CN105030668B - Oral posaconazole supensoid agent and preparation method thereof - Google Patents
Oral posaconazole supensoid agent and preparation method thereof Download PDFInfo
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- CN105030668B CN105030668B CN201510360335.9A CN201510360335A CN105030668B CN 105030668 B CN105030668 B CN 105030668B CN 201510360335 A CN201510360335 A CN 201510360335A CN 105030668 B CN105030668 B CN 105030668B
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Abstract
The invention belongs to pharmaceutical technology field, and in particular to a kind of oral posaconazole supensoid agent and preparation method thereof.Its by following weight than composition form：4 parts of posaconazole, 1 part of polyoxyethylene sorbitan monoleate, 0.3 part of dimeticone, 0.2 part of sodium benzoate, sodium citrate part, in right amount, appropriate citric acid, 10 parts of glycerine, 0.3 part of xanthans, 35 parts of malt syrup, 0.4 part of titanium dioxide, 0.3 part of essence, add purified water to 100ml.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to a kind of oral posaconazole supensoid agent and preparation method thereof.
Background technology
At present, fungal infection is harmful human health, jeopardizes a kind of common disease of human life.In recent years, due to human body
Immunologic deficiency disease（HIV）Prevalence and cancer, Organ Transplantation Patients have been used with stronger immunosuppressive drug, serious fungal
Infection and its case fatality rate are in rising trend.Triazole antifungal agent is stronger compared with amphotericin B and Flucytosine antibacterial activity, toxicity
It is lower, thus clinic is widely used in, but first generation triazole type medicine narrow antimicrobial spectrum, bioavilability are low and have medicine
The problems such as interaction and drug resistance, clinical active demand can not be met.Second generation antifungal drug in triazole class posaconazole
Research and development successfully overcome above-mentioned a variety of limitations.
Posaconazole is triazole antifungal agent of new generation.Experiment and clinical infection studies have shown that posaconazole in vitro
There is antibacterial activity to microorganism such as aspergillus, Mycotoruloides etc., also have to the yeast and mould of other azole drug resistances
Broad-spectrum antifungal activity.
Invasive candidiasis is current clinically most common studies of invasive fungal infections, and it is the huge of clinic all the time that it, which is treated,
One of challenge.The multicenter of the hostings such as Vazquez, random, double blinding research are found, are merging human immunodeficiency virus（HIV）
Posaconazole and Fluconazole treating oral cavity monilial infection are respectively adopted in the patient of infection, the patient CD4 for participating in the research is thin
Born of the same parents count average 80/mm3, most of patient do not receive antiviral therapy, treats the 1st day oral Fluconazole and posaconazole respectively
200mg, gives 100mg for hereafter continuous 13 days, posaconazole and the clinical cure rate of Fluconazole group patient difference after treatment end
For 91.7% and 92.5%, aetology success rate is 68%, but behind in the follow-up of the 42nd day, posaconazole group fungi
Learn success rate（40.6%）Higher than Fluconazole group（26.4%）.Another research finds that posaconazole is refractory in treatment Fluconazole
Property thrush and Esophageal candidiasis, clinical cure rate is up to 73%.
The aspergillus infection rate of patients with malignant hematological diseases exceedes candida albicans, and case fatality rate is more up to 70-90%, merges maincenter god
Case fatality rate is higher after system infections, but limited the effect of conventional antifungal medicine.Walsh etc. closes to 193 malignant hematologic diseases
And intractable aspergillus infection is total using posaconazole, voriconazole or echinocandin class medicine rescue therapy, posaconazole respectively
Efficient highest（42% to 26%）；The effect of to invasive pulmonary aspergillosis, is best（39% to 25%）, to dissemination aspergillosis more
Effectively（53% to 45%）.It is husky that Raad etc. gives pool again after Malignancy and the failure of Aspergillosis initial treatment
Health azoles row rescue therapy, total effective rate are up to 40% (21/53), and high dose AM Bison（≥7.5mg·kg-1·
d-1）The effective percentage of group is 8%（4/52）, the effective percentage of high dose AM Bison joint Caspofungin group is 11%（4/
38）, the attribution case fatality rate of 3 kinds of therapeutic schemes is respectively 40%, 65% and 68%.Another retrospective study is found in hematological system
Malignant tumour merges the patient of lung aspergillus infection, combines her with AM Bison the effect of posaconazole rescue therapy
Triaconazole is suitable, better than the former single therapy, it is necessary to which the patient for receiving Failure Treated with Mechanical Ventilation is less.
As Antifungal resistance increases, posaconazole as antifungal drug in triazole class of new generation, have wide spectrum, efficiently,
Drug resistance is strong, the advantages such as adverse reaction is small, will be widely used in clinic, has good development prospect.
Posaconazole is the antifungal drug in triazole class of new generation of Mo Shadong drugmakers of U.S. exploitation,
Chemical name：4- [4- [4- [4- [[(3R, 5R) -5- (2,4 difluorobenzene base) tetrahydro -5- (1H-1,2,4- tri-
Azoles -1- methyl) -3- furans] methoxyl group] phenyl] -1- piperazinyls] phenyl] -2- [(1S, 2S) -1- ethyl -2- hydroxypropyls] -2,
4- dihydros -3H-1,2,4- triazole -3- ketone,
Principal component structural formula：
Its oral administration mixed suspension in November, 2005 in European Initial Public Offering, in 2013 in Discussion on Chinese Listed, trade name：
Noxafil.Posaconazole is as antifungal drug in triazole class of new generation, and with has a broad antifungal spectrum, activity is high, resistance is strong, security
The advantage such as good, is widely used to clinic, has preferable development prospect at present.Glucose syrup substantially conversion values are higher, and half
Solid, in-convenience in use, to dissolve.Its complex manufacturing, other grinding modes are needed to be pre-processed.Low pressure processing pair is set
Standby to require high, production equipment cost is high.
The content of the invention
The present invention provides a kind of posaconazole suspension, it is characterised in that its by following weight than composition form：
（1）Posaconazole raw material, Tween-80, dimeticone, sodium benzoate, citron are weighed by batch production instruction order
Acid, sodium citrate, glycerine, xanthans and malt syrup.
（2）The purified water and Tween-80 for preparing total amount 30% are added into mixer, prescription is added after stirring and dissolving
Posaconazole is measured, continues stirring and dimeticone is continuously added to after being uniformly dispersed, and is uniformly dispersed, it is standby.
（3）Above-mentioned finely dispersed decoction homogenization, homogeneous terminate to add the purified water of preparation in backward homogenizer, punching
Residual liquor is washed, is added into mixer.
（4）The decoction through homogenization is added into mixer, adds sodium benzoate, stirring is until well mixed match somebody with somebody backward
Xanthans is slowly added in flow container, the stirring of side edged constant speed, continues to stir after adding xanthans, is stood in the case where not stirring
30min, it is rear to add in dispensing filling.
（5）Glycerine, malt syrup are added into Agitation Tank, edged constant speed stirring in side is until well mixed.
（6）Take recipe quantity titanium dioxide to add purified water to be added to after being uniformly dispersed in Agitation Tank, side edged constant speed stirring until
Essence is added after well mixed, stirring is until well mixed.
（7）With pH4.0 citric acid-sodium citrate buffer regulation pH to 4.3-4.7.
（8）Add purified water into Agitation Tank to full dose and to be well mixed, intermediate sampling carries out middle control detection, closes
For filling after lattice.
Wherein step 3）Middle homogenization pressure is 30-60MPa.
Wherein step 3）Middle homogenization is to raw material particle size：Granule number >=65% less than 3 μm, the granule number less than 10 μm
>=99%, median [d (0.5)] is between 1.5 ~ 1.85 μm；
Wherein step 3）Homogeneous terminates to add the purified water for preparing total amount 10% in backward homogenizer.
Step 6）Purified water is total amount 5%,
Citric acid-sodium citrate buffer is prepared with 1mol/L citric acids, 1mol/L sodium citrates.
Wherein, step 8）Prepare terminate to start it is filling be no more than 4 hours, as intermediate is examined and do not terminated in 4 hours, then
Intermediate assay is not to wait for, is directly carried out filling.
The oral posaconazole suspension self-control sample average dissolution rate of 30 minutes of the present invention is all higher than 85%.
The oral posaconazole suspension uniformity of dosage units of the present invention should be the 95.0 ~ 105.0% of labelled amount, containing benzoic acid
Sodium（C7H5NaO2）It should be 1.80 ~ 2.20mg/ml.
The present invention limit of the oral posaconazole suspension about material be：Impurity I is no more than 0.2%, and impurity II does not surpass
0.2% is crossed, other lists are miscellaneous to be no more than 0.2%, and total impurities is no more than 0.4%.
The oral posaconazole suspension viscosity of the present invention is 900 ~ 3200cp.
The oral posaconazole suspension simple production process of the present invention, has saved some processes, it is only necessary to 8 procedures
The preparation of this product is completed, can substantially reduce and produce time-consuming and production cost；
Posaconazole raw material only needs progress low pressure processing to can reach target grain size, and is carried out in advance without other grinding modes
Processing.Low pressure processing is low for equipment requirements, can substantially reduce production equipment cost；
Malt syrup has low conversion values, liquid direct use；
In terms of preparation prescription technical study result, process stabilizing, it is adapted to industrialization production；Quality research result and stability
Result of study shows, this product it is stable and controllable for quality, the packaging of this product meets the requirement during transport, storage and use.
Embodiment
Embodiment 1
Prescription
Preparation method：
（1）Posaconazole raw material, Tween-80, dimeticone, sodium benzoate, citron are weighed by batch production instruction order
Acid, sodium citrate, glycerine, xanthans, malt syrup, titanium dioxide, essence, the people of strict implement one weighs, people review, simultaneously
Fill in weighing, review record.
（2）The purified water and Tween-80 for preparing total amount 30% are added into mixer, prescription is added after stirring and dissolving
Posaconazole is measured, continues stirring and dimeticone is continuously added to after being uniformly dispersed, and is uniformly dispersed, it is standby.
（3）Above-mentioned finely dispersed decoction is through homogenizer（Pressure 30-60MPa）Processing, to raw material particle size：Less than 3 μm
Granule number >=65%, granule number >=99% less than 10 μm, between 1.5 ~ 1.85 μm, homogeneous terminates backward median [d (0.5)]
The purified water for preparing total amount 10% is added in homogenizer, residual liquor in homogenizer is rinsed, adds into mixer.
（4）The decoction handled through homogenizer is added into mixer, adds sodium benzoate, stirring is until well mixed backward
Xanthans is slowly added in Agitation Tank, the stirring of side edged constant speed, continues to stir after adding xanthans, it is quiet in the case where not stirring
Put 30min and allow xanthans aquation, it is rear to add during dispensing fills.
（5）Glycerine, malt syrup are added into Agitation Tank, edged constant speed stirring in side is until well mixed.
（6）The purified water of recipe quantity titanium dioxide plus preparation total amount 5% is taken to be added to after being uniformly dispersed in Agitation Tank, Bian Jia
Side constant speed stirring is until add essence after well mixed, stirring is until well mixed；
（7）Citric acid-sodium citrate buffer is prepared with 1mol/L citric acids, 1mol/L sodium citrates, with pH4.0 Chinese holly
Rafter acid-sodium citrate buffer-regulation pH to 4.3-4.7.
（8）Add purified water into Agitation Tank to full dose and to be well mixed, intermediate lab technician is by intermediate sampling code
（SOP1-QC-005）Control detection among sampling progress, is supplied filling after qualified.
Note：Prepare terminate to start it is filling be no more than 4 hours, as intermediate is examined and do not terminated in 4 hours, then in being not to wait for
Mesosome assay, directly carry out filling.
The dissolution determination method of test example 1
Take test sample to shake 15 seconds, draw about 5ml in the middle part of bottle using syringe（The density of oral posaconazole suspension is
1.145g/ml）, it is accurately weighed, according to dissolution method（The second methods of C of two annex of Chinese Pharmacopoeia version in 2010 Ⅹ）, with 3%0
Sodium dialkyl sulfate 900ml is dissolution medium, and rotating speed is 25 turns per minute, and dissolution medium temperature is 37 DEG C, by equipped with sample
Needle tubing connects syringe needle and syringe needle is in stirring slurry top edge and dissolution medium liquid level middle part, and rapid sample introduction and starting stirs
Mix, during through 30 minutes, take solution 10ml, filter, discard primary filtrate 3ml, it is appropriate that precision measures subsequent filtrate, is diluted with dissolution medium
It is made containing about the solution of 18 μ g posaconazoles in every 1ml, according to UV-VIS spectrophotometry（China's coastal port two
Annex IVA）.Determine absorbance respectively at 262nm wavelength, it is appropriate separately to weigh posaconazole reference substance, is dissolved with dissolution medium
And dilute and be made in every 1ml containing about 18 μ g solution, it is measured in the same method, calculates stripping quantity.
The dissolution rate testing result of table 1
As a result show：The self-control sample average dissolution rate of 30 minutes is all higher than 85%, has no bright during stability test
Aobvious change, dissolution rate meet regulation.
The content assaying method of test example 2 and determination of foreign matter
According to high performance liquid chromatography（Two annex VD of Chinese Pharmacopoeia version in 2010）Measure.
Chromatographic condition is filler with phenyl silane bonded silica gel with system suitability（It is proposed with ZorbaxSB-
Pheny1,3.5 μm, 75 × 4.6mmI.D.）；Mobile phase A is water-tetrahydrofuran-phosphoric acid（7600：2400：15）, Mobile phase B is
Water-acetonitrile-tetrahydrofuran-phosphoric acid（2500：5000：2500：15）；Flow velocity is 1.5ml per minute, linear gradient elution：Detection
Wavelength is 254nm；Column temperature is 40 °C.Posaconazole reference substance about 10mg is taken, is put in vial, in about 175 °C of baking oven
Heating melts reference substance, cools down, and precision adds solvent【Water-acetonitrile-phosphoric acid（75：25：1）】10ml, ultrasound make dissolving, take 10
μ l inject liquid chromatograph, record chromatogram, and the retention time at posaconazole peak should be 9.9 ± 0.5 minutes, posaconazole peak with
Front and rear impurity peaks separating degree should meet regulation.The reference substance solution that precision is measured under assay item is appropriate, quantitative dilute with solvent
Release the solution for being made and containing 0.5 μ g in every 1ml, take 10 μ l to inject liquid chromatograph, the peak height at posaconazole peak and baseline noise it
Than should be greater than 10.
Determination method takes this product, is well mixed, takes 5.7 ± 0.6g（Sampled with pipette in bottle middle part, Bo Shakang
The density of azoles oral administration mixed suspension is 1.145g/ml）, it is accurately weighed, put in 200ml measuring bottles, add solvent about 150ml, fully shake
Shaking makes dissolving, is diluted to scale with solvent, shakes up, and stands, takes 0.45 μm of membrane filtration mistake of supernatant, take subsequent filtrate as test sample
Solution.It is another to take sodium benzoate reference substance 25mg, it is accurately weighed, put in 100ml measuring bottles, solubilizer dissolves and is diluted to scale, shakes
It is even, as storing solution.Posaconazole reference substance 25mg is taken, it is accurately weighed, put in 25ml measuring bottles, precision adds sodium benzoate deposit
Liquid 5ml, solubilizer dissolve and are diluted to scale, shake up, as reference substance solution.Precision measures reference substance solution and tried with supplying respectively
Each 10 μ l injections liquid chromatograph of product solution, is recorded chromatogram, is calculated respectively in test sample with peak area by external standard method and moor husky health
Azoles（C37H42F2N8O4）And sodium benzoate（C7H5NaO2）Content.
The Related substances separation result of table 2
As a result show：Oral posaconazole suspension makes sample and reference preparation by oneself under acceleration conditions, and both is relevant
Material variation tendency is identical, and self-control sample long term test stability has no significant change.With reference to the above results and《Chemicals is miscellaneous
Technological guidance's principle of matter research》, limit of this product about material be：Impurity I is no more than 0.2%, and impurity II is no more than 0.2%,
Other lists are miscellaneous to be no more than 0.2%, and total impurities is no more than 0.4%.
The viscosity measurement of test example 3
This product is taken, according to viscosimetry（Chinese Pharmacopoeia two methods of annex VIG second of version in 2010）, rotated using rotor-type
Viscosimeter determines, and using No. 2 rotors, rotating speed 6rpm, measurement temperature is 25 °C, is determined in accordance with the law, after rotating 3 minutes, records phase
To viscosity, viscosity should be 900 ~ 3200cp.
The viscosity measurement result of table 3
Viscosity measurement, each batch sample viscosity are carried out to the stability test sample of six batches of pilot scales of this product using the above method
Meet regulation, this product viscosity is 900 ~ 3200cp.
The cloud test of test example 4
1 bottle of test sample is taken, is shaken 15 seconds, is sampled respectively at the top of bottle, centre and bottom, according under assay item
Method determines.Each position contains posaconazole（C37H42F2N8O4）The 95.0 ~ 105.0% of labelled amount are should be, containing sodium benzoate
（C7H5NaO2）It should be 1.80 ~ 2.20mg/ml.
The uniformity test result of table 4
As a result show：Oral posaconazole suspension makes sample by oneself and the stability test sample of reference preparation carries out content
Cloud test, each batch sample meet regulation, and this product uniformity of dosage units should be the 95.0 ~ 105.0% of labelled amount, first containing benzene
Sour sodium（C7H5NaO2）It should be 1.80 ~ 2.20mg/ml.
Above-mentioned detailed description is illustrating for one of them possible embodiments of the present invention, and the embodiment is simultaneously not used to
The scope of the claims of the present invention is limited, all equivalence enforcements or change without departing from carried out by the present invention, is intended to be limited solely by the technology of the present invention
In the range of scheme.
Claims (5)
1. a kind of posaconazole suspension, it is characterised in that it is made up of the composition of following proportioning：
Posaconazole 4g
Tween-80 1g
Dimeticone 0.3g
Sodium benzoate 0.2g
Appropriate sodium citrate
Appropriate citric acid
Glycerine 10g
Xanthans 0.3g
Malt syrup 35g
Titanium dioxide 0.4g
Essence 0.3g
Add purified water to 100ml
Its preparation method comprises the following steps：
（1）Posaconazole raw material, Tween-80, dimeticone, sodium benzoate, citric acid, Chinese holly are weighed by batch production instruction order
Rafter acid sodium, glycerine, xanthans and malt syrup；
（2）The purified water and Tween-80 for preparing total amount 30% are added into mixer, recipe quantity pool is added after stirring and dissolving
Saperconazole, continue stirring and dimeticone is continuously added to after being uniformly dispersed, and be uniformly dispersed, it is standby；
（3）Above-mentioned finely dispersed decoction homogenization, homogenization pressure are 30-60MPa, and homogeneous terminates in backward homogenizer
Purified water is added, residual liquor is rinsed, adds into mixer；
（4）The decoction through homogenization is added into Agitation Tank, adds sodium benzoate, stirring is until be well mixed backward Agitation Tank
In be slowly added to xanthans, the stirring of side edged constant speed, continue to stir after adding xanthans；
（5）Glycerine, malt syrup are added into Agitation Tank, edged constant speed stirring in side is until well mixed；
（6）Recipe quantity titanium dioxide is taken to add purified water to be added to after being uniformly dispersed in Agitation Tank, edged constant speed stirring in side is until mixing
Essence is added after uniformly, is stirred to well mixed；
（7）Adjust pH to 4.3-4.7；
（8）Add purified water into Agitation Tank to full dose and to be well mixed, intermediate sampling carries out middle control detection, after qualified
For filling.
2. posaconazole suspension as claimed in claim 1, it is characterised in that wherein step 3）Middle homogenization is to raw material grain
Footpath：Granule number >=65% less than 3 μm, granule number >=99% less than 10 μm, median d (0.5) is between 1.5-1.85 μm.
3. posaconazole suspension as claimed in claim 1, it is characterised in that wherein step 3）Middle homogeneous terminates backward homogeneous
The purified water for preparing total amount 10% is added in machine.
4. posaconazole suspension as claimed in claim 1, it is characterised in that wherein step 6）Middle purified water is preparation total amount
5%.
5. posaconazole suspension as claimed in claim 1, it is characterised in that with 1mol/L citric acids and 1mol/L citric acids
Sodium prepares citric acid-sodium citrate buffer.
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| CN107625729A (en) * | 2017-09-29 | 2018-01-26 | 重庆华邦制药有限公司 | Oral posaconazole suspension and preparation method thereof |
| CN110507609B (en) * | 2018-05-21 | 2021-09-17 | 上海医药工业研究院 | Preparation method of posaconazole oral suspension |
| CN109260148A (en) * | 2018-10-18 | 2019-01-25 | 南京安伦化工科技有限公司 | A kind of preparation method of high-purity posaconazole suspension |
| CN111658610B (en) * | 2020-07-31 | 2022-05-24 | 上海方予健康医药科技有限公司 | Triazole antifungal medicine suspension for atomizer |
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| CN102805731B (en) * | 2012-08-22 | 2014-04-30 | 北京莱瑞森医药科技有限公司 | Posaconazole dry suspension and preparation method thereof |
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