CN1853634A - Composition comprising itraconazole for oral administration - Google Patents
Composition comprising itraconazole for oral administration Download PDFInfo
- Publication number
- CN1853634A CN1853634A CNA2006100651366A CN200610065136A CN1853634A CN 1853634 A CN1853634 A CN 1853634A CN A2006100651366 A CNA2006100651366 A CN A2006100651366A CN 200610065136 A CN200610065136 A CN 200610065136A CN 1853634 A CN1853634 A CN 1853634A
- Authority
- CN
- China
- Prior art keywords
- itraconazole
- solid dispersion
- weight portion
- orally administered
- administered composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 69
- 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 description 83
- 229960004130 itraconazole Drugs 0.000 title claims description 83
- 239000007962 solid dispersion Substances 0.000 claims abstract description 62
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 21
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- 239000001863 hydroxypropyl cellulose Substances 0.000 claims abstract description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims abstract description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical group C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 42
- -1 hydroxypropyl Chemical group 0.000 claims description 24
- 241001597008 Nomeidae Species 0.000 claims description 21
- 238000010521 absorption reaction Methods 0.000 claims description 19
- 239000003623 enhancer Substances 0.000 claims description 18
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- 238000000034 method Methods 0.000 claims description 13
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- 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 11
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- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 6
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 claims description 6
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 5
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 5
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
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- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 claims description 4
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- 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 3
- 235000010323 ascorbic acid Nutrition 0.000 claims description 3
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- 229910001629 magnesium chloride Inorganic materials 0.000 claims description 3
- 235000011147 magnesium chloride Nutrition 0.000 claims description 3
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 claims description 2
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 claims description 2
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000004380 Cholic acid Substances 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 2
- 239000003613 bile acid Substances 0.000 claims description 2
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 claims description 2
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- 229960002471 cholic acid Drugs 0.000 claims description 2
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 claims description 2
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 24
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- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229960000540 polacrilin potassium Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- WVWZXTJUCNEUAE-UHFFFAOYSA-M potassium;1,2-bis(ethenyl)benzene;2-methylprop-2-enoate Chemical compound [K+].CC(=C)C([O-])=O.C=CC1=CC=CC=C1C=C WVWZXTJUCNEUAE-UHFFFAOYSA-M 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 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 1
- 238000012216 screening Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 239000001540 sodium lactate Substances 0.000 description 1
- 229940005581 sodium lactate Drugs 0.000 description 1
- 235000011088 sodium lactate Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 235000011008 sodium phosphates Nutrition 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 238000009492 tablet coating Methods 0.000 description 1
- 239000002700 tablet coating Substances 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 235000019222 white chocolate Nutrition 0.000 description 1
Images
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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Physiology (AREA)
- Nutrition Science (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an intake composition with Yiqu-pyrazole, which comprises the following parts: 40-69.9 wt% solid dispersion, 0.1-30 wt% penetrating inducer and 0.1-30 wt% disintegration agent, wherein the solid dispersion is prepared by dispersing 1 wt% Yiqu-pyrazole in the 0.1-10wt% methyl hydroxypropylcellulose to mix with 0.01-5wt% absorbing accelerating agent in the composition at amorphous pattern.
Description
The mutual reference of related application
The application requires the priority of the korean patent application No.10-2005-0022312 that submits on March 17th, 2005, and this description is included in described application by reference mode hereby in, so that it is as complete in this manual proposition.
Invention field
The present invention relates to a kind of Orally administered composition, described compositions contains the solid dispersion of 40～69.9wt% (percentage by weight), the infiltration derivant of 0.1～30wt% and the disintegrating agent (disintegrant) of 0.1～30wt%, wherein, described solid dispersion is dispersed in by the itraconazole with 1 weight portion in the absorption enhancer mixture of the hydroxypropyl emthylcellulose of 0.1～10 weight portion and 0.01～5 weight portion and prepares with amorphism.
Background technology
Itraconazole, be called again (±)-suitable-4-that (((((2-(2 for 4-for 4-for 4-, the 4-Dichlorobenzene base)-2-(1H-1,2,4-triazol-1-yl methyl)-1,3-dioxolanes-4-yl) phenyl methoxyl group))-and the 1-piperazinyl)-2,4-dihydro-2-(1-methyl-propyl)-3H-1,2,4-triazole-3-ketone, having known it is a kind of fungicidal agents with antifungal broad spectrum activity, particularly a kind of safe and effective medicine for the treatment of dermatomycosis.Yet although itraconazole has effective Fungicidally active, it is a kind of insoluble drugs, and its water solublity and pKa value are all lower, is respectively below the 1 μ g/ml with 3.7, so promptly be ionized under very low pH.Therefore, there is the low-down problem of its bioavailability in itraconazole when oral administration.
For the water solublity that improves itraconazole to improve its bioavailability, WO 85/002767 and US 4,764,604 disclose the clathrate (includedcomplex) of a kind of itraconazole and cyclodextrin, but all fail to improve the water solublity of itraconazole.In addition, US 5,504,105 disclose a kind of oral Pharmaceutical composition, this pharmaceutical composition is characterised in that active component is dispersed in hydrogenated vegetable oil, medium chain triglycerides, white chocolate and the soybean lecithin, but its bioavailability has only improved 1.2～1.8 times at the most, and is very little to the influence of active component effect.
WO 97/44014 discloses a kind of solid dispersion of itraconazole, this solid dispersion has the influence of high bioavailability and unable to take food thing, its preparation is by adopting fusion-extrusion molding with itraconazole with such as mixture heated to 245～265 of water-soluble polymers such as hydroxypropyl emthylcellulose ℃, so that fused itraconazole is dispersed in the unfused water-soluble polymer.Yet wherein have several problems: fusion method should carry out under up to 245～265 ℃ temperature, and fused itraconazole is difficult to be evenly dispersed in the polymer.In addition, unfused itraconazole is in vivo residual, thereby stripping or absorption in vivo had side effects.
Korean Patent communique No.2001-0098419 discloses a kind of method that realizes solid dispersion, be about in the mixture that insoluble itraconazole is dispersed in polyvinylpyrrolidone and a kind of absorption enhancer, thereby the crystal form medicine is made for the amorphism medicine, to significantly improve water solublity.Yet, its problem is that the disintegrate of solid dispersion does not take place for a long time, and the dissolution of itraconazole (dissolution rate) is low, and this is because used excessive polyvinylpyrrolidone, even when in mimic gastric juice, solid preparation being carried out dissolution test, also be like this.
Therefore, needing a kind of insoluble drugs of exploitation is the higher Orally administered composition of bioavailability of itraconazole.
Summary of the invention
The present inventor finds, to permeate derivant, for example potassium chloride, magnesium carbonate etc., and disintegrating agent is when being added in the solid dispersion in the mixture that itraconazole wherein is scattered in hydroxypropyl emthylcellulose and absorption enhancer, the dissolving out capability of insoluble itraconazole can suitably be controlled and be significantly improved, thereby realizes the present invention.
Therefore, the object of the present invention is to provide a kind of Orally administered composition, described Orally administered composition contains solid dispersion, infiltration derivant and disintegrating agent, and wherein said solid dispersion is by preparing with amorphism in the mixture that itraconazole is dispersed in hydroxypropyl emthylcellulose and absorption enhancer.
Another object of the present invention is to provide a kind of preparation to contain the method for the Orally administered composition of itraconazole, the itraconazole of said composition has high bioavailability, described method comprises: itraconazole is dispersed in the mixture of hydroxypropyl emthylcellulose and absorption enhancer to prepare amorphous solid dispersion, then described solid dispersion is mixed mutually with infiltration derivant and disintegrating agent.
Another object of the present invention is to provide a kind of solid dispersion, and this solid dispersion is by in the mixture that itraconazole is dispersed in hydroxypropyl emthylcellulose and absorption enhancer and prepare with amorphism.
Description of drawings
It is the result of 1.2 o'clock dissolution test at pH that Fig. 1 shows the compositions that is made by the embodiment of the invention and Comparative Examples.
●: embodiment 2,
Zero: embodiment 3,
▲: Comparative Examples 1,
△: Comparative Examples 2.
Fig. 2 shows the result of the dissolution test of the compositions that made by the embodiment of the invention 2 and commercial preparation.
●: embodiment 2,
: the commercial preparation (Sporanox of Janssen Korea Ltd.
TMCapsule).
Fig. 3 shows the result of the dissolution test of compositions when pH4.0 and pH6.8 that is made by the embodiment of the invention 2 and Comparative Examples 2.
▲: pH4.0+1% polysorbate80 (Polysorbate 80), the compositions of embodiment 2,
■: the pH4.0+1% polysorbate80, the compositions of Comparative Examples 2,
△: the pH6.8+1% polysorbate80, the compositions of embodiment 2,
: pH6.8+1% polysorbate80, the compositions of Comparative Examples 2.
The result of the dissolution test of solid dispersion (SDH) when pH1.2 and pH4.0 that Fig. 4 shows the solid dispersion (SDP) that contains polyvinylpyrrolidone and contains hydroxypropyl emthylcellulose.
▲：SPD-pH1.2，
△：SDH-pH1.2，
■：SDP-pH4.0，
□：SDH-pH4.0。
The specific embodiment
In conjunction with following detailed description, evaluation and the attendant advantages thereof more complete to the present invention will be more obvious along with the intensification of understanding.
The present invention relates to a kind of Orally administered composition, described compositions contains the solid dispersion of 40～69.9wt%, the infiltration derivant of 0.1～30wt% and the disintegrating agent of 0.1～30wt%, wherein, described solid dispersion is dispersed in by the itraconazole with 1 weight portion in the absorption enhancer mixture of the hydroxypropyl emthylcellulose of 0.1～10 weight portion and 0.01～5 weight portion and prepares with amorphism.
In addition, the invention still further relates to the method that a kind of preparation contains the Orally administered composition of itraconazole, the itraconazole of said composition has high bioavailability, and described method comprises the steps:
The itraconazole of 1 weight portion is dispersed in the absorption enhancer mixture of the hydroxypropyl emthylcellulose of 0.1～10 weight portion and 0.01～5 weight portion preparing amorphous solid dispersion,
The described solid dispersion of 40～69.9wt% is mixed mutually with the infiltration derivant of 0.1～30wt% and the disintegrating agent of 0.1～30wt%.
And, the invention still further relates to a kind of solid dispersion, this solid dispersion is dispersed in by the itraconazole with 1 weight portion in the absorption enhancer mixture of the hydroxypropyl emthylcellulose of 0.1～10 weight portion and 0.01～5 weight portion and prepares with amorphism.
Korean Patent communique No.2001-0098419 discloses a kind of itraconazole preparation, and wherein the bioavailability of this itraconazole preparation is improved by itraconazole is made for amorphism.Yet, there is a problem like this, when itraconazole preparation during with solid dispersion form oral administration, active component, be the stripping meeting time-delay of itraconazole in simulated gastric fluid, this is because used excessive water-soluble polymer polyvinylpyrrolidone when the preparation solid dispersion.
For solving the problem of above-mentioned itraconazole stripping time-delay in gastric environment, in the present invention, water-soluble polymer is adopted in the preparation of itraconazole solid dispersion, it is hydroxypropyl emthylcellulose, and absorption enhancer, citric acid for example, thus in the solution that contains simulated gastric fluid and 1% (w/w) polysorbate80 of pH1.2 and pH4.0, dissolution has been significantly improved more than 20%.And in the present invention, also the solid dispersion to itraconazole adds the infiltration derivant, as potassium chloride, magnesium carbonate etc., and disintegrating agent, as microcrystalline Cellulose, sodium starch glycollate etc., so that the effectively stripping in gastric environment of insoluble itraconazole.
In the present invention, the itraconazole solid dispersion can be dispersed in by the itraconazole with 1 weight portion in the absorption enhancer mixture of the hydroxypropyl emthylcellulose of 0.1～10 weight portion and 0.01～5 weight portion and make with amorphism.The content of itraconazole solid dispersion is preferably 40～69.9wt%, in the gross weight of Orally administered composition.If the content of itraconazole solid dispersion less than 40wt%, will be not enough to obtain required drug effect; And if the content of itraconazole solid dispersion will have side effects to effective stripping of itraconazole greater than 69.9wt%.
In the present invention, absorption enhancer can be selected from one or more in citric acid, ascorbic acid, bile acid, cholic acid, mannitol, salicylic acid, glucose, dextrose, sucrose, sorbitol and the maltose.
In the present invention, the infiltration derivant can be selected from one or more in sodium chloride, potassium chloride, magnesium chloride, potassium sulfate, sodium sulfate, magnesium sulfate, magnesium carbonate, calcium bicarbonate, mannitol, glucose, lactose and the sucrose.The content of infiltration derivant is preferably 0.1～30wt%, in the gross weight of Orally administered composition.If the content of infiltration derivant is less than 0.1wt%, the then itraconazole stripping of will delaying time; If the content of infiltration derivant is greater than 30wt%, then the stripping of itraconazole improves fast, causes side effect, for example skin allergy etc.
In the present invention, disintegrating agent can be selected from one or more in microcrystalline Cellulose, low hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose (croscamellose sodium), sodium starch glycollate, sodium carboxymethyl cellulose, carboxymethyl cellulose and the crospolyvinylpyrrolidone (crospovidone) that replaces.The content of disintegrating agent is preferably 0.1～30wt%, in the gross weight of Orally administered composition.If the content of disintegrating agent is less than 0.1wt%, disintegrate will be delayed time; If the content of disintegrating agent is greater than 30wt%, solid preparation will to have flowability and compressibility difference etc. former thereby be difficult to preparation owing to granule.
In addition, Orally administered composition of the present invention also can comprise and is selected from pharmaceutically acceptable excipient, binding agent and the lubricant one or more.
In the present invention, excipient can be selected from one or more in lactose, white sugar, glucose, fructose, mannitol, corn starch, potato starch, wheaten starch, pre-gelatinized starch, microcrystalline Cellulose or cellulose derivative, dextrin, calcium hydrogen phosphate, dalcium biphosphate, calcium carbonate, polacrilin potassium, acetic acid, ammonium carbonate, ammonium phosphate, boric acid, lactic acid, citric acid, potassium phosphate, sodium phosphate, sodium acetate, sodium citrate, sodium lactate, ascorbic acid and the ascorbic palmitate.The content of excipient is preferably 2～90wt%, in the gross weight of Orally administered composition.
In the present invention, binding agent can be selected from one or more in hydroxypropyl cellulose, hydroxypropyl emthylcellulose, hydroxylated cellulose, methylcellulose, ethyl cellulose, hydroxyethyl-cellulose, polyvinylpyrrolidone, polyvinyl alcohol, gelatin, dextrin and the microcrystalline Cellulose.The content of binding agent is preferably 2～40wt%, in the gross weight of Orally administered composition.
In the present invention, lubricant can be selected from one or more in magnesium stearate, sodium stearyl fumarate, stearic acid, Talcum, silicon dioxide and the colloidal silica.The content of lubricant is preferably 0.1～20wt%, in the gross weight of Orally administered composition.
Orally administered composition of the present invention can preferably be made the solid that is used for oral administration, for example tablet, capsule, granule, powder, pill, dry syrup or the like, preferred tablet or capsule.
Orally administered composition of the present invention can be made into and contains 100～400mg, the unit dosage forms of preferred 150～300mg itraconazole solid dispersion.Dosage unit is preferably tablet or capsular form.In one week of administration, Orally administered composition of the present invention is administered twice preferred every day, each 200mg itraconazole.
As shown in Figure 4, use the itraconazole solid dispersion of water-soluble polymer hydroxypropyl emthylcellulose and absorption enhancer citric acid preparation to show higher dissolution in the solution of pH1.2 that contains simulated gastric fluid and 1% (w/w) polysorbate80 and pH4.0, this speed is than dissolution height at least 20% disclosed according to Korean Patent communique No.2001-0098419, that adopt the itraconazole solid dispersion of water-soluble polymer polyvinylpyrrolidone preparation.And, Orally administered composition of the present invention except that contain the itraconazole solid dispersion external, also contain the infiltration derivant, for example potassium chloride, magnesium carbonate etc., and disintegrating agent, for example microcrystalline Cellulose, sodium starch glycollate etc., thus show the effective stripping of insoluble itraconazole in gastric environment.
Further the present invention will be described in more detail in conjunction with following embodiment.These embodiment only are intended to the present invention exemplarily is described, and should not be construed as by any way the scope of the invention are limited.
Embodiment 1
One hectogram raw material itraconazole preparation (Sigma Chemical) is dissolved in 1, in the 000g dichloromethane.Then, 22.2g fully is dissolved in 2 as the citric acid and the 100g hydroxypropyl emthylcellulose (Dow Chemical, weight average molecular weight is 10,000～1,500,000) of absorption enhancer, and 000g dichloromethane/ethanol (1: 1, v/v) in the mixed solvent.Adopt spray dryer (B-191 mini spray exsiccator, Buchi Co., Switzerland) mixture solution of itraconazole solution and hydroxypropyl emthylcellulose and citric acid is sprayed, be scattered in solid dispersion in hydroxypropyl emthylcellulose and the citric acid to form itraconazole, generate white amorphous powder.Itraconazole: hydroxypropyl emthylcellulose: the weight ratio of citric acid is 45: 45: 10.
Embodiment 2
The itraconazole solid dispersion that embodiment 1 is made also fully mixes by the screening of 30 purpose mesh screens with colloidal silica.Then, other component in wherein adding tabulation 1 down except that magnesium stearate and Talcum is mixed, and dry and pelletize is crossed 25 order mesh screens and obtained the size homogeneous granules.Subsequently, to wherein adding magnesium stearate and Talcum and fully mixing, mixture is made tablet.120g Opadry AMB (Opadry AMB) (Colorcon) is added in the 546g pure water, fully mix with the preparation coating solution.Adopt tablet coating machine (the automatic coating machine of SFC-30FN type, Sejong Pharmatech, Korea S), keeping inlet temperature is 60～70 ℃, outlet temperature is 40～43 ℃, and coating solution is filmed on the tablet that makes, and wherein every tablet scribbles the coating solution of 20mg.
[table 1]
| The itraconazole solid dispersion | 222.2mg |
| Microcrystalline Cellulose | 58.0mg |
| The dehydration lactose | 143.0mg |
| Cross-linking sodium carboxymethyl cellulose | 120.0mg |
| Magnesium carbonate | 20.0mg |
| Colloidal silica | 8.0mg |
| Talcum | 7.0mg |
| Magnesium stearate | 6.0mg |
Embodiment 3
Component in itraconazole solid dispersion that employing embodiment 1 makes and the following tabulation 2 prepares tablet.Adopt and prepare tablet and it is carried out coating as method identical among the embodiment 2.
[table 2]
| The itraconazole solid dispersion | 222.2mg |
| Microcrystalline Cellulose | 58.0mg |
| The dehydration lactose | 153.0mg |
| Cross-linking sodium carboxymethyl cellulose | 120.0mg |
| Magnesium carbonate | 10.0mg |
| Colloidal silica | 8.0mg |
| Talcum | 7.0mg |
| Magnesium stearate | 6.0mg |
Embodiment 4
Component in itraconazole solid dispersion that employing embodiment 1 makes and the following tabulation 3 prepares tablet.Adopt and prepare tablet and it is carried out coating as method identical among the embodiment 2.
[table 3]
| The itraconazole solid dispersion | 222.2mg |
| Microcrystalline Cellulose | 83.0mg |
| The dehydration lactose | 123.0mg |
| Cross-linking sodium carboxymethyl cellulose | 115.0mg |
| Magnesium chloride | 20.0mg |
| Colloidal silica | 8.0mg |
| Talcum | 7.0mg |
| Magnesium stearate | 6.0mg |
Embodiment 5
Itraconazole solid dispersion and colloidal silica that embodiment 1 is made sieve by 30 order mesh screens, and fully mix.Then, other component in wherein adding tabulation 4 down except that magnesium stearate is mixed, and dry and pelletize is crossed 25 order mesh screens and obtained the size homogeneous granules.Subsequently, to wherein adding magnesium stearate and fully mixing with the preparation tablet.After tablet forms, by tablet being carried out coating as method identical among the embodiment 2.
[table 4]
| The itraconazole solid dispersion | 222.2mg |
| Microcrystalline Cellulose | 80.0mg |
| The dehydration lactose | 173.0mg |
| Cross-linking sodium carboxymethyl cellulose | 75.0mg |
| Potassium chloride | 20.0mg |
| Colloidal silica | 8.0mg |
| Magnesium stearate | 6.0mg |
Embodiment 6
Component in itraconazole solid dispersion that employing embodiment 1 makes and the following tabulation 5 prepares tablet.Adopt and prepare tablet and it is carried out coating as method identical among the embodiment 2.
[table 5]
| The itraconazole solid dispersion | 222.2mg |
| Microcrystalline Cellulose | 70.0mg |
| The dehydration lactose | 133.0mg |
| Cross-linking sodium carboxymethyl cellulose | 135.0mg |
| Calcium bicarbonate | 10.0mg |
| Colloidal silica | 8.0mg |
| Magnesium stearate | 6.0mg |
Comparative Examples 1
Component in itraconazole solid dispersion that employing embodiment 1 makes and the following tabulation 6 prepares tablet.Adopt and prepare tablet and it is carried out coating as method identical among the embodiment 2.
[table 6]
| The itraconazole solid dispersion | 222.2mg |
| Microcrystalline Cellulose | 93.0mg |
| The dehydration lactose | 158.0mg |
| Cross-linking sodium carboxymethyl cellulose | 90.0mg |
| Colloidal silica | 8.0mg |
| Talcum | 7.0mg |
| Magnesium stearate | 6.0mg |
Comparative Examples 2
Component in itraconazole solid dispersion that employing embodiment 1 makes and the following tabulation 7 prepares tablet.Adopt and prepare tablet and it is carried out coating as method identical among the embodiment 2.
[table 7]
| The itraconazole solid dispersion | 222.2mg |
| Microcrystalline Cellulose | 78.0mg |
| The dehydration lactose | 143.0mg |
| Cross-linking sodium carboxymethyl cellulose | 120.0mg |
| Colloidal silica | 8.0mg |
| Talcum | 7.0mg |
| Magnesium stearate | 6.0mg |
Comparative Examples 3
One hectogram raw material itraconazole preparation (Sigma Chemical) is dissolved in 1, in the 000g dichloromethane.Then, 22.2g fully is dissolved in 2 as the citric acid and the 200g polyvinylpyrrolidone (BASF, weight average molecular weight is 2,500～3,000,000) of absorption enhancer, and 000g dichloromethane/ethanol (1: 1, v/v) in the mixed solvent.Adopt spray dryer (B-191 mini spray exsiccator, Buchi Co., Switzerland) mixture solution of itraconazole solution and polyvinylpyrrolidone and citric acid is sprayed, be scattered in solid dispersion in polyvinylpyrrolidone and the citric acid to form itraconazole, generate white amorphous powder.Itraconazole: polyvinylpyrrolidone: the weight ratio of citric acid is 45: 45: 10.
Experimental example 1: dissolution test
Compositions and commercial preparation (Janssen Korea Ltd.Sporanox that embodiment 2～6 and Comparative Examples 1～2 are made
TMCapsule) carries out dissolution test.The results are shown in down among tabulation 8 and Fig. 1 and 2.The solution (Korean Pharmacopeia) of pH1.2 as dissolution fluid, and is determined dissolution by the stripping quantity of the itraconazole that recorded by efficient liquid phase chromatographic analysis (HPLC).In this manual, dissolution is all measured according to above-mentioned identical mode.
[table 8]
| Compositions | Dissolution (%) | |||
| 30 | 60 | 90 | 120 minutes | |
| Embodiment 2 | 22.4 | 50.1 | 70.8 | 77.7 |
| Embodiment 3 | 27.0 | 57.4 | 68.8 | 74.9 |
| Embodiment 4 | 28.9 | 49.4 | 61.5 | 72.0 |
| Embodiment 5 | 17.3 | 41.1 | 56.6 | 67.9 |
| Embodiment 6 | 30.2 | 70.6 | 80.4 | 83.0 |
| Comparative Examples 1 | 13.2 | 17.8 | 20.1 | 22.3 |
| Comparative Examples 2 | 10.8 | 25.9 | 34.1 | 37.8 |
| The commercial preparation | 14.1 | 40.0 | 59.4 | 73.9 |
As table 8 and shown in Figure 1, contain disintegrating agent in Comparative Examples 1 and 2 but do not contain in the compositions of permeating derivant, dissolution is significantly lower, and is difficult to control, because the slight change of each constituent content will cause the remarkable change of dissolution.And contain in the compositions of infiltration derivant and disintegrating agent at embodiment 2～6, dissolution significantly improves, and can (referring to Fig. 1) control dissolution in wide region.
In addition, as table 8 and shown in Figure 2, the compositions of the embodiment of the invention 2 also shows the dissolution equal or higher with the commercial preparation.
And below the experiment of carrying out will show that the present invention contains the compositions of permeating derivant and all have higher dissolution under pH4.0 and pH6.8 and pH1.2.Measure the dissolution that embodiment 2 (containing infiltration derivant and disintegrating agent) and Comparative Examples 2 contain (not containing the infiltration derivant) compositions of itraconazole respectively in the solution that contains 1% polysorbate80 of pH4.0 and in the solution that contains 1% polysorbate80 of pH6.8.The results are shown in Fig. 3.As shown in Figure 3, the present invention contains the compositions of infiltration derivant and disintegrating agent, and its dissolution all is higher than the compositions of Comparative Examples under pH4.0 and pH6.8.
In addition, for the kind of check water-soluble polymer to the influence of dissolution, respectively embodiment 1 is contained hydroxypropyl emthylcellulose and contains polyvinylpyrrolidone as the solid dispersion of water-soluble polymer and Comparative Examples 3 and carry out dissolution test as the solid dispersion of water-soluble polymer.Fill No. 0 capsule with the various solid dispersion of 222.2mg (corresponding to the 100g itraconazole), and in the solution that contains 1% (w/w) polysorbate80 of pH1.2 and pH4.0, each solid dispersion is carried out dissolution test respectively.The results are shown in following table 9 and Fig. 4.
[table 9]
| Compositions | Dissolution (%) | ||||
| 30 | 60 | 90 | 120 minutes | ||
| Embodiment 1 | pH1.2 | 80.8 | 79.7 | 78.4 | 77.6 |
| pH4.0 | 14.4 | 11.7 | 10.0 | 8.8 | |
| Comparative Examples 3 | pH1.2 | 72.0 | 95.5 | 97.9 | 99.8 |
| pH4.0 | 69.7 | 76.4 | 55.8 | 46.7 | |
As table 9 and shown in Figure 4, compare with the dissolution that Comparative Examples 3 contains in the solid dispersion of polyvinylpyrrolidone, contain in the solid dispersion of hydroxypropyl emthylcellulose at embodiment 1, dissolution improves at least 20% in the solution of pH1.2, and improves at least 60% in the solution of pH4.0.
As previously mentioned, in Orally administered composition of the present invention, can effectively control and significantly improve the dissolution in gastric environment, thereby solve the low problem of the insoluble bioavailability that causes by itraconazole.And Orally administered composition of the present invention also has economic benefit, because can directly prepare tablet by dry granulation by it.
Claims (7)
1. Orally administered composition, contain:
The solid dispersion of 40～69.9wt% wherein is dispersed in the itraconazole of 1 weight portion in the absorption enhancer of the hydroxypropyl emthylcellulose of 0.1～10 weight portion and 0.01～5 weight portion;
0.1 the infiltration derivant of～30wt%; And
0.1 the disintegrating agent of～30wt%.
2. the Orally administered composition of claim 1, wherein said absorption enhancer is selected from citric acid, ascorbic acid, bile acid, cholic acid, mannitol, salicylic acid, glucose, dextrose, sucrose, sorbitol and maltose.
3. the Orally administered composition of claim 1, wherein said infiltration derivant is selected from one or more in sodium chloride, potassium chloride, magnesium chloride, potassium sulfate, sodium sulfate, magnesium sulfate, magnesium carbonate, calcium bicarbonate, mannitol, glucose, lactose and the sucrose.
4. the Orally administered composition of claim 1, wherein said disintegrating agent are selected from one or more in microcrystalline Cellulose, low hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, sodium starch glycollate, sodium carboxymethyl cellulose, carboxymethylcellulose calcium and the crospolyvinylpyrrolidone that replaces.
5. the Orally administered composition of claim 1 further comprises being selected from pharmaceutically acceptable excipient, binding agent and the lubricant one or more.
6. amorphous solid dispersion wherein is dispersed in the itraconazole of 1 weight portion in the citric acid of the hydroxypropyl emthylcellulose of 0.1～10 weight portion and 0.01～5 weight portion.
7. method for preparing the Orally administered composition that contains itraconazole, the itraconazole of said composition has high bioavailability, and described method comprises the steps:
The itraconazole of 1 weight portion is dispersed in the absorption enhancer mixture of the hydroxypropyl emthylcellulose of 0.1～10 weight portion and 0.01～5 weight portion with prepare amorphous solid dispersion and
The described solid dispersion of 40～69.9wt% is mixed mutually with the infiltration derivant of 0.1～30wt% and the disintegrating agent of 0.1～30wt%.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020050022312A KR100555794B1 (en) | 2005-03-17 | 2005-03-17 | Composition comprising itraconazole for oral administration |
| KR1020050022312 | 2005-03-17 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1853634A true CN1853634A (en) | 2006-11-01 |
| CN100479819C CN100479819C (en) | 2009-04-22 |
Family
ID=37179259
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2006100651366A Expired - Fee Related CN100479819C (en) | 2005-03-17 | 2006-03-17 | Composition comprising itraconazole for oral administration |
Country Status (3)
| Country | Link |
|---|---|
| KR (1) | KR100555794B1 (en) |
| CN (1) | CN100479819C (en) |
| HK (1) | HK1098059A1 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101780046B (en) * | 2009-01-16 | 2011-09-21 | 北京化工大学 | Itraconazole composite powder and preparation method thereof |
| CN102309488A (en) * | 2010-07-02 | 2012-01-11 | 北京京卫燕康药物研究所有限公司 | Itraconazole medicinal composition and preparation method thereof |
| CN104055747A (en) * | 2013-03-22 | 2014-09-24 | 四川滇虹医药开发有限公司 | Itraconazole pharmaceutical composition, preparation method and application thereof |
| CN112641756A (en) * | 2020-12-29 | 2021-04-13 | 卓和药业集团有限公司 | Posaconazole enteric-coated pellet and preparation method thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100694667B1 (en) * | 1999-12-08 | 2007-03-14 | 동아제약주식회사 | Antifungal compositions containing itraconazole with both improved bioavailability and narrow intra- and inter-individual variation of its absorption |
-
2005
- 2005-03-17 KR KR1020050022312A patent/KR100555794B1/en not_active IP Right Cessation
-
2006
- 2006-03-17 CN CNB2006100651366A patent/CN100479819C/en not_active Expired - Fee Related
-
2007
- 2007-04-26 HK HK07104478A patent/HK1098059A1/en not_active IP Right Cessation
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101780046B (en) * | 2009-01-16 | 2011-09-21 | 北京化工大学 | Itraconazole composite powder and preparation method thereof |
| CN102309488A (en) * | 2010-07-02 | 2012-01-11 | 北京京卫燕康药物研究所有限公司 | Itraconazole medicinal composition and preparation method thereof |
| CN104055747A (en) * | 2013-03-22 | 2014-09-24 | 四川滇虹医药开发有限公司 | Itraconazole pharmaceutical composition, preparation method and application thereof |
| CN112641756A (en) * | 2020-12-29 | 2021-04-13 | 卓和药业集团有限公司 | Posaconazole enteric-coated pellet and preparation method thereof |
| CN112641756B (en) * | 2020-12-29 | 2022-08-19 | 卓和药业集团股份有限公司 | Posaconazole enteric-coated pellet and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| KR100555794B1 (en) | 2006-03-03 |
| CN100479819C (en) | 2009-04-22 |
| HK1098059A1 (en) | 2007-07-13 |
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