CN115721601A - Oral solid pharmaceutical composition of posaconazole nanocrystals and preparation method thereof - Google Patents
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- CN115721601A CN115721601A CN202211475031.3A CN202211475031A CN115721601A CN 115721601 A CN115721601 A CN 115721601A CN 202211475031 A CN202211475031 A CN 202211475031A CN 115721601 A CN115721601 A CN 115721601A
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- RAGOYPUPXAKGKH-XAKZXMRKSA-N posaconazole Chemical group O=C1N([C@H]([C@H](C)O)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@H]3C[C@@](CN4N=CN=C4)(OC3)C=3C(=CC(F)=CC=3)F)=CC=2)C=C1 RAGOYPUPXAKGKH-XAKZXMRKSA-N 0.000 title claims abstract description 66
- 229960001589 posaconazole Drugs 0.000 title claims abstract description 65
- 239000002159 nanocrystal Substances 0.000 title claims abstract description 37
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 29
- 239000007787 solid Substances 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000003085 diluting agent Substances 0.000 claims abstract description 7
- 239000000314 lubricant Substances 0.000 claims abstract description 7
- 239000000463 material Substances 0.000 claims abstract description 7
- 239000004094 surface-active agent Substances 0.000 claims abstract description 7
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims abstract description 3
- 239000008213 purified water Substances 0.000 claims abstract description 3
- 238000000227 grinding Methods 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 14
- 239000000725 suspension Substances 0.000 claims description 11
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 10
- 238000002156 mixing Methods 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 6
- 229910002012 Aerosil® Inorganic materials 0.000 claims description 5
- 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 5
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- QCWXUUIWCKQGHC-UHFFFAOYSA-N Zirconium Chemical compound [Zr] QCWXUUIWCKQGHC-UHFFFAOYSA-N 0.000 claims description 5
- 239000011324 bead Substances 0.000 claims description 5
- 238000011049 filling Methods 0.000 claims description 5
- 239000007902 hard capsule Substances 0.000 claims description 5
- 239000008101 lactose Substances 0.000 claims description 5
- 235000019359 magnesium stearate Nutrition 0.000 claims description 5
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 5
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 5
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 5
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 5
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 5
- 238000003825 pressing Methods 0.000 claims description 5
- 238000007873 sieving Methods 0.000 claims description 5
- 238000001694 spray drying Methods 0.000 claims description 5
- 229910052726 zirconium Inorganic materials 0.000 claims description 5
- 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 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 4
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 claims description 4
- 229920002472 Starch Polymers 0.000 claims description 3
- 239000007884 disintegrant Substances 0.000 claims description 3
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 3
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 3
- 229920000053 polysorbate 80 Polymers 0.000 claims description 3
- 229940068968 polysorbate 80 Drugs 0.000 claims description 3
- 239000008107 starch Substances 0.000 claims description 3
- 235000019698 starch Nutrition 0.000 claims description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 2
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 2
- 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 claims description 2
- 229960000913 crospovidone Drugs 0.000 claims description 2
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 2
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 2
- 229940068977 polysorbate 20 Drugs 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 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 1
- 229930195725 Mannitol Natural products 0.000 claims 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims 1
- 239000002202 Polyethylene glycol Substances 0.000 claims 1
- 238000011068 loading method Methods 0.000 claims 1
- 239000000594 mannitol Substances 0.000 claims 1
- 235000010355 mannitol Nutrition 0.000 claims 1
- 229920001983 poloxamer Polymers 0.000 claims 1
- 229960000502 poloxamer Drugs 0.000 claims 1
- 229920001223 polyethylene glycol Polymers 0.000 claims 1
- 239000011347 resin Substances 0.000 claims 1
- 229920005989 resin Polymers 0.000 claims 1
- 150000003445 sucroses Chemical class 0.000 claims 1
- 239000002245 particle Substances 0.000 abstract description 8
- 238000010521 absorption reaction Methods 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000003826 tablet Substances 0.000 description 9
- 238000001727 in vivo Methods 0.000 description 5
- 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 class 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 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000002662 enteric coated tablet Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000002572 peristaltic effect Effects 0.000 description 3
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 3
- 239000001253 polyvinylpolypyrrolidone Substances 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 229960004130 itraconazole Drugs 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 229940100692 oral suspension Drugs 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 241000228212 Aspergillus Species 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 208000037026 Invasive Fungal Infections Diseases 0.000 description 1
- 229930182558 Sterol Natural products 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229940099075 noxafil Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000009522 phase III clinical trial Methods 0.000 description 1
- 239000012716 precipitator Substances 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a posaconazole nanocrystal oral solid pharmaceutical composition which is characterized by comprising the following components: posaconazole, a hydrophilic material, a disintegrating agent, a diluent, a surfactant, a glidant, a lubricant and a proper amount of purified water. The D10 of posaconazole is 0.01-0.1 μm, the D50 is 0.15-0.25 μm and the D90 is 1.2-5.5 μm. The oral solid pharmaceutical composition of posaconazole nanocrystal provided by the invention has the advantages that the oral absorption speed and the bioavailability are improved. The invention also discloses a preparation method of the oral solid pharmaceutical composition of posaconazole nanocrystals, which has the advantages of simple operation, stable process and uniform particle size of the solid pharmaceutical composition and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a posaconazole nanocrystal oral solid pharmaceutical composition and a preparation method thereof.
Background
Posaconazole (posaconazole), a derivative of itraconazole, was effective in preventing invasive fungal infections, and was marketed by the FDA in 2006 as a second-generation triazole antifungal drug. Under the trade name NOXAFIL, which is marketed by Schering-Plough, USA. Posaconazole (posaconazole) is derived from itraconazole. Phase iii clinical trials are currently underway. The pharmacological effect is similar to azole drugs, but compared with itraconazole, the compound has stronger effect of inhibiting the demethylation of sterol C14, especially against aspergillus. Posaconazole is a weakly basic drug with a high solubility in the acidic environment of the stomach, about 0.8mg/mL, and < 0.001mg/mL in buffered saline at pH 5-7. The result shows that when posaconazole reaches intestinal tracts, the dissolved posaconazole is precipitated, and the main absorption part of posaconazole is positioned in the small intestine, which is the main reason of low bioavailability of posaconazole.
The preparation of posaconazole on the market at present has 2 dosage forms of enteric-coated tablets and oral suspension. However, enteric-coated tablets and oral suspensions have the defects of low bioavailability, large in-vivo absorption difference and the like. Oral suspension dosage forms are also inconvenient to carry and administer.
Therefore, there is a need for a novel oral posaconazole nanocrystal formulation that overcomes the above-mentioned problems.
Disclosure of Invention
In order to solve the problems, the invention provides a posaconazole nanocrystal oral solid pharmaceutical composition and a preparation method thereof, and the posaconazole oral solid pharmaceutical composition has high bioavailability and small in-vivo absorption difference.
On one hand, the invention discloses a posaconazole nanocrystal oral solid pharmaceutical composition, which consists of the following components: posaconazole, a hydrophilic material, a disintegrating agent, a diluent, a surfactant, a glidant, a lubricant and a proper amount of purified water. The D10 of posaconazole is between 0.01 and 0.1 μm, the D50 is between 0.15 and 0.25 μm and the D90 is between 1.2 and 5.5 μm.
In some embodiments, the hydrophilic material is hypromellose acetate succinate or hydroxypropyl cellulose phthalate. The disintegrating agent is one or two of crospovidone and sodium carboxymethyl starch. The diluent is microcrystalline cellulose and lactose. The lubricant is magnesium stearate, and the glidant is aerosil.
On the other hand, the invention also discloses a preparation method of the posaconazole nanocrystal oral solid pharmaceutical composition, which comprises the following steps:
a. carrying out superfine grinding on posaconazole, and sieving with a 100-mesh sieve;
b. taking a proper amount of water, adding a surfactant, and uniformly stirring; b, adding the crushed posaconazole in the step a, and uniformly stirring; adding hydrophilic material, and mixing;
c. circularly grinding with a grinder to obtain a nanocrystal suspension with D10 of posaconazole of 0.01-0.1 μm, D50 of 0.15-0.25 μm and D90 of 1.2-5.5 μm;
d. c, spray drying the nanocrystal suspension in the step c to obtain a drug-containing nanocrystal dry mixture; adding diluent, disintegrant, glidant and lubricant into the mixture, mixing, and filling into hard capsules or pressing into tablets.
Compared with the prior art, the invention has the beneficial effects that:
the oral solid pharmaceutical composition of posaconazole nanocrystals provided by the invention improves the oral absorption speed and bioavailability.
The preparation method of the oral solid pharmaceutical composition of posaconazole nanocrystals provided by the invention is simple to operate, stable in process, uniform in particle size of the solid pharmaceutical composition, and suitable for industrial production.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to specific embodiments, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments.
Example 1
The oral solid pharmaceutical composition of posaconazole nanocrystal disclosed by the embodiment comprises the following components in parts by weight:
the preparation method of the posaconazole nanocrystal oral solid pharmaceutical composition comprises the following steps:
a. carrying out superfine grinding on posaconazole by using a jet mill under the condition that the grinding pressure is controlled to be 0.6-0.8MPa, and sieving by using a 100-mesh sieve;
b. adding appropriate amount of water into polysorbate 20 and polyethylene glycol 6000, and stirring; b, adding the posaconazole crushed in the step a, and uniformly stirring; adding hydroxypropyl cellulose phthalate, and mixing uniformly;
c. circularly grinding with a grinder to obtain a nanocrystal suspension with D10 of posaconazole of 0.01-0.1 μm, D50 of 0.15-0.25 μm and D90 of 1.2-5.5 μm; 70 percent of zirconium beads with the diameter of 0.3mm are filled in the grinder, the peristaltic pump is 10-30rpm, the grinder is used for grinding for 1.5 hours in a circulating way at 1000rpm, the particle size of the posaconazole is controlled in a proper range by sampling detection, and the end point particle size is detected as follows:
d. c, spray drying the nanocrystal suspension in the step c to obtain a drug-containing nanocrystal dry mixture; adding microcrystalline cellulose, lactose, sodium bicarbonate, polyvinylpolypyrrolidone, aerosil and magnesium stearate into the mixture, mixing, and filling into hard capsule or pressing into tablet.
Example 2
The oral solid pharmaceutical composition of posaconazole nanocrystal disclosed in the embodiment comprises the following components in parts by weight:
the preparation method of the oral solid pharmaceutical composition of posaconazole nanocrystals comprises the following steps:
a. carrying out superfine grinding on posaconazole by using a jet mill under the condition that the grinding pressure is controlled to be 0.6-0.8MPa, and sieving by using a 100-mesh sieve;
b. adding appropriate amount of water into polysorbate 80 and polyethylene glycol 6000, and stirring; b, adding the crushed posaconazole in the step a, and uniformly stirring; adding hydroxypropyl cellulose phthalate, and mixing uniformly;
c. circularly grinding with a grinder to obtain a nanocrystal suspension with D10 of posaconazole of 0.01-0.1 μm, D50 of 0.15-0.25 μm and D90 of 1.2-5.5 μm; 70 percent of zirconium beads with the diameter of 0.3mm are filled in the grinder, the peristaltic pump is 10-30rpm, the grinder is used for grinding for 1.5 hours in a circulating way at 1000rpm, the particle size of the posaconazole is controlled in a proper range by sampling detection, and the end point particle size is detected as follows:
d. c, spray drying the nanocrystal suspension in the step c to obtain a drug-containing nanocrystal dry mixture; adding microcrystalline cellulose, lactose, sodium bicarbonate, polyvinylpolypyrrolidone, aerosil and magnesium stearate into the mixture, mixing, and filling into hard capsule or pressing into tablet.
Example 3
The oral solid pharmaceutical composition of posaconazole nanocrystal disclosed in the embodiment comprises the following components in parts by weight:
the preparation method of the posaconazole nanocrystal oral solid pharmaceutical composition comprises the following steps:
a. carrying out superfine grinding on posaconazole by using a jet mill under the condition that the grinding pressure is controlled to be 0.6-0.8MPa, and sieving by using a 100-mesh sieve;
b. adding appropriate amount of water into polysorbate 80 and polyethylene glycol 6000, and stirring; b, adding the posaconazole crushed in the step a, and uniformly stirring; adding hydroxypropyl methylcellulose acetate succinate, and mixing;
c. circularly grinding with a grinder to obtain a nanocrystal suspension with D10 of posaconazole of 0.01-0.1 μm, D50 of 0.15-0.25 μm and D90 of 1.2-5.5 μm; 70 percent of zirconium beads with the diameter of 0.3mm are filled in the grinder, the peristaltic pump is 10-30rpm, the grinder is used for grinding for 1.5 hours in a circulating way at 1000rpm, the particle size of the posaconazole is controlled in a proper range by sampling detection, and the end point particle size is detected as follows:
d. c, spray drying the nanocrystal suspension in the step c to obtain a drug-containing nanocrystal dry mixture; adding microcrystalline cellulose, lactose, sodium bicarbonate, polyvinylpolypyrrolidone, aerosil and magnesium stearate into the mixture, mixing, and filling into hard capsule or pressing into tablet.
Example 4
In vivo pharmacodynamic studies were performed using the posaconazole nanocrystal solid pharmaceutical composition (tablet) prepared in example 3 as a test formulation (T) and a commercially available tablet as a reference formulation (R). The commercially available tablet is posaconazole enteric-coated tablet manufactured by Merck company.
The 12 healthy adult beagle dogs are randomly crossed and orally administered with 100mg of each tablet (T) and commercially available tablet (R) of example 3, blood is taken from the hind leg vein, 1ml of blood is taken from 0h (before administration), 0.5h, 1.0h, 1.5h, 2.0h, 3.0h, 4.0h, 6.0h, 8.0h, 12h and 24h respectively, serum is centrifugally taken, precipitator-containing precipitated protein is added, supernatant liquid is collected, the supernatant liquid is dried by blowing at room temperature under nitrogen, 100 microliters of acetonitrile aqueous solution is added for redissolution, and then the posaconazole content is detected on a computer. The results are given in the following table:
| Subject | R_Tmax | R_Cmax | t _ Tmax mean | T _ Cmax-mean | T/R mean ratio |
| C001 | 10.00 | 3403.69 | 10.00 | 5678.2195 | 1.67 |
| C002 | 6.00 | 5525.703 | 6.25 | 11227.403 | 2.03 |
| C003 | 10.00 | 6287.057 | 14.00 | 5866.036 | 0.93 |
| C004 | 36.00 | 270.605 | 22.00 | 638.043 | 2.36 |
| C005 | 11.00 | 2926.402 | 8.00 | 4891.49 | 1.67 |
| C006 | 7.00 | 5288.175 | 6.25 | 3850.32 | 0.73 |
| C007 | 6.50 | 6623.58 | 5.50 | 7613.8705 | 1.15 |
| C008 | 9.50 | 6313.169 | / | / | / |
| C009 | 6.50 | 6626.501 | 9.75 | 2051.5835 | 0.31 |
| C010 | 11.00 | 4088.723 | 9.50 | 11011.711 | 2.69 |
| C011 | 6.00 | 6627.995 | 6.25 | 5054.3525 | 0.76 |
| C012 | 3.50 | 5467.955 | 8.00 | 5600.4825 | 1.02 |
| Mean | 10.250 | 4954.130 | 9.591 | 5771.228 | 1.16 |
| CV％ | 82.4 | 66.9 | 49.9 | 56.4 | 0.84 |
As can be seen from the above table, the mean value of the Cmax ratio of posaconazole of the test preparation (T) and the reference preparation (R) is 1.16, and CV% is 0.84, which indicates that the absorption of the test preparation (T) in vivo is greater than that of the reference preparation, and the coefficient of variation in vivo is smaller than that of the reference preparation.
The foregoing describes only some embodiments of the present invention and modifications and variations thereof will be apparent to those skilled in the art without departing from the spirit and scope of the invention.
Claims (8)
1. The oral solid pharmaceutical composition of posaconazole nanocrystal is characterized by comprising the following components: posaconazole, a hydrophilic material, a disintegrating agent, a diluent, a surfactant, a glidant, a lubricant and a proper amount of purified water; the D10 of the posaconazole is 0.01-0.1 mu m, the D50 is 0.15-0.25 mu m, and the D90 is 1.2-5.5 mu m.
2. The posaconazole nanocrystalline oral solid pharmaceutical composition according to claim 1, wherein the surfactant is one or more of polysorbate 20, polysorbate 80, poloxamer, polyethylene glycol and sucrose esters, and the amount of the surfactant is 2% -8% of the composition.
3. The posaconazole nanocrystalline oral solid pharmaceutical composition according to claim 2, wherein the hydrophilic material is one or more of hypromellose acetate succinate, methacrylic acid resin, and hydroxypropyl cellulose phthalate.
4. The posaconazole nanocrystalline oral solid pharmaceutical composition according to claim 3, wherein the disintegrant is one or both of crospovidone and sodium carboxymethyl starch.
5. The posaconazole nanocrystalline oral solid pharmaceutical composition according to claim 4, wherein the diluent is one or more of microcrystalline cellulose, lactose, mannitol and starch.
6. The posaconazole nanocrystal oral solid pharmaceutical composition according to claim 5, wherein the lubricant is magnesium stearate and the glidant is aerosil.
7. The preparation method of the posaconazole nanocrystal oral solid pharmaceutical composition according to claim 6, which comprises the following steps:
a. carrying out superfine grinding on posaconazole, and sieving with a 100-mesh sieve;
b. taking a proper amount of water, adding a surfactant, and uniformly stirring; b, adding the posaconazole crushed in the step a, and uniformly stirring; adding hydrophilic material, and mixing;
c. circularly grinding with a grinder to obtain a nanocrystal suspension with D10 of posaconazole of 0.01-0.1 μm, D50 of 0.15-0.25 μm and D90 of 1.2-5.5 μm;
d. c, spray drying the nanocrystal suspension in the step c to obtain a drug-containing nanocrystal dry mixture; adding diluent, disintegrant, glidant and lubricant into the mixture, mixing uniformly, and filling into hard capsules or pressing into tablets.
8. The method for preparing the posaconazole nanocrystalline oral solid pharmaceutical composition according to claim 7, wherein the grinding medium in the step c is zirconium beads with a diameter of 0.2mm to 0.8mm, and the loading of the zirconium beads is 30% to 90%.
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| CN101495096A (en) * | 2006-05-30 | 2009-07-29 | 伊兰制药国际有限公司 | Nanoparticulate posaconazole formulations |
| CN102065842A (en) * | 2008-04-15 | 2011-05-18 | 先灵公司 | Oral pharmaceutical compositions in a solid dispersion comprising preferably posaconazole and HPMCAS |
| CN106265526A (en) * | 2016-09-22 | 2017-01-04 | 山东大学 | The solid dispersion of a kind of antifungal drug posaconazole and preparation method and application |
| CN106619521A (en) * | 2016-12-30 | 2017-05-10 | 广州新济药业科技有限公司 | Itraconazole enteric solid dispersion and preparation method and application thereof |
| CN108125921A (en) * | 2017-12-28 | 2018-06-08 | 广州玻思韬控释药业有限公司 | A kind of posaconazole solid dispersion composition that can inhibit crystallization and be precipitated and preparation method thereof |
| EP3342399A1 (en) * | 2016-12-31 | 2018-07-04 | Abdi Ibrahim Ilac Sanayi ve Ticaret A.S. | Pharmaceutical compositions comprising posaconazole and manufacturing method |
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2022
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| CN106619521A (en) * | 2016-12-30 | 2017-05-10 | 广州新济药业科技有限公司 | Itraconazole enteric solid dispersion and preparation method and application thereof |
| EP3342399A1 (en) * | 2016-12-31 | 2018-07-04 | Abdi Ibrahim Ilac Sanayi ve Ticaret A.S. | Pharmaceutical compositions comprising posaconazole and manufacturing method |
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