CN109381432A - A kind of preparation method of Itraconazole composite particles - Google Patents
A kind of preparation method of Itraconazole composite particles Download PDFInfo
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- CN109381432A CN109381432A CN201710694269.8A CN201710694269A CN109381432A CN 109381432 A CN109381432 A CN 109381432A CN 201710694269 A CN201710694269 A CN 201710694269A CN 109381432 A CN109381432 A CN 109381432A
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- China
- Prior art keywords
- itraconazole
- preparation
- composite particles
- solution
- kettle
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- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 title claims abstract description 64
- 229960004130 itraconazole Drugs 0.000 title claims abstract description 64
- 238000002360 preparation method Methods 0.000 title claims abstract description 46
- 239000011246 composite particle Substances 0.000 title claims abstract description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 66
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 42
- 239000012046 mixed solvent Substances 0.000 claims abstract description 21
- 235000019441 ethanol Nutrition 0.000 claims abstract description 19
- 239000012530 fluid Substances 0.000 claims abstract description 19
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 18
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 18
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 18
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims abstract description 18
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229960003511 macrogol Drugs 0.000 claims abstract description 9
- 239000000243 solution Substances 0.000 claims description 45
- 239000013078 crystal Substances 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 14
- 238000002425 crystallisation Methods 0.000 claims description 10
- 230000008025 crystallization Effects 0.000 claims description 10
- 239000011259 mixed solution Substances 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 7
- 230000001105 regulatory effect Effects 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 5
- 239000002775 capsule Substances 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 239000002245 particle Substances 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 239000006185 dispersion Substances 0.000 claims description 2
- 238000011049 filling Methods 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- OBRNDARFFFHCGE-QDSVTUBZSA-N arformoterol fumarate Chemical compound OC(=O)\C=C\C(O)=O.C1=CC(OC)=CC=C1C[C@@H](C)NC[C@H](O)C1=CC=C(O)C(NC=O)=C1.C1=CC(OC)=CC=C1C[C@@H](C)NC[C@H](O)C1=CC=C(O)C(NC=O)=C1 OBRNDARFFFHCGE-QDSVTUBZSA-N 0.000 claims 2
- 229960000193 formoterol fumarate Drugs 0.000 claims 1
- -1 hydroxypropyl Chemical group 0.000 claims 1
- 229920000609 methyl cellulose Polymers 0.000 claims 1
- 239000001923 methylcellulose Substances 0.000 claims 1
- 238000004064 recycling Methods 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 abstract description 15
- 239000000463 material Substances 0.000 abstract description 9
- VHVPQPYKVGDNFY-ZPGVKDDISA-N itraconazole Chemical compound O=C1N(C(C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-ZPGVKDDISA-N 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 229940063138 sporanox Drugs 0.000 abstract description 4
- 230000003321 amplification Effects 0.000 abstract description 3
- 238000003199 nucleic acid amplification method Methods 0.000 abstract description 3
- 239000007921 spray Substances 0.000 description 12
- 230000001276 controlling effect Effects 0.000 description 10
- 238000004090 dissolution Methods 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 239000007791 liquid phase Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000000126 substance Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000002131 composite material Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229920001992 poloxamer 407 Polymers 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 239000012296 anti-solvent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 235000013339 cereals Nutrition 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 229940100688 oral solution Drugs 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 230000000149 penetrating effect Effects 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000011112 process operation Methods 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 238000001507 sample dispersion Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
Classifications
-
- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
- A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, 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
- A61K9/14—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
- A61K9/14—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
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
Landscapes
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of preparation methods of Itraconazole composite particles, it is prepared by crystalization in supercritical fluid equipment system, the composite particles are dissolved in methylene chloride/ethyl alcohol mixed solvent by the Itraconazole and the hydroxypropyl methylcellulose of 30%-60% and the Macrogol 6000 of 0%-20% that weight percent is 30-60%, and preparation is precipitated in crystalization in supercritical fluid.Auxiliary material used in the present invention is the auxiliary material in the Itraconazole preparation Sporanox formula of commercialization, sufficiently verifying and Itraconazole is without consistency problem, prescription safety and stability is effective, methanol is not used in preparation process, it is easier to production amplification, and unit time yield is higher, and the dispersibility for obtaining product is more preferable, the Itraconazole preparation and itraconazole similar factors > 50 being prepared, meet Conformance Assessment requirement.
Description
Technical field
The present invention relates to a kind of preparation methods of Itraconazole composite particles.
Background technique
Itraconazole is the antifungal of triazole type, and Itraconazole has strong lipophilicity, it is extremely difficult to water is dissolved in, in pH neutral
The saturation solubility < 1ng/mL of its lower aqueous solution, saturation solubility is 6 μ g/mL in the hydrochloric acid solution of pH=1, takes orally life
Object availability is determined by the rate of dissolution of drug in the gastrointestinal tract.Since Itraconazole is insoluble in water, so that it is in the gastrointestinal tract
Rate of dissolution it is small, oral administration biaavailability is low.Sporanox (SPORANOX, main component are Itraconazole) injection, mouth
It takes liquid and capsule is the Itraconazole preparation being commercialized at present.Injection and oral solution are by by Itraconazole and 2- hydroxypropyl-
Beta-cyclodextrin complexing increases its dissolubility, but 2-HP-BETA-CD mainly passes through kidney elimination, so for severe renal
The patient of dysfunction, elimination time can substantially extend, and may cause accumulation of poisoning.
CN201510057090.2, which is disclosed, a kind of prepares Itraconazole high-efficiency preparation with crystalization in supercritical fluid technology
Method, this method includes following four step: 1) preparation of mixed solution: Itraconazole and accounting for Itraconazole quality percentage
The mixed solvent of methanol and methylene chloride is added in the mixture of L-AA than 42.8%, 25%, 18.2%, 50%,
After dissolution, hydroxypropyl methylcellulose and pluronic F-127 is added, adds methylene chloride, makes to be completely dissolved；2) CO2 is fed: will
CO in steel cylinder2It is inputted by pressure-regulating valve in the high pressure crystal kettle of crystalization in supercritical fluid equipment system；3) composite particles
Be precipitated: the solution that step 1) is obtained sprays into high pressure crystal kettle through the nozzle of crystalization in supercritical fluid equipment system, compound micro-
Grain is precipitated from solution and is collected in the bottom of high pressure crystal kettle；4) obtained composite particles are encapsulated.Supercritical fluid knot
Crystal technique makes Itraconazole and high polymer adjuvant form micron order composite particles, ensure that the solubility of drug, and improves drug
Bioavilability and curative effect, and avoid the toxic side effect for reducing drug using 2-HP-BETA-CD.But
L-AA and pluronic F-127 are used in CN201510057090.2, L-AA is molten in methylene chloride/methanol
Solution property is very poor, and sample introduction pipeline blockage is easily caused in preparation process；And L-AA is easily oxidized denaturation, is unfavorable for the storage of product
It deposits.For F-127 as novel macromolecule nonionic surfactant, price is high and should not be excessively used.Use methanol as molten
Agent needs strict control to remain, and is also unfavorable for production amplification.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of suitable industrialized production, the Itraconazole of ingredient safety is compound
Particle.
In order to solve the above technical problems, passing through the invention discloses a kind of preparation method of Itraconazole composite particles
The preparation of crystalization in supercritical fluid equipment system, the Itraconazole and 30%- that the composite particles are 30-60% by weight percent
60% hydroxypropyl methylcellulose and the Macrogol 6000 of 0%-20% are dissolved in methylene chloride/ethyl alcohol mixed solvent, overcritical
Preparation is precipitated in crystallization of fluids.
Preparation process includes the following steps: the preparation of 1) mixed solution: in Itraconazole and hydroxypropyl methylcellulose and poly- second
The mixed solvent of ethanol/dichloromethane is added in the mixture of glycol 6000, is completely dissolved；2)CO2Charging: liquefaction CO2By high pressure
Pump is through symmetrical two channels and solution channel be at 45 ° or 60 ° of high voltage junctions for being continually introduced into crystalization in supercritical fluid equipment system
In brilliant kettle, temperature in the kettle and pressure are regulated and controled by heating device and pressure-regulating valve, make CO in kettle2Reach supercriticality；3)
Solution sample introduction: being first passed through the mixed solvent of ethanol/dichloromethane by intermediate solution channel, after system reaches balance, will mix
Solvent replacement is the solution continuous sample introduction of step 1) configuration, and solvent is quickly and supercritical CO2It is sufficiently mixed and is flowed out back through bottom
It receives, the particles of solute of formation falls to crystallization kettle bottom；4) dry: after sample introduction, to continue to be passed through CO210-40min is to remove
Sample in autoclave is collected in remaining organic solvent, subsequent pressure release.
The weight percent preferably 30%: 55%: 15% of Itraconazole and hydroxypropyl methylcellulose and Macrogol 6000 is dense
Spend preferred 25mg/mL；The volume ratio of mixed solvent ethanol/dichloromethane preferably 1: 1；CO2The preferred 50-100mL/min of flow rate, pressure
Power is 90-200bar, 30-70 DEG C of temperature, more preferable CO2Flow rate is that 50mL/min pressure is 110bar, temperature 50 C, solution stream
Speed is 1mL/min.
Itraconazole composite particles directly compressible disclosed by the invention is prepared into itraconazole dispersible tablets, or for filling
Capsule, or other dosage forms such as be prepared into dry suspensoid agent, inhalant.
Auxiliary material hydroxypropyl methylcellulose and polyethylene glycol used in the present invention are this skin of the Itraconazole preparation of commercialization
Auxiliary material in benevolence promise formula, sufficiently verifying and Itraconazole are without consistency problem, and prescription safety and stability is effective, preparation process
In do not use methanol, it is easier to production amplification；The spray head that we use is 3 channels, and solution passes through nozzle (50- from intermediate channel
800 microns) it sprays into crystallization kettle, CO2Through symmetrical two channels and solution channel it is at 45 ° or 60 ° penetrating.Surpass compared to traditional
Critical anti-solvent technology, solution and CO2It sprays at an angle of 90, which is more conducive to the dispersion of solution, and and CO2Uniform mixing；
Solution is outside nozzle and CO simultaneously2Mixing improves CO2Spray nozzle clogging caused by kettle is sprayed into as same channel with solution；The present invention
The preparation method unit time yield of disclosed Itraconazole composite particles is higher, and the dispersibility for obtaining product is more preferable,
The Itraconazole preparation and itraconazole similar factors > 50 being prepared, meet Conformance Assessment requirement.
Detailed description of the invention
Fig. 1 is the schematic diagram of crystalization in supercritical fluid equipment；
Fig. 2 is the electron microscope scanning map of Itraconazole bulk pharmaceutical chemicals；
Fig. 3 is the electron microscope scanning map of composite particles；
Fig. 4 is Itraconazole bulk pharmaceutical chemicals X- powder diffraction spectrum；
Fig. 5 is the X- powder diffraction spectrum of composite particles；
Fig. 6 is commercially available sporanox and composite particles preparation dissolution curve.
Specific embodiment
Above content of the invention is described in further detail again below by way of specific embodiment.But this should not be managed
Solution is limited only to example below for the range of the above-mentioned theme of the present invention.The case where not departing from above-mentioned technical idea of the invention
Under, the various replacements or change made according to ordinary skill knowledge and customary means, should all include in model of the invention
In enclosing.
Embodiment 1
Prescription:
| Material composition | Prescription matches (%) |
| Itraconazole | 35 |
| Hydroxypropyl methylcellulose | 50 |
| Macrogol 6000 | 15 |
Preparation method:
1) 1.75g Itraconazole and 2.50g hydroxypropyl methylcellulose and 0.75g polyethylene glycol the preparation of mixed solution: are accurately weighed
6000 mixture is placed in 500mL conical flask, and the mixed solvent (volume ratio 1: 2) of 200mL ethyl alcohol and methylene chloride is added, makes
It is completely dissolved；
2) CO2 is fed: as shown in Figure 1, opening CO2 cylinder valve, the CO2 that liquefies is by high-pressure pump through symmetrical two channels of kettle head
(with intermediate solution channel at 60o) is continually introduced into the high pressure crystal kettle of crystalization in supercritical fluid equipment system, coutroi velocity
50mL/min；
3) regulating and controlling temperature and pressure: by adjusting counterbalance valve shown in Fig. 1, controlling pressure in high pressure crystal kettle is 11MPa, and is passed through
Preheater and insulating box control temperature in the kettle are 50 DEG C, and CO2 in kettle is made to reach supercriticality；
4) solution sample introduction: as shown in Figure 1, opening high pressure liquid phase pump, the solution that step 1 is configured is passed through by the intermediate channel of kettle head
100 μm of nozzle sprays into crystallization kettle.Before being passed through solution, it is first passed through the ethyl alcohol of 15min and the mixed solvent (volume of methylene chloride
Than 1: 2), system being made to reach balance.The control of sample introduction flow rate is 1mL/min；
5) dry: after sample introduction, to continue to be passed through CO2 20min to remove remaining organic solvent；
6) sample in autoclave is collected in pressure release.
Embodiment 2
Prescription:
| Material composition | Prescription matches (%) |
| Itraconazole | 40 |
| Hydroxypropyl methylcellulose | 50 |
| Macrogol 6000 | 10 |
Preparation method: 1) preparation of mixed solution: accurately weighing 1.6g Itraconazole and 2.0g hydroxypropyl methylcellulose and 0.4g is poly-
The mixture of ethylene glycol 6000 is placed in 500mL conical flask, and the mixed solvent (volume ratio 1 of 200mL ethyl alcohol and methylene chloride is added
: 1), make to be completely dissolved；
2)CO2Charging: as shown in Figure 1, opening CO2Cylinder valve, liquefy CO2By high-pressure pump through symmetrical two channels of kettle head (with
Intermediate solution channel is at 45 °) it is continually introduced into the high pressure crystal kettle of crystalization in supercritical fluid equipment system, coutroi velocity 75mL/
min；
3) regulating and controlling temperature and pressure: by adjusting counterbalance valve shown in Fig. 1, controlling pressure in high pressure crystal kettle is 11MPa, and is passed through
Preheater and insulating box control temperature in the kettle are 40 DEG C, make CO in kettle2Reach supercriticality；
4) solution sample introduction: as shown in Figure 1, opening high pressure liquid phase pump, the solution that step 1 is configured is passed through by the intermediate channel of kettle head
200 μm of nozzle sprays into crystallization kettle.Before being passed through solution, it is first passed through the ethyl alcohol of 15min and the mixed solvent (volume of methylene chloride
Than 1: 1), system being made to reach balance.The control of sample introduction flow rate is 2.5mL/min；
5) dry: after sample introduction, to continue to be passed through CO230min is to remove remaining organic solvent；
6) sample in autoclave is collected in pressure release.
Embodiment 3
Prescription:
| Material composition | Prescription matches (%) |
| Itraconazole | 40 |
| Hydroxypropyl methylcellulose | 40 |
| Macrogol 6000 | 20 |
Preparation method: 1) preparation of mixed solution: accurately weighing 2.0g Itraconazole and 2.0g hydroxypropyl methylcellulose and 1.0g is poly-
The mixture of ethylene glycol 6000 is placed in 500mL conical flask, and the mixed solvent (volume ratio 1 of 200mL ethyl alcohol and methylene chloride is added
: 1), make to be completely dissolved；
2)CO2Charging: as shown in Figure 1, opening CO2Cylinder valve, liquefy CO2By high-pressure pump through symmetrical two channels of kettle head (with
Intermediate solution channel is at 60 °) it is continually introduced into the high pressure crystal kettle of crystalization in supercritical fluid equipment system, coutroi velocity 75mL/
min；
3) regulating and controlling temperature and pressure: by adjusting counterbalance valve shown in Fig. 1, controlling pressure in high pressure crystal kettle is 12MPa, and is passed through
Preheater and insulating box control temperature in the kettle are 60 DEG C, make CO in kettle2Reach supercriticality；
4) solution sample introduction: as shown in Figure 1, opening high pressure liquid phase pump, the solution that step 1 is configured is passed through by the intermediate channel of kettle head
100 μm of nozzle sprays into crystallization kettle.Before being passed through solution, it is first passed through the ethyl alcohol of 15min and the mixed solvent (volume of methylene chloride
Than 1: 1), system being made to reach balance.The control of sample introduction flow rate is 3mL/min；
5) dry: after sample introduction, to continue to be passed through CO220min is to remove remaining organic solvent；
6) sample in autoclave is collected in pressure release.
Embodiment 4
Prescription:
| Material composition | Prescription matches (%) |
| Itraconazole | 50 |
| Hydroxypropyl methylcellulose | 50 |
Preparation method: 1) preparation of mixed solution: the mixture for accurately weighing 3g Itraconazole and 3g hydroxypropyl methylcellulose is placed in
In 500mL conical flask, the mixed solvent (volume ratio 1: 1) of 200mL ethyl alcohol and methylene chloride is added, makes to be completely dissolved；
2)CO2Charging: as shown in Figure 1, opening CO2Cylinder valve, liquefy CO2By high-pressure pump through symmetrical two channels of kettle head (with
Intermediate solution channel is at 60 °) it is continually introduced into the high pressure crystal kettle of crystalization in supercritical fluid equipment system, coutroi velocity 50mL/
min；
3) regulating and controlling temperature and pressure: by adjusting counterbalance valve shown in Fig. 1, controlling pressure in high pressure crystal kettle is 9MPa, and is passed through
Preheater and insulating box control temperature in the kettle are 50 DEG C, make CO in kettle2Reach supercriticality；
4) solution sample introduction: as shown in Figure 1, opening high pressure liquid phase pump, the solution that step 1 is configured is passed through by the intermediate channel of kettle head
650 μm of nozzle sprays into crystallization kettle.Before being passed through solution, it is first passed through the ethyl alcohol of 15min and the mixed solvent (volume of methylene chloride
Than 1: 1), system being made to reach balance.The control of sample introduction flow rate is 1mL/min；
5) dry: after sample introduction, to continue to be passed through CO230min is to remove remaining organic solvent；
6) sample in autoclave is collected in pressure release.
Embodiment 5
Prescription:
| Material composition | Prescription matches (%) |
| Itraconazole | 40 |
| Hydroxypropyl methylcellulose | 60 |
Preparation method: 1) preparation of mixed solution: the mixture of 2.0g Itraconazole and 3.0g hydroxypropyl methylcellulose is accurately weighed
It is placed in 500mL conical flask, the mixed solvent (volume ratio 1: 1) of 200mL ethyl alcohol and methylene chloride is added, makes to be completely dissolved；
2)CO2Charging: as shown in Figure 1, opening CO2Cylinder valve, liquefy CO2By high-pressure pump through symmetrical two channels of kettle head (with
Intermediate solution channel is at 60 °) it is continually introduced into the high pressure crystal kettle of crystalization in supercritical fluid equipment system, coutroi velocity 75mL/
min；
3) regulating and controlling temperature and pressure: by adjusting counterbalance valve shown in Fig. 1, controlling pressure in high pressure crystal kettle is 13MPa, and is passed through
Preheater and insulating box control temperature in the kettle are 45 DEG C, make CO in kettle2Reach supercriticality；
4) solution sample introduction: as shown in Figure 1, opening high pressure liquid phase pump, the solution that step 1 is configured is passed through by the intermediate channel of kettle head
200 μm of nozzle sprays into crystallization kettle.Before being passed through solution, it is first passed through the ethyl alcohol of 15min and the mixed solvent (volume of methylene chloride
Than 1: 1), system being made to reach balance.The control of sample introduction flow rate is 4mL/min；
5) dry: after sample introduction, to continue to be passed through CO220min is to remove remaining organic solvent；
6) sample in autoclave is collected in pressure release.
The analysis test result of Itraconazole composite particles and preparation prepared by above embodiments of the present invention:
1) equipment operation condition: crystalization in supercritical fluid device used in the present invention is as shown in Fig. 1, due to the improvement of spray head, and
Formula components can be dissolved in solvent for use well, and process operation is steady, be not present spray nozzle clogging phenomenon, temperature fluctuation ±
0.10 DEG C, pressure oscillation ± 0.15MPa；
2) yield and drug-loading efficiency: preparation process of the present invention is higher than 90% without cumbersome solvent removal step, sample yield.And
In operation temperature and pressure limit defined by the present invention, Itraconazole is practically insoluble in supercritical CO2In, gained sample carries
Drug effect rate (percentage of practical drugloading rate and theoretical drugloading rate) is higher than 95%；
3) electron microscope scanning result: as shown in Fig. 2, Itraconazole bulk pharmaceutical chemicals are irregular bulk crystals, and size is uneven.
And sample prepared by the present invention is fluffy white powder, sample dispersion is uniform, and as shown in Fig. 3, primitive is that diameter 1 is micro-
The microballoon of rice or so, size is uniform, no bulk crystals, and this micro-structure of powder is conducive to solubilising, is possible to play in vivo
Better effect；
4) X- powder diffraction characterization result: as shown in Fig. 4, the model that Itraconazole bulk pharmaceutical chemicals are 10 ° -30 ° at the angle of diffraction (2 θ)
In enclosing, there is high-intensitive crystal diffraction peak.And present invention gained Itraconazole composite particles, as shown in Fig. 5, no crystal is special
Diffraction maximum is levied, shows that contained Itraconazole is converted into unformed by crystal type in composite particles.Compared with crystal type, it is unformed by
It is fettered in no lattice, free energy is big, therefore solubility and solution rate are larger；
4) it dissolves out test result: using slurry processes (50 revs/min of revolving speed), measure 50mg Itraconazole raw material and containing same dose
The composite micro-powder of Itraconazole, the dissolution curve in the aqueous solution (37 DEG C of temperature) of pH value 1.2, test result such as 6 institute of attached drawing
Show.As it can be seen that comparing Itraconazole raw material, the dissolution that composite micro-powder is made in the present invention is greatly improved, and curve presents ideal
Almost linear, conducive to effective absorption of drug, and with itraconazole (50mg, JANSSEN disclosed in Japanese orange paper
PHARMACEUTICAL K.K.) dissolution curve similar factors > 60, in subsequent related preparations application and development, be easy to meet one
The evaluation of cause property requires.
Claims (8)
1. a kind of preparation method of Itraconazole composite particles, is prepared, feature exists by crystalization in supercritical fluid equipment system
In: the composite particles are the Itraconazole of 30-60% and the hydroxypropyl methylcellulose and 0%- of 30%-60% by weight percent
20% Macrogol 6000 is dissolved in the mixed solvent of ethanol/dichloromethane, and preparation is precipitated in crystalization in supercritical fluid.
2. the preparation method of Itraconazole composite particles as described in claim 1, is characterized in that: preparation process includes following step
It is rapid:
1) second the preparation of mixed solution: is added in the mixture of Itraconazole and hydroxypropyl methylcellulose and Macrogol 6000
Alcohol/methylene chloride mixed solvent, is completely dissolved；
2)CO2Charging: liquefaction CO2It is at 45 ° through symmetrical two channels and solution channel by high-pressure pump or 60 ° are continually introduced into super face
In the high pressure crystal kettle of boundary's crystallization of fluids equipment system, temperature in the kettle and pressure are regulated and controled by heating device and pressure-regulating valve,
Make CO in kettle2Reach supercriticality；
3) solution sample introduction: being first passed through the mixed solvent of ethanol/dichloromethane by intermediate solution channel, after system reaches balance,
Mixed solvent is changed to the solution continuous sample introduction of step 1) configuration, solvent is quickly and supercritical CO2It is sufficiently mixed and through bottom
Outflow recycling, the particles of solute of formation fall to crystallization kettle bottom；
4) dry: after sample introduction, to continue to be passed through CO210-40min to remove remaining organic solvent, collect high by subsequent pressure release
Press sample in kettle.
3. the preparation method of Itraconazole composite particles as claimed in claim 2, is characterized in that: the Itraconazole and hydroxypropyl
The weight percent of methylcellulose and Macrogol 6000 is 30%: 55%: 15%.
4. the preparation method of Itraconazole composite particles as claimed in claim 2, is characterized in that: the mixed solvent ethyl alcohol/
The volume ratio of methylene chloride is 1: 1.
5. the preparation method of Itraconazole composite particles as claimed in claim 2, is characterized in that: the mass concentration of mixed solution
For 10-50mg/mL.
6. the preparation method of Itraconazole composite particles as claimed in claim 2, is characterized in that: the CO2Flow rate is 50-
100mL/min, pressure 90-200bar, 30-70 DEG C of temperature, the solution flow velocity is 1-10mL/min, and solution channel lower section is pre-
Nozzle diameter processed is 50-800 μm.
7. the preparation method of Itraconazole composite particles as claimed in claim 6, is characterized in that: CO2 flow rate is 50mL/min
Pressure is 110bar, and temperature 50 C, solution flow velocity is 1mL/min, and prefabricated nozzle diameter is 100 μm below solution channel.
8. the purposes of Itraconazole composite particles as described in claim 1, is characterized in that: for direct tablet compressing preparation dispersion
Piece, prepares dry suspensoid agent or Foradil Aerolizer formoterol fumarate at filling capsule.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20020096602A (en) * | 2001-06-21 | 2002-12-31 | 한미약품공업 주식회사 | Process for preparing of itraconazole formulation having improved bioavailability using super-critical fluid |
| CN101780046A (en) * | 2009-01-16 | 2010-07-21 | 北京化工大学 | Itraconazole composite powder and preparation method thereof |
| CN104688536A (en) * | 2015-02-03 | 2015-06-10 | 常州制药厂有限公司 | Preparation method of itraconazole preparation |
-
2017
- 2017-08-03 CN CN201710694269.8A patent/CN109381432A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20020096602A (en) * | 2001-06-21 | 2002-12-31 | 한미약품공업 주식회사 | Process for preparing of itraconazole formulation having improved bioavailability using super-critical fluid |
| CN101780046A (en) * | 2009-01-16 | 2010-07-21 | 北京化工大学 | Itraconazole composite powder and preparation method thereof |
| CN104688536A (en) * | 2015-02-03 | 2015-06-10 | 常州制药厂有限公司 | Preparation method of itraconazole preparation |
Non-Patent Citations (1)
| Title |
|---|
| 康永强等: "基于超临界流体抗溶剂原理的造粒技术及其装置研究进展", 《化工进展》 * |
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