CN106176674A - A kind of preparation method of bicalutamide transparent aqueous phase Nanodispersion - Google Patents

A kind of preparation method of bicalutamide transparent aqueous phase Nanodispersion Download PDF

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CN106176674A
CN106176674A CN201610539244.6A CN201610539244A CN106176674A CN 106176674 A CN106176674 A CN 106176674A CN 201610539244 A CN201610539244 A CN 201610539244A CN 106176674 A CN106176674 A CN 106176674A
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bicalutamide
aqueous phase
preparation
reactor
nanodispersion
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蒲源
林立峰
王丹
何相磊
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Beijing University of Chemical Technology
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Beijing University of Chemical Technology
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    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5138—Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biomedical Technology (AREA)
  • Nanotechnology (AREA)
  • Optics & Photonics (AREA)
  • Physics & Mathematics (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention discloses the preparation method of a kind of bicalutamide transparent aqueous phase Nanodispersion, appropriate bicalutamide and water are added simultaneously in reactor；Being dissolved in by dispersant in water, be configured to adjuvant aqueous solution, and the temperature controlling adjuvant aqueous solution is 0 20 DEG C, stir speed (S.S.) is 500 800rpm；N it is passed through in reactor2Gas, regulates temperature of reaction system value preset temperature, and regulates reaction system pressure and reach preset pressure；Being sprayed into rapidly by liquid in reactor dissolved with in the aqueous solution of dispersant, liquid spouting velocity is 5 10ml/min, bicalutamide nano-particle i.e. Precipitation, forms aqueous phase Nanodispersion.Due to the fact that and use water as anti-solvent, greatly reduce the usage amount of organic solvent so that whole technique is nontoxic, pollution-free, product no solvent residue, low production cost, human body and environment are had extraordinary protective effect.

Description

A kind of preparation method of bicalutamide transparent aqueous phase Nanodispersion
Technical field
The present invention relates to medicine and health food preparation field, particularly relate to a kind of bicalutamide transparent aqueous phase nanometer and divide The preparation method of a prose style free from parallelism.
Background technology
Bicalutamide belongs to nonsteroidal androgen antagonist medicine, with luteinizing hormone releasing hormone (LHRH) analog or outer Section's orchiectomy is united and applied in the treatment of advanced prostate cancer.In Clinical practice, bicalutamide makes with the form of tablet Oral, but bicalutamide is slightly water-soluble compound, which prevent the absorption of this compounds, thus greatly limit than card The therapeutic effect of Shandong amine, so, the heat that the dissolubility of raising bicalutamide and bioavailability are always in drug research Point.
Showing after deliberation, the change of dissolution rate is the key factor of the bioavailability improving poorly water soluble drugs.Root Showing according to Ostwald Freundrich equation, drug-eluting speed and size of pharmaceutical particles are inversely proportional to, and reduce drug particles grain Footpath can be greatly improved its dissolution rate.In recent years, along with the development of medicine nanotechnology, many poorly water soluble drugs are by receiving Rice technology is prepared as nano-particle or Nanodispersion so that it is bioavailability is greatly improved.Patent CN 101322682A reports A kind of method preparing Nano medication dispersion with high pressure homogenization method；Patent CN 102188372A discloses a kind of use Spray drying method prepares the method for medicament nano granule.These methods can make medicament nano, and then improves its dissolution rate, But itself also have the limitation of its application, such as complicated process of preparation, particle diameter is big, skewness, containing chemistry examination Agent, works the mischief etc. to human body and environment.
Summary of the invention
The technical problem to be solved is to provide the preparation method of a kind of bicalutamide granule, and the method uses Asia Critical anti-solvent technology prepares bicalutamide nano-particle, owing to using water as anti-solvent, greatly reduces organic molten The usage amount of agent so that whole technique is nontoxic, pollution-free, product no solvent residue, low production cost, human body and environment are had There is extraordinary protective effect.
For solving the problems referred to above, the technical solution used in the present invention is to provide a kind of bicalutamide transparent aqueous phase nano-dispersed The preparation method of body, the method comprises the steps:
1) appropriate bicalutamide and water are added simultaneously in reactor；
2) dispersant is dissolved in water, be configured to adjuvant aqueous solution, and the temperature controlling adjuvant aqueous solution is 0-20 DEG C, stirs Mixing speed is 500-800rpm；
3) in reactor, N it is passed through2Gas, regulates temperature of reaction system value preset temperature, and regulates reaction system pressure Reach preset pressure；
4) being sprayed into rapidly by liquid in reactor dissolved with in the aqueous solution of dispersant, liquid spouting velocity is 5-10ml/ Min, bicalutamide nano-particle i.e. Precipitation, form aqueous phase Nanodispersion.
Preferably, step 1) described bicalutamide quality is 18-50mg, the volume of water is 40-60ml.
Preferably, step 2) described dispersant concentration in water is 0.1-5mg/ml, dispersant selected from Polyethylene Glycol, β- Cyclodextrin, hydroxypropyl methyl cellulose, polyvinylpyrrolidone.
Preferably, step 3) preset pressure of reaction kettle for reaction system is 5-78MPa, reaction temperature is 110-180 DEG C, Stir speed (S.S.) is 150-200rpm, and reaching the dissolution equilibrium time is 10-20min.
Preferably, step 4) described) reactor ejection bicalutamide aqueous solution volume is 5-10ml, the body of adjuvant aqueous solution Amass as 10-50ml.
The particle diameter of described bicalutamide rice grain is 40-90nm；Granule in described bicalutamide Nanodispersion molten Going out speed is dissolution 92.9%-94.6% in 120min, faster than the dissolution rate of crude drug powder body 5-10 times
In step 1) in reactor be vertical closing container, be arranged on filter in the middle part of reactor and be connected in probe tube, The aperture of filter is 500 nanometers.
In step 3) in by the subcritical water dissolved with bicalutamide through filter, be ejected in nano-particle catcher, dimension Hold catcher temperature constant, make the rapid crystallization nucleation of nano-particle, accelerate particles collision by two-forty stirring, form nanometer Grain.
The concentration of bicalutamide transparent aqueous phase Nanodispersion is 0.1-2mg/ml.
The invention has the beneficial effects as follows:
1. the present invention uses subcritical water anti-solvent technology to prepare bicalutamide nano-particle first.Subcritical water is the most molten Agent technology is the granulation technique received significant attention in recent years, owing to using water as anti-solvent, greatly reduces organic solvent Usage amount so that whole technique is nontoxic, pollution-free, product no solvent residue, low production cost, human body and environment are had non- The best protective effect.
2. the bicalutamide nano-particle obtained by the present invention has particle diameter little (particle diameter is 40-90nm), narrowly distributing, stablizes The feature that property is strong.
3. the bicalutamide granule transparent nano dispersion composition obtained by the present invention is fairly simple, and stabilizer is common medicine Use adjuvant.
4. the dissolution rate of the bicalutamide nano-particle that prepared by the present invention is obviously improved, can be the most molten in 20 minutes Go out, and under equal state, crude drug only has the 10-20% dissolution of total amount.
Accompanying drawing explanation
Fig. 1 is the scanning electron microscope (SEM) photograph of granule in the bicalutamide Nanodispersion in embodiment 1；
Fig. 2 is the scanning electron microscope (SEM) photograph of granule in the bicalutamide Nanodispersion in embodiment 2；
Fig. 3 is the scanning electron microscope (SEM) photograph of granule in the bicalutamide Nanodispersion in embodiment 3；
Fig. 4 is the scanning electron microscope (SEM) photograph of granule in the bicalutamide Nanodispersion in embodiment 4；
Fig. 5 is the scanning electron microscope (SEM) photograph of granule in the bicalutamide Nanodispersion in embodiment 5；
Fig. 6 is the scanning electron microscope (SEM) photograph of granule in the bicalutamide Nanodispersion in embodiment 6；
Fig. 7 is the scanning electron microscope (SEM) photograph of granule in the bicalutamide Nanodispersion in embodiment 7；
Fig. 8 is the scanning electron microscope (SEM) photograph of bicalutamide crude drug granule；
Fig. 9 is bicalutamide dissolution in varied situations；
Detailed description of the invention
Below in conjunction with the accompanying drawings and the present invention is illustrated by embodiment further, but present disclosure is not merely limited to In the following examples or other similar examples.
Embodiment 1
1) weigh 50mg bicalutamide and 50ml deionized water, be simultaneously introduced in reactor；
2) experimental provision is after air-leakage test, controls system temperature by heater and is increased to 140 DEG C, N2By height Press pump is passed in the middle of reaction unit and makes whole experimental provision boost in pressure make whole to 5.5MPa, adjusting high-pressure pump in 5min Individual experimental provision pressure keeps constant, after system stability, opens the agitating device in reactor, and regulation mixing speed is 160r/min, stirring 20min make system reach dissolution equilibrium；
3) being ejected into the subcritical water solution dissolved with bicalutamide equipped with in the collection beaker of deionized water, aqueous phase i.e. has Bicalutamide nanoparticle precipitate separates out, and forms transparent nano dispersion, and its drug concentration is 1mg/ml.Nano-particle is average Particle diameter is 2 μm.
Embodiment 2
1) weigh 50mg bicalutamide and 50ml deionized water, be simultaneously introduced in reactor；
2) experimental provision is after air-leakage test, controls system temperature by heater and is increased to 170 DEG C, N2By height Press pump is passed in the middle of reaction unit and makes whole experimental provision boost in pressure make whole to 5.5MPa, adjusting high-pressure pump in 5min Individual experimental provision pressure keeps constant, after system stability, opens the agitating device in reactor, and regulation mixing speed is 160r/min, stirring 20min make system reach dissolution equilibrium；
3) being ejected into the subcritical water solution dissolved with bicalutamide equipped with in the collection cups of deionized water, aqueous phase i.e. has ratio Card Shandong amine nanoparticle precipitate separates out, and forms transparent nano dispersion, and its drug concentration is 1mg/ml, nano-particle average particle Footpath is 1 μm.
Embodiment 3
1) weigh 50mg bicalutamide and 50ml deionized water, be simultaneously introduced in reactor,；
2) weighing 10mg lactose to be dissolved in 5ml deionized water, pour in collection beaker, the beaker that will be equipped with this aqueous solution is put In ice-water bath, controlling bath temperature is 18 DEG C, and stir speed (S.S.) is 800rpm.
3) experimental provision is after air-leakage test, controls system temperature by heater and is increased to 140 DEG C, N2By height Press pump is passed in the middle of reaction unit and makes whole experimental provision boost in pressure make whole to 5.5MPa, adjusting high-pressure pump in 5min Individual experimental provision pressure keeps constant, after system stability, opens the agitating device in reactor, and regulation mixing speed is 160r/min, stirring 20min make system reach dissolution equilibrium；
4) being ejected into the subcritical water solution dissolved with bicalutamide equipped with in the collection cups of deionized water, aqueous phase i.e. has ratio Card Shandong amine nanoparticle precipitate separates out, and forms transparent nano dispersion, and its drug concentration is 1mg/ml, nano-particle average particle Footpath is 60nm.
Embodiment 4
1) weigh 50mg bicalutamide and 50ml deionized water, be simultaneously introduced in reactor；
2) weigh 50mg lactose to be dissolved in 5ml deionized water, pour into collect in beaker and will be equipped with the beaker of this aqueous solution and put In ice-water bath, controlling bath temperature is 18 DEG C, and stir speed (S.S.) is 800rpm.
3) experimental provision is after air-leakage test, controls system temperature by heater and is increased to 140 DEG C, N2By height Press pump is passed in the middle of reaction unit and makes whole experimental provision boost in pressure make whole to 5.5MPa, adjusting high-pressure pump in 5min Individual experimental provision pressure keeps constant, after system stability, opens the agitating device in reactor, and regulation mixing speed is 160r/min, stirring 20min make system reach dissolution equilibrium；
4) being ejected into the subcritical water solution dissolved with bicalutamide equipped with in the collection cups of deionized water, aqueous phase i.e. has ratio Card Shandong amine nanoparticle precipitate separates out, and forms transparent nano dispersion, and its drug concentration is 1mg/ml, nano-particle average particle Footpath is 1 μm.
5) embodiment 5
1) weigh 50mg bicalutamide and 50ml deionized water, be simultaneously introduced in reactor；
2) weigh 10mg Polyethylene Glycol in 5ml deionized water, pour in collection beaker, will be equipped with the beaker of this aqueous solution Being placed in ice-water bath, controlling bath temperature is 0 DEG C, and stir speed (S.S.) is 800rpm.
3) experimental provision is after air-leakage test, controls system temperature by heater and is increased to 140 DEG C, N2By height Press pump is passed in the middle of reaction unit and makes whole experimental provision boost in pressure make whole to 6MPa, adjusting high-pressure pump in 5min Experimental provision pressure keeps constant, after system stability, opens the agitating device in reactor, and regulation mixing speed is 160r/ Min, stirring 20min make system reach dissolution equilibrium；
4) being ejected into the subcritical water solution dissolved with bicalutamide equipped with in the collection cups of deionized water, aqueous phase i.e. has Bicalutamide nanoparticle precipitate separates out, and forms transparent nano dispersion, and its drug concentration is 1mg/ml, and nano-particle is average Particle diameter is 50nm.
Embodiment 6
1) weigh 50mg bicalutamide and 50ml deionized water, be simultaneously introduced in reactor；
2) experimental provision is after air-leakage test, controls system temperature by heater and is increased to 140 DEG C, N2By height Press pump is passed in the middle of reaction unit and makes whole experimental provision boost in pressure make whole to 5.5MPa, adjusting high-pressure pump in 5min Individual experimental provision pressure keeps constant, after system stability, opens the agitating device in reactor, and regulation mixing speed is 160r/min, stirring 20min make system reach dissolution equilibrium；
3) being ejected into the subcritical water solution dissolved with bicalutamide equipped with in 0 DEG C of deionized water collection cups, aqueous phase i.e. has Bicalutamide nanoparticle precipitate separates out, and forms transparent nano dispersion, and its drug concentration is 1mg/ml, and nano-particle is average Particle diameter is 2 μm.
Embodiment 7
1) weigh 50mg bicalutamide and 50ml deionized water, be simultaneously introduced in reactor；
2) experimental provision is after air-leakage test, controls system temperature by heater and is increased to 170 DEG C, N2By height Press pump is passed in the middle of reaction unit and makes whole experimental provision boost in pressure make whole to 5.5MPa, adjusting high-pressure pump in 5min Individual experimental provision pressure keeps constant, after system stability, opens the agitating device in reactor, and regulation mixing speed is 160r/min, stirring 20min make system reach dissolution equilibrium；
3) the subcritical water solution dissolved with bicalutamide is ejected into step 2) collection beaker in, aqueous phase i.e. has ratio card Shandong It is 1mg/ml that amine nanoparticle precipitate separates out its drug concentration, and nano-particle mean diameter is 1 μm.

Claims (9)

1. the preparation method of a bicalutamide transparent aqueous phase Nanodispersion, it is characterised in that: the method comprises the steps,
1) appropriate bicalutamide and water are added simultaneously in reactor；
2) dispersant is dissolved in water, be configured to adjuvant aqueous solution, and the temperature controlling adjuvant aqueous solution is 0-20 DEG C, stirring speed Rate is 500-800rpm；
3) in reactor, N it is passed through2Gas, regulates temperature of reaction system value preset temperature, and regulates reaction system pressure and reach pre- If pressure；
4) being sprayed into rapidly by liquid in reactor dissolved with in the aqueous solution of dispersant, liquid spouting velocity is 5-10ml/min, than The card Shandong i.e. Precipitation of amine nano-particle, forms aqueous phase Nanodispersion.
The preparation method of a kind of bicalutamide transparent aqueous phase Nanodispersion the most according to claim 1, it is characterised in that: Step 1) described bicalutamide quality is 18-50mg, the volume of water is 40-60ml.
The preparation method of a kind of bicalutamide transparent aqueous phase Nanodispersion the most according to claim 1, it is characterised in that: Step 2) described dispersant concentration in water is 0.1-5mg/ml, dispersant is selected from Polyethylene Glycol, beta-schardinger dextrin-, hydroxypropyl first Base cellulose, polyvinylpyrrolidone.
The preparation method of a kind of bicalutamide transparent aqueous phase Nanodispersion the most according to claim 1, it is characterised in that: Step 3) preset pressure of reaction kettle for reaction system is 5-78MPa, reaction temperature is 110-180 DEG C, and stir speed (S.S.) is 150- 200rpm, reaching the dissolution equilibrium time is 10-20min.
The preparation method of a kind of bicalutamide transparent aqueous phase Nanodispersion the most according to claim 1, it is characterised in that: Step 4) reactor ejection bicalutamide aqueous solution volume be 5-10ml, the volume of adjuvant aqueous solution is 10-50ml.
The preparation method of a kind of bicalutamide transparent aqueous phase Nanodispersion the most according to claim 1, it is characterised in that: The particle diameter of described bicalutamide rice grain is 40-90nm.
The preparation method of a kind of bicalutamide transparent aqueous phase Nanodispersion the most according to claim 1, it is characterised in that: In step 1) in reactor be vertical closing container, be arranged on filter in the middle part of reactor and be connected in probe tube, filter Aperture is 500 nanometers.
The preparation method of a kind of bicalutamide transparent aqueous phase Nanodispersion the most according to claim 1, it is characterised in that: In step 3) in by the subcritical water dissolved with bicalutamide through filter, be ejected in nano-particle catcher, maintain catcher Temperature constant, makes the rapid crystallization nucleation of nano-particle, accelerates particles collision by two-forty stirring, forms nano-particle.
The preparation method of a kind of bicalutamide transparent aqueous phase Nanodispersion the most according to claim 1, it is characterised in that: The concentration of bicalutamide transparent aqueous phase Nanodispersion is 0.1-2mg/ml.
CN201610539244.6A 2016-07-10 2016-07-10 A kind of preparation method of bicalutamide transparent aqueous phase Nanodispersion Pending CN106176674A (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104784696A (en) * 2014-01-16 2015-07-22 北京化工大学 Preparation method for water-insoluble drug water-phase nanoparticles

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104784696A (en) * 2014-01-16 2015-07-22 北京化工大学 Preparation method for water-insoluble drug water-phase nanoparticles

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
TARIQUE ALI MEER,ET AL: "Liquid antisolvent precipitation process for solubility modulation of bicalutamide", 《ACTA PHARM.》 *
季华等: "反溶剂重结晶法制备多晶型比卡鲁胺", 《北京化工大学学报》 *
美木哪: "Solubility and Particles Formation of Bicalutamide Using Subcritical Water Technology", 《中国优秀硕士学位论文全文数据库 工程科技I辑》 *

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