CN109172532A - A kind of itraconazole dispersible tablets and its preparation method and application - Google Patents
A kind of itraconazole dispersible tablets and its preparation method and application Download PDFInfo
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- CN109172532A CN109172532A CN201811243532.2A CN201811243532A CN109172532A CN 109172532 A CN109172532 A CN 109172532A CN 201811243532 A CN201811243532 A CN 201811243532A CN 109172532 A CN109172532 A CN 109172532A
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- itraconazole
- dispersion
- dispersible
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- 239000007919 dispersible tablet Substances 0.000 title claims abstract description 57
- 229960004130 itraconazole Drugs 0.000 title claims abstract description 55
- 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 54
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 239000006185 dispersion Substances 0.000 claims abstract description 43
- 239000012876 carrier material Substances 0.000 claims abstract description 17
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 15
- 239000000945 filler Substances 0.000 claims abstract description 13
- 239000000314 lubricant Substances 0.000 claims abstract description 12
- 239000004615 ingredient Substances 0.000 claims abstract description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 24
- 235000019359 magnesium stearate Nutrition 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 10
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 10
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 10
- 239000000463 material Substances 0.000 claims description 10
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 9
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 9
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 9
- GUBGYTABKSRVRQ-UHFFFAOYSA-N 2-(hydroxymethyl)-6-[4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol Chemical compound OCC1OC(OC2C(O)C(O)C(O)OC2CO)C(O)C(O)C1O GUBGYTABKSRVRQ-UHFFFAOYSA-N 0.000 claims description 8
- 239000012943 hotmelt Substances 0.000 claims description 7
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 7
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 6
- 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 description 6
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 5
- 229960000913 crospovidone Drugs 0.000 claims description 5
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 5
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 5
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 5
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 5
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 5
- 239000000377 silicon dioxide Substances 0.000 claims description 5
- 150000003851 azoles Chemical class 0.000 claims description 3
- 238000003860 storage Methods 0.000 claims description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 2
- 239000003429 antifungal agent Substances 0.000 claims description 2
- -1 hydroxypropyl Chemical class 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 238000012372 quality testing Methods 0.000 claims description 2
- RSWGJHLUYNHPMX-UHFFFAOYSA-N 1,4a-dimethyl-7-propan-2-yl-2,3,4,4b,5,6,10,10a-octahydrophenanthrene-1-carboxylic acid Chemical compound C12CCC(C(C)C)=CC2=CCC2C1(C)CCCC2(C)C(O)=O RSWGJHLUYNHPMX-UHFFFAOYSA-N 0.000 claims 1
- 229960003943 hypromellose Drugs 0.000 claims 1
- 238000005461 lubrication Methods 0.000 claims 1
- 238000003825 pressing Methods 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 11
- 208000019505 Deglutition disease Diseases 0.000 abstract description 2
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 239000007962 solid dispersion Substances 0.000 description 31
- 239000003814 drug Substances 0.000 description 23
- 238000004090 dissolution Methods 0.000 description 21
- 229940079593 drug Drugs 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 238000000034 method Methods 0.000 description 12
- 238000012360 testing method Methods 0.000 description 10
- 239000008186 active pharmaceutical agent Substances 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- 239000002775 capsule Substances 0.000 description 7
- 238000001514 detection method Methods 0.000 description 5
- 238000005516 engineering process Methods 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 229920000858 Cyclodextrin Polymers 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001125 extrusion Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 3
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 3
- 238000010586 diagram Methods 0.000 description 2
- 238000009474 hot melt extrusion Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000005498 polishing Methods 0.000 description 2
- 238000010298 pulverizing process Methods 0.000 description 2
- 238000007873 sieving Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- ZUAAPNNKRHMPKG-UHFFFAOYSA-N acetic acid;butanedioic acid;methanol;propane-1,2-diol Chemical compound OC.CC(O)=O.CC(O)CO.OC(=O)CCC(O)=O ZUAAPNNKRHMPKG-UHFFFAOYSA-N 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000009507 drug disintegration testing Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229920000578 graft copolymer Polymers 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 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 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000011812 mixed powder Substances 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229940048490 onmel Drugs 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000007500 overflow downdraw method Methods 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000035943 smell Effects 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940042055 systemic antimycotics triazole derivative Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000010148 water-pollination Effects 0.000 description 1
Classifications
-
- 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
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of itraconazole dispersible tablets and its preparation method and application.Itraconazole dispersible tablets of the invention include dispersion and ingredient；Wherein, the dispersion is made of Itraconazole and carrier material, and the ingredient includes filler, disintegrating agent and lubricant；Wherein, the weight ratio ratio of the Itraconazole in the dispersion and carrier material is 1:1.5~2；The dispersion accounts for the 40~45% of dispersible tablet gross weight, and the filler accounts for the 50~55% of dispersible tablet gross weight, and the disintegrating agent accounts for the 1~5% of dispersible tablet gross weight, and the lubricant accounts for the 0.05~0.1% of dispersible tablet gross weight.Itraconazole dispersible tablets prepared by the present invention are taken after water dispersion can be added uniform, the use suitable for special populations such as patients that is old, young and having dysphagia.Preparation process of the present invention is simple, can be continuously produced, and preparation section is few, is suitable for large-scale production.
Description
Technical field
The present invention relates to a kind of itraconazole dispersible tablets and its preparation method and application, belong to pharmaceutical technology field.
Background technique
Itraconazole is artificial synthesized triazole derivatives, is a kind of broad-spectrum antifungal medicine of synthesis, pka 3.7,
With stronger lipophilicity, it is practically insoluble in water, BCS is classified as II class, belongs to the drug of high osmosis low solubility.It is dissolved
Degree has pH dependence, and in the hydrochloric acid solution of pH=1, saturation solubility is about 5ug/ml, in solution of the pH greater than 2 almost
It cannot dissolve.Due to the slightly solubility of Itraconazole, lead to its dissolution rate very little in the gastrointestinal tract, takes orally Absolute oral and utilize
Spend it is low, about 55% or so, limit the performance of Itraconazole drug effect.Therefore it studies a kind of effective dosage form and technology improves medicine
The oral absorption of object is very important.
By insoluble drug prepared composition discrete piece, drug disintegration and evenly dispersed, conventional tablet rapidly in water can be made
Or capsule haves the shortcomings that disintegration rate is slow, absorption of drugs has a certain impact.Dispersible tablet is in 19~21 DEG C of water
It is disintegrated completely in general 3min, greatly increases the trap of drug.The specification of Itraconazole preparation is 100 or 200mg, city
The Itraconazole tablet ONMEL piece sold weighs 900mg or so, for old, young and have the Case treatment of dysphagia to have one
Fixed difficulty, will be convenient to taking for special population for Itraconazole prepared composition discrete piece.
The bioavilability major way for improving insoluble drug can be by reducing the partial size of bulk pharmaceutical chemicals, increasing hydrophily
The modes such as auxiliary material, for Itraconazole compound itself the characteristics of, by reduce raw material particle size can no longer meet demand, and
Dispersion technology can effectively improve the bioavilability of drug.Common dispersion technology has polishing, solvent method, fusion method
Deng it is limited forming dispersion effect by comparing above-mentioned three kinds of methods, in polishing time-consuming, although solvent method can greatly improve
Its solubility, but a large amount of organic solvent can be used during the preparation process, problem of environmental pollution has to be solved and industrialization difficulty
Greatly, and hot melt solves the limitation of above two method, can be very good the dissolubility for improving drug, and then can be effective
Raising bioavilability.
Solid dispersions refer to that drug is highly dispersed at a kind of solid matter formed in suitable carrier material, are similar to
The solution or suspension of liquid system.In solid dispersions, the dissolution rate of drug is largely dependent on the property of carrier
With preparation process.Requirement to carrier is: water solubility, physiology inert, nontoxic；It is not chemically reacted with drug, does not influence to lead
The chemical stability of medicine；It is easy to make drug in optimum dispersion state；Source is easy, low in cost.Solid dispersions have developed
Three generations, the first generation are using crystal materials such as urea as material, and it is material that the second generation, which is then PEG, PVP etc., the third generation then with
Surfactant is material, and the solid dispersions listed in recent years are then using HPMC or HPMCAS as the in the majority of carrier.The technology can be with
The solubility and dissolution rate for increasing insoluble medicine, delay or Drug controlled release, improve the stabilization of drug, cover adverse drug
The advantages of smell and irritation, reduction toxic side effect, but simultaneously because the stability of drug dispersity is not high, storage can generate long
Aging phenomenon, the validity period disadvantage shorter compared with tablet.Therefore the solid dispersions in China also need constantly to explore and develop.
Summary of the invention
Itraconazole is insoluble drug, and bioavilability is low, disintegration rapidly after prepared composition discrete piece can make it oral,
Accelerate the absorption and utilization of drug in vivo, to improve bioavilability.
The purpose of the present invention is to provide a kind of itraconazole dispersible tablets and its preparation method and application.
Specifically, the present invention provides a kind of itraconazole dispersible tablets, which is characterized in that including dispersion and ingredient；Its
In, the dispersion is made of Itraconazole and carrier material, and the ingredient includes filler, disintegrating agent and lubricant；Wherein,
The weight ratio ratio of Itraconazole and carrier material in the dispersion is 1:1.5~2；The dispersion accounts for dispersible tablet gross weight
40~45%, the filler accounts for the 15~55% of dispersible tablet gross weight, and the disintegrating agent accounts for the 2~40% of dispersible tablet gross weight,
The lubricant accounts for the 0.05~3% of dispersible tablet gross weight.
Preferably, the carrier material is hydroxypropyl methylcellulose；It is furthermore preferred that the carrier material is hydroxypropyl methylcellulose
E3。
Preferably, the filler is selected from one of microcrystalline cellulose, lactose, silicified microcrystalline cellulose or combinations thereof；
It is furthermore preferred that the filler is silicified microcrystalline cellulose.
Preferably, the disintegrating agent be selected from low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium its
One of or combinations thereof；It is furthermore preferred that the disintegrating agent is croscarmellose sodium.
Preferably, the lubricant is selected from one of magnesium stearate, stearic acid, silica or combinations thereof；More preferably
, the lubricant is magnesium stearate.
Preferably, the weight ratio ratio of the Itraconazole in the dispersion and carrier material is 1:2.
Preferably, the dispersion accounts for the 42.89% of dispersible tablet gross weight, and the filler accounts for dispersible tablet gross weight
54.05%, the disintegrating agent accounts for the 3.00% of dispersible tablet gross weight, and the lubricant accounts for the 0.06% of dispersible tablet gross weight.
Preferably, the average grain diameter of the dispersion is 80~425 μm；It is furthermore preferred that the average grain diameter of the dispersion
It is 125~150 μm.
The present invention also provides the preparation methods of the itraconazole dispersible tablets, which comprises the following steps:
(1) Itraconazole and carrier material are weighed by parts by weight of the invention, the two are uniformly mixed, form mixture,
It is spare；
(2) mixture obtained step (1) is added in hot-melt extruded machine, sets the temperature of extruder as 120~170
DEG C, screw speed is 40~100rpm, will squeeze out obtained club and carries out physical mechanical crushing, then leads to and sieve with 100 mesh sieve, can
Obtain dispersion；
(3) dispersion that step (2) obtains is mixed by parts by weight of the invention and filler, disintegrating agent, lubricant
Dispersible tablet is made in tabletting after conjunction；
(4) dispersible tablet for obtaining step (3) carries out quality testing, packs after qualified, labels, storage.
The present invention also provides the itraconazole dispersible tablets to prepare the application in antifungal drug.
Itraconazole dispersible tablets prepared by the present invention are taken after water dispersion can be added uniform, suitable for old, young and swallow function
The use of the special populations such as the patient of energy obstacle.Preparation process of the present invention is simple, can be continuously produced, and preparation section is few, is suitble to
In large-scale production.
Detailed description of the invention
Fig. 1 is solubility three-dimensional curve diagram of the Itraconazole in different pH value and various concentration solubilizer；
Fig. 2 is the DSC map of the solid dispersions of the API:HPMC-E3=1:2 of the embodiment of the present invention 1；
Fig. 3 is the DSC map of the solid dispersions of the API:Soluplus=1:3 of the embodiment of the present invention 1；
Fig. 4 be the embodiment of the present invention 2 API and HPMC-E3 under different proportion 10 days solid dispersions of high temperature and humidity
DSC map；
Fig. 5 be 60~80 mesh partial sizes of the embodiment of the present invention 3 solubility of the solid dispersions under testing conditions (1) with
The linear relationship chart of time；
Fig. 6 is solubility of the solid dispersions of 80~100 mesh partial sizes of the embodiment of the present invention 3 under testing conditions (1)
With the linear relationship chart of time；
Fig. 7 is solubility of the solid dispersions of 100~120 mesh partial sizes of the embodiment of the present invention 3 under testing conditions (1)
With the logarithmic relationship figure of time；
Fig. 8 is dissolution of the 120 smaller solid dispersions of mesh partial size of ratio of the embodiment of the present invention 3 under testing conditions (1)
The logarithmic relationship figure of degree and time；
Fig. 9 is that intrinsic dissolution of the solid dispersions under testing conditions (1) under 3 different-grain diameter of the embodiment of the present invention is bent
Line；
Figure 10 is that intrinsic dissolution of the solid dispersions under testing conditions (2) under 3 different-grain diameter of the embodiment of the present invention is bent
Line；
Figure 11 is the In Vitro Dissolution curve graph and Model fitting figure of reference capsule in the embodiment of the present invention 4~6；
Figure 12 is the embodiment of the present invention 4~6 and dissolution curve of the reference capsule in 0.1M hydrochloric acid.
Specific embodiment
The invention will now be further described with reference to specific embodiments, the advantages and features of the present invention will be with description and
It is apparent.But examples are merely exemplary for these, and it is not intended to limit the scope of the present invention in any way.Those skilled in the art
Member it should be understood that without departing from the spirit and scope of the invention can details to technical solution of the present invention and form into
Row modifications or substitutions, but these modifications and replacement are fallen within the protection scope of the present invention.
Itraconazole reference capsule used in this part is purchased from Xian-Janssen Pharmaceutical Ltd., trade name (Itraconazole Capsules), lot number 160901267；Hydroxypropyl methylcellulose E3 (HPMC-
E3) it is purchased from DOW Chemical；Polyvinylcaprolactame-polyvinyl acetate-polyethyleneglycol-graft copolymer (Soluplus) is purchased from
German BASF.
The preparation method of dispersion
Firstly, by Itraconazole different pH value (2.0~6.8) and various concentration solubilizer (cyclodextrin 0~
50%) (referring to Fig. 1, wherein X-axis is pH value to solubility three-dimensional curve diagram, and Z axis is cyclodextrin concentration, and Y-axis is saturation solubility
(mg/L)) as can be seen that the solubility for increasing bulk pharmaceutical chemicals need to keep pH value in lower situation (such as pH value is less than 1) and
The concentration of cyclodextrin is improved, which is not suitable for industrialization production, therefore hot-melt extruded is more suitable for.
The selection of 1 carrier material of embodiment
Weigh two parts of 100g Itraconazole, then weigh 200g HPMC-E3 and 300g Soluplus, respectively with Yi Qukang
Two kinds of mixtures of azoles composition API:HPMC-E3=1:2 and API:Soluplus=1:3.After mixing, it is separately added into hot melt
In extruder, twin screw hot melt extrusion temperature is set as 150~155 DEG C.After temperature reaches set temperature, screw rod is opened, is turned
Speed is set as 40rpm.Object to be mixed is after screw rod extrusion in a strip shape, by pulverization process after extrudate cooling.Inspection measurement respectively
DSC map.
Testing result is as shown in figures 2-3, it can be seen that the two at 166 DEG C without endothermic peak, it is possible thereby to determine bulk pharmaceutical chemicals
Solid dispersions have been formed with carrier.From obtaining channel and cost angle Selection HPMC-E3 as carrier material of the invention more
It is suitble to industrialization.
The selection of embodiment 2 Itraconazole and carrier material usage ratio
Weigh three parts of 200g Itraconazole, then weigh 200g, 300g, 400g hydroxypropyl methylcellulose E3, respectively with Yi Qu
Health azoles composition API:HPMC ratio is respectively three kinds of mixtures of 1:1,1:1.5,1:2.After mixing, half is respectively taken out to be added
In hot-melt extruded machine, the other half is spare.Twin screw hot melt extrusion temperature is set as 150~155 DEG C.When temperature reaches set temperature
Afterwards, screw rod is opened, revolving speed is set as 5~40rpm.Object to be mixed will crush after screw rod extrusion in a strip shape after extrudate cooling
80 mesh screens are crossed in processing.Then by obtained three kinds of solid dispersions, and the solid of three kinds of previously spare physical mixeds
Powder is put into hydrochloric acid solution respectively, forms supersaturated solution.Appropriate each solution filtering is taken in 15min and for 24 hours respectively, is carried out
Detect API content detection.
Testing result is as shown in Figure 4 and Table 1, wherein it is 1 that the curve in Fig. 4, which is from top to bottom followed successively by API:HPMC ratio:
It 60 DEG C of high temperature of 1 places to place within 10 days, ratio be 1:1.5 60 DEG C of high temperature 10 days, ratio be 1:2 60 DEG C of high temperature and places 10
It, ratio be 1:1 high humidity 92.5% place 10 days, ratio be 1:1.5 high humidity 92.5% place 10 days, ratio be 1:2's
High humidity 92.5% is placed 10 days.As can be seen that the solubility of three kinds of physical mixed powder itself is extremely low, and it is prepared into solid dispersion
Itraconazole own solubility can be obviously increased after body.In addition, the poor solubility of three kinds of solid dispersions in 15min and for 24 hours
It is different smaller, and increasing with HPMC-E3 dosage, difference fades away, therefore the present invention selects the faster 1:2 ratio of rate of dissolution
Preferred proportion of the example as Itraconazole and carrier material.
Table 1
The selection of 3 Itraconazole dispersion particle diameters of embodiment
100g Itraconazole is weighed, 200g hydroxypropyl methylcellulose E3, physical mixed is uniform, and setting twin screw hot melt squeezes out temperature
Degree is 150~155 DEG C.After temperature reaches set temperature, screw rod is opened, revolving speed is set as 40~100rpm.Object warp to be mixed
After screw rod extrusion in a strip shape, by extrudate it is cooling after pulverization process, be sieved respectively, obtain 60~80 mesh, 80~100 mesh, 100~
120 mesh and solid dispersions more smaller than 120 mesh partial sizes.Then it is intrinsic molten it to be detected respectively to the solid dispersions of four kinds of partial sizes
Curve out, Detection wavelength 254nm, testing conditions are divided into: (1) 0.04N hydrochloric acid solution, paddle method 50rpm, dissolve out volume:
1000ml；(2) 0.1M hydrochloric acid solution, paddle method 75rpm dissolve out volume: 1000ml.
Testing result is as shown in Figure 5-10, it can be seen that in condition (2), the dissolution of the solid dispersions of different-grain diameter
Curve difference is little, and the smaller dissolution rate of partial size is faster.And in condition (1), the solid dispersions of different-grain diameter have difference
Dissolution trend, can preferably distinguish the solid dispersions of different-grain diameter, specifically: the solid dispersions of 60~100 mesh
Dissolution curve linear trend is presented, and the trend of logarithmic form is then presented in dispersion more smaller than 100 mesh partial sizes.Therefore, originally
The solid dispersions of invention preferable particle size (can lead to and sieve with 100 mesh sieve) smaller than 100 mesh.
Embodiment 4
The group of the itraconazole dispersible tablets of the present embodiment becomes (1000):
| Weight (g) | Account for gross weight percentage (%) | |
| Solid dispersions made from embodiment 3 | 300 | 41.76 |
| Low-substituted hydroxypropyl cellulose | 250 | 34.80 |
| Microcrystalline cellulose | 110 | 15.31 |
| Silica | 18 | 2.51 |
| Croscarmellose sodium | 40 | 5.57 |
| Magnesium stearate | 0.4 | 0.06 |
| Gross weight | 718.4 | —— |
| Slice weight | 0.7184 | —— |
Taking the partial size prepared according to embodiment 3 is respectively 60~80 mesh, 120 mesh grains of 80~100 mesh, 100~120 mesh and ratio
Each 300g of the smaller solid dispersions of diameter, separately weighs auxiliary material low-substituted hydroxypropyl cellulose, microcrystalline cellulose by the formula of the present embodiment
Element, silica, croscarmellose sodium and magnesium stearate.Each dispersion and auxiliary material are sufficiently mixed uniformly respectively, pressed
Slice weight is according to reason discussed, itraconazole dispersible tablets are suppressed using special-shaped stamping die.
The present embodiment maximum can press hardness 15kg in tableting processes.The dispersible tablet extruded using 60~80 mesh dispersions, piece
Agent stain is more, rough surface.After dispersing in water, particle is larger and coarse.As dispersion particle diameters are smaller, one-sided situation by
Gradually improve.Using dispersion tabletting more smaller than 100 mesh partial sizes, tablet stain is less, and tablet surface is smooth, room temperature condition
Under disintegration is completely dispersed in 3min in 0.1M hydrochloric acid, disintegration is completely dispersed in 2min in water.
In Vitro Dissolution detection, experiment condition: dissolution medium 0.1M hydrochloric acid solution 1000ml, revolving speed are carried out to each dispersible tablet
75rpm, detection method: UV, Detection wavelength: 254nm.The results show that the dispersion that dispersion more smaller than 100 mesh partial sizes is extruded
Piece dissolution rate in 15min has been above the 85% of labelled amount, hence it is evident that higher than commercial reference capsule dissolution rate (referring to Figure 11-
12).Therefore speculate that the dispersible tablet for taking the present embodiment can disperse rapidly to be disintegrated in vivo, quick release accelerates the suction of drug
It receives, is conducive to improve the intracorporal bioavilability of people.By the dispersible tablet that is extruded by dispersion more smaller than 100 mesh partial sizes
Better effect, therefore it is elected to be the preferred solution of the invention, and will sieve with 100 mesh sieve in the present embodiment and subsequent embodiment as default
Operation.
Embodiment 5
The group of the itraconazole dispersible tablets of the present embodiment becomes (1000):
| Weight (g) | Account for gross weight percentage (%) | |
| Solid dispersions made from embodiment 3 | 300 | 42.96 |
| Crospovidone | 20 | 2.86 |
| Silicified microcrystalline cellulose | 378 | 54.12 |
| Magnesium stearate | 0.4 | 0.06 |
| Gross weight | 698.4 | —— |
| Slice weight | 0.6984 | —— |
Since supplementary product kind is excessive in the formula of embodiment 4, production process is complicated, therefore using crospovidone instead of low
Replace hydroxypropylcellulose and croscarmellose sodium, replaces microcrystalline cellulose with silicified microcrystalline cellulose, use magnesium stearate
Instead of magnesium stearate and silica.
It is micro- separately to weigh crospovidone, silication by the solid dispersions 300g (sieving 100 mesh) prepared in Example 3
Crystalline cellulose and magnesium stearate.Dispersion and auxiliary material are sufficiently mixed uniformly, according to theoretical slice weight, suppressed using special-shaped stamping die
Itraconazole dispersible tablets.
It is 20kg that tableting processes maximum, which can press hardness, unilateral preferable, cannot be disintegrated completely in 3min in water.
Its dissolution curve is detected under conditions of same as Example 4.The results show that its dissolution rate is excessively slow, it is main former
Because being that the disintegration of tablet performance is poor, tablet surface forms one layer of mucous membrane after meeting water, and moisture is stopped to enter, and tablet can not be disintegrated point
It dissipates, causes dissolution rate relatively low (referring to Figure 12).
Embodiment 6
The group of the itraconazole dispersible tablets of the present embodiment becomes (1000):
| Weight (g) | Account for gross weight percentage (%) | |
| Solid dispersions | 300 | 42.89 |
| Silicified microcrystalline cellulose | 378 | 54.05 |
| Croscarmellose sodium | 21 | 3.00 |
| Magnesium stearate | 0.4 | 0.06 |
| Gross weight | 699.4 | —— |
| Slice weight | 0.6994 | —— |
For the disintegrating property for improving dispersible tablet in embodiment 5, disintegrating agent is changed to croscarmellose sodium.
The solid dispersions 30g (100 mesh of sieving) prepared in Example 3, separately weighs silicified microcrystalline cellulose, crosslinking
Sodium carboxymethylcellulose and magnesium stearate.Dispersion and auxiliary material are sufficiently mixed uniformly, according to theoretical slice weight, using special-shaped punch die
Tool compacting itraconazole dispersible tablets.
It is 20kg that tableting processes maximum, which can press hardness, unilateral preferable, complete in 1min in 0.1M hydrochloric acid under room temperature
Dispersion disintegration, is completely dispersed disintegration in water in 30s.
Its dissolution curve is detected under conditions of same as Example 4.The results show that its in 15min, dissolution rate has been
Greater than the 85% of labelled amount, hence it is evident that be higher than commercial reference capsule (referring to Figure 12).Therefore speculate and in vivo may be used after this prescription is taken
With rapid dispersion disintegration, then quick release, accelerates the absorption of drug, is conducive to improve it in the intracorporal bioavilability of people,
And it is less compared with the used supplementary product kind of embodiment 4, and it is essentially identical to be disintegrated level, therefore selects the present embodiment as of the invention
Preferred embodiment is more advantageous to industrialization.
Claims (10)
1. a kind of itraconazole dispersible tablets, which is characterized in that including dispersion and ingredient；Wherein, the dispersion is by Yi Qukang
Azoles and carrier material composition, the ingredient includes filler, disintegrating agent and lubricant；
Wherein, the weight ratio ratio of the Itraconazole in the dispersion and carrier material is 1:1.5~2；The dispersion accounts for
The 40~45% of dispersible tablet gross weight, the filler account for the 15~55% of dispersible tablet gross weight, and the disintegrating agent accounts for dispersible tablet gross weight
2~40%, the lubricant accounts for the 0.05~3% of dispersible tablet gross weight.
2. itraconazole dispersible tablets according to claim 1, which is characterized in that the carrier material is hypromellose
Element, preferably hydroxypropyl methylcellulose E3.
3. itraconazole dispersible tablets according to claim 1, which is characterized in that the filler be selected from microcrystalline cellulose,
One of lactose, silicified microcrystalline cellulose or combinations thereof, preferably silicified microcrystalline cellulose.
4. itraconazole dispersible tablets according to claim 1, which is characterized in that it is fine that the disintegrating agent is selected from low-substituted hydroxypropyl
Tie up one of element, crospovidone, croscarmellose sodium or combinations thereof, preferably croscarmellose sodium.
5. itraconazole dispersible tablets according to claim 1, which is characterized in that the lubricant is selected from magnesium stearate, hard
One of resin acid, silica or combinations thereof, preferably magnesium stearate.
6. itraconazole dispersible tablets according to claim 1, which is characterized in that Itraconazole and load in the dispersion
The weight ratio ratio of body material is 1:2.
7. itraconazole dispersible tablets according to claim 1, which is characterized in that the dispersion accounts for dispersible tablet gross weight
42.89%, the filler accounts for the 54.05% of dispersible tablet gross weight, and the disintegrating agent accounts for the 3.00% of dispersible tablet gross weight, the profit
Lubrication prescription accounts for the 0.06% of dispersible tablet gross weight.
8. itraconazole dispersible tablets according to claim 1, which is characterized in that the average grain diameter of the dispersion be 80~
425 μm, preferably 125~150 μm.
9. the preparation method of itraconazole dispersible tablets as described in any one of claims 1 to 8, which is characterized in that including following
Step:
(1) proportion for pressing claim 1, weighs Itraconazole and carrier material, the two is uniformly mixed, and forms mixture, standby
With；
(2) mixture obtained step (1) is added in hot-melt extruded machine, sets the temperature of extruder as 120~170 DEG C, spiral shell
Bar revolving speed is 40~100rpm, will squeeze out obtained club and carries out physical mechanical crushing, then leads to and sieve with 100 mesh sieve, can be obtained
Dispersion；
(3) after the proportion by dispersion that step (2) obtains according to claim 1 is mixed with filler, disintegrating agent, lubricant
Dispersible tablet is made in tabletting；
(4) dispersible tablet for obtaining step (3) carries out quality testing, packs after qualified, labels, storage.
10. itraconazole dispersible tablets as described in any one of claims 1 to 8 are preparing the application in antifungal drug.
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| CN114652685A (en) * | 2022-04-19 | 2022-06-24 | 苏州中化药品工业有限公司 | Itraconazole capsule with high bioavailability |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1209740A (en) * | 1996-05-20 | 1999-03-03 | 詹森药业有限公司 | Anti-fungus composition with improved biological utilization ratio |
| CN1285746A (en) * | 1997-12-31 | 2001-02-28 | 中外制药株式会社 | Method and composition of an oral preparation of itraconazole |
| WO2002100407A1 (en) * | 2001-06-12 | 2002-12-19 | Smartrix Technologies Inc. | Itraconazole granulations: pharmaceutical formulations for oral administration and method of preparing same |
| WO2007017248A2 (en) * | 2005-08-08 | 2007-02-15 | Abbott Gmbh & Co. Kg | Itraconazole compositions with improved bioavailability |
| CN102499909A (en) * | 2011-12-27 | 2012-06-20 | 哈尔滨三联药业有限公司 | Itraconazole dispersible tablets and preparation method thereof |
-
2018
- 2018-10-24 CN CN201811243532.2A patent/CN109172532A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1209740A (en) * | 1996-05-20 | 1999-03-03 | 詹森药业有限公司 | Anti-fungus composition with improved biological utilization ratio |
| CN1285746A (en) * | 1997-12-31 | 2001-02-28 | 中外制药株式会社 | Method and composition of an oral preparation of itraconazole |
| WO2002100407A1 (en) * | 2001-06-12 | 2002-12-19 | Smartrix Technologies Inc. | Itraconazole granulations: pharmaceutical formulations for oral administration and method of preparing same |
| WO2007017248A2 (en) * | 2005-08-08 | 2007-02-15 | Abbott Gmbh & Co. Kg | Itraconazole compositions with improved bioavailability |
| CN102499909A (en) * | 2011-12-27 | 2012-06-20 | 哈尔滨三联药业有限公司 | Itraconazole dispersible tablets and preparation method thereof |
Non-Patent Citations (3)
| Title |
|---|
| KEEN,JM ET AL: "Development of Itraconazole Tablets Containing Viscous KinetiSol Solid Dispersions: In Vitro and In Vivo Analysis in Dogs", 《AAPS PHARMSCITECH》 * |
| 关志宇: "《药物制剂辅料与包装材料》", 31 January 2017 * |
| 单利等: "基于流化床包衣工艺的伊曲康唑速释微丸的制备和评价研究", 《中国药学杂志》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114652685A (en) * | 2022-04-19 | 2022-06-24 | 苏州中化药品工业有限公司 | Itraconazole capsule with high bioavailability |
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