CN103483353A - Dithiolopyrrolone compound nanoparticles and preparation method thereof - Google Patents

Dithiolopyrrolone compound nanoparticles and preparation method thereof Download PDF

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CN103483353A
CN103483353A CN201210195057.2A CN201210195057A CN103483353A CN 103483353 A CN103483353 A CN 103483353A CN 201210195057 A CN201210195057 A CN 201210195057A CN 103483353 A CN103483353 A CN 103483353A
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water
nanoparticle
oil phase
dithiole
pyrrolidone
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CN103483353B (en
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赵锋
栾瀚森
王浩
杨莉
徐凤兰
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Shanghai Modern Pharmaceutical Engineering Research Center Co Ltd
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    • 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
    • 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
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
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    • 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
    • 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
    • A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
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    • 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
    • A61K9/5192—Processes
    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
    • B—PERFORMING OPERATIONS; TRANSPORTING
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    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y40/00—Manufacture or treatment of nanostructures

Abstract

The present invention discloses dithiolopyrrolone compound nanoparticles, a preparation method and an apparatus thereof. The dithiolopyrrolone compound nanoparticles comprise, by weight, 0.007-20% of a dithiolopyrrolone compound, 0-89.85% of a biodegradable polymer, 0.07-95% of an additive, and 0.1-80% of a freeze-drying stent agent, wherein an average diameter of the nanoparticles is 10-800 nm. According to the invention, an ultrasonic-static mixing apparatus is adopted to prepare the nanometer crystal and the nanoparticles; and the dithiolopyrrolone compound nanoparticles have significant characterization characteristics of nanoparticles, have a particle size of 60-300 nm and a Zeta potential of -30 to 20 mv, can be used for oral or intravenous administration, and have characteristics of high bioavailability, prolonged circulation time in vivo, and wide development prospects.

Description

The nanoparticle of dithiole pyrrolidone compound and preparation method
Technical field
The present invention relates to preparation and the preparation method of dithiole pyrrolidone compound.
Technical background
Dithiole pyrrolidone compound, 6-amino-4-(2 as disclosed as CN101381371, US20100210856A1, the 4-dimethoxy phenyl)-4-hydrogen [1,2] dithiole [4,3-b]-pyrrolidone-ethyl formate (hereinafter to be referred as ZL-004), by mother nucleus structure 1,2-dithiole [4,3-b] pyrroles-5 (4H)-one ring is modified the compound that transformation forms.Synthetic voluntarily by the flat researcher of kingdom of Shanghai Institute of Pharmaceutical Industry; this type of structural compounds has patent report; there are antibiotic, anti-tumor activity characteristics; as (Helvetica ChimicaActa 2002 such as (wo2003/080624), Stachel such as Webster; 85; 4453), (US6020360, WO99/12543), the Godfrey such as (JP63-284181, JP11-279179), Webster such as river Tian Xiusi; Dell(GB 2170498) report.
Through non-clinical pharmacology, toxicological experiment, ZL-004 shows the characteristic of stronger rising peripheral leukocytes quantity.There is wide potential applicability in clinical practice.
But, because ZL-004 belongs to insoluble drug, in 37 ℃ of water, solubleness only has 90 – 120 μ gmL -1, 0.90-1.50mgmL only in methyl alcohol -1, belong to the soluble,very slightly material.On microcosmic, its insoluble makes it see through microbial film with molecularity, is scattered in the water miscible recycle system, acts on biological target cell.On macroscopic view, increased difficulty oral, the mucosal route administration, previous experiments also confirms giving full play to of its specific physical character restriction drug effect, only has modification or the change of preparation aspect by self structure to improve its target cell activity ratio.
In view of its insoluble characteristics, necessary and adopt that the exploitation of technology of pharmaceutics method is a kind of can improve it and see through microbial film, improve the preparation of the active function usefulness of compound, for research is from now on provided convenience.
Summary of the invention
The nanoparticle and the preparation method that the purpose of this invention is to provide dithiole pyrrolidone compound, the defect existed to overcome prior art, further improve its action effect and range of application.
The nanoparticle of described dithiole pyrrolidone compound comprises the component of following weight percent:
Figure BDA00001760103600011
Figure BDA00001760103600021
The mean diameter 10nm-800nm of described nanometer;
Preferably, the component that comprises following weight percent:
Figure BDA00001760103600022
The mean diameter of described nanometer is 90nm-180nm;
Described thia cyclopenta pyrrolidone compound is 6-amino-4-(2,4-dimethoxy phenyl)-4-hydrogen [1,2] dithiole [4,3-b]-pyrrolidone-ethyl formate; (being called for short ZL-004)
Described biodegradable polymers comprises more than one in poly(lactic acid), poly lactic coglycolic acid, lactic-co-glycolic acid-ethylene glycol copolymer, lactic-co-glycolic acid-polyethyleneglycol block copolymer, the polyoxyethylene glycol-glycolide-lactide copolymer that methylates, polycaprolactone or polyacrylamide;
Polyoxyethylene glycol-glycolide-lactide copolymer preferably methylates;
Preferably, in the polyoxyethylene glycol-glycolide-lactide copolymer that methylates, the scope of monomer molar ratio is 50: 50-25: 75;
Preferably, the weight-average molecular weight of biodegradable polymer is 5,000-60,000 dalton, wherein, and 7,000-50,000 dalton is comparatively suitable;
Preferably, described additive is selected from polyethylene glycol stearate or polyoxyethylene hydrogenated castor oil;
Described freeze-drying caffolding agent is selected from N.F,USP MANNITOL, sucrose, lactose, sodium alginate.
The nanoparticle preparation method of dithiole of the present invention pyrrolidone compound is to adopt following nanoparticle preparation facilities to realize:
Described nanoparticle preparation facilities comprises: water reservoir, oil phase reservoir, ultrasonic generator, ultrasonication chamber, frame, the static mixer that is provided with inner member, circulation tube, fluid are accepted cup and agitator;
What described static mixer was vertical by anchor is fixed on described frame;
The outlet of described water reservoir is connected and is connected with described ultrasonication chamber by the water pipeline, and the outlet of described oil phase reservoir is connected with described ultrasonication chamber by the oil phase pipeline, and the probe of described ultrasonic generator is inserted in described ultrasonication chamber;
Described ultrasonic generator is fixed on frame by mechanical system;
Described fluid is accepted the below that cup is arranged on the outlet of described static mixer bottom;
Described circulation tube one end inserts described fluid and accepts in cup, and the other end is connected with described water reservoir by handling equipment;
And method of the present invention comprises the steps:
(1) water in the oil phase in the oil phase reservoir and water reservoir is sent into to described ultrasonication chamber simultaneously, and start ultrasonic generator, ultrasonic wave is sent into to the ultrasonication chamber;
Described oil phase is the organic solvent that contains thia cyclopenta pyrrolidone compound, biodegradable polymer and additive;
Described organic solvent is selected from alcohols, the N of tetrahydrofuran (THF), acetone, carbon atom 1 to 4, water-soluble or the methylene dichloride such as N-dimethylformamide or dimethyl sulfoxide (DMSO), dioxane, acetonitrile, trichloromethane, ethyl acetate, N, the water such as N-dimethyl pyrrolidone or phenylcarbinol are soluble solvent slightly;
Described water is the aqueous solution that contains polyvinyl alcohol;
In ultrasonic wave and static mixer under the acting in conjunction of inner member, oil phase and water form oil-in-water nano level emulsion, from the outlet of static mixer bottom, flow out, enter fluid and accept cup, the nano level emulsion that fluid is accepted in cup is sent the water reservoir back to, the said process that moves in circles, until the nanoparticle particle diameter reaches requirement;
(2) then fluid is accepted to the material in cup, centrifugal, collect solid matter, wash, add the freeze-drying caffolding agent, freeze-drying, obtain the described nanoparticle that contains dithiole pyrrolidone compound;
In the situation that the add-on of biodegradable polymers is 0mg, what obtain is the nano-crystal grains that contains 6-amino-4-(2,4-dimethoxy phenyl)-4-hydrogen [1,2] dithiole [4,3-b]-pyrrolidone-ethyl formate.
Method of the present invention, different from traditional method for preparing nanocrystal, nanoparticle, traditional preparation nanocrystal comprises the preparation methods such as solvent precipitation, emulsification-solvent evaporation method, salting-out process, supercritical fluid technology, compound emulsion method, interface polycondensation.The present invention adopts ultrasonic-static mixing device is for the preparation of nanocrystal and nanoparticle.Relevant static mixer prepares the patent US2011/0237748A1 of nanoparticle, although it uses static mixer, can only use water miscible organic solvent in oil phase, as acetone, acetonitrile, tetrahydrofuran (THF), N-Methyl pyrrolidone etc., limited the use that water section dissolves organic solvent, as the application of methylene dichloride, trichloromethane, ethyl acetate etc., this kind solvent can increase solubleness, raising encapsulation rate, the drug loading of nonpolar medicine.And provided by the invention ultrasonic-static mixing device can change into superfine drop by organic solvent and APM before mixing, can obtain that height is sealed, the nanoparticle of size distribution homogeneous after by mixing tank, is easy to amplification quantity production, can break through nanoparticle and prepare bottleneck.
The nanoparticle of dithiole of the present invention pyrrolidone compound, have significant nanoparticle characteristic features, particle diameter 60-300nm, Zeta potential, at-30-20mv, can be used for oral or intravenously administrable, and bioavailability is high, the body-internal-circulation time lengthening, the exploitation said preparation has broad prospects.
The accompanying drawing explanation
Fig. 1 is nanoparticle preparation facilities structural representation.
The size distribution figure that Fig. 2 is embodiment 3 (quantity footpath).
The size distribution figure that Fig. 3 is embodiment 3 (volumetric diameter).
Fig. 4 is extracorporeal releasing test.
The body inner analysis ultrahigh pressure liquid phase chromatogram that Fig. 5 is ZL-004-dual level Four bar mass spectrum typical case mass spectrum.
Fig. 6 is the zl-004UPLC-MS/MS color atlas.
Fig. 7 is pharmacokinetics behavior in the intravenous injection body.
Fig. 8 is pharmacokinetics behavior in oral body.
Embodiment
Referring to Fig. 1, nanoparticle preparation facilities of the present invention comprises: water reservoir 1, oil phase reservoir 2, ultrasonic generator 6, ultrasonication chamber 9, frame 4, the static mixer 5 that is provided with inner member 501, circulation tube 10, fluid are accepted cup 7, agitator 8;
What described static mixer 5 was vertical by anchor 401 is fixed on described frame 4; The aspect ratio of static mixer 5 is 50-80;
Described inner member 501 adopts the universal products, and as model is the inner members such as SV, SL, SK, SX, SD, the structure of described inner member and correlation parameter, " be described later in detail on the pipeline static mixer handbook, the present invention repeats no more;
The outlet of described water reservoir 1 is connected and is connected with described ultrasonication chamber 9 by the water pipeline, the outlet of described oil phase reservoir 2 is connected with described ultrasonication chamber 9 by the oil phase pipeline, the probe 601 of described ultrasonic generator 6 is inserted in described ultrasonication chamber 9, preferably, be provided with handling equipment 11 with the oil phase pipeline on described water pipeline, as peristaltic pump;
Described ultrasonic generator 6 is general-purpose equipment, can adopt the ultrasound probe that the power variable range is 30-200w, pops one's head in as cylindric, and head is coniform (cone diameter is 0.5-2.0cm, and long is 0.5-2.0cm), by mechanical system, is fixed on frame 4;
Described fluid is accepted the below that cup 7 is arranged on the outlet 503 of described static mixer 5 bottoms;
Described circulation tube 10 1 ends insert described fluid and accept in cup 7, and the other end is connected with described water reservoir 1 by handling equipment;
Preferably, also comprise agitator 8, described fluid is accepted cup 7 and is placed on described agitator 8, the preferred magnetic stirring apparatus of described agitator 8;
And method of the present invention comprises the steps:
(1) water in the oil phase in oil phase reservoir 2 and water reservoir 1 is sent into to described ultrasonication chamber 9 simultaneously, and start ultrasonic generator 6, ultrasonic wave is sent into to ultrasonication chamber 9;
Described oil phase is the organic solvent that contains thia cyclopenta pyrrolidone compound, biodegradable polymer and additive;
Described organic solvent is selected from alcohols, the N of tetrahydrofuran (THF), acetone, carbon atom 1 to 4, water-soluble or the methylene dichloride such as N-methyl nitrosourea or dimethyl sulfoxide (DMSO), dioxane, acetonitrile, trichloromethane, ethyl acetate, N, the water such as N-dimethyl pyrrolidone or phenylcarbinol are soluble solvent slightly;
In described oil phase, total concentration of thia cyclopenta pyrrolidone compound, biodegradable polymer and additive is 7.0～680 grams per liters;
Described water is the aqueous solution that contains polyvinyl alcohol, wherein:
The concentration of polyvinyl alcohol is the 0.1-15 grams per liter, comparatively suitable with 1.0～12 grams per liters;
With the volumeter of organic solvent and water, organic solvent: water=1: 9.0～1: 480;
The speed of oil phase is 1.0-4.0mlmin -1; The speed of water is 150-350mlmin -1;
In described organic solvent, the residence time of oil phase is 20～70 seconds, preferably 27～66 seconds;
The residence time of oil phase is relevant with the effect of ultrasonication, and for controlling index, the residence time is defined as follows:
T=(S1+S2)/υ, unit is second;
Wherein: the length that S1 is the static mixer cavity, unit is cm; S2 is ultrasonication chamber 9 length, and unit is cm; The speed that υ is material, unit is cm/ second;
Described ultrasonication chamber 9 volumes of take are benchmark, and ultrasonic power is 4.0-235wcm -3;
In ultrasonic wave and static mixer 5 under the acting in conjunction of inner member, oil phase and water form oil-in-water nano level emulsion, from the outlet of static mixer 5 bottoms, flow out, enter fluid and accept cup 7, under the stirring of agitator 8, the nano level emulsion that fluid is accepted in cup 7 is sent water reservoir 1 back to by circulation tube 11, and the said process that moves in circles, until the nanoparticle particle diameter reaches requirement;
(2) then fluid is accepted to the material in cup 7, centrifugal at 3-20 ℃, 10000-50000rmp, collect solid matter, wash, add the freeze-drying caffolding agent, freeze-drying, obtain the described nanoparticle that contains dithiole pyrrolidone compound.
Embodiment 1
Adopt water-miscible organic solvent acetone to prepare the nano-crystal grains of 6-amino-4-(2,4-dimethoxy phenyl)-4-hydrogen [1,2] dithiole [4,3-b]-pyrrolidone-ethyl formate;
Prescription:
ZL-004 10mg
Polyethylene glycol stearate 100mg
N.F,USP MANNITOL 22mg
The median size of nanocrystal is 95 ± 8nm;
Adopt the device of Fig. 1, the nano-crystal grains that preparation contains 6-amino-4-(2,4-dimethoxy phenyl)-4-hydrogen [1,2] dithiole [4,3-b]-pyrrolidone-ethyl formate;
The constitutional features of equipment:
Static mixer 5: be highly 60cm, internal diameter is 1.0cm, and aspect ratio is 60;
Ultrasonication chamber 9: diameter: 1.0cm; Highly; 6cm; Aspect ratio: 6; Volume: (1/2) 2* 3.14 * 10=0.785cm 3;
Ultrasonic power is: 30w; Ultrasonication chamber 9 upper volume of take are benchmark, and ultrasonic power is: 38.22wcm -3;
Inner member 501 models are that the Sk type is (long: 40cm; Internal diameter: 0.6cm);
6-amino-4-(2,4-dimethoxy phenyl)-4-hydrogen [1,2] dithiole [4,3-b]-pyrrolidone-ethyl formate and polyethylene glycol stearate are dissolved in organic solvent 10ml acetone, dissolve, obtain oil phase;
0.5 gram polyvinyl alcohol is dissolved in 300ml water liquid, is water;
Described water and oil phase are placed in respectively to water reservoir 1 and oil phase reservoir 2, then send into the upper end entrance 502 of described static mixer 5, start ultrasonic generator (6) simultaneously, the static mixer 5 that ultrasonic wave is sent into;
The speed of oil phase is 1.0mlmin -1; The speed of water is 150mlmin -1;
The oil phase residence time: T=(S1+S2)/υ=(60+6)/1.0=66 second;
In ultrasonic wave and static mixer 5 under the acting in conjunction of inner member, oil phase and water form oil-in-water nano level emulsion, from the outlet of static mixer 5 bottoms, flow out, enter fluid and accept cup 7, under the stirring of agitator, the nano level emulsion that fluid is accepted in cup 7 is sent water reservoir 1 back to, and the said process 3 times of moving in circles is to until the nanoparticle particle diameter reaches 95 ± 8nm.
10 ℃, 12000rpm centrifugation, collect the solid of centrifugal acquisition, uses the distilled water Eddy diffusion, and three times repeatedly, add N.F,USP MANNITOL, freeze-drying, obtain product.
Embodiment 2
Adopt the water-miscible organic solvent acetonitrile to prepare the nano-crystal grains of 6-amino-4-(2,4-dimethoxy phenyl)-4-hydrogen [1,2] dithiole [4,3-b]-pyrrolidone-ethyl formate
Prescription 2:
ZL-004 40g
Polyethylene glycol stearate 400g
Sucrose 220g
Making the nanocrystal median size is 180 ± 14nm;
The preparation method:
Adopt the device of Fig. 1, the nano-crystal grains that preparation contains 6-amino-4-(2,4-dimethoxy phenyl)-4-hydrogen [1,2] dithiole [4,3-b]-pyrrolidone-ethyl formate:
The constitutional features of equipment:
Static mixer 5: be highly 100cm, internal diameter is 2.0cm, and aspect ratio is 50;
Ultrasonication chamber 9: diameter: 1.5cm; Highly; 10cm; Aspect ratio: 6.7;
Ultrasonic power is: 100w; The volume of above-mentioned static mixer 5 upper ends of take is benchmark, and ultrasonic power is: 5.66wcm -3;
It is the SV type that inner member 501 adopts model, (long: 80cm; Internal diameter: 1.8cm)
6-amino-4-(2,4-dimethoxy phenyl)-4-hydrogen [1,2] dithiole [4,3-b]-pyrrolidone-ethyl formate and polyethylene glycol stearate are dissolved in 10 liters of acetonitriles of organic solvent, dissolve, filter, obtain oil phase;
0.5 kilogram of polyvinyl alcohol is dissolved in 95 premium on currency liquid, is water;
Described water and oil phase are placed in respectively to water reservoir 1 and oil phase reservoir 2, then send into the upper end entrance 502 of described static mixer 5, start ultrasonic generator (6) simultaneously, the static mixer 5 that ultrasonic wave is sent into;
The speed of oil phase is 4.0mlmin -1; The speed of water is 350mlmin -1;
The oil phase residence time: T=(S1+S2)/υ=(100+10)/4.0=27.5 second;
In ultrasonic wave and static mixer 5 under the acting in conjunction of inner member, oil phase and water form oil-in-water nano level emulsion, from the outlet of static mixer 5 bottoms, flow out, enter fluid and accept cup 7, under the stirring of agitator, the nano level emulsion that fluid is accepted in cup 7 is sent water reservoir 1 back to, and the said process 3 times that moves in circles is until the nanoparticle particle diameter reaches requirement.10 ℃, 12000rpm centrifugation, collect the solid of centrifugal acquisition, uses the distilled water Eddy diffusion, and three times repeatedly, add sucrose, freeze-drying, obtain product.
Embodiment 3
Containing adopting water to omit the nano-crystal grains that the solubleness organic solvent methylene dichloride prepares 6-amino-4-(2,4-dimethoxy phenyl)-4-hydrogen [1,2] dithiole [4,3-b]-pyrrolidone-ethyl formate.
ZL-004 150mg
Polyoxyethylene hydrogenated castor oil 1500mg
Sodium alginate 495mg
Making the nanocrystal median size is 123 ± 20nm;
The preparation method:
Adopt the device of Fig. 1, the nano-crystal grains that preparation contains 6-amino-4-(2,4-dimethoxy phenyl)-4-hydrogen [1,2] dithiole [4,3-b]-pyrrolidone-ethyl formate:
The constitutional features of equipment:
Static mixer 5: be highly 60cm, internal diameter is 1.0cm, and aspect ratio is 60, and effective volume is; 47.1cm -3
Ultrasonication chamber 9: diameter: 1.0cm; Highly; 6cm; Aspect ratio: 6; Volume: (1/2) 2* 3.14 * 10=0.785cm 3
Ultrasonic power is: 200w; The volume in ultrasonication chamber 9 of take is benchmark, and ultrasonic power is: 254.78wcm -3;
It is the Sk type that inner member 501 adopts model, (long: 40cm; Internal diameter: 0.8cm)
By 6-amino-4-(2,4-dimethoxy phenyl)-4-hydrogen [1,2] dithiole [4; 3-b]-pyrrolidone-ethyl formate and polyoxyethylene hydrogenated castor oil be dissolved in 22ml mixed organic solvents (methylene dichloride: acetone=10:1, volume ratio), dissolve; filter, obtain oil phase;
6 gram polyvinyl alcohol are dissolved in 594ml water liquid, are water;
Described water and oil phase are placed in respectively to water reservoir 1 and oil phase reservoir 2, then send into the upper end entrance 502 of described static mixer 5, start ultrasonic generator (6) simultaneously, the static mixer 5 that ultrasonic wave is sent into;
The speed of oil phase is 1.0mlmin -1; The speed of water is 150mlmin -1;
The oil phase residence time: T=(S1+S2)/υ=(60+6)/1.0=66 second;
In ultrasonic wave and static mixer 5 under the acting in conjunction of inner member, oil phase and water form oil-in-water nano level emulsion, from the outlet of static mixer 5 bottoms, flow out, enter fluid and accept cup 7, under the stirring of agitator, the nano level emulsion that fluid is accepted in cup 7 is sent water reservoir 1 back to, and the said process 3 times that moves in circles is until the nanoparticle particle diameter reaches requirement.10 ℃, 12000rpm centrifugation, collect the solid of centrifugal acquisition, uses the distilled water Eddy diffusion, and three times repeatedly, add sodium alginate, freeze-drying, obtain product.Size distribution figure (quantity footpath) is shown in Fig. 2; Size distribution (volumetric diameter) is shown in Fig. 3.
Embodiment 4
Containing adopting water to omit the nano-crystal grains that the solubleness organic solvent ethyl acetate prepares 6-amino-4-(2,4-dimethoxy phenyl)-4-hydrogen [1,2] dithiole [4,3-b]-pyrrolidone-ethyl formate.
Nanocrystal prescription 4:
Figure BDA00001760103600091
The preparation method:
Adopt the device of Fig. 1, preparation contains 4-N(2,4-p-methoxy-phenyl)-nano-crystal grains of 6-amino-4-(2,4-dimethoxy phenyl)-4-hydrogen [1,2] dithiole [4,3-b]-pyrrolidone-ethyl formate:
The constitutional features of equipment:
Static mixer 5: be highly 100cm, internal diameter is 2.0cm;
Ultrasonication chamber 9: diameter: 1.5cm; Highly; 10cm; Aspect ratio: 6.7; Volume: (15/2) 2* 3.14 * 10=17.66cm 3
Ultrasonic power is: 160w; Ultrasonication chamber 9 volumes of take are benchmark, and ultrasonic power is: 9.06wcm -3;
Inner member 501 adopts the SL type (long: 80cm; Internal diameter: 1.8cm).
By 6-N-ethyl ester formyloxy-1,2-dithiole pyrrolidone and polyoxyethylene hydrogenated castor oil are dissolved in 400ml mixed organic solvents (ethyl acetate: acetone=10:1), dissolve, filter, obtain oil phase;
120 gram polyvinyl alcohol are dissolved in 11.88 premium on currency, are water;
Described water and oil phase are placed in respectively to water reservoir 1 and oil phase reservoir 2, then send into the upper end entrance 502 of described static mixer 5, start ultrasonic generator (6) simultaneously, the static mixer 5 that ultrasonic wave is sent into;
The speed of oil phase is 3mlmin -1; The speed of water is 250mlmin -1;
The oil phase residence time: T=(S1+S2)/υ=(100+10)/3.0=36.67 second;
In ultrasonic wave and static mixer 5 under the acting in conjunction of inner member, oil phase and water form oil-in-water nano level emulsion, from the outlet of static mixer 5 bottoms, flow out, enter fluid and accept cup 7, under the stirring of agitator, the nano level emulsion that fluid is accepted in cup 7 is sent water reservoir 1 back to, and the said process 3 times that moves in circles is until the nanoparticle particle diameter reaches requirement.10 ℃, 12000rpm centrifugation, collect the solid of centrifugal acquisition, uses the distilled water Eddy diffusion, and three times repeatedly, add the sucrose freeze-drying, obtain product.
Embodiment 5
Containing adopting the preparation of water-miscible organic solvent tetrahydrofuran (THF), the polymer nanoparticle of 6-amino-4-(2,4-dimethoxy phenyl)-4-hydrogen [1,2] dithiole [4,3-b]-pyrrolidone-ethyl formate.
Polymer nanoparticle prescription 1:
Figure BDA00001760103600101
In MPEG-PLGA, MPEG:LA:GA=10:67.5:22.5, weight-average molecular weight is 50000 dalton, the median size of nanoparticle is 97 ± 7nm;
Adopt the device of Fig. 1, the polymer nanoparticle that preparation contains 6-amino-4-(2,4-dimethoxy phenyl)-4-hydrogen [1,2] dithiole [4,3-b]-pyrrolidone-ethyl formate:
The constitutional features of equipment:
Static mixer 5: be highly 100cm, internal diameter is 1.25cm, and aspect ratio is 80;
Ultrasonication chamber 9: diameter: 1.25cm; Highly; 8cm; Aspect ratio: 6.4; Volume: (1.25/2) 2* 3.14 * 8=9.81cm 3
Ultrasonic power is: 60w; The volume of above-mentioned static mixer 5 upper ends of take is benchmark, and ultrasonic power is: 6.12wcm -3;
It is that the Sk type is (long: 80cm that inner member 501 adopts model; Internal diameter: 1.10cm)
6-amino-4-(2,4-dimethoxy phenyl)-4-hydrogen [1,2] dithiole [4,3-b]-pyrrolidone-ethyl formate and polyethylene glycol stearate are dissolved in organic solvent 250ml tetrahydrofuran (THF), dissolve, filter, obtain oil phase;
0.6 kilogram of polyvinyl alcohol is dissolved in 119.4 premium on currency, obtains water;
The speed of oil phase is 4.0mlmin -1; The speed of water is 350mlmin -1;
The oil phase residence time: T=(S1+S2)/υ=(100+8)/4.0=27 second;
Described water and oil phase are placed in respectively to water reservoir 1 and oil phase reservoir 2, then send into the upper end entrance 502 of described static mixer 5, start ultrasonic generator (6) simultaneously, the static mixer 5 that ultrasonic wave is sent into;
In ultrasonic wave and static mixer 5 under the acting in conjunction of inner member, oil phase and water form oil-in-water nano level emulsion, from the outlet of static mixer 5 bottoms, flow out, enter fluid and accept cup 7, under the stirring of agitator, the nano level emulsion that fluid is accepted in cup 7 is sent water reservoir 1 back to, move in circles above-mentioned 3 times to until the nanoparticle particle diameter reaches requirement.10 ℃, 12000rpm centrifugation, collect the solid of centrifugal acquisition, uses the distilled water Eddy diffusion, and three times repeatedly, add the N.F,USP MANNITOL freeze-drying, obtain product.
Embodiment 6
Containing adopting the preparation of water-miscible organic solvent acetone, the polymer nanoparticle of 6-amino-4-(2,4-dimethoxy phenyl)-4-hydrogen [1,2] dithiole [4,3-b]-pyrrolidone-ethyl formate.
Polymer nanoparticle prescription 2:
Figure BDA00001760103600111
In MPEG-PLGA, MPEG:LA:GA=20:40:40, weight-average molecular weight is 7000 dalton, the median size of nanoparticle is 139 ± 23nm;
Adopt the device of Fig. 1, the polymer nanoparticle that preparation contains 6-amino-4-(2,4-dimethoxy phenyl)-4-hydrogen [1,2] dithiole [4,3-b]-pyrrolidone-ethyl formate:
The constitutional features of equipment:
Static mixer 5: be highly 100cm, internal diameter is 1.25cm, and aspect ratio is 80;
Ultrasonication chamber 9: diameter: 1.25cm; Highly; 10cm; Aspect ratio: 8; Volume: (1.25/2) 2* 3.14 * 10=12.27cm 3
Ultrasonic power is: 140w; Ultrasonication chamber 9 volumes of take are benchmark, and ultrasonic power is: 11.41wcm -3;
It is that the Sk type is (long: 40cm that inner member 501 adopts model; Internal diameter: 0.6cm)
6-amino-4-(2,4-dimethoxy phenyl)-4-hydrogen [1,2] dithiole [4,3-b]-pyrrolidone-ethyl formate and polyoxyethylene hydrogenated castor oil are dissolved in organic solvent 1000ml acetone, dissolve, filter, obtain oil phase;
0.6 kilogram of polyvinyl alcohol is dissolved in 119.4 premium on currency, is water;
The speed of oil phase is 4.0mlmin -1; The speed of water is 150mlmin -1;
The oil phase residence time: T=(S1+S2)/υ=(100+10)/4.0=27.5 second;
Described water and oil phase are placed in respectively to water reservoir 1 and oil phase reservoir 2, then send into the upper end entrance 502 of described static mixer 5, start ultrasonic generator (6) simultaneously, the static mixer 5 that ultrasonic wave is sent into;
In ultrasonic wave and static mixer 5 under the acting in conjunction of inner member, oil phase and water form oil-in-water nano level emulsion, from the outlet of static mixer 5 bottoms, flow out, enter fluid and accept cup 7, under the stirring of agitator, the nano level emulsion that fluid is accepted in cup 7 is sent water reservoir 1 back to, move in circles above-mentioned 3 times to until the nanoparticle particle diameter reaches requirement.10 ℃, 36000rpm centrifugation, collect the solid of centrifugal acquisition, uses the distilled water Eddy diffusion, and three times repeatedly, add the lactose freeze-drying, obtain product.
Embodiment 7
Containing adopting water to omit the polymer nanoparticle that the solubleness organic solvent methylene dichloride prepares 6-amino-4-(2,4-dimethoxy phenyl)-4-hydrogen [1,2] dithiole [4,3-b]-pyrrolidone-ethyl formate.
Polymer nanoparticle prescription 3:
Figure BDA00001760103600121
In MPEG-PLGA, MPEG:LA:GA=10:45:45, weight-average molecular weight is 24000 dalton, the median size of nanoparticle is 157 ± 23nm;
Adopt the device of Fig. 1, the nano-crystal grains that preparation contains 6-amino-4-(2,4-dimethoxy phenyl)-4-hydrogen [1,2] dithiole [4,3-b]-pyrrolidone-ethyl formate:
The constitutional features of equipment:
Static mixer 5: be highly 60cm, internal diameter is 0.75cm, and aspect ratio is 80;
Ultrasonic power is: 110w;
Ultrasonication chamber 9: diameter: 0.75cm; Highly: 6cm; Aspect ratio: 8; Volume: (0.75/2) 2* 3.14 * 6=0.84cm 3
The volume of above-mentioned static mixer 5 upper ends of take is benchmark, and ultrasonic power is: 130.95wcm -3;
It is that the Sk type is (long: 40cm that inner member 501 adopts model; Internal diameter: 0.65cm)
By 6-amino-4-(2,4-dimethoxy phenyl)-4-hydrogen [1,2] dithiole [4,3-b]-pyrrolidone-ethyl formate and polyethylene glycol stearate be dissolved in 22ml mixed organic solvents (methylene dichloride: N, N-dimethyl pyrrolidone=10:1), dissolve, filter, obtain oil phase;
It is water that 6 gram polyvinyl alcohol are dissolved in 594ml water liquid;
The speed of oil phase is 1.5mlmin -1; The speed of water is 150mlmin -1;
The oil phase residence time: T=(S1+S2)/υ=(60+6)/1.5=44 second;
Described water and oil phase are placed in respectively to water reservoir 1 and oil phase reservoir 2, then send into the upper end entrance 502 of described static mixer 5, start ultrasonic generator (6) simultaneously, the static mixer 5 that ultrasonic wave is sent into;
In ultrasonic wave and static mixer 5 under the acting in conjunction of inner member, oil phase and water form oil-in-water nano level emulsion, from the outlet of static mixer 5 bottoms, flow out, enter fluid and accept cup 7, under the stirring of agitator, the nano level emulsion that fluid is accepted in cup 7 is sent water reservoir 1 back to, and the said process 3 times that moves in circles is until the nanoparticle particle diameter reaches requirement.10 ℃, 45000rpm centrifugation, collect the solid of centrifugal acquisition, uses the distilled water Eddy diffusion, and three times repeatedly, add sodium alginate, freeze-drying, obtain product.
Embodiment 8
Containing adopting water to omit the polymer nanoparticle that the solubleness organic solvent methylene dichloride prepares 6-amino-4-(2,4-dimethoxy phenyl)-4-hydrogen [1,2] dithiole [4,3-b]-pyrrolidone-ethyl formate.
Figure BDA00001760103600131
In MPEG-PLGA, MPEG:LA:GA=10:45:45, weight-average molecular weight is 12000 dalton, the median size of nanoparticle is 139 ± 23nm;
Adopt the device of Fig. 1, the polymer nanoparticle that preparation contains 6-amino-4-(2,4-dimethoxy phenyl)-4-hydrogen [1,2] dithiole [4,3-b]-pyrrolidone-ethyl formate:
The constitutional features of equipment:
Static mixer 5: be highly 100cm, internal diameter is 2.0cm, and aspect ratio is 50;
Ultrasonication chamber 9: diameter: 1.5cm; Highly; 10cm; Aspect ratio: 6.7; Volume: (1.5/2) 2* 3.14 * 10=17.66cm 3
Ultrasonic power is: 132w, and the volume of above-mentioned static mixer 5 upper ends of take is benchmark, ultrasonic power is: 7.47wcm -3;
It is that the Sk type is (long: 40cm that inner member 501 adopts model; Internal diameter: 0.6cm)
By 6-amino-4-(2,4-dimethoxy phenyl)-4-hydrogen [1,2] dithiole [4,3-b]-pyrrolidone-ethyl formate and polyoxyethylene hydrogenated castor oil be dissolved in 88ml mixed organic solvents (methylene dichloride: phenylcarbinol=10:1), dissolve, organic membrane filter, obtain oil phase;
24 gram polyvinyl alcohol are dissolved in 2.4 premium on currency, are water;
The speed of oil phase is 2mlmin -1; The speed of water is 200mlmin -1;
The oil phase residence time: T=(S1+S2)/υ=(100+10)/2.0=55 second;
Described water and oil phase are placed in respectively to water reservoir 1 and oil phase reservoir 2, then send into the upper end entrance 502 of described static mixer 5, start ultrasonic generator (6) simultaneously, the static mixer 5 that ultrasonic wave is sent into;
In ultrasonic wave and static mixer 5 under the acting in conjunction of inner member, oil phase and water form oil-in-water nano level emulsion, from the outlet of static mixer 5 bottoms, flow out, enter fluid and accept cup 7, under the stirring of agitator, the nano level emulsion that fluid is accepted in cup 7 is sent water reservoir 1 back to, move in circles above-mentioned 3 times to until the nanoparticle particle diameter reaches requirement.10 ℃, 36000rpm centrifugation, collect the solid of centrifugal acquisition, uses the distilled water Eddy diffusion, and three times repeatedly, add the lactose freeze-drying, obtain product.
Embodiment 9
Extracorporeal releasing test:
The measuring method of nanoparticle slowly-releasing:
Precision takes 6-amino-4-(2, the 4-dimethoxy phenyl)-4-hydrogen [1,2] dithiole [4,3-b]-pyrrolidone-ethyl formate bulk drug, zl-004 nanocrystal and MPEG-PLGA nano-granule freeze-dried powder, put in dialysis tubing, and (compound method of PBS is got potassium primary phosphate 27.2g, sodiumazide 0.2g, sodium lauryl sulphate 1g, sodium-chlor 4.32g to add physiology isotonic phosphate buffer liquid (pH6.8), sodium hydroxide 0.944g, be dissolved in water into 1000mL, shake up) form colloidal solution, making ZL-004 is 1mgmL -1, get wherein 1.5mL and be placed in dialysis tubing, after exhaust, tighten port, be put in the tool plug Erlenmeyer flask of 40ml phosphate buffered saline buffer.
Erlenmeyer flask is placed in to 37 ℃ of water bath with thermostatic control concussion casees, and timing sampling, mend with the fresh release medium of volume after every sub-sampling, and sample adopts the concentration of HPLC-UV mensuration ZL-004, calculates burst size and the rate of release of ZL-004 nanoparticle.
Test-results is shown in Fig. 4, and as seen from Figure 4, the ZL-004 nanoparticle discharges slowly under physiological condition, meets the long characteristic that circulates, reaches the slow release of target site in its body.
Embodiment 10
Pharmacokinetic studies in 6-amino-4-(2,4-dimethoxy phenyl)-4-hydrogen [1,2] dithiole [4,3-b]-pyrrolidone-ethyl formate body:
Get 6-amino-4-(2, the 4-dimethoxy phenyl)-4-hydrogen [1,2] dithiole [4,3-b]-the ZL-004 polymer nanoparticle of the zl-004 lyophilized powder of pyrrolidone-ethyl formate (zl-004) bulk drug, embodiment 5, the ZL-004 nanocrystal of embodiment 2, embodiment 6 is appropriate, with physiological saline, redissolve, making concentration is 3mgmL -1(pressing ZL-004 calculates).
15 of SD rats, be divided into 5 groups at random, presses 3mgkg -1dosage give respectively first group of gavage bulk drug, second group of gavage ZL-004 nanocrystal, the 3rd group of gavage ZL-004 nanoparticle, the 4th group give tail vein injection ZL-004 nanocrystal, the 5th group of tail vein injection ZL-004 polymer nanoparticle.Get blood respectively at forward and backward 0.25,0.5,0.75,1,2,4,6,8,12,16,24,36,48 hour vena ophthalmica clump of administration, in anticoagulant tube, immediately-20 ℃ of preservations of centrifuging and taking blood plasma, measure by UPLC-MS/MS through extracting.
Result: the body inner analysis ultrahigh pressure liquid phase chromatogram of embodiment 5ZL-004-dual level Four bar mass spectrum typical case mass spectrum is shown in Fig. 5, and color atlas is shown in Fig. 6.The medicine moving curve is shown in Fig. 7,8, with bulk drug is oral, compares, and nanocrystal and nanoparticles oral administration after preparation, all can significantly improve C max, AUC 0 → tvalue, bioavailability significantly improves.And, after intravenously administrable, with the ZL-004 nanocrystal, compare, the ZL-004 polymer nanoparticle can improve AUC 0 → t, reduce C max, extend MRT.
After nanoparticle of the present invention, orally can improve the ZL-004 bioavailability.After intravenously administrable, the ZL-004 polymer nanoparticle energy extension body internal recycle time.
UPLC-MS/MS method: chromatographic column: shim-pack XR-ODS III (1.6um), 2.0mm * 50mm;
Moving phase: methyl alcohol-damping fluid (5mM ammonium acetate, 0.1% acetic acid); Flow velocity: 0.3ml; Column temperature: 40 ℃; Sample introduction: 10ul;
Gradient:
Embodiment 11
Rising peripheral leukocytes experimental study:
To 6-amino-4-(2, the 4-dimethoxy phenyl)-4-hydrogen [1,2] model mice leukocyte increasing and the relevant cell effect of the nanocrystal (embodiment 4) of dithiole [4,3-b]-pyrrolidone-ethyl formate (zl-004) and mPEG-PLGA nanoparticle (embodiment 8) are investigated.By endoxan modeling (modeling foundation: for peripheral leukocytes quantity lower than 3.0 * 10 9), take ZL-004 nanocrystal (embodiment 2) and ZL-004mPEG-PLGA nanoparticle (embodiment 6), commercial preparation GM-CSF, not administration model group and physiological saline group is study group, with periphery quantity of leucocyte and medullary cell, monocyte colony, cultivates and is counted as index evaluation and rises white effect.Experimental group: get 45 mouse, be divided at random 5 groups, every group of difference intraperitoneal injection of cyclophosphamide (120mg/kg), once a day, continuous 4 days.With blood analyser, measure and respectively to organize the murine interleukin sum afterwards, by modeling according to determining selected mouse.Administration: ZL-004 nanocrystal and mPEG-PLGA nanoparticle calculate with ZL-004 by 3mg/kg() tail vein injection; GM-CSF presses the 25ug/kg subcutaneous injection; Once a day, successive administration is 7 days.With the 1st, 4,7 days every group get 3, eye socket is got blood 0.5ml, through blood analysis-e/or determining quantity of leucocyte, the femur marrow smear is got in rear execution, calculates medullary cell and monocytic colony quantity.Result shows: by the index that is changed to of quantity of leucocyte, medullary cell and amount of mononuclear cells, with commercial preparation, GM-CSF compares, and zl-004 nanocrystal group, zl-004-MPEG-PLGA nanoparticle group have significant leukocyte increasing function.Specifically in Table 1,2.
The variation (embodiment 11) of quantity of leucocyte after the different preparation intravenously administrables of table 1 zl-004
Compare " * " p<0.05. with the endoxan group
The variation (embodiment 11) of medullary cell and amount of mononuclear cells after the different preparation administrations of table 2
Figure BDA00001760103600162
Compare " * " p<0.05. with the endoxan group

Claims (12)

1. the nanoparticle of dithiole pyrrolidone compound, is characterized in that, comprises the component of following weight percent:
Figure FDA00001760103500011
The mean diameter 10nm-800nm of described nanometer.
2. the nanoparticle of dithiole according to claim 1 pyrrolidone compound, is characterized in that, comprises the component of following weight percent:
Figure FDA00001760103500012
The mean diameter of described nanometer is 90nm-180nm.
3. the nanoparticle of dithiole according to claim 1 and 2 pyrrolidone compound, it is characterized in that, described thia cyclopenta pyrrolidone compound is 6-amino-4-(2,4-dimethoxy phenyl)-4-hydrogen [1,2] dithiole [4,3-b]-pyrrolidone-ethyl formate.
4. the nanoparticle of dithiole according to claim 3 pyrrolidone compound, it is characterized in that, described biodegradable polymers comprises more than one in poly(lactic acid), poly lactic coglycolic acid, lactic-co-glycolic acid-ethylene glycol copolymer, lactic-co-glycolic acid-polyethyleneglycol block copolymer, the polyoxyethylene glycol-glycolide-lactide copolymer that methylates, polycaprolactone or polyacrylamide.
5. the nanoparticle of dithiole according to claim 4 pyrrolidone compound, it is characterized in that, described biodegradable polymers is the polyoxyethylene glycol-glycolide-lactide copolymer that methylates, methylate in polyoxyethylene glycol-glycolide-lactide copolymer, the scope of monomer molar ratio is 50: 50-25: 75.
6. the nanoparticle of dithiole according to claim 5 pyrrolidone compound, is characterized in that, the weight-average molecular weight of biodegradable polymer is 5,000-60,000 dalton.
7. the nanoparticle of dithiole according to claim 1 and 2 pyrrolidone compound, is characterized in that, described additive is selected from polyethylene glycol stearate or polyoxyethylene hydrogenated castor oil; Described freeze-drying caffolding agent is selected from N.F,USP MANNITOL, sucrose, lactose, glucose or sodium alginate.
8. the nanoparticle preparation method of the preparation described dithiole of claim 1～7 any one pyrrolidone compound, is characterized in that, is to adopt following nanoparticle preparation facilities to realize:
The nanoparticle preparation facilities comprises water reservoir (1), oil phase reservoir (2), ultrasonic generator (6), ultrasonication chamber (9), frame (4), the static mixer (5) that is provided with inner member (501), circulation tube (11), fluid acceptance cup (7), an agitator (8);
What described static mixer (5) was vertical by anchor (401) is fixed on described frame (4);
The outlet of described water reservoir (1) is connected and is connected with described ultrasonication chamber (9) by the water pipeline, the outlet of described oil phase reservoir (2) is connected with described ultrasonication chamber (9) by the oil phase pipeline, and the probe (601) of described ultrasonic generator (6) is inserted in described ultrasonication chamber (9);
Described ultrasonic generator (6) is fixed on frame (4) by mechanical system;
Described fluid is accepted the below that cup (7) is arranged on the outlet (503) of described static mixer (5) bottom;
Described circulation tube (9) one ends insert described fluid and accept in cup (7), and the other end is connected with described water reservoir (1) by handling equipment.
9. the described method of according to Claim 8 ~ 11 any one, is characterized in that comprising the steps:
(1) water in the oil phase in oil phase reservoir (2) and water reservoir (1) is sent into to described ultrasonication chamber (9) simultaneously, and start ultrasonic generator (6);
Described oil phase is the organic solvent that contains thia cyclopenta pyrrolidone compound, biodegradable polymer and additive;
Described water is the aqueous solution that contains polyvinyl alcohol;
Oil phase and water form oil-in-water nano level emulsion, from the outlet of static mixer (5) bottom, flow out, enter fluid and accept cup (7), under the stirring of agitator (8), the nano level emulsion that fluid is accepted in cup (7) is sent water reservoir (1) back to by circulation tube (11), the said process that moves in circles, until the nanoparticle particle diameter reaches requirement;
(2) then fluid is accepted to the material in cup (7), centrifugal at 3-20 ℃, 10000-50000rmp, collect solid matter, wash, add the freeze-drying caffolding agent, freeze-drying, obtain the described nanoparticle that contains dithiole pyrrolidone compound.
10. method according to claim 12, it is characterized in that, described organic solvent is selected from alcohols, the N of tetrahydrofuran (THF), acetone, carbon atom 1 to 4, N-dimethylformamide or dimethyl sulfoxide (DMSO), dioxane, acetonitrile, methylene dichloride, trichloromethane, ethyl acetate, N, N-dimethyl pyrrolidone or phenylcarbinol.
11. method according to claim 12, is characterized in that, in described oil phase, total concentration of thia cyclopenta pyrrolidone compound, biodegradable polymer and additive is 7.0～680 grams per liters.
12. method according to claim 12, is characterized in that, with the volumeter of organic solvent and water, and organic solvent: water=1: 9.0～1: 480;
The speed of oil phase is 1.0-4.0mlmin -1; The speed of water is 150-350mlmin -1;
In described organic solvent, the residence time of oil phase is 20～70 seconds;
Described ultrasonication chamber 9 volumes of take are benchmark, and ultrasonic power is 4.0-235wcm -3.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107281100A (en) * 2016-03-30 2017-10-24 上海现代药物制剂工程研究中心有限公司 A kind of preparation method of insoluble drug nanosuspension

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107308109A (en) * 2016-04-27 2017-11-03 上海现代药物制剂工程研究中心有限公司 Dithiole and pyrrolidone compound nano suspension and preparation method

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1373657A (en) * 1999-07-13 2002-10-09 法马索尔股份有限公司 Method for controlled production of ultrafine microparticles and nanoparticles
WO2003026611A2 (en) * 2001-09-26 2003-04-03 Baxter International Inc. Preparation of submicron sized nanoparticles via dispersion and solvent or liquid phase removal
CN101132853A (en) * 2004-11-17 2008-02-27 万罗赛斯公司 Process for making or treating an emulsion using microchannel technology
CN101322719A (en) * 2007-06-15 2008-12-17 杭州民生药业集团有限公司 Arsenic trioxide solid lipid nano granule, formulation and preparation thereof
CN101322682A (en) * 2008-07-29 2008-12-17 沈阳药大制剂新技术有限公司 Preparation of indissoluble medicament nano granule
CN101422615A (en) * 2008-12-09 2009-05-06 沈阳药科大学 Oridonin polymer micelle administration preparation and preparation method thereof
CN101541313A (en) * 2006-10-05 2009-09-23 万能药生物有限公司 Novel injectable depot compositions and process of preparation of such compositions
CN101653420A (en) * 2009-09-08 2010-02-24 中国科学院化学研究所 Ultrasonically controlled-release target medicinal preparation and production method thereof
CN101909732A (en) * 2007-12-28 2010-12-08 金伯利-克拉克环球有限公司 Be used to prepare the ultrasonic treatment chamber of anti-microbial agents
WO2010146606A1 (en) * 2009-06-19 2010-12-23 Sun Pharma Advanced Research Company Ltd., Nanodispersion of a drug and process for its preparation
CN102357075A (en) * 2011-09-30 2012-02-22 武汉平华生物医药科技有限公司 Docetaxel nano preparation and preparation method thereof
WO2012095543A1 (en) * 2011-01-10 2012-07-19 Universidade De Santiago De Compostela Nanocapsules with a polymer shell

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1373657A (en) * 1999-07-13 2002-10-09 法马索尔股份有限公司 Method for controlled production of ultrafine microparticles and nanoparticles
WO2003026611A2 (en) * 2001-09-26 2003-04-03 Baxter International Inc. Preparation of submicron sized nanoparticles via dispersion and solvent or liquid phase removal
CN101132853A (en) * 2004-11-17 2008-02-27 万罗赛斯公司 Process for making or treating an emulsion using microchannel technology
CN101541313A (en) * 2006-10-05 2009-09-23 万能药生物有限公司 Novel injectable depot compositions and process of preparation of such compositions
CN101322719A (en) * 2007-06-15 2008-12-17 杭州民生药业集团有限公司 Arsenic trioxide solid lipid nano granule, formulation and preparation thereof
CN101909732A (en) * 2007-12-28 2010-12-08 金伯利-克拉克环球有限公司 Be used to prepare the ultrasonic treatment chamber of anti-microbial agents
CN101322682A (en) * 2008-07-29 2008-12-17 沈阳药大制剂新技术有限公司 Preparation of indissoluble medicament nano granule
CN101422615A (en) * 2008-12-09 2009-05-06 沈阳药科大学 Oridonin polymer micelle administration preparation and preparation method thereof
WO2010146606A1 (en) * 2009-06-19 2010-12-23 Sun Pharma Advanced Research Company Ltd., Nanodispersion of a drug and process for its preparation
CN101653420A (en) * 2009-09-08 2010-02-24 中国科学院化学研究所 Ultrasonically controlled-release target medicinal preparation and production method thereof
WO2012095543A1 (en) * 2011-01-10 2012-07-19 Universidade De Santiago De Compostela Nanocapsules with a polymer shell
CN102357075A (en) * 2011-09-30 2012-02-22 武汉平华生物医药科技有限公司 Docetaxel nano preparation and preparation method thereof

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107281100A (en) * 2016-03-30 2017-10-24 上海现代药物制剂工程研究中心有限公司 A kind of preparation method of insoluble drug nanosuspension
CN107281100B (en) * 2016-03-30 2021-05-07 上海现代药物制剂工程研究中心有限公司 Preparation method of insoluble drug nanosuspension

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