinate (e.g. polyethylene glycol succinate
Figure BDA0003325761890000027
TPGS), poloxamer, or polysorbate. Preferably, the plasticizer is a water-soluble tocopherol polyethylene glycol succinate. Preferably, the plasticizer is
Figure BDA0003325761890000028
TPGS。
In some embodiments, the solid dispersion provided herein comprises solitinib, a polymeric carrier material, and a plasticizer in a mass ratio of about 1:2 to 8:0.1 to 0.5, for example about 1:2 to 5: 0.3 to 0.5 or about 1:2 to 5: 0.1 to 0.3.
In some embodiments, the solid dispersion provided herein is characterized in that the solid dispersion is prepared by a hot melt extrusion process.
In some embodiments, the parameters of the hot-melt extrusion process are a heating temperature of 80-200 ℃, e.g., 190 ℃ at 110-.
In one aspect, the present invention provides a tablet comprising any one of the solid dispersions described herein and an adjuvant comprising a filler, a disintegrant, and a lubricant.
In some embodiments, the tablet provided by the present invention comprises 10% to 60%, preferably 30% to 50%, more preferably 30% to 40% by mass of the solid dispersion. In some embodiments, the tablets provided herein comprise 20% to 80%, preferably 30% to 70%, more preferably 40% to 60% filler by mass. In some embodiments, the tablets provided herein comprise 5% to 30% such as 5% to 20%, 10% to 25%, or 8% to 15% by mass of a disintegrant. In some embodiments, the tablets provided herein comprise 0.5% to 10%, preferably 1% to 5%, more preferably 1% to 3% by mass of a lubricant.
In some embodiments, the tablet provided by the invention comprises 10-50% of solid dispersion, 20-80% of filler, 5-30% of disintegrant and 0.5-10% of lubricant by mass percentage.
In some embodiments, the filler is selected from one or more of microcrystalline cellulose, starch, lactose monohydrate, cyclodextrin and mannitol, preferably microcrystalline cellulose, mannitol or lactose monohydrate or a combination thereof, more preferably a combination of microcrystalline cellulose and lactose monohydrate. Preferably, the mass ratio of microcrystalline cellulose to lactose monohydrate is from about 5:1 to 1:2, for example 3: 1 to 1: 1, 2.5:1 to 1.5: 1, such as 2.5:1 or 5: 3.
In some embodiments, the disintegrant is selected from one or more of croscarmellose sodium, crospovidone, low substituted hydroxypropyl cellulose, preferably, croscarmellose sodium or crospovidone.
In some embodiments, the lubricant is selected from one or more of magnesium stearate, silicon dioxide, talc, preferably magnesium stearate, silicon dioxide, or a combination thereof, more preferably a combination of magnesium stearate and silicon dioxide. Preferably, the mass ratio of silicon dioxide to magnesium stearate is from about 5:1 to 1:2, e.g. 3: 1 to 1: 1, 2: 1 to 1: 1, such as 1.5: 1.
In some embodiments, the tablet provided by the present invention comprises excipients consisting of microcrystalline cellulose, crospovidone, silicon dioxide and magnesium stearate, preferably in a mass ratio of about 250:150:6: 4.
In some embodiments, the tablets provided herein comprise excipients consisting of microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, silicon dioxide, and magnesium stearate, preferably in a mass ratio of about 312.5:125:94:7.5:5 or 250: 100: 75: 6: 4.
In some embodiments, the present invention provides a tablet comprising the solid dispersion, microcrystalline cellulose, crospovidone, silicon dioxide, and magnesium stearate in a mass ratio of about 220:250:150:6:4, and wherein the solid dispersion comprises solitinib, magnesium stearate, and optionally magnesium stearate,
Figure BDA0003325761890000031
VA64 and
Figure BDA0003325761890000032
TPGS。
in some embodiments, the present invention provides a tablet comprising the solid dispersion, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, silicon dioxide, and magnesium stearate in a mass ratio of about 250:312.5:125:94:7.5:5, and wherein the solid dispersion comprises solitinib and HPMCAS-MG.
In one aspect, the present invention provides a method of preparing a solid dispersion according to the present invention using a hot melt extrusion process comprising the steps of: mixing the Sofantinib and the high polymer carrier material uniformly according to the required proportion, extruding the mixture by a hot-melt extruder, cooling the mixture, crushing the cooled mixture and sieving the cooled mixture.
In some embodiments, the hot melt extrusion process is performed using the following parameters: the heating temperature is 80-200 ℃, for example, 190 ℃ at 110-.
In another aspect, the present invention provides a process for preparing the tablet of the present invention, which comprises mixing the above pulverized and sieved solid dispersion with a filler, a disintegrant and a lubricant in a single or stepwise manner, followed by direct compression.
The solid dispersion of the solitinib provided by the invention has the advantages that the dissolution rate and the dispersing capacity of the solitinib are obviously improved, the solid dispersion and the tablet thereof have good stability, the dissolution rate of the solitinib can be maintained when the pH value is changed violently, and the solid dispersion has the potential of reducing the individual difference of oral administration and improving the bioavailability. In addition, compared with the original wet granulation process, the solid dispersion preparation process provided by the invention has the advantages of continuity, simplicity and high production efficiency.
It will be understood that the terms "comprises" and "comprising," as used herein, also encompass embodiments comprised of the recited elements or features, unless otherwise indicated or clearly contradicted by context. For example, the technical solution "a tablet comprising a solid dispersion, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, silicon dioxide and magnesium stearate" covers the technical solution "a tablet consisting of a solid dispersion, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, silicon dioxide and magnesium stearate".
The term "about" means about, within, roughly, or around. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the upper and lower bounds of the numerical values set forth above. In general, the term "about" is used herein to modify a numerical value by a 10% variation above and below the stated value.
The term "adjuvant" refers to pharmaceutically acceptable adjuvants suitable for use in the preparation of pharmaceutical formulations, including, but not limited to, fillers, disintegrants and/or lubricants.
Drawings
FIG. 1: dissolution profiles of tablets obtained in examples 1-10 in phosphate buffer pH6.8 (0.20% Tween80)
FIG. 2: dissolution curves of the tablets obtained in example 8 before storage and after 1 month storage under accelerated conditions
FIG. 3: two-stage process (pH 1.2-6.8) dissolution profiles of the tablets obtained in examples 7 and 8
Examples
The present invention is further illustrated by the following examples, but the scope of the invention is not limited thereto.
Example 1:
20g of Sofantinib (Wako Junyaku Co., Ltd.) and 60g of Sofantinib were weighed
Figure BDA0003325761890000051
Epo (evonik), mixed well. Adding the above mixture into a hot melt extruder (Omicron 12P, Steer) preheated to about 150 deg.C, preparing at screw rotation speed of 200 rpm, cooling the extrudate, pulverizing, and sieving with 300 μm sieve to obtain solid dispersion.
Taking the solid dispersion after being crushed and sieved, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, silicon dioxide and magnesium stearate in a ratio of 200: 250: 100: 75: 6:4, mixing uniformly and directly tabletting, wherein the weight of each tablet is about 635mg, and the hardness is about 180N. The dissolution profile of the resulting tablets in 900mL of phosphate buffer pH6.8 (0.20% Tween80) was measured by paddle method at 100rpm and 37.5 ℃ and the dissolution results are shown in Table 1 and FIG. 1.
Example 2:
weighing 20g of Sofantinib and 60g of Sofantinib
Figure BDA0003325761890000052
VA64(BASF), 8g
Figure BDA0003325761890000053
Tpgs (basf), mixed well. Adding the mixture into a hot-melting extruder preheated to about 145 ℃, preparing at the screw rotation speed of 100 revolutions per minute, cooling and crushing the extrudate, and sieving the extrudate through a 300-micron sieve to obtain the solid dispersion.
Taking the solid dispersion after being crushed and sieved, microcrystalline cellulose, crospovidone, silicon dioxide and magnesium stearate in a ratio of 220:250:150:6:4, mixing uniformly and directly tabletting, wherein the weight of each tablet is about 630mg, and the hardness is about 160N. The dissolution rate of the obtained tablet was measured as described in example 1 and was higher, exceeding 95% at 15min, and the dissolution results are shown in Table 1 and FIG. 1.
Example 3:
20g of Sofantinib and 60g of HPMC-HP55(Shin-Etsu) were weighed and mixed well. Adding the mixture into a hot-melt extruder preheated to about 170 ℃, preparing at the screw rotation speed of 100 revolutions per minute, cooling and crushing the extrudate, and sieving the extrudate through a 300-micron sieve to obtain the solid dispersion.
Taking the solid dispersion after being crushed and sieved, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, silicon dioxide and magnesium stearate in a ratio of 200: 250: 100: 75: 6:4, mixing uniformly and directly tabletting, wherein the weight of each tablet is about 635mg, and the hardness is about 140N. The dissolution of the obtained tablet was measured by the method in example 1, and the dissolution results are shown in Table 1 and FIG. 1.
Example 4:
20g of Sofantinib and 60g of HPMCAS-LG (Shin-Etsu) were weighed and mixed well. Adding the mixture into a hot-melt extruder preheated to about 175 ℃, preparing at the screw rotation speed of 80 rpm, cooling the extrudate, crushing, and sieving with a 300 mu m sieve to obtain the solid dispersion.
Taking the solid dispersion after being crushed and sieved, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, silicon dioxide and magnesium stearate in a ratio of 200: 250: 100: 75: 6:4, mixing uniformly and directly tabletting, wherein the weight of each tablet is about 635mg, and the hardness is about 146N. The dissolution of the obtained tablet was measured by the method in example 1, and the dissolution results are shown in Table 1 and FIG. 1.
Example 5:
20g of Sofantinib and 60g of HPMCAS-MG (Shin-Etsu) were weighed and mixed well. Adding the mixture into a hot-melt extruder preheated to about 170 ℃, preparing at the screw rotation speed of 100 revolutions per minute, cooling and crushing the extrudate, and sieving the extrudate through a 300-micron sieve to obtain the solid dispersion.
Taking the solid dispersion after being crushed and sieved, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, silicon dioxide and magnesium stearate in a ratio of 200: 250: 100: 75: 6:4, mixing uniformly and directly tabletting, wherein the weight of a single tablet is about 635mg, and the hardness is about 103N. The dissolution of the obtained tablet was measured by the method in example 1, and the dissolution results are shown in Table 1 and FIG. 1.
Example 6
Weighing 30g of Sofantinib and 90g of Sofantinib
Figure BDA0003325761890000061
(BASF), and mixing uniformly. Adding the mixture into a hot-melt extruder preheated to about 130 ℃, preparing at the screw rotation speed of 100 revolutions per minute, cooling and crushing the extrudate, and sieving the extrudate through a 300-micron sieve to obtain the solid dispersion.
Taking the solid dispersion after being crushed and sieved, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, silicon dioxide and magnesium stearate in a ratio of 200: 250: 100: 75: 6:4, mixing uniformly and directly tabletting, wherein the weight of a single tablet is about 635mg, and the hardness is about 131N. The dissolution of the obtained tablet was measured by the method in example 1, and the dissolution results are shown in Table 1 and FIG. 1.
Example 7
Weighing 80g of Sofantinib and 320g of Sofantinib
Figure BDA0003325761890000062
(BASF), and mixing uniformly. Adding the mixture into a hot-melt extruder preheated to about 135 deg.C, preparing at a screw rotation speed of 100rpm, cooling the extrudatePulverizing, and sieving with 300 μm sieve to obtain solid dispersion.
Taking the solid dispersion after being crushed and sieved, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, silicon dioxide and magnesium stearate in a ratio of 250:312.5:125:94:7.5:5, mixing uniformly and directly tabletting, wherein the weight of each tablet is about 794mg, and the hardness is about 132N. The dissolution of the obtained tablet was measured by the method in example 1, and the dissolution results are shown in Table 1 and FIG. 1.
Example 8
80g of Sofantinib and 320g of HPMCAS-MG are weighed and mixed evenly. Adding the mixture into a hot-melt extruder preheated to about 170 ℃, preparing at the screw rotation speed of 100 revolutions per minute, cooling and crushing the extrudate, and sieving the extrudate through a 300-micron sieve to obtain the solid dispersion.
Taking the solid dispersion after being crushed and sieved, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, silicon dioxide and magnesium stearate in a ratio of 250:312.5:125:94:7.5:5, mixing uniformly and directly tabletting, wherein the weight of each tablet is about 794mg, and the hardness is about 125N. The dissolution of the obtained tablet was measured by the method in example 1, and the dissolution results are shown in Table 1 and FIG. 1.
Example 9
Preparation of common sovatinib tablets: the raw material medicaments of the solitinib, the microcrystalline cellulose, the lactose monohydrate, the croscarmellose sodium, the silicon dioxide and the magnesium stearate are uniformly mixed according to the proportion of 50: 250: 100: 75: 6:4 and then directly tabletted, wherein the weight of a single tablet is about 485mg, and the hardness is about 103N. The dissolution of the obtained tablets was measured in the same manner as in example 1, and the dissolution results are shown in Table 1 and FIG. 1 as a control.
Example 10
Preparing tablets after physically mixing the Sofantinib, the carrier material and the tablet auxiliary materials: taking a Sofantinib raw material medicine,
Figure BDA0003325761890000071
VA64、
Figure BDA0003325761890000072
TPGS, microcrystalline cellulose, crosslinked polyethyleneKetone, silicon dioxide and magnesium stearate are mixed evenly according to the proportion of 50:150: 20:250:150:6:4 and then directly compressed into tablets, the weight of each tablet is about 630mg, and the hardness is about 150N. The dissolution of the obtained tablets was measured in the same manner as in example 1, and the dissolution results are shown in Table 1 and FIG. 1 as a control.
The dissolution results of the tablets obtained in examples 1 to 10 are shown in Table 1.
TABLE 1 dissolution results of tablets obtained in examples 1 to 10
Time (min) 15 30 45 60 120 180
Example 1 46.6 62.0 72.8 79.7 88.5 91.3
Example 2 95.2 95.0 95.1 95.8 95.6 95.7
Example 3 68.2 83.3 90.5 94.7 100.4 102.4
Example 4 62.0 79.6 89.0 94.8 103.0 105.1
Example 5 59.1 77.1 86.6 92.2 101.4 103.9
Example 6 61.8 74.6 80.3 81.8 82.6 84.0
Practice ofExample 7 47.0 69.0 73.0 75.0 78.0 79.0
Example 8 57.0 82.0 91.0 95.0 102.0 102.0
Example 9 45.2 46.7 47.4 47.8 48.2 48.5
Example 10 44.2 46.9 48.0 48.6 49.5 49.8
Note: paddle method, 100rpm, 37.5 ℃, 900mL pH6.8 phosphate buffer (0.20% Tween80)
Example 11
Stability study of sovatinib solid dispersion and its tablets: the solid dispersion and the tablet thereof obtained in example 8 were selected and stored under accelerated conditions (40 ℃, 75% RH) for 1 month, and the change of total impurities, moisture, and dissolution of the tablet was examined in the same manner as in example 1, and the results are shown in table 2 and fig. 2. The total impurities, moisture and the dissolution of the tablet are not obviously changed, and the solid dispersion and the tablet have better stability.
Table 2 solid dispersion obtained in example 8 and its tablet stability investigation
Figure BDA0003325761890000073
Figure BDA0003325761890000081
TABLE 3 dissolution Profile of tablets obtained in example 8 after storage for one month under accelerated conditions (40 ℃, 75% RH)
Figure BDA0003325761890000082
Note: paddle method, 100rpm, 37.5 ℃, 900mL pH6.8 phosphate buffer (0.20% Tween80)
Example 12
Effect of pH change on tablet dissolution of sovitinib solid dispersion: tablets of the solid dispersions obtained in examples 7 and 8 were selected and the effect on the dissolution of the tablets when the pH was changed was examined by a two-stage method. The dissolution conditions were: 900mL of medium, a paddle method, a rotating speed of 100rpm, a temperature of 37.5 ℃, 0-30 min: hydrochloric acid solution with pH of 1.2, 30-180 min: pH6.8 phosphate buffer (0.20% Tween80) showed no effect on dissolution of the tablets described in example 8 when the pH was significantly changed (see table 4 and figure 3).
TABLE 4 dissolution data of the tablets obtained in examples 7 and 8 in a two-stage dissolution medium (pH 1.2-pH6.8)
Time (min) 15 30 45 60 120 180
Example 7 96.0 108.0 71.0 71.0 70.0 69.0
Example 8 99.0 103.0 101.0 103.0 102.0 102.0
Note: paddle method, 100rpm, 37.5 ℃, 900 mL; 0-30 min: pH1.2 hydrochloric acid solution, 30-180 min: pH6.8 phosphate buffer (0.20% Tween80)
From the above examples, it can be seen that the dissolution rates of the solid dispersion tablets described in examples 1 to 8 were greatly improved compared to those of the tablets of example 9 (obtained by physically mixing and tabletting the drug substance and the tablet excipients) and example 10 (obtained by physically mixing and tabletting the drug substance, the polymeric carrier material and the tablet excipients), and particularly the dissolution rate of the tablet of example 2 was over 95% at 15min in a poorly soluble medium. In addition, the solid dispersion described in example 8 was superior in tablet stability, and the dissolution was not affected by pH change.
The sovantinib solid dispersion and the tablet thereof have simple and continuous preparation process, can remarkably improve the dissolution rate of the sovantinib, have good stability, are expected to improve the oral bioavailability of the sovantinib, and reduce the oral absorption individual difference caused by the change of the pH condition of the gastrointestinal tract and the like.

Claims (15)

1. A solid dispersion comprises solitinib and a high-molecular carrier material, wherein the mass ratio of the solitinib to the high-molecular carrier material is 1: 2-1: 8.
2. The solid dispersion of claim 1, wherein the polymeric carrier material is selected from the group consisting of copolymers of vinylpyrrolidone and vinyl acetate (e.g., vinyl pyrrolidone and vinyl acetate)
Figure FDA0003325761880000011
VA64), hydroxypropyl methylcellulose acetate succinate (e.g., HPMCAS-MG, HPMCAS-LG), hydroxypropyl methylcellulose phthalate (e.g., HPMCP-HP55), butyl methacrylate/dimethylaminoethyl methacrylate (e.g., HPMCAS-HP 55)
Figure FDA0003325761880000012
EPO) or polyethylene glycol/vinylcaprolactam (e.g. polyethylene glycol/vinylcaprolactam
Figure FDA0003325761880000013
) One or more of (a).
3. A solid dispersion according to claim 1 or claim 2 wherein the polymeric carrier material is selected from a copolymer of vinylpyrrolidone and vinyl acetate (e.g. vinyl pyrrolidone and vinyl acetate)
Figure FDA0003325761880000014
VA64), hydroxypropyl methylcellulose acetate succinate (e.g. HPMCAS-MG, HPMCAS-LG), and hydroxypropyl methylcellulose phthalate (e.g. HPMCP-HP 55).
4. A solid dispersion according to any one of claims 1 to 3 wherein the polymeric carrier material is a copolymer of vinylpyrrolidone and vinyl acetate (e.g. vinyl pyrrolidone and vinyl acetate)
Figure FDA0003325761880000015
VA64) or hydroxypropyl methylcellulose acetate succinate (e.g. HPMCAS-MG).
5. The solid dispersion according to any one of claims 1 to 4, characterized in that it comprises sofvanine and a copolymer of vinylpyrrolidone and vinyl acetate (e.g. in a mass ratio of about 1: 3)
Figure FDA0003325761880000016
VA64), or a mass ratio of about 1:4 solitinib to hydroxypropyl methylcellulose acetate succinate (e.g., HPMCAS-MG).
6. The solid dispersion according to any one of claims 1 to 5, characterized in that it further comprises a plasticizer selected from polyethylene glycol, water-soluble tocopheryl polyethylene glycol succinate (e.g. polyethylene glycol succinate)
Figure FDA0003325761880000017
TPGS), poloxamer or polysorbate, preferably water soluble tocopherol polyethylene glycol succinate (e.g. polyethylene glycol succinate)
Figure FDA0003325761880000018
TPGS); preferably, the mass ratio of the solitinib, the polymeric carrier material and the plasticizer is about 1: 2-8: 0.1-0.5.
7. The solid dispersion according to any one of claims 1 to 6, characterized in that it is prepared by a hot-melt extrusion process.
8. A tablet comprising the solid dispersion of any one of claims 1-7 and an adjuvant comprising a filler, a disintegrant, and a lubricant.
9. The tablet according to claim 8, comprising 10 to 60 mass% of the solid dispersion, 20 to 80 mass% of the filler, 5 to 30 mass% of the disintegrant, and 0.5 to 10 mass% of the lubricant.
10. The tablet according to claim 8 or 9, wherein the filler is selected from one or more of microcrystalline cellulose, starch, lactose monohydrate, cyclodextrin and mannitol; the disintegrant is selected from one or more of croscarmellose sodium, crospovidone and low-substituted hydroxypropyl cellulose; the lubricant is selected from one or more of magnesium stearate, silicon dioxide and talcum powder.
11. The tablet according to claim 8, comprising the solid dispersion, microcrystalline cellulose, crospovidone, silicon dioxide, and magnesium stearate in a mass ratio of about 220:250:150:6:4, and wherein the solid dispersion comprises solitinib,
Figure FDA0003325761880000021
VA64 and
Figure FDA0003325761880000022
TPGS。
12. the tablet of claim 8, comprising the solid dispersion, microcrystalline cellulose, lactose monohydrate, croscarmellose sodium, silicon dioxide, and magnesium stearate in a mass ratio of about 250:312.5:125:94:7.5:5, and wherein the solid dispersion comprises solitinib and HPMCAS-MG.
13. A method of preparing the solid dispersion of any one of claims 1-7 using a hot melt extrusion process comprising the steps of: mixing the Sofantinib and the high polymer carrier material uniformly according to the required proportion, extruding the mixture by a hot-melt extruder, cooling the mixture, crushing the cooled mixture and sieving the cooled mixture.
14. The method of claim 13, wherein the hot melt extrusion process is performed using the following parameters: heating at 80-200 deg.c and screw rotation speed of 50-250 rpm, cooling the extrudate, crushing and sieving with 100-400 micron sieve.
15. A process for the preparation of a tablet as claimed in any of claims 8 to 12, characterized in that the solid dispersion obtained according to claim 13 or 14 is mixed with fillers, disintegrants and lubricants, singly or in steps, and compressed directly.
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CN111617028A (en) * 2020-07-14 2020-09-04 扬子江药业集团江苏紫龙药业有限公司 Oral preparation containing ibrutinib and preparation method
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