CN110403936A - A kind of Fluconazole pharmaceutical composition and preparation method thereof - Google Patents

A kind of Fluconazole pharmaceutical composition and preparation method thereof Download PDF

Info

Publication number
CN110403936A
CN110403936A CN201910839775.0A CN201910839775A CN110403936A CN 110403936 A CN110403936 A CN 110403936A CN 201910839775 A CN201910839775 A CN 201910839775A CN 110403936 A CN110403936 A CN 110403936A
Authority
CN
China
Prior art keywords
fluconazole
microcrystalline cellulose
pharmaceutical composition
compound
cellulose composite
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.)
Pending
Application number
CN201910839775.0A
Other languages
Chinese (zh)
Inventor
熊卫艳
陈晓萍
邹永华
楼金芳
沈意康
邵赛
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hangzhou Baicheng Pharmaceutical Technology Co Ltd
Original Assignee
Hangzhou Baicheng Pharmaceutical Technology Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Hangzhou Baicheng Pharmaceutical Technology Co Ltd filed Critical Hangzhou Baicheng Pharmaceutical Technology Co Ltd
Priority to CN201910839775.0A priority Critical patent/CN110403936A/en
Publication of CN110403936A publication Critical patent/CN110403936A/en
Priority to CN202010930894.XA priority patent/CN112023056B/en
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention provides a kind of Fluconazole pharmaceutical composition and preparation method thereof.The composition auxiliary material group becomes Microcrystalline cellulose composite, and Microcrystalline cellulose composite is silicified microcrystalline cellulose, microcrystalline cellulose-lactose compound, microcrystalline cellulose-carboxyrnethyl starch sodium compound, microcrystalline cellulose-mannitol compound, microcrystalline cellulose-glycerin monostearate compound one kind；The invention preparation method is direct hybrid technique method, and Fluconazole, Microcrystalline cellulose composite are crossed sieve, mixes, is filled in gelatin hollow capsule.Auxiliary material of the present invention contains only Microcrystalline cellulose composite, reduces supplementary product kind, reduces auxiliary material and mixes uneven risk, and preparation process is simple, reduces energy consumption, reduces environmental pollution, and improves production efficiency, is suitble to Enterprise business large-scale production.Obtained Fluconazole pharmaceutical composition mobility is good, and difference is small in batch, and dissolution rate is fast, has better stability and higher bioavilability.

Description

A kind of Fluconazole pharmaceutical composition and preparation method thereof
Technical field
The invention belongs to field of pharmaceutical preparations, it is related to a kind of Fluconazole pharmaceutical composition and preparation method thereof.
Background technique
Fluconazole is the pyroles wide spectrum that pfizer inc (Pfizer Pharmaceuticals Ltd) is developed Antifungal, high selectivity interferes the activity of the cytochrome P-450 of fungi, to inhibit ergosterol on fungal cell membrane Biosynthesis, so that intracellular organic matter is leaked and dead.Clinic is mainly used for vaginal candidiasis, thrush, and atrophic oral cavity is read Pearl bacterium disease, fungal meningitis, Pulmonary Fungal Infections, abdominal infection, urethral infection and dermatophyte sense bacterium etc..Molecular action Target spot are as follows: Lanosterol 14-alpha demethylase.
Fluconazole chemical name is α-(2,4 difluorobenzene base)-α-(1H-1,2,4- triazol-1-yl methyl) -1H-1,2,4- Triazol-1-yl ethyl alcohol.Structural formula is as shown in following formula I, molecular formula C13H12F2N6O, molecular weight 306.28, CAS 86386-73-4, Fluconazole is off-white color crystalline powder, odorless, 137 DEG C -141 DEG C of fusing point, readily soluble in methyl alcohol, is dissolved in ethanol, two Slightly soluble in chloromethanes, water or acetic acid, it is insoluble in ether.
According to report (tight small red etc., the polycrystallinity and Study on Transformation of Fluconazole；Chinese Journal of Modern Applied Pharmacy in August, 2012 The 8th phase of volume 29), Fluconazole has I crystal form, II crystal form, four kinds of crystal forms of III crystal form and monohydrate crystal form, I crystal form and II crystal form With preferable thermal stability, monohydrate crystal form is converted into II crystal form at 60 DEG C~160 DEG C.
Fluconazole capsule that Pfizer is announced in French Bureau of Drugs Supervision official website (trade name:) specification, it is auxiliary Material includes lactose, cornstarch, lauryl sodium sulfate, silica, magnesium stearate, gelatin, titanium dioxide (E171), blue No. 5 (E131).Simultaneously inquire Argentina listing fluconazole capsule (trade name:Specification: 50mg) prescription letter Table is ceased, learns in fluconazole capsule prescription lactose 49.708mg/, cornstarch 16.500mg/, lauryl sodium sulfate 0.117mg/, silica and magnesium stearate mixture (ratio 1:9) 1.175mg/.Fluconazole capsule Middle supplementary product kind is various, and lauryl sodium sulfate dosage is low, is easy mixing unevenly, influences drug-eluting and body absorption.
Patent CN108578377A discloses a kind of Fluconazole piece and preparation method thereof, prepares Fluconazole quick-release tablet, medicine It include filler, disintegrating agent, adhesive, lubricant with auxiliary material；Preparation process include supplementary material crush, mixing, wet granulation and Dry, mixing, tabletting.The invention prescription component is various, and preparation process is complicated, and production efficiency is low.
It is disclosed in patent CN1812783A with the fluconazole capsule for improving release, which is to provide can be quickly And the fluconazole capsule of consistent dissolution, Fluconazole are lived with the reagent that can provide hydrophilic surface character for particle and optionally in surface At particle, obtained particle mixes property dosage form with filler, disintegrating agent, lubricant and glidant, is filled in capsule.The invention Middle Fluconazole and hydrophilic surfactant active are formed in particle process, because dosage of surfactant is few, are easy to appear table in particle Face activating agent is unevenly distributed, and influences dissolution and body absorption.
The Fluconazole pharmaceutical composition of existing preparation method manufacture, poor fluidity and batch in difference it is big, dissolution rate is low, surely Qualitative difference is low with bioavilability.
Summary of the invention
The present invention, as auxiliary material, prepares a kind of new Fluconazole pharmaceutical composition using single Microcrystalline cellulose composite Object increases powder fluidity, improves medicaments uniformity degree, dissolution rate, stability and bioavilability.
The present invention is a kind of Fluconazole pharmaceutical composition, and the composition is by Fluconazole and Microcrystalline cellulose composite group At weight percent is Fluconazole: Microcrystalline cellulose composite=1:4-2:1.
Fluconazole size distribution D in the Fluconazole pharmaceutical composition90It is 150 μm~300 μm, D50It is 50 μm~120 μm, D10It is 10 μm~30 μm.
The Microcrystalline cellulose composite of the Fluconazole pharmaceutical composition is one of the following: silicified microcrystalline cellulose, crystallite Cellulose-lactose compound, microcrystalline cellulose-carboxyrnethyl starch sodium compound, microcrystalline cellulose-mannitol compound, crystallite are fine Tie up element-glycerin monostearate compound.
Microcrystalline cellulose composite heap density in the Fluconazole pharmaceutical composition is 0.20g/ml~0.40g/ml, vibration Real density is 0.40g/ml~0.60g/ml.
Fluconazole crystal form in the Fluconazole pharmaceutical composition is I crystal form, II crystal form, III crystal form and monohydrate crystal form One of or it is a variety of.
The Fluconazole pharmaceutical composition is filled in gelatin hollow capsule, three kinds below gelatin hollow capsule model One of: No. 2, No. 3 or No. 4.
Fluconazole pharmaceutical composition of the present invention is prepared according to following method:
(1) Fluconazole, Microcrystalline cellulose composite are crossed into sieve, it is spare；
(2) Fluconazole, Microcrystalline cellulose composite are added into mixing machine, are uniformly mixed；
(3) into step (2), gained total mix powder is filled in gelatin hollow capsule.
Specific embodiment
The present invention is further described with reference to embodiments, and embodiment does not limit the scope of the invention.
Embodiment 1: Fluconazole pharmaceutical composition composition: specification 50mg, recipe quantity are 1000 (referring to table 1).
Table 1: 1 prescription table of embodiment
Fluconazole 50.00g
Silicified microcrystalline cellulose 75.00g
No. 3 gelatin hollow capsules 1000 sets
Fluconazole size distribution D in embodiment 190=215.28 μm, D50=94.39 μm, D10=15.14 μm, Fluconazole is II crystal form；Silicified microcrystalline cellulose heap density is 0.25g/ml, tap density 0.42g/ml.
The preparation method of embodiment 1:
(1) Fluconazole, silicified microcrystalline cellulose are crossed into 40 mesh screens respectively, it is spare；
(2) Fluconazole, silicified microcrystalline cellulose are added into mixing machine, revolving speed 10rpm is set, mix 15min；
(3) it is filled in No. 3 gelatin hollow capsules.
Embodiment 2: Fluconazole pharmaceutical composition composition: specification 50mg, recipe quantity are 1000 (referring to table 2).
Table 2: 2 prescription table of embodiment
Fluconazole 50.00g
Microcrystalline cellulose-lactose compound 200.00g
No. 2 gelatin hollow capsules 1000 sets
Fluconazole size distribution D in embodiment 290=169.40 μm, D50=55.91 μm, D10=12.83 μm, Fluconazole is Monohydrate crystal form；Microcrystalline cellulose-lactose compound is 0.39g/ml, tap density 0.57g/ml.
The preparation method of embodiment 2:
(1) Fluconazole, microcrystalline cellulose-lactose compound are crossed into 40 mesh screens, it is spare；
(2) Fluconazole, microcrystalline cellulose-lactose compound are added into mixing machine, revolving speed 10rpm, mixing is set 25min；
(3) it is filled in No. 2 gelatin hollow capsules；
Embodiment 3: Fluconazole pharmaceutical composition composition: specification 50mg, recipe quantity are 1000 (referring to table 3)
Table 3: 3 prescription table of embodiment
Fluconazole 50.00g
Microcrystalline cellulose-mannitol compound 25.00g
No. 4 gelatin hollow capsules 1000 sets
Fluconazole size distribution D in embodiment 390=296.39 μm, D50=118.70 μm, D10=28.98 μm, Fluconazole For III crystal form；Microcrystalline cellulose-mannitol compound heap density is 0.30g/ml, tap density 0.49g/ml.
The preparation method of embodiment 3:
(1) Fluconazole, microcrystalline cellulose-mannitol compound are crossed into 40 mesh screens, it is spare；
(2) Fluconazole, microcrystalline cellulose-mannitol compound are added into mixing machine, revolving speed 10rpm, mixing is set 20min；
(3) it is filled in No. 4 gelatin hollow capsules.
Comparative formulation 1: Fluconazole pharmaceutical composition composition: specification 50mg, recipe quantity are 1000 (referring to table 4)
Table 4: 1 prescription table of Comparative formulation
Fluconazole 50.00g
Microcrystalline cellulose-lactose compound 12.50g
No. 4 gelatin hollow capsules 1000 sets
Fluconazole size distribution D in Comparative formulation 190=169.40 μm, D50=55.91 μm, D10=12.83 μm, Fluconazole For monohydrate crystal form；Microcrystalline cellulose-lactose compound heap density is 0.39g/ml, tap density 0.57g/ml.
The preparation method of Comparative formulation 1:
(1) Fluconazole, microcrystalline cellulose-lactose compound are crossed into 40 mesh screens, it is spare；
(2) Fluconazole, microcrystalline cellulose-lactose compound are added into mixing machine, revolving speed 10rpm, mixing is set 20min；
(3) it is filled in No. 4 gelatin hollow capsules.
Comparative formulation 2: composition: specification 50mg, recipe quantity are 1000 (referring to table 5)
Table 5: 2 prescription table of Comparative formulation
Fluconazole 50.00g
Lactose 50.00g
Cornstarch 16.70g
Silica 0.12g
Magnesium stearate 1.18g
No. 3 gelatin hollow capsules 1000 sets
Fluconazole size distribution D in Comparative formulation 290=169.40 μm, D50=55.91 μm, D10=12.83 μm, Fluconazole For III crystal form.
The preparation method of Comparative formulation 2:
(1) Fluconazole, lactose, cornstarch, silica and magnesium stearate are crossed into 40 mesh screens, it is spare；
(2) Fluconazole, lactose, cornstarch, silica are added into mixing machine, revolving speed 10rpm, mixing is set 20min；
(3) revolving speed 10rpm is arranged in the magnesium stearate being added, and mixes 5min；
(4) it is filled in No. 3 gelatin hollow capsules.
Select pfizer inc fluconazole capsule (trade name:Specification: 50mg) it is used as reference system Agent.
One, powder fluidity testing
Powder fluidity test.Cake compressibility: a certain amount of powder is fitted into graduated cylinder by measurement under the conditions of vibrationless, is surveyed Determine apparent volume V1, tapping to the unconverted percussion volume V of final volume2；
Cake compressibility=(V1-V2)/V1× 100%
Mobility and cake compressibility judgment criteria are as follows in USP<1174>:
Mobility Cake compressibility (%)
It is fabulous ≤10
It is good 11~15
Generally 16~20
It can pass through 21~25
Difference 26~31
It is very poor 32~37
It is excessively poor > 38
Angle of repose measurement: it is measured referring to USP<1174>powder fluidity, using fixed funnel method, funnel is fixed on water The height for being suitable on the graph paper of placing flat, makes distance H of the mouth away from graph paper under funnel, carefully pours into powder in funnel, Until the outlet of the nib contacts funnel of the cone formed under funnel, the radius r of circular cone can be measured by graph paper.Stop The calculation method of angle α is as follows: α=tan-1(H/r)
Mobility and angle of repose judgment criteria are as follows in USP<1174>:
Mobility Angle of repose (°)
It is very good 25~30
Very well 31~35
Good-it is not necessary that adminicle is added 36~40
It is subjected to-needs that adminicle is added 41~45
Difference 46~55
It is excessively poor 55~65
It is extremely poor >66
Testing result.Fluconazole pharmaceutical composition (1~embodiment of embodiment 3) of the present invention, Comparative formulation 1, Comparative formulation 2 And reference preparation powder characteristics testing result is shown in Table 6.
Table 6: Fluconazole pharmaceutical composition (1~embodiment of embodiment 3), Comparative formulation 1, Comparative formulation 2 and reference preparation Powder characteristics
Sample ID Cake compressibility (%) Angle of repose (°)
Embodiment 1 18.7 37.5
Embodiment 2 16.2 36.2
Embodiment 3 18.9 39.3
Comparative formulation 1 26.6 46.3
Comparative formulation 2 28.3 47.4
Reference preparation 29.0 48.6
Test result.According to the criterion at cake compressibility and angle of repose, Comparative formulation 1, Comparative formulation 2 and reference preparation Prepared powder compression index is between 26%~31%, and angle of repose is between 46 °~55 °, poor fluidity；Embodiment Powder compression index prepared by 1~3 is between 16%~20%, and between 36 °~40 °, flow model is preferable at angle of repose. The above results show the powder fluidity of Fluconazole pharmaceutical composition (Examples 1 to 3) of the present invention than Comparative formulation 1, comparison system The powder fluidity of agent 2 and reference preparation is good.
Two, dissolution in vitro is tested
The measurement of Fluconazole oral solid formulation In Vitro Dissolution curve is with the following method: Example 1~3, comparison system Agent 1, Comparative formulation 2 and reference preparation (manufacturer: pfizer inc, trade name: Specification: 50mg) fluorine health Danazol capsule, according to dissolution rate and drug release determination method (Chinese Pharmacopoeia 0,931 first method of version general rule in 2015), with 0.1mol/L hydrochloric acid Solution (measuring 9ml hydrochloric acid, be diluted with water to 1000ml), pH4.5 acetate buffer (take sodium acetate 18g, acetic acid on the rocks 9.8ml is added water and is diluted to 1000ml) 500ml be dissolution medium, revolving speed be 100 turns per minute, operate according to methods, respectively at 5min, 10min, 15min, 30min and 45min sampling, take solution appropriate, filter, take subsequent filtrate as test solution；Another essence It is close to weigh that Fluconazole reference substance is appropriate, add dissolution medium to dissolve and quantify dilution solution in every 1ml containing about 0.1mg is made, makees For reference substance solution.It is measured according to method under content determination item, calculates every dissolution rate.
Study on the stability is in the following way:
Influence factor test: Example 1~3, Comparative formulation 1, Comparative formulation 2 and reference preparation fluconazole capsule are in height Warm (60 ± 2 DEG C), high humidity (90% ± 5%RH), illumination (4500Lx ± 500Lx) condition are placed 10 days, are sampled in the 10th day, inspection Dissolution rate is surveyed, and compares dissolution rate with 0 day sample.
Acceleration keeps sample: 2 fluconazole capsule of Example 1~3, Comparative formulation 1 and Comparative formulation, aluminum-plastic packaged, housing is multiple Close film bag；Reference preparation commercially available back, in 40 DEG C, 75%RH condition is placed 6 months, and placing terminates sampling, detects dissolution rate, and Dissolution rate is compared with 0 day sample.
Keep sample for a long time: 2 fluconazole capsule of Example 1~3, Comparative formulation 1 and Comparative formulation, aluminum-plastic packaged, housing is multiple Close film bag；Reference preparation commercially available back, in 25 DEG C, 60%RH condition is placed 12 months, and placing terminates sampling, detects dissolution rate, And dissolution rate is compared with 0 day sample.
Fluconazole pharmaceutical composition (Examples 1 to 3) of the present invention, Comparative formulation 1,0 day of Comparative formulation 2 and reference preparation Dissolution data see the table below 7.
Examples 1 to 3 15min in 0.1mol/L hydrochloric acid and pH4.5 acetate buffer accumulates the amount of dissolution and is all larger than 85%, belong to Fast Stripping, dissolves out indifference.
Comparative formulation 1, Comparative formulation 2 15min in 0.1mol/L hydrochloric acid accumulate the amount of dissolution and are all larger than 85%；In pH4.5 It is respectively 70.5%, 57.6% that 15min, which accumulates the amount of dissolution, in acetate buffer, is below 85%, and 5min dissolution rate RSD value It is all larger than 10% greater than 20%, 10min~30min dissolution rate RSD value, dissolution differs greatly in batch.
Reference preparation 15min in 0.1mol/L hydrochloric acid accumulates the amount of dissolution and is greater than 85%, in pH4.5 acetate buffer It is 62.9% that 15min, which accumulates the amount of dissolution, and less than 85%, and 5min dissolution rate RSD value is greater than 20%, 10min~15min dissolution rate RSD value is all larger than 10%, and dissolution differs greatly in batch.The above results show and Comparative formulation 1, Comparative formulation 2 and reference preparation It compares, Fluconazole pharmaceutical composition (Examples 1 to 3) of the invention, there is higher dissolution rate, and dissolve out batch interior difference It is small.
Table 7: Fluconazole pharmaceutical composition (Examples 1 to 3), Comparative formulation 1, Comparative formulation 2 and reference preparation 0 day are external Accumulate the amount of dissolution
Note: "/" expression is placed at room temperature for, no specific condition processing.
1 fluconazole capsule study on the stability cumulative in vitro the amount of dissolution of Comparative formulation is shown in Table 8.1 influence factor of Comparative formulation is (high Temperature, high humidity, illumination) it accumulates the amount of dissolution and is all larger than 85% within 10 days and 15min in 0.1mol/L hydrochloric acid in long-term December, it is molten with 0 day Out-degree indifference.It is 72.5% that Comparative formulation 1, which accelerates 15min in 0.1mol/L hydrochloric acid in June to accumulate the amount of dissolution, compared with 0 day, 15min, which accumulates the amount of dissolution, reduces about 17%.
Table 8: 1 fluconazole capsule study on the stability cumulative in vitro the amount of dissolution of Comparative formulation
Note: "/" expression is placed at room temperature for, no specific condition processing.
2 fluconazole capsule study on the stability cumulative in vitro the amount of dissolution of Comparative formulation is shown in Table 9.Comparative formulation influence factor is (high Temperature, high humidity, illumination) it accumulates the amount of dissolution and is all larger than 85% within 10 days and 15min in 0.1mol/L hydrochloric acid in long-term December, with 0 day phase Than dissolution rate indifference.It was 65.6% that Comparative formulation 2, which accelerates 15min in 0.1mol/L hydrochloric acid in June to accumulate the amount of dissolution, with 0 day It compares, 15min, which accumulates the amount of dissolution, reduces about 20%.
Table 9: 2 fluconazole capsule study on the stability cumulative in vitro the amount of dissolution of Comparative formulation
Note: "/" expression is placed at room temperature for, no specific condition processing.
Reference preparation fluconazole capsule study on the stability cumulative in vitro the amount of dissolution is shown in Table 10.Reference preparation influence factor is (high Temperature, high humidity, illumination) it accumulates the amount of dissolution and is all larger than 85% within 10 days and 15min in 0.1mol/L hydrochloric acid in long-term December, with 0 day phase Than dissolution rate indifference.It was 72.3% that reference preparation, which accelerates 15min in 0.1mol/L hydrochloric acid in June to accumulate the amount of dissolution, with 0 day phase Than 15min, which accumulates the amount of dissolution, reduces about 27%.
Table 10: reference preparation fluconazole capsule study on the stability cumulative in vitro the amount of dissolution
Note: "/" expression is placed at room temperature for, no specific condition processing.
1 fluconazole capsule study on the stability cumulative in vitro the amount of dissolution of the embodiment of the present invention is shown in Table 11.Embodiment 1 influence because Plain (high temperature, high humidity, illumination) 10 days, accelerate June and long-term the December 15min in 0.1mol/L hydrochloric acid to accumulate the amount of dissolution to be all larger than 85%, with 0 day dissolution rate indifference.
Table 11: 1 fluconazole capsule study on the stability cumulative in vitro the amount of dissolution of embodiment
Note: "/" expression is placed at room temperature for, no specific condition processing.
2 fluconazole capsule study on the stability cumulative in vitro the amount of dissolution of the embodiment of the present invention is shown in Table 12.Embodiment 2 influence because Plain (high temperature, high humidity, illumination) 10 days, accelerate June and long-term the December 15min in 0.1mol/L hydrochloric acid to accumulate the amount of dissolution to be all larger than 85%, with 0 day dissolution rate indifference.
Table 12: 2 fluconazole capsule study on the stability cumulative in vitro the amount of dissolution of embodiment
Note: "/" expression is placed at room temperature for, no specific condition processing.
3 fluconazole capsule study on the stability cumulative in vitro the amount of dissolution of the embodiment of the present invention is shown in Table 13.Embodiment 3 influence because Plain (high temperature, high humidity, illumination) 10 days, accelerate June and long-term the December 15min in 0.1mol/L hydrochloric acid to accumulate the amount of dissolution to be all larger than 85%, with 0 day dissolution rate indifference.
Table 13: 3 fluconazole capsule study on the stability cumulative in vitro the amount of dissolution of embodiment
Note: "/" expression is placed at room temperature for, no specific condition processing.
Test result.From 8~table of table, 13 result it is found that Examples 1 to 3, Comparative formulation 1, Comparative formulation 2 and reference preparation Study on the stability the result shows that, without slowing down, it is big that 15min accumulates the amount of dissolution to Examples 1 to 3 for dissolution after acceleration environment places June In 85%, with 0 day dissolution rate indifference；Comparative formulation 1, Comparative formulation 2 and reference preparation place 15min accumulation dissolution after June Amount is respectively 72.5%, 65.6%, 72.3%, and 15min accumulation the amount of dissolution slows down about 17%~27%, and 5min compared with 0 day Dissolution rate RSD value is greater than 20%, and 10~15min dissolution rate RSD value is greater than 10%.This shows Fluconazole pharmaceutical composition of the invention Object (Examples 1 to 3) quality stability is better than Comparative formulation 1, Comparative formulation 2 and reference preparation stability.
Three, bioavilability detects
Observation check under subject's Postprandial blood concentration after single oral dose through when process, estimate corresponding medicine generation Kinetic parameter, to evaluate Fluconazole pharmaceutical composition (Examples 1 to 3) of the present invention, Comparative formulation 2 and the biology of reference preparation Availability.
Subject's selection: 20 healthy adult males and the non-lactation period female volunteers that are not pregnant, age 20~55 are selected Meet health standards through physical examination in year, test does not take any other drug in first 3 months.
Experimental design: using random, opening, single dose, five preparations, five period crossover control designs.
Postprandial test: meeting the healthy adult male of inclusion criteria and be not pregnant non-lactation period female subjects 20, by Statistician is randomly assigned to first group, second group, third group, fourth group, one of penta group, carries out Examples 1 to 3, Comparative formulation 2 and reference Preparation pharmacokinetic.
Take a blood sample point: 0.25h, 0.50h after (0h) before administration, administration, 0.75h, 1.00h, 1.25h, 1.50h, 2.00h, 3.00h、4.00h、5.00h、6.00h、8.00h、10.00h、12.00h、16.00h、24.00h、48.00h、72.00h、 96.00h totally 20 time points.
Testing result such as table 14 and table 15.Examples 1 to 3, Comparative formulation 2, reference preparation peak time TmaxRespectively 1.5h, 1.5h, 1.5h, 2.5h, 2.5h, Examples 1 to 3 work faster compared with Comparative formulation 2, reference preparation.Embodiment 1 with The C of Comparative formulation 2max、AUC0-t、AUC0-∞Geometric mean than be respectively 111.47%, 114.45% and 112.40%, implement The C of example 2 and Comparative formulation 2max、AUC0-t、AUC0-∞Geometric mean than be respectively 108.80%, 113.89% and 111.82%, The C of embodiment 3 and Comparative formulation 2max、AUC0-t、AUC0-∞Geometric mean than be respectively 113.84%, 115.25% and 114.85%, Examples 1 to 3 has more high bioavilability compared to Comparative formulation 2；The C of embodiment 1 and reference preparationmax、 AUC0-t、AUC0-∞Geometric mean than being respectively 109.58%, 114.20% and 111.97%, embodiment 2 and reference preparation Cmax、AUC0-t、AUC0-∞Geometric mean than being respectively 106.95%, 113.64% and 111.40%, embodiment 3 and reference system The C of agentmax、AUC0-t、AUC0-∞Geometric mean than be respectively 111.91%, 115.01% and 114.42%, Examples 1 to 3 Bioavilability is better than reference preparation.
Table 14: the C of Examples 1 to 3 and Comparative formulation 2max、AUC0-t、AUC0-∞Testing result
Table 15: the C of Examples 1 to 3 and reference preparationmax、AUC0-t、AUC0-∞Testing result
Test result.Fluconazole pharmaceutical composition (Examples 1 to 3) prepared by the present invention and Comparative formulation 2, reference preparation It compares, there is more high bioavilability.

Claims (8)

1. a kind of Fluconazole pharmaceutical composition, described pharmaceutical composition are made of Fluconazole and Microcrystalline cellulose composite, the two Weight ratio is Fluconazole: Microcrystalline cellulose composite=1:4-2:1.
2. pharmaceutical composition according to claim 1, it is characterised in that the Fluconazole size distribution D90For 150 μm~ 300 μm, D50It is 50 μm~120 μm, D10It is 10 μm~30 μm.
3. pharmaceutical composition according to claim 1, it is characterised in that the Microcrystalline cellulose composite be it is following it One: silicified microcrystalline cellulose, microcrystalline cellulose-lactose compound, microcrystalline cellulose-carboxyrnethyl starch sodium compound, microcrystalline cellulose Element-mannitol compound, microcrystalline cellulose-glycerin monostearate compound.
4. pharmaceutical composition according to claim 1, it is characterised in that the Microcrystalline cellulose composite heap density is 0.20g/ml~0.40g/ml, tap density are 0.40g/ml~0.60g/ml.
5. pharmaceutical composition according to claim 1, it is characterised in that the Fluconazole crystal form be I crystal form, II crystal form, It is one or more among III crystal form or monohydrate crystal form.
6. pharmaceutical composition according to claims 1 to 5, feature is filled in gelatin hollow capsule in the composition In, one of following model of the gelatin hollow capsule selection: No. 2, No. 3 or No. 4.
7. Fluconazole pharmaceutical composition according to claim 1~6, it is characterised in that the preparation method is as follows:
(1) Fluconazole, Microcrystalline cellulose composite are crossed into sieve, it is spare；
(2) Fluconazole, Microcrystalline cellulose composite are added into mixing machine, are uniformly mixed；
(3) gained total mix powder in step (2) is filled in gelatin hollow capsule.
8. Fluconazole pharmaceutical composition according to claim 1~7, it is characterised in that the preparation method is as follows:
(1) Fluconazole, Microcrystalline cellulose composite are crossed into 40 mesh screens, it is spare；
(2) Fluconazole, Microcrystalline cellulose composite are added into mixing machine, revolving speed 10rpm is set, mix 15~25min；
(3) gained total mix powder in step (2) is filled in gelatin hollow capsule.
CN201910839775.0A 2019-09-05 2019-09-05 A kind of Fluconazole pharmaceutical composition and preparation method thereof Pending CN110403936A (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201910839775.0A CN110403936A (en) 2019-09-05 2019-09-05 A kind of Fluconazole pharmaceutical composition and preparation method thereof
CN202010930894.XA CN112023056B (en) 2019-09-05 2020-09-07 Fluconazole pharmaceutical composition and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201910839775.0A CN110403936A (en) 2019-09-05 2019-09-05 A kind of Fluconazole pharmaceutical composition and preparation method thereof

Publications (1)

Publication Number Publication Date
CN110403936A true CN110403936A (en) 2019-11-05

Family

ID=68370478

Family Applications (2)

Application Number Title Priority Date Filing Date
CN201910839775.0A Pending CN110403936A (en) 2019-09-05 2019-09-05 A kind of Fluconazole pharmaceutical composition and preparation method thereof
CN202010930894.XA Active CN112023056B (en) 2019-09-05 2020-09-07 Fluconazole pharmaceutical composition and preparation method thereof

Family Applications After (1)

Application Number Title Priority Date Filing Date
CN202010930894.XA Active CN112023056B (en) 2019-09-05 2020-09-07 Fluconazole pharmaceutical composition and preparation method thereof

Country Status (1)

Country Link
CN (2) CN110403936A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113476610A (en) * 2021-08-13 2021-10-08 云南中医药大学 Antifungal medicine composition composed of glycerin derivative and antifungal medicine

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1593405A (en) * 2004-07-09 2005-03-16 沈阳药科大学 Prescription for liquid status of fluconazole and its preparation
WO2011101862A1 (en) * 2010-02-17 2011-08-25 Fdc Limited Stabilized fluconazole polymorph iii formulation
CN107737112B (en) * 2017-11-07 2020-05-19 海南锦瑞制药有限公司 Letrozole tablet and preparation method thereof

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113476610A (en) * 2021-08-13 2021-10-08 云南中医药大学 Antifungal medicine composition composed of glycerin derivative and antifungal medicine

Also Published As

Publication number Publication date
CN112023056A (en) 2020-12-04
CN112023056B (en) 2023-05-23

Similar Documents

Publication Publication Date Title
CA2785857A1 (en) Production method of solid preparations and the solid preparations produced by the method
CN112494437A (en) Hydroxychloroquine compound-containing pharmaceutical composition, tablet and preparation method thereof
CN103717209B (en) The combination of oral medication of the stabilization containing prasugrel of quick-release
CN109044983A (en) A kind of tablet and preparation method thereof containing Febustat
CN102711761A (en) Elution-stabilized preparation
CN110403936A (en) A kind of Fluconazole pharmaceutical composition and preparation method thereof
CN109674754B (en) Flupentixol and melitracen pharmaceutical composition and preparation thereof
CN102429912B (en) Pharmaceutical composition prepared with micronized prasterone or sodium prasterone sulfate and use thereof
CN112294770A (en) Isosorbide mononitrate compound preparation and application and preparation method thereof
CN105769872B (en) A kind of mosapride citrate composition of Fast Stripping
CN100577157C (en) Dispersant tablet containing hypolipidemic component and preparation method thereof
CN102488667B (en) Glimepiride tablet and preparation method thereof
CN109771380A (en) Desmethylvenlafaxine hydrochloride drug composition and preparation method thereof
CN114272219A (en) Donepezil hydrochloride tablet and preparation method thereof
WO2007090595A1 (en) Solid formulations of valacyclovir hydrochloride
CN112546018A (en) Cefaclor capsule and preparation method thereof
CN106214646A (en) A kind of silybin meglumine preparation
Ojoe et al. Influence of cellulose polymers type on in vitro controlled release tablets containing theophylline
CN108379235A (en) It being capable of quickly disintegrated tacrolimus sustained-release tablet composition
CN112691084A (en) Pharmaceutical composition and preparation method thereof
CN111053772A (en) Levatinib pharmaceutical composition and application thereof
CN105078913B (en) A kind of Irbesartan Tablets and preparation method thereof
CN101474167A (en) Preparation method of estradiol capsule for vagina
CN104337783B (en) A kind of capecitabine tablet and preparation method thereof
CN114099506B (en) Pharmaceutical composition containing sorafenib

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
WD01 Invention patent application deemed withdrawn after publication
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20191105